Claudia Piazza

New Methods for the Synthesis of Organozinc and Organocopper Reagents

Mnchen 2002

Dissertation zur Erlangung des Doktorgrades der Fakultt fr Chemie und Pharmazie der Ludwig-Maximilians-Universitt Mnchen

New Methods for the Synthesis of Organozinc and Organocopper Reagents

Claudia Piazza

aus

Treviso, Italien

Mnchen, 2002

Erklrung

Diese Dissertation wurde im Sinne von 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29. Januar 1998 von Professor Dr. Paul Knochel betreut.

Ehrenwrtliche Versicherung

Diese Dissertation wurde selbstndig, ohne unerlaubte Hilfe erarbeitet.

Mnchen, am 30. Oktober 2002

Claudia Piazza

Dissertation eingereicht am 30. Oktober 2002

1. Gutachter: Prof. Dr. Paul Knochel 2. Gutachter: Prof. Dr. em. Wolfgang Steglich

Mndliche Prfung am 4. Dezember 2002

Table of Contents Introduction

1 1.1 1.2 Overview Organozinc reagents Uncatalysed reactions of zinc organometallics 1.2.1 1.2.2 1.2.3 1.3 1.4 Aminomethylation Fragmentation of homoallylic zinc alcoholates Generation of benzylic zinc reagents 2 2 5 5 6 9 10 11 13

Transition metal catalysed reactions of zinc organometallics Organocopper reagents 1.4.1 Vinylic organocuprates

Objectivies

16

Results and Discussion

1 1.1 2 2.1 3 3.1 Aminomethylation of Functionalized Organozinc Reagents and Grignard Reagents Summary Preparation of Benzylic Zinc Reagents via a Fragmentation Reaction Summary Preparation of Allylic Zinc Reagents via a Cyclization-Fragmentation Reaction Attempted synthesis of functionalized allylic zinc reagents via a cyclization-fragmentation reaction 3.2 4 4.1 4.2 4.3 4.4 4.5 4.6 Summary Preparation of Highly Functionalized Organocuprates via Halogen-Copper Exchange Higher order cyanocuprates Non-transferable ligands Functionalized aryl cyanocuprates Screening of other non-transferable groups Neopentyl and neophyl group as non-transferable ligands Halogen-copper exchange on functionalized arylic compounds 4.6.1 Reactions of lithium dineopentylcuprate 34 35 36 36 36 38 39 41 42 43 19 23 24 27 28

4.6.2 4.7 4.8 4.9 4.10 5 5.1 6 6.1 7

Aldehydes and ketones: reactions of neophylcuprate

46 50 54 54 56 57 60 61 65 66

Regioselective functionalization of polyiodinated arylic substrates The role of copper cyanide Substitution reactions with functionalized mixed cuprates Summary

Iodine-Copper Exchange on Vinylic Substrates Summary Halogen-Copper Exchange on Heterocycles Summary Summary and Outlook

Experimental Section
1 2 General Conditions Typical Procedures (TP) TP 1 Typical procedure for the aminomethylation of functionalized organozinc and Grignard reagents TP 2 Typical procedure for palladium-catalyzed deprotection of allylamines 75 75 72 75

TP 3 Typical procedure for the preparation of benzylic alcohols via a fragmentation reaction TP 4 Typical procedure for the generation of homoallylic zinc reagents via a cyclization-fragmentation reaction 76 TP 5 Typical procedure for the halogen-copper exchange on arylic substrates TP 6 Typical procedure for the iodine-copper exchange on ethyl (2Z)-3-iodo-3-phenylpropenoate TP 7 Typical procedure for the bromine-copper exchange on N,N-diallyl-2-bromo-3-methyl-butenamide TP 8 Typical procedure for the iodine-copper exchange on imidazole derivatives 3 Synthesis of Organozinc and Organocopper Reagents 78 79 77 77 76 75

Aminomethylation of Functionalized Organozinc Reagents and Grignard Reagent Using Immonium Trifluoroacetates 82 91 101

5 6 7

Preparation of Benzylic Zinc Reagents via a Fragmentation Reaction Preparation of Allylic Zinc Reagents via a Cyclization-Fragmentation Reaction Preparation of Highly Functionalized Organocuprates via Halogen-Copper Exchange

116 133 140 151

8 9 10

Iodine-Copper Exchange on Vinylic Substrates Halogen-Copper Exchange on Heterocycles Abbreviations

Introduction

Overview

Organozinc and organocopper reagents are an indispensable part of the synthetic chemists knowledge. Nowadays, almost every synthesis of natural product has at least one step which involves the use of this kind of compounds. Therefore, there is a constant need for the development of new methods for a straightforward and efficient preparation of zinc and copper organometallics. In this work the attention was focused on a new approach for the preparation of benzylic and allylic organozincs, which are among the most reactive zinc species. Even if diorganozincs and organozinc halides display only moderate reactivity toward most organic electrophiles, the scope and synthetic application of these species were greatly extended when it was found that they can accommodate a wide range of functional groups. An important C-C bond forming reaction for the construction of nitrogen-containing molecules is the addition of carbon nucleophiles to iminium intermediates. For this reason, the use of zinc reagents with these highly reactive elctrophiles for the synthesis of functionalised amines will also be described.

The vast majority of experimental protocols for the preparation of organocopper complexes involve the transmetalation process from other organometallic species. This places a limitation in the functional groups that can be present in the molecule, depending on the precursor of choice. The search for a method that avoids the transmetalation step, allowing the preparation of organocoppers bearing any kind of functionalities by direct halogen-copper exchange reaction, was considered to be of a remarkable synthetic utility and was therefore attempted.

1.1

Organozinc reagents

With the synthesis of diethylzinc in 1849, E. Frankland lay the foundation stone for modern organometallic chemistry.1 However, organomagnesium2 and organolithium3 reagents were the first reagents to dominate this branch of organic chemistry. Although almost ignored for more than 100 years after their discovery, organozinc compounds are today one of the most useful class of organometallic reagents, due to their easy preparation and higher functional group
1 2

a) Frankland, E. Liebigs Ann. Chem. 1848-49, 71, 171. b) Frankland, E. J. Chem. Soc. 1848-49, 2, 263. Grignard, V. Compt. Rend. 1900, 130, 1322. 3 a) Schlenk, W.; Holtz, J. Chem. Ber. 1917, 50, 262. b) Ziegler, K.; Colonius, H. Liebigs Ann. Chem. 1930, 479, 135.

3 compatibility in comparison with organolithium and Grignard reagents. Furthermore, their excellent reactivity in the presence of the appropriate catalyst makes them a very powerful tool for natural product synthesis, as illustrated in the preparation of prostaglandin intermediates 1 and 24 (Scheme 1).
O O

O 1) IZnCH2OPiv CuCN TBDMSO Pent TBDMSO 2 LiCl TBDMSO

OPiv

TMSCl, THF 2) 1N HCl

Pent TBDMSO 83 %

TBDMSO Pent TBDMSO 1

O O 1) IZn TBDMSO Pent TBDMSO CuCN 2 LiCl TMSCl, THF 2) L-Selectride 3) aq. HF, CH3CN TBDMSO 58 % 2 CO 2Me TBDMSO Pent CO2Me

Scheme 1

There are three main classes of organozinc compounds:5

organozinc halides (RZnX),

diorganozincs (R2 Zn) and lithium or magnesium zincates. Organozinc halides are readily available by the direct insertion of zinc dust into organic halides6 (Scheme 2).

a) Miyaji, K.; Ohara, Y.; Miyauchi, Y.; Tsuruda, T.; Arai, K. Tetrahedron Lett. 1993, 34, 5597. b) Yoshino, T.; Okamoto, S.; Sato, F. J. Org. Chem. 1991, 56, 3205. c) Koga, M.; Fujii, T.; Tanaka, T. Tetrahedron 1995, 51, 5529. 5 Knochel, P.; Jones, P. Organozinc Reagents. A Practical Approach, Oxford University Press, 1999. 6 a) Berk, S. C.; Yeh, M. C. P.; Jeong, N.; Knochel, P. Organometallics 1990, 9, 3053; b) Berger, S.; Langer, F.; Lutz, C.; Knochel, P.; Mobley, A.; Reddy, C. K. Angew. Chem. 1997, 109, 1603; Angew. Chem. Int. Ed. 1997, 36, 1496. c) Rottndler, M.; Knochel, P. Tetrahedron Lett. 1997, 38, 1749. d) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445.

4
Zn RX THF RZnX X = I, Br

O IZn NHBoc CO2Bn ZnI

Scheme 2

Diorganozinc reagents require different methods of preparation, like iodine-zinc and boron-zinc exchange.7 These methods are applicable to the formation of primary and secondary diorganozinc species8 (Scheme 3).

R -(CH 2)2-I

Et2Zn CuX cat. AcO

1 R (CH2) 2 Zn 2

1) Et2BH 2) Et2Zn TIPSO R

Zn
2

Zn
2

Scheme 3

Remarkably, by using i-Pr2 Zn, configurationally defined secondary dialkylzinc reagents have been prepared7c (Scheme 4).

OBn Ph

1) Et2BH (3 equiv) 50 C, 16 h 2) i-Pr2Zn (3 equiv) 25 C, 5 h

OBn Ph

2 1 3

1) CuCN 2LiCl -78 C, 30 min 2) 1-bromo-1-hexyne (5 equiv) -55 C, 2 d

OBn Ph

Zni-Pr

dr(1,2) = 93 : 7

Bu dr(1,2) > 99 : 1 overall yield 47 %

Scheme 4

a) Langer, F.; Waas, J.; Knochel, P Tetrahedron Lett. 1993, 34, 5261. b) Langer, F.; Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org. Chem. 1996, 61, 8229. c) Boudier, A.; Hupe, E.; Knochel, P. Angew. Chem. 2000, 112, 2396; Angew. Chem. Int. Ed. 2000, 39, 2294. 8 a) Schwink, L.; Knochel, P. Tetrahedron Lett. 1994, 35, 9007. b) Devasagayaraj, A.; Schwink, L.; Knochel, P. J. Org. Chem. 1995, 60, 3311.

5 Diorganozincs display enhanced chemical reactivity compared to alkylzinc halides, but even more reactive are lithium or magnesium zincates, which are readily prepared by transmetalation reactions from the corresponding magnesium or lithium reagents and are well suited to halogenzinc exchange reactions9 (Scheme 5).
R2Zn + RM Br Br R3 ZnLi R 3ZnM Br Zn(L) ZnCl2 + 3RM Br R'

R'Br Pd (0)

Scheme 5

1.2

Uncatalysed reactions of zinc organometallics

1.2.1 Aminomethylation

In contrast with organolithium and Grignard reagents, organozincs have a relatively covalent carbon-metal bond, resulting in their more moderate reactivity than that of organometallics containing a more polar carbon-metal bond. Only reactive classes of organozinc reagents like allylic zinc halides10 and zinc enolates11 efficiently undergo additions to carbonyl compounds. On the other hand, a few classes of highly reactive electrophilic reagents directly react with zinc organometallics, among them immonium salts. Iminium salts are important intermediates in organic synthesis12 and aminomethylation is a transformation which has been performed with various immonium salts13 or iminium salt precursors.14 The reaction of these intermediates with functionalised organozinc reagents was first reported by Saidi,15 who performed a three component aminoalkylation of aldehydes promoted by lithium perchlorate. In this way N,Ndialkylamino esters are obtained in good to moderate yields (Scheme 6).

Uchiyama, M.; Koike, M.; Kameda, M.; Kondo, Y.; Sakamoto, T. J. Am Chem. Soc. 1996, 118, 8733. a) Miginiac, L. The chemistry of the metal-carbon bond (ed. F.R. Harvley and S. Patai), Wiley, New York, 1985, Vol.3, pp. 99-141. b) Courtois, G.; Miginiac, L. J. Organomet. Chem. 1973, 52, 214. 11 Frstner, A. Synthesis 1989, 571. 12 a) Jung, M. E. Comprehensive Organic Synthesis (ed. B. Trost and I. Fleming), Pergamon Press, Oxford, 1991, Vol.2, p. 893. b) Henry, K. J. jr.; Grieco, P. A. J. Chem. Soc. Chem.Commun. 1993, 510. c) Grieco, P. A.; Moher, E. D. Tetrahedron Lett. 1993, 34, 5567. 13 For a review see : Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 110, 1044. 14 Katritzky, A. R.; Jiang, J.; Urogdi, L. Tetrahedron Lett. 1989, 30, 3303. 15 Saidi, M.; Khalaji. H. R.; Ipaktschi, J. J. Chem. Soc. Perkin Trans.1 1997, 1983.
10

CHO + Me 3SiN(C2 H5 )2 N

LiClO4 Et2 O N

OSiMe3 N N N Me3 SiO

-

BrZnCH2 CO2 CH3

N CO2CH3 N 74 %

Scheme 6

1.2.2 Fragmentation of homoallylic zinc alcoholates

Transition metal-catalysed organic reactions involving the cleavage of C-C single bonds have recently attracted much attention. 16 Although the cleavage is energetically unfavourable, various unique catalytic transformations including ring-expansion, fragmentation and coupling with another molecule17 can be realised when appropriately designed. Utilising the cleavage to form MC species and ketones (or aldehydes), Pd-catalysed ring-opening reactions of cyclic allylic carbonates,18 cyclobutanols,19 and cyclopropanols 20 have been reported. The driving force of these reactions originates from the release of ring strain or the formation of a relatively stable allylmetal intermediate. Kondo developed a Ru-catalysed fragmentation of homoallylic alcohols21 which constitutes the first example of catalytic deallylation of tertiary homoallylic alcohols via selective cleavage of a C-C bond (Scheme 7).

16 17

For a review see: Crabtree, R. H. Angew. Chem. Int. Ed. 1999, 111, 918. Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407. 18 Harayama, H.; Kuroki, T.; Kimura, M.; Tanaka, S.; Tamaru, Y. Angew. Chem. Int. Ed. 1997, 36, 2352. 19 Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2000, 122, 12049. 20 Park, S. -B.; Cha, J. K. Org. Lett. 2000, 2, 147. 21 Kondo, T.; Kodoi, K.; Nishinaga, E.; Okada, T.; Morisaki, Y.; Watanabe, Y.; Mitsudo, T. J. Am. Chem. Soc. 1998, 120, 5587.

7
HO O

RuCl2(PPh3)3 (5 mol %) CO 10 atm, 200 C, 60 h OAc

(8-en : 7-en = 26:74) 76 % total yield

Scheme 7

The development and use of allylic organometallic reagents has been an underlying theme of modern organic synthesis.22 Nokami described an allyl transfer reaction of homoallylic alcohols catalysed by tin(II) triflate23 which corresponds to a conceptually new allylation of aldehydes. In this case tin(II) triflate does not react to form an allylic tin compound but simply assists the formation of the carbocation through hemiacetalization of the initial aldehyde (Scheme 8).
R1 R2 R
3 1 2

R R RCHO OH Sn(OTf)2 R
3

- "OH-" O OH

R R R3

R R R
3

R1 R
3

O R R

O R

R2 O

"OH "

R R
3

O R
2

OH

R1 R
2

70 - 97 %

O R OH

Scheme 8

Despite the plethora of methods which are currently available for the introduction of allylic moieties into complex molecules, several problems remain, especially that of contamination of the products with the Wurtz-coupling adduct. It has been shown by Knochel that sterically hindered homoallylic zinc alcoholates undergo a smooth fragmentation reaction providing highly

22 23

Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207. Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609.

8 substituted allylic zinc compounds with the absence of formation of any homocoupling product.24 This methodology has also revealed excellent stereocontrol in the subsequent reaction with aldehydes (Scheme 9).
OH t-Bu t-Bu OH Ph 83 % 94:6 anti : syn

1) n-BuLi, -78 C 2) PhCHO, ZnCl2 -78 C to rt, 3 h

Scheme 9

A new application of homoallylic zinc alcoholates for the preparation of cyclic allylzinc reagents and the performance of a zinc-mediated ene cyclisation have also been described (Scheme 10). 25

O t-Bu

1) n-BuLi, THF 0 C, 5 min 2) ZnCl2, -78 C to rt, 3h

ZnCl H

ZnCl

3) CuCN LiCl 0 C 4) PhCOCl 0 C, 2 h

O Ph

60 % syn:anti > 98:2

Scheme 10

More recently, Nokami developed the first highly enantioselective crotylation of aldehydes via an allyl transfer reaction from a chiral crotyl donor,26 but attempts to apply this concept to an asymmetric allylation of aldehydes gave only moderate success.

24

a) Jones, P.; Knochel, P. Chem. Commun. 1998, 2407. b) Jones, P.; Millot, N.; Knochel, P. Chem. Commun. 1998, 2405. c) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64, 186. 25 Millot, N.; Knochel, P. Tetrahedron Lett. 1999, 40, 7779. 26 Nokami, J.; Masanori, O.; Nakamoto, H.; Matsubara, T.; Hussain, I.; Kataoka, K. J. Am. Chem. Soc. 2001, 123, 9168.

1.2.3

Generation of benzylic zinc reagents

Benzylic

organometallics

are

important

intermediates

in

the

synthesis

of

polyfunctional

molecules of pharmaceutical interest.27 Although several methods are available for the preparation of benzylic lithium and magnesium compounds,28 these reactions are all complicated by the formation of homocoupling products. Benzylic zinc reagents prepared by the direct insertion of zinc dust are obtained in a more straightforward fashion and the formation of Wurtzcoupling products is minimized in many cases.6a However, where electron-rich benzylic halides are used for the preparation of benzylic zinc reagents, the formation of Wurtz-coupling is a serious side-reaction. 29 This is due to the radical nature of the reaction of a metal like magnesium or zinc with a benzylic halide. Knochel et al. described the preparation of secondary alkyl and benzylic zinc bromides using activated zinc metal deposited on titanium oxide.30 This method minimizes the amount of Wurtz-coupling side product to less than 1 %, but the study was not comprehensive and no functionalised secondary zinc compounds were reported. A new method for preparing benzylic zinc reagents has been developed by Harada and is based on the homologation of triorganozincates.31 Arylzincates undergo facile 1,2-migration at low temperatures to give benzylzinc reagents which can be utilized in reactions with a variety of electrophiles (Scheme 11).

I R3ZnLi OMs

R EX Zn(L)

R 48 - 80 % E

R = Bu, s-Bu, t-Bu, Me

EX = RCHO, RCOCl, R2CO TsCN, PhMe 2SiCl

Scheme 11

27 28

Lednicer, D.; Mitscher, L. A. Organic Chemistry of Drug Synthesis Wiley, New York, 1977. a) Raston, C. L.; Salem, G. J. Chem. Soc. Chem. Commun. 1984, 1702. b) Harvey, S.; Junk, P. C.; Raston; C. L.; Salem, G. J. Org. Chem. 1988, 53, 3134. c) Bogdanovich, B. Acc. Chem. Res. 1988, 21, 261. 29 Knochel, P.; Singer, R. B. Chem. Rev. 1993, 93, 2117. 30 Stadtmller, H.; Greve, B.; Lennick, K.; Chair, A.; Knochel, P. Synthesis 1995, 70. 31 Harada, T.; Kaneko, T.; Fujiwara, T.; Oku, A. J. Org. Chem. 1997, 62, 8966.

10 Also in this case, due to the presence of the highly reactive triorganozincate, no investigation into functional group tolerance has been carried out.

1.3

Transition metal catalysed reactions of zinc organometallics

The low reactivity of zinc organometallic reagents can be increased by adding a transition metal catalyst. The covalent character of the zinc-carbon bond allows these reagents to undergo transmetalation reactions with a wide variety of transition metal salts,32 producing intermediate transition metal organometallics which display enhanced reactivity towards many electrophiles due to the presence of d-orbitals. The moderate activity of zinc organometallics is an essential factor for the success of these transmetalations, since it prevents the transfer of several organic groups to the same metal centre and therefore reduces the possible decomposition pathways. Of special interest for synthetic application is the transmetalation of organozincs to give mixed copper-zinc reagents represented as RCu(CN)ZnX. The resulting copper species display a similar, but somewhat reduced, reactivity compared with organocuprates prepared from magnesium or lithium organometallics.33 On the other hand the better functional group tolerance displayed by organozinc reagents, makes them particularly attractive and versatile building blocks, for example in cross-coupling reactions (Scheme 12).34, 35

EtO 2C

Cu(CN)ZnI
3

EtO 2C +

CO2Et SO 2Ph

EtO 2C THF -80 to -55 C 1h

CO 2Et 90 %

EtO 2C

Scheme 12

32

For reviews see: a) Erdik, E. Tetrahedron 1987, 43, 2203. b) Knochel, P.; Perea, J. J.; Jones, P. Tetrahedron 1998, 54, 8275. 33 a) Posner, G. Org. React. 1972, 19, 1. b) Lipshutz, B.H. Synthesis 1987, 325. c) Lipshutz, B.H.; Sengupta, S. Org. React. 1992, 41, 135. d) Posner, G. Org. React. 1975, 22, 253. 34 Tucker, C. E.; Knochel, P. Synthesis 1993, 530. 35 Giovannini, R.; Stdemann, T.; Dussin, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 78, 2387.

11 1.4 Organocopper reagents

Gilman and Woods published a synthesis of methylcopper in 1943,36 and in 1952 Gilman et al. reported for the first time the preparation of organocuprates (Gilman reagents).37 Soon after, the use of copper salts as catalysts in organometallic reactions became popular. House et al. demonstrated the intermediacy of organocopper species in copper-catalyzed conjugated addition reactions.38 It was soon shown that organocuprates react in a synthetically useful manner with a range of alkyl and aryl halides.39 In 1968 Corey et al. described the synthesis of Cecropia juvenile hormone using this methodology,40 demonstrating the value of stoichiometric

organocopper reagents for the synthesis of complex natural products (Scheme 13).
I Et OH E t2 CuLi, Et 2O -30 C, 78 % Et Et OH

Et Et I OH

Me2 CuLi, Et 2 O, 0 C 53 %

Et Et Me OH

O Et

Et CO2Me Me

Scheme 13

Since then, the development of organocopper reagents has had an enormous impact on practically every aspect of organic synthesis.41 Organocopper complexes are correlated with such major pathways for carbon-carbon bond formation as conjugate additions to ,-unsaturated carbonyl compounds, nucleophilic displacement of halides,42 sulfonates43 and allylic acetates,44 epoxide ring openings45 and addition to acetylenes.46 However, the vast majority of experimental

36 37

Gilman, H.; Woods, L. A. J. Am. Chem. Soc. 1943, 65, 435. Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17, 1630. 38 House, H. O.; Respess, W. L.; Whitesides, G. M. J. Org. Chem. 1966, 31, 3128. 39 a) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1967, 89, 3911. b) Corey, E. J.; Posner, G. H. J. Am. Chem. Soc. 1968, 90, 5615. c) Whitesides, G. M.; Fischer, W. F.; San Filippo, J.; Bashe, R. W.; House, O. J. Am. Chem. Soc. 1969, 91, 4871. 40 Corey, E. J.; Katzenellenbogen, J. A.; Gilman, N. W.; Roman, S. A.; Erickson, B. W. J. Am. Chem. Soc. 1968, 90, 5618. 41 For a review see: Wipf, P. Synthesis 1993, 537. 42 a) Marfat, A.; McGuirk, P. R.; Helquist, P. J. Org. Chem. 1979, 44, 3888. b) Normant, J. F.; Alexakis, A. Synthesis 1981, 841. 43 Johnson, C. R.; Dutra, G. A. J. Am. Chem. Soc. 1973, 95, 7783. 44 Anderson, R. J.; Henrick, C. A.; Siddal, J. B.; Zurflh, R. J. J. Am. Chem. Soc. 1972, 94, 5379. 45 Johnson, C. R.; Herr, R. W.; Wieland, D. M. J. Org. Chem. 1973, 38, 4263. 46 Normant, J. F.; Cahiez, G.; Bourgain, M.; Chuit, C.; Villieras, J. J. Bull. Chim. Soc. Fr. 1974, 1656.

12 protocols for the preparation of organocopper complexes involve organolithium or Grignard reagents as intermediates.47,48 This route places an obvious limitation on the types of functionalities which are compatible with the preparative procedure. Major improvements have been achieved in the direct synthesis of copper organometallics from halides and highly activated copper metal. Most notably Rieke and coworkers have developed several reactive forms of zerovalent copper in combination with additives that allow the direct use of functionalised alkyl halides,49 allylic chorides and acetates50 and aryl, vinyl and alkynyl halides (Scheme 14).51

Br CuI PEt3 + 2 Li Cu** + EtO2C

H2O 0 C, 3 min EtO2C 62 %

Scheme 14

Other remarkable advances have been made by means of organozinc reagents and via vinylzirconium intermediates and transmetalation using higher order cyanocuprates.52 Quite surprisingly, the formation of functionalised organocopper reagents via halogen-metal exchange has not yet been extensively studied. The first iodine-copper exchange was reported by Corey and Posner,40b who observed that lithium dialkylcuprates react with aryl iodides leading to the expected cross-coupling product and a competitive halogen-metal exchange reaction. More recently, Kondo and Sakamoto described the use of lithium dimethylcuprate, which allows the performance of an iodine-copper exchange on a functionalised aryl iodide bearing an ester group.53 An excess of the cuprate is required to quench the methyl iodide formed during the exchange reaction (Scheme 15).

47

a) Posner, G. H. An Introduction to Synthesis Using Organocopper Reagents Wiley, New York, 1980. b) Yamamoto, Y. Angew. Chem. Int. Ed. 1986, 25, 947. c) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J. A. Tetrahedron 1984, 40, 5005. d) Lipshutz, B. H. Synlett 1991, 119. 48 a) Nakamura, E. Synlett 1991, 539. b) Chapdelaine, M. J.; Hulce, M. Org. React. 1990, 38, 225. c) Tucker, C. E.; Majid, T. N.; Knochel, P. J. Am. Chem. Soc. 1992, 114, 3983. 49 a) Ebert, G. W.; Rieke, R. D. J. Org. Chem. 1984, 49, 5280. b) Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1987, 52, 5056. c) Wehmeyer, R. M.; Rieke, R. D. Tetrahedron Lett. 1988, 29, 565. 50 Stack, D. E.; Dawson, B. T.; Rieke, R. D. J. Am. Chem. Soc. 1992, 114, 5110. 51 Ebert, G. W.; Rieke, R. D. J. Org. Chem. 1988, 53, 4482. 52 a) Lipshutz, B. H.; Keil, R. J. Am. Chem. Soc. 1992, 114, 7919. b) Venanzi, L. M.; Lehmann, R.; Keil, R.; Lipshutz, B. H. Tetrahedron Lett. 1992, 33, 5857. 53 Kondo, Y.; Matsudaira, T.; Sato, J.; Muraka, N.; Sakamoto, T. Angew. Chem. 1996, 108, 818; Int. Ed. 1996, 35, 736.

13

I MeO2 C

2 Me 2Cu(CN)Li 2 THF, -78 C MeO2 C

Me Cu(CN)Li 2

NH4 Cl aq. -40 C MeO2 C 85 %

Scheme 15

1.4.1

Vinylic organocuprates

The addition of organocopper reagents to terminal alkynes and to acetylene represents an efficient way to synthesize vinylcopper reagents with a given geometry.54 The addition proceeds in a Markownikov way in a syn-specific fashion. The organic cuprate is normally prepared from a Grignard or a lithium reagent and a copper(I) salt (Scheme 16).
R R1 Cu MgX2 R R1 E

RMgX + CuX

RCu

MgX2

R1C CH

E+

Scheme 16

Normant and Alexakis55 extensively studied this methodology and its application in the synthesis of conjugated dienes, allylic thioethers and allylic amides. Cahiez and Knochel prepared polyfunctional and stereochemically pure (E) or (Z) alkenylcopper reagents by carbocupration of terminal alkynes and reacted with alkylidenemalonates.56 More recently a variety of metalated vinylcuprate intermediates resulting from silyl- or stannylcupration of silyl- and tin-containing acetylenes were obtained, affording interesting functionalised polymetalated olefins.57 A different approach was developed by Hosomi,58 who reported the reductive cupration of ketene dithioacetals as a way to generate functionalised (Z) and (E) vinylcopper reagents (Scheme 17).

54

Normant, J. F. Organocopper Reagents. A Practical Approach (ed. R.J.K. Taylor), Oxford Unversity Press, 1994, cp.11, p. 237. 55 a) Jabri, N.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1981, 22, 3851. b) Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1982, 23, 5151. c) Germon, C.; Alexakis, A.; Normant, J. F. Synthesis 1984, 40. d) Germon, C.; Alexakis, A.; Normant, J. F. Synthesis 1984, 43. 56 Cahiez, G.; Venegas, P.; Tucker, C. E.; Majid, T. N.; Knochel, P. J. Chem. Soc. Chem. Commun. 1992, 1406. 57 Cuadrado, P.; Gonzlez-Nogal, A.; Snchez, A. J. Org. Chem. 2001, 66, 1961. 58 Hojo, M.; Harada, H.; Watanabe, C.; Hosomi, A. Bull. Chem. Soc. Jpn. 1994, 67, 1495.

14
R MeS CO2Et SMe 2 Me2Cu(CN)Li2 Et2O R MeS CO2Et Cu E
+

R MeS

CO2Et E

R MeS

CN SMe

2 Me2Cu(CN)Li2 Et2O

R Cu

CN SMe

R E

CN SMe

Scheme 17

A second way of preparing vinylic cuprates involves the carbometalation of an alkyne and a subsequent transmetalation to copper. Thus, vinylic stannanes,59 tellurides60 and zirconates61 readily exchange their vinylic ligands for alkyl groups on copper. Vinylic alanes, formed via a Negishi-type carbometalation with Me3 Al/catalytic Cp2 ZrCl2 62 have also been converted into mixed higher order cyanocuprates which transfer vinylic residues in a Michael sense to enones63 (Scheme 18).
O O R H Me3 Al cat. Cp2ZrCl2 CH2Cl2 , rt R Me H AlMe 2 10 mol % CuCN THF, Et2O, 0 C H LiCl Me R

Scheme 18 A very recent and interesting application of vinylic cuprates has been reported by Hall,64 who described the carbocupration of readily available alkynoate esters for the preparation of isomerically pure tetrasubstituted allylboronates, which were then employed for the

enantioselective construction of quaternary carbon centres (Scheme 19).

59

Behling, J. R.; Babiak, K. A.; Ng, J. S.; Campbell, A. L.; Moretti, R.; Koerner, M.; Lipshutz, B. H. J. Am. Chem. Soc. 1988, 110, 2641. 60 a) Comasseto, J. V.; Berriel, J. N. Synth. Commun. 1990, 20, 1681. b) Moraes, D. N.; Barrientos-Astigarraga, R.E.; Castelani, P.; Comasseto, J. V Tetrahedron 2000, 56, 3327. 61 a) Lipshutz, B. H.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112, 7440. b) Babiak, K. A.; Behling, J. R.; Dygos, J. H.; McLaughlin, K. T.; Ng, J. S.; Kalish, V. J.; Kramer, S. W.; Shone, R. L. J. Am. Chem. Soc. 1990, 112, 7741. c) Lipshutz, B. H.; Kato, K. Tetrahedron Lett. 1991, 32, 5647. 62 Negishi, E. Pure Appl. Chem. 1981, 53, 2333. 63 a) Ireland, R. E.; Wipf, P. J. Org. Chem. 1990, 55, 1425. b) Lipshutz, B. H.; Dimock, S. H. J. Org. Chem. 1991, 56, 5761. 64 Kennedy, J. W. J.; Hall, D. G. J. Am. Chem. Soc. 2002, 124, 898.

15

O R
1

CO2R'

(R )2CuLi THF, -78 C

CuLn CO2R'

ICH2B

R2 R
1

B(OR)2 CO2R'

R1

R CHO

(RO) 2BO R3
1

CO2R' O
2

R R

- (RO)2BOR' R
3

R1 R
2

Scheme 19

16

2. Objectives

The first project studied concerned the preparation of functionalised primary amines via aminomethylation (Scheme 20). of organozinc and Grignard reagents using immonium trifluoroacetates

R1ZnX or R12Zn +

H H

N OCOCF 3

THF, CH2Cl2 R
1

Pd(PPh3)4 (2 mol %) N CH2 Cl 2

R1CH2NH2

Scheme 20

Following the successful development of a new approach for the preparation of allylic zinc reagents based on the fragmentation of sterically hindered homoallylic alcohols., it was of interest to study a similar protocol for the generation of secondary benzylic zinc reagents via a fragmentation reaction (Scheme 21).
ZnX O RL RL THF, -78 C to rt R RL O RL Ph ZnX R E+ Ph E R

Scheme 21

The possibility of preparing allylic zinc reagents (eventually functionalised) via a cyclizationfragmentation reaction, and reacting these in a diastereoselective manner with aldehydes, was also explored (Scheme 22).

17
O R ZnX OH R'CHO R' 2) ZnBr 2, -40 C F R

1) BuLi, -90 C I

Scheme 22

A second project of particular interest was the generation of highly functionalised mixed cuprates via a halogen-copper exchange. Following the preparation of two new sterically hindered lithium dialkylcuprates (neopentyl and neophylcuprate), the halogen-copper exchange on functionalised arylic, vinylic and heterocyclic substrates was studied, in order to determine its range of applicability and in particular its functional group compatibility (Scheme 23).

X FG

R2CuLi THF FG

CuR Li

E+ FG

R2 R1

R3 X

R2CuLi THF

R2 R1

R3 CuR Li

E+

R2 R1

R3 E

Br N

Br R2CuLi N N THF

Br N

CuR Li N N

Br N

E N N

Scheme 23

18

Results and Discussion

19

Aminomethylation of Functionalised Organozinc Reagents and Grignard Reagents

Among the various iminium salts known,13,14 the allyl and benzyl moieties were chosen, as they could be removed to afford the desired aminomethylated products. The preparation of the immonium trifluoroacetates was based on the work of Tietze.65 Thus, heating an aqueous solution of formaldehyde with diallylamine or dibenzylamine resulted in the formation of the aminals 3 and 4, in 74 % and 30 % yield respectively. The treatment of 3 in CH2 Cl2 (25 C, 1 h) or 4 in ether (25 C, 1 h) with trifluoroacetic anhydride provided solutions of the immonium trifluorocetates 1 or 2 in essentially quantitative yields (Scheme 24).

(CF 3CO) 2O CH2Cl2 , 25 C, 1 h -(allyl) 2NCOCF3 aq.CH2O R2NH R = allyl, Bn R2N NR2

H H

N OCOCF3

R = allyl : 74 % R = Bn : 30 % Ph (CF3CO)2O ether, 25 C, 1 h - Bn2NCOCF3 H H N Ph OCOCF3

Scheme 24

The immonium salts 1 and 2 were readily soluble in CH2 Cl2 /THF and ether/THF mixtures and rapidly reacted with various functionalised organozinc reagents (R1 ZnX or R1 2 Zn) providing the aminomethylated products 5a-h (Scheme 25 and Table 1).

65

Kinast, G. Tietze, L.-F. Angew. Chem. 1976, 88, 261; Angew. Chem. Int. Ed. 1976, 15, 239.

20

R1ZnX or R1 2Zn

THF, CH 2Cl2

H H

N
30 min

R 1CH2N

OCOCF3
1 5a-f : 68-96 %

Ph
R1ZnX or R1 2Zn THF, Et2O

Ph Ph
30 min

H H

R 1CH2N

Ph

OCOCF3
2 5g-h : 73-92 %

Scheme 25

21 Table 1. Aminomethylated products 5a-h obtained by reaction of organozinc halides or diorganozincs with the immonium salts 1 or 2.

Entry

Organozinc reagent

Immonium salts 1 or 2

Temperature (C) -78

Product of type 5 5a

Yield (%)a

NC ZnBr

96

NC(CH2 )3 ZnI EtO2 C(CH2 )3 ZnI

25

5b

68

25

5c

73

c-HexZnI

25

5d

83

Zn

25

5e

91

6
NC

ZnBr

-78

5f

72

NC ZnBr

-78

5g

92

Zn

25

5h

73

Isolated yield of analytically pure product.

Whereas arylzinc halides and benzylic zinc halides already underwent addition at -78 C (entries 1 and 6), best results using alkylzinc halides were obtained when they were added at 25 C. The reactions were always complete within 30 min. Ester group (entry 3) and cyano groups (entries 1, 2 and 6) were perfectly tolerated.

22 Interestingly, functionalised organomagnesium compounds like ethyl 5-bromo-2-

thiophenecarboxylate, prepared by iodine-magnesium exchange,66 reacted at low temperature with the immonium salt 1, smoothly undergoing addition at -40 C (Scheme 26).

EtO 2C

MgBr

H H

THF, CH2Cl2 -40 C, 30 min OCOCF3 N EtO 2C S

6a

7a : 77 %

Scheme 26 The resulting bis-allylated amines could be deprotected according to the method of Guib.67 Thus, the reaction of diallylamines of type 7 with N,N-dimethylbarbituric acid in presence of Pd(PPh3 )4 (2 mol %) in CH2 Cl2 at 35 C produced within 1 to 3 h t e primary amines 8a-g in h satisfactory yields (Scheme 4 and Table 2). Debenzylations of the amines 5g-h were unsuccessful under a variety of hydrogenation conditions using Pearlmans catalyst and no other efficient deprotection was found.68
O R CH2N
5a-f or 7a
1

O N O N

Pd(PPh3)4 (2 mol%)

R1CH2NH2 Me CH2 Cl2, 35 C, 1 to 3 h

8a-g : 57-80 %

Me

Scheme 27

66 67

Boymond, L; Rottndler, M.; Cahiez, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 110, 1801. Garro-Helion, F.; Merzouk, A.; Guib, F. J. Org. Chem. 1993, 58, 6109. 68 Greene, T.W. Protective Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999.

23 Table 2. Deallylation of bis-allylamines 5 or 7a using N,N-dimethylbarbituric acid leading to primary amines 8a-g.

Amine

Product of type 8

Yield (%)a

NC

NH2

5a 8a 5b NC(CH2 )4 NH2 8b
NH

63

59

5c 8c

57

NH2

5e 8e
NH2

74

5f

NC

80 8f

7a
EtO 2C S

NH2

60

8g
a

Isolated yield of analytically pure product.

1.1

Summary

In summary, a range of functionalised primary amines were prepared in a two step sequence from organozinc and magnesium reagents via aminomethylation and selective desallylation.

24

Preparation of Benzylic Zinc Reagents via a Fragmentation Reaction

Based on the method recently developed by Knochel et al. for the preparation of allylic zinc reagents via a fragmentation reaction, a similar concept was applied to benzylic substrates. It was rationalized that the generation of a zinc alkoxide of a sterically hindered tertiary homobenzylic alcohol would result in decomposition to the ketone and a benzylic zinc reagent, which in the presence of a suitable electrophile could be utilized synthetically (Scheme 28).
OH Ph R
1 1 1

t-Bu t-Bu

1) n-BuLi, -78 C 2) ZnCl2, -78 C 3) R2CHO, -78 C to rt, 12 h

OH Ph R
1

9a : R = allyl 9b : R = methyl

13a-i : 46-80 %

Scheme 28

The required homobenzylic alcohols 9 were readily prepared starting from commercially available phenylacetyl chloride 10. First, reaction of the acid chloride 10 with t-BuCuMgX2 33c provided the ketone 11 in 68 % yield. Treatment of the ketone 11 with sodium hydride (rt, 1 h), followed by the addition of an electrophile (allyl bromide or methyl iodide), furnished, after a reaction time of 3 h, the expected alkylated products 12a and 12b in 98 % and 91 % yield respectively (Scheme 29). The ketones 12a and 12b were treated with t-BuLi at -78 C for 1 h in diethyl ether, leading to the desired alcohols 9a and 9b in 93 % and 89 % yield. These alcohols were treated at -78 C with n-BuLi (1.1 equiv) followed by the addition of a THF solution of zinc chloride (1.1 equiv) and subsequent addition of an aldehyde (1.1 equiv). The reaction mixture was allowed to reach rt within 12 h, leading to the expected homobenzylic alcohols 13a-i in 4680 % yield (Scheme 28 and Table 3).

25
O Ph R
1

O Ph Cl 10

t-BuCu MgX2 THF, 0 C, 1 h Ph

O t-Bu

1) NaH, THF, rt 2) R1-X, 3 h

t-Bu

11 : 68 %

12a: R1 = allyl 98 % 12b: R1 = methyl 91 %

12a-b

t-BuLi, Et2O -78 C, 1 h

OH Ph R1 t-Bu t-Bu

9a : 93 % 9b : 89 %

Scheme 29

Table 3. Homobenzylic alcohols 13a-j prepared by the fragmentation of zinc alcoholates obtained from the corresponding homobenzylic alcohols 9a-b and subsequent reaction with an aldehyde.

Entry

Alcohol of type 9

Aldehyde

Product of type 13

Diastereomeric ratio syn : anti

Yield (%)a

OH Ph

9a

PhCHO 13a
CHO
Ph OH

Ph

48 : 52

74

9a

1-Napht

48 : 52

63

13b
OH Ph O

9a

CHO

32 : 68 13c

73

26
CHO

OH Ph Ph

9a

Ph

45 : 55 13d

46

CHO

OH Ph

9a

40 : 60

70

13e
OH Ph

9a

c-HexCHO 13f
OH Ph

45 : 55

60

9b

PhCHO

Ph

43 : 57 13g

73

CHO

OH 1-Napht Ph

9b

36 : 64

80

13h
OH Ph O

9b

CHO

40 : 60 13j

66

Isolated yield of analytically pure product.

Aromatic aldehydes like benzaldehyde (entries 1 and 7), 1-naphthaldehyde (entries 2 and 8) and furfural (entries 3 and 9) reacted rapidly, to give the alcohols as a mixture of diastereoisomers. The reaction also proceeded with ,-unsaturated aldehydes such as trans-cinnamaldehyde (entry 4) and perillaldehyde (entry 5). Finally, the aliphatic aldehyde cyclohexanecarboxaldehyde also gave the expected alcohol 13f in 60 % yield (entry 6). All the products were obtained as an almost 1:1 mixture of the syn and anti diastereomers, indicating that little sterochemical control is involved in the reaction mechanism.

27

2.1

Summary

A new preparation of benzylic zinc reagents via the fragmentation of sterically hindered homobenzylic zinc alcoholates was developed. This method completely avoids the formation of Wurtz byproducts. The starting homobenzylic alcohols are readily prepared, making this an efficient method, complementary to other known procedures.

28

Preparation of Allylic Zinc Reagents via a Cyclization-Fragmentation Reaction

Although the use of allylic organometallics for carbon-carbon bond formation in stereoselective synthesis has received much attention over the past decades,22 several problems associated with the generation of allyl organometallic reagents still remain unresolved and the search for new methodologies continues to be a matter of investigation. According to the method for the preparation of masked allylic zinc reagents developed by Knochel et al., treatment of a sterically hindered homoallylic alcohol first with n-BuLi and then with zinc chloride was known to give the zinc alkoxide which fragmented in situ to generate an allyl zinc reagent.24b Addition of an electrophile such as a ketone or an aldehyde led to the expected addition products in very good yields and, in the case of substituted allylic organozincs, with excellent regiodiastereoselectivities. The proposed mechanism involves a double allylic and

transposition:

generation of the zinc alkoxide 14 results in a cyclic six-member ring intermediate where the zinc is complexed to the reacting carbonyl compound (Scheme 30). Allylic transposition gives rise to a zinc reagent 15 complexed to the parent di(tert-butyl)ketone and the carbonyl oxygen atom of the aldehyde, the zinc reagent bearing solely a trans-configuration. At -78 C this species is stable and undergoes no isomerisation. 69 Owing to the complexation of the reacting partner with the zinc, the formation of a new six-centred intermediate 16 is possible, whereby all the substituents lie in a pseudo-equatorial position; allylic transposition then gives rise to the product 17, predominantly as the anti-diastereomer.

69

Bis (3-Methylallyl)zinc is known to be a rapidly isomering system at room temperature, hence explaining the 1:1 anti:syn selectivity in addition to aldehydes. See Benn, R.; Hoffmann, E. G.; Lehmkuhl, H.; Nehl, H. J. Organomet. Chem. 1978, 146, 103.

29
R t-Bu O t-Bu Zn O Me H 14 allylic transposition Me H 15 t-Bu t-Bu O Zn O R

H R Me H 17 allylic transposition OH Me H R

H O ZnX

16

Scheme 30

In a similar way, cyclic homoallylic zinc alcoholates underwent a fragmentation reaction in the presence of zinc salts affording highly substituted cyclic allylzinc reagents which could be trapped with a range of aldehydes in satisfactory yields and excellent diastereoselectivities (up to > 98:2, Scheme 31).

O t-Bu

1) LDA, THF/HMPA -78 C, 3 h 2) MeI 3) s-BuLi, -78 C, ether

OH t-Bu s-Bu Me 87 %

1) n-BuLi, THF, -78 C 2) RCHO

H R Me O ZnCl H R

OH Me 77 - 86 % syn:anti up to > 98:2

3) ZnCl2, -78 C to rt 3h

Scheme 31

30 In order to explore the possibility of generating functionalised substituted allylic zinc reagents, addition of s- or t-BuLi had to be avoided. Therefore, a new sterically hindered cyclic homoallylic alcoholate such as 26 had to be formed, which can be obtained by a rapid exchange reaction of n-BuLi with an aryl iodide and subsequent intramolecular attack to the carbonyl group (Scheme 32).
MX O R R F F 26

Li

Scheme 32

To facilitate the iodine-lithium exchange a fluorine atom is present in the benzene ring and two methyl groups are placed alpha to the ketone to help the cyclization step. The required compound was then identified in the ketone 18 which was obtained in five steps from commercially available starting materials (Scheme 33).
R 1) LDA, -78 C, 1 h 2) RX, -78 C to rt, 1 h R KOH EtOH, H2O , 1 h

COOEt

COOEt

COOH

SOCl 2

19

20a : R = Methyl 65 % 20b : R = Benzyl 74 %

21

COCl

i-PrCu

MgBr 2

O 1) LDA, -10 C, 2 h 2) Br I F 25 , rt, 1 h

THF, -20 C, 2 h 23a : R = Methyl 56 % 23b : R = Benzyl 40 %

F 18a : R = Methyl 69 % 18b : R = Benzyl 40 %

Scheme 33 The -deprotonation of 19 with LDA in THF led to the expected lithium dienolate. Its methylation or benzylation at the -position afforded an intermediate ,-unsaturated ester 20 in 65 and 74 % yield respectively. Saponification and treatment with thionyl chloride gave the

31 corresponding unsaturated acid chloride which was converted into the ketone 23 by cuprate addition. Finally, alkylation at the -position with a previously prepared benzyl bromide derivative led to the desired ketones 18a and 18b in 69 % and 40 % yield respectively. Upon addition of n-BuLi at -90 C to a 1:1 THF/DMPU solution of the ketone 18, a fast iodinelithium exchange took place and, upon warming to 0 C, a subsequent cyclization occurred, leading to the formation of a five-member cyclic lithium alcoholate. Transmetalation to zinc by addition of a THF solution of zinc bromide generated the alcoholate 26 which, upon addition of an aldehyde, led to a rapid fragmentation reaction to afford the syn -adduct 27 in good yield and very good selectivity (Scheme 34 and Table 4).
ZnX O R R F 18 2) ZnBr2 , 0 C, 15 min THF F 26 F R'CHO 0 C to r.t. O ZnX

1) n-BuLi -90 C to 0 C, 30 min THF / DMPU 1:1

OH 68 - 96 % syn:anti up to > 98:2 R' R 27

Scheme 34

32 Table 4. Homoallylic alcohols 27a-f prepared by the fragmentation of zinc alcoholates obtained from the ketones 18a-b in the presence of an aldehyde.

Entry

Ketone of type 18

Aldehyde

Product of type 27

Diastereomeric ratioa syn : anti c

Yieldb (%)

OH

18a

PhCHO

Ph Me

97:3 27a
OH

68

18a

CHO

1-Napht Me

88:12

80

27b

18a
O CHO

OH O Me

97:3

96

27c
OH 1-Napht Ph

18b

CHO

> 2:98

87

27d
OH

18b

c-HexCHO
Ph

> 2:98

80

27e
OH

18b

CHO
Ph

9:91

79

27f

33

a1 b c

H NMR determined ratio

Isolated yield of analytically pure product.

The relative diastereoselectivity of compounds 27 was assigned according to the previously published NMR data

(see footnote 25).

As illustrated in Table 4, both aromatic and aliphatic aldehydes reacted well with the in situ allylic zinc reagents. The reaction was usually complete within 45 min and led to the expected products in good to excellent yield. The rate of fragmentation depends on the steric hindrance of the alcoholate. When R is methyl the reaction was slower and sometimes stopped at the cyclic alcoholate 26. Thus, from reaction of 18a in the presence of aliphatic aldehydes like cyclohexane carboxaldehyde or n-butanal, only aldol-condensation products were isolated. On the other hand, if the steric hindrance was increased (R = Benzyl), fragmentation occurred within 30 min and quenching with an aliphatic aldehyde (entry 5) afforded the desired product in good yield. An ,-unsaturated aldehyde was also tolerated, giving exclusively the 1,2-addition product in 79 % yield (entry 6).

The diastereoselectivity is influenced by the size of the substituent R in the cyclic alcoholate and, to a minor extent, by the steric hindrance of the R group of the aldehyde. Reaction of the ketone 18a with 1-naphthaldehyde gave the expected product with a diastereomeric ratio of 88:12 (entry 2), while the fragmentation of the alcoholate derived from the ketone 18b in presence of the same electrophile, led only to the anti diastereoisomer (entry 4). The role of the R group in determining the diastereomeric ratio can be elucidated by entries 4, 5 and 6: as expected, moving from arylic or cyclic to linear substituents causes a significant decrease of diastereoselectivity.

The role of DMPU as a polar cosolvent has proved to be quite important in terms of yield and reaction rate. When the reaction was performed in pure THF, the mixture needed to be heated to 70 C in order for the fragmentation to take place, and after addition of benzaldehyde the expected homoallylic alcohol was isolated in just 51 % yield. In a more polar solvent system like THF/DMPU 2:1, cyclisation occurred at room temperature but no migration of the allylic group was observed. Finally, in a 1:1 THF/DMPU mixture the reaction proceeded smoothly to give the desired product in 68 % yield (Table 4, entry 1).

Attempts to perform the cyclization and fragmentation step with a Grignard reagent were unsuccessful. i-PrMgBr was added at -30 C to a THF solution of the ketone 18a and after 15

34 min a THF solution of zinc bromide was added and the mixture was allowed to warm to room temperature. After addition of benzaldehyde the only product isolated was the cyclic alcohol 28 (Scheme 35). The use of a polar cosolvent (THF/HMPA 2:1, THF/DMPU 1:1) did not bring any improvement, indicating that the transmetalation process probably did not proceed. The use of different zinc salts was then considered, upon the addition of THF solutions of zinc chloride or zinc triflate, however no improvement was detected.
MX O PhCHO

1) i-PrMgBr -30 C to 0 C, 15 min THF/DMPU F 2) ZnBr2, 0 C to rt, 15 min THF

HO

F 18a 26

F 28 : 97 %

Scheme 35

3.1

Attempted synthesis of functionalised allylic zinc reagents via a cyclizationfragmentation reaction

Having optimised the conditions for the generation of substituted allylic zinc reagents, it was of interest to explore the functional group compatibility of such a method. In order to do so, the synthesis of functionalised analogues of the ketone 18 was attempted. The starting 1cyclohexene-1-carboxylic acid methyl ester 29 was deprotonated with LDA and alkylated at the -position with 4-(bromomethyl)-benzonitrile in 77 % yield (Scheme 36). Saponification and treatment with thionyl chloride afforded the corresponding acid chloride which was then reacted with iso-propylcuprate to give the ketone 31 in a disappointing 40 % yield, due to partial attack of the Grignard to the cyano group. Surprisingly, any attempt to obtain the desired ketone 18c from 31 failed. LDA, lithium diethylamine and NaH were all ineffective at deprotonating 31 to the carbonyl group and the unreacted starting material was recovered in all cases.

35
CO2Me 1) LDA, -50 C, 3 h THF/HMPA 2:1 2) Br 29 , -50 C to rt, 3 h CN 30 CO2 Me CO2H CN 21c

KOH CN EtOH, H2 O D, 1 h

COCl SOCl2 CN 22c i-BuCu MgBr2 THF, -20 C, 2 h

CN 31

NC 1) LDA, -10 C to rt 2) Br I F 25 , rt F 18c O I

Scheme 36

3.2 Summary

The generation of allylic zinc reagents via a cyclization-fragmentation reaction is an efficient method for the preparation of allylic zinc species free of any Wurtz homocoupling products and allows the synthesis of a variety of homoallylic alcohols with high degree of diastereoselectivity. The reaction is influenced by the polarity of the solvent and, as regards the diastereomeric excess, by the bulkyness of the substituents R and R. This approach could in principle allow the preparation of functionalised allylic zinc compounds and this possibility should be further explored developing a different retro synthetic pathway for the functionalised ketone of type 18.

36

Preparation of Highly Functionalised Organocuprates via HalogenCopper Exchange

4.1

Higher order cyanocuprates

Beginning of 1981, Lipshutz et al.70,47c,d introduced the concept of higher order mixed organocuprates. On the basis of improved yields and (where relevant) different stereochemical outcomes,71 it was claimed that these species were different from lower-order or Gilman-like cuprates, R2 CuLi, in that the Cu-cluster contained an additional ligand (negatively charged). While no unambiguous structure determination work had yet been carried out, the higher order species were described as Cu(I) dianionic salts.72 It has been unequivocally asserted that the cyano group is bonded to copper by means of a Cu-(CN) bond.73 The higher order claim has been strongly challenged74 and subsequently defended.75 Computational analysis,76 NMR77 and EXAFS studies78 later showed that tricovalent Cu(I) is neither obligatory nor sufficiently stable to describe the structure around the copper centre in R2 Cu(CN)Li2 . A recent NMR study by Bertz79 showed that these very effective organocopper reagents, obtained from the reaction of two equivalents of organolithium RLi and one equivalent of CuCN, are modified Gilman reagents and not higher order cyanocuprates. Consequently, they should be called Cyano-Gilman reagents and represented as R2 CuLiLiCN.

4.2

Non-transferable ligands

70

a) Lipshutz, B. H.; Wilhelm, R. S.; Floyd, D. M. J. Am. Chem. Soc. 1981, 103, 7672. b) Limited spectroscopic studies were reported: Lipshutz, B. H.; Kozlowski, J. A.; Wilhelm, R. S. J. Org. Chem. 1984, 49, 3943. 71 Lipshutz, B. H.; Wilhelm, R. S. J. Am. Chem. Soc. 1982, 104, 4696. 72 Lipshutz, B. H.; Kozlowski, J. A.; Brenemann, C. M. J. Am. Chem. Soc. 1985, 107, 3197. 73 Lipshutz, B. H.; Ellsworth, E. L.; Siahaan, T. J. J. Am. Chem. Soc. 1988, 102, 4834. 74 Bertz, S. H. J. Am. Chem. Soc. 1990, 112, 4031. 75 Lipshutz, B. H.; Sharma, S.; Ellsworth, E. L. J. Am. Chem. Soc. 1990, 112, 4032. 76 Snyder, J. P.; Spangler, D. P.; Behling, J. R.; Rossiter, B. E. J. Org. Chem. 1994, 59, 2665. 77 Bertz, S. H. J. Am. Chem. Soc. 1991, 113, 5470. 78 a) Stemmler, T.; Penner-Hahn, J. E.; Knochel, P. J. Am. Chem. Soc. 1993, 115, 348. b) Stemmler, T. L.; Barnhart, T. M.; Penner-Hahn, J. E.; Tucker, C. E.; Knochel, P.; Bhme, M.; Frenking, G. J. Am. Chem. Soc. 1995, 117, 12489. 79 Bertz, S. H.; Nilsson, K.; Davidsson, .; Snyder, J. P. Angew. Chem. Int. Ed. 1998, 37, 314.

37 Homocuprate reagents (R2 CuLi or R2 CuMgX) are the most widely used of the organocopper reagents. Usually only one of the organic ligands is transferred to form a new C bond, and if -C the organometallic precursors are expensive or difficult to prepare, this presents a serious drawback. To overcome this problem, in 1972 Corey and Beames80 introduced mixed homocuprates derived from pentynyl copper, having demonstrated that alkynyl ligands are transferred much more slowly than other organic groups. Since that time, a number of nontransferable (dummy) ligands (Rt ) have been proposed,81 which combine with a valuable organolithium (RLi) and CuCN to form a mixed higher order cyanocuprate (Scheme 37).

Rt Li +

R Li + CuCN

RtRCuLi LiCN

Rt =

N N

CH3O

Scheme 37

Since organozinc reagents offer higher functional group tolerance than organolithium, an interesting extension of this approach has been developed by Knochel,6b,
82

who showed that

mixed organozinc reagents of the type FG-R-Zn-CH2 SiMe3 , carrying one transferable alkyl group and one non-transferable trimethylsilylmethyl group, maintain the reactivity, albeit slightly less than typical diorganozincs. Further investigation83 led to the discovery of two new cheaper non-transferable ligands, the neopentyl group (CH2 CMe3 ) and the structurally similar neophyl group (CH2 CMe2 Ph) which proved to be suitable also for organocopper chemistry (Scheme 38).

80 81

Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210. a) Lipshutz, B. H.; Kozlowski, J. A.; Parker, D. A.; Nguyen, S. L.; McCarthy, K. E. J. Organomet. Chem. 1985, 285, 437. b) Malmberg, H.; Nilsson, M.; Ullenius, C. Tetrahedron Lett. 1982, 23, 3823. c) Lipshutz, B. H.; Fatheree, P.; Hagen, W.; Stevens, K. L. Tetrahedron Lett. 1992, 33, 1041. d) Corey, E. J.; Floyd, D.; Lipshutz, B. H. J. Org. Chem. 1978, 43, 3418. e) Johnson, C. R.; Dhanoa, D. S. J. Org. Chem. 1987, 52, 1885. 82 a) Lutz, C.; Knochel, P. J. Org. Chem. 1997, 62, 7895. c) Jones, P.; Knochel, P. J. Chem. Soc. Perkin Trans. 1 1997, 3117. d) Jones, P.; Reddy, C. K.; Knochel, P. Tetrahedron 1998, 54, 1471. 83 Lutz, C.; Jones, P.; Knochel, P. Synthesis 1999, 312.

38
1) CuI, THF 2) BuLi

Li Bu-Cu-CH2CMe3 A

Me3CCH2Li

PhMe2CCH2Li

1) CuI, THF 2) BuLi

Li Bu-Cu-CH2CMe2Ph B

O A/B -78 C, 10 min

Bu 84 % from A 70 % from B

Scheme 38

Thus, copper(I) iodide was treated with neopentyllithium and then butyllithium to yield the mixed neopentyl(butyl)cuprate A. Treatment of this reagent with 2-cyclohexen-1-one gave, within 10 min, 84 % yield of 3-butylcyclohexanone. No neopentyl migration was observed. Similarly, a mixed neophyl(butyl)cuprate B was prepared. This material was treated likewise with cyclohex-2-enone and after 10 min at -78 C, 3-butylcyclohexanone was isolated in 70 % yield. Again, no transfer of the neophyl group was observed.

4.3

Functionalised aryl organocuprates

The halogen-metal exchange is one of the most useful methods for the preparation of metalated aryl compounds, especially lithium84 and magnesium85 ones. Functionalised organocuprates are usually obtained via transmetalation from the corresponding zinc reagents6d,
86

or by direct

oxidative addition of reactive copper into a carbon-halogen bond.51 Even if the possibility of a

84

a) Wakefield, B. J. The Chemistry of Organolithium Compounds Pergamon Press, Oxford, 1974. b) Wakefield, B. J. Organolithium Method Academic Press, London, 1988. 85 Tamborski, C.; Moore, G. J. J. Organomet. Chem. 1971, 26, 153. b) Paradies, H. H.; Gorbing, M. Angew. Chem. Int. Ed. Engl. 1969, 8, 279. 86 a) Zhu, L.; Rieke, R. D. Tetrahedron Lett. 1991, 32, 2865. b) Knochel, P.; Rao, S. J. Am. Chem. Soc. 1990, 112, 6146. c) Knochel, P. ibid. 1990, 112, 6146. d) Rao, S.; Knochel, P. ibid. 1991, 113, 5735. e) Wipf, P. Synthesis 1993, 537.

39 halogen-copper exchange has been suggested for a long time,87 it has not so far been extensively studied. In the work of Kondo and Sakamoto,54 the higher order cuprate Me2 CuLiLiCN performed an iodine-copper exchange on methyl 4-iodobenzoate and, after addition of benzaldehyde, furnished the expected product in 56 % yield (Scheme 39).
OH PhCHO -78 C to rt I MeO2 C Me2CuLi LiCN (2 equiv) THF MeO2C NH4Cl aq. -40 C MeO2 C 85 % Me Cu(CN)Li2 MeO2 C 56 % Ph

Scheme 39

An excess (2 equiv) of cuprate has to be used to quench the methyl iodide formed during the exchange reaction. In this way the MeCuLiCN obtained in situ is less reactive towards the electrophile than MeArCuLiCN and does not interfere in the coupling process. Clearly, this method has some drawbacks and is not totally efficient. The formation of the mixed cuprate is not quantitative, as demonstrated by the yield of the hydrolysed product recovered after treatment with NH4 Cl, but its considerable synthetic potential makes it worth further exploration.

4.4

Screening of other non-transferable groups

In order to find the most suitable ligand and based on the previous results obtained for organozinc chemistry, a range of lithium dialkylcuprates were prepared, including the cuprate of Sakamoto. These were then tested in the iodine-copper exchange of ethyl 4 -iodobenzoate and the subsequent reaction with allyl bromide (Scheme 40 and Table 5).

87

a) House, H. O.; Koepsell, W. J.; Campbell, W. J. J. Org. Chem. 1972, 37, 1003. b) Barri, F.; Di Nunno, L.; Florio, S.; Marchese, G.; Naso, F. J. Organomet. Chem. 1979, 169, 263.

40

I R2 Cu(CN)Li2 + EtO2 C EtO2C

R Cu(CN)Li

Br EtO2 C

Scheme 40

Table 5. Yields of ethyl 4-allylbenzoate obtained by iodine-copper exchange of lithium dialkylcuprates cuprates bearing different non-transferable ligands with ethyl 4iodobenzoate.

Entry

T ( C)

t (h)

Yield (%)a

1 2

Me (2 equiv) Bu

- 40 - 78

1 3

65 58

- 20

95

25

10

88

Ph

3.5

90

TMSCH2

74

Isolated yield of analytically pure product

41 The allylated product was isolated in all cases, in moderate to excellent yield. As reported by Sakamoto, two equivalents of lithium dimethylcuprate were necessary to obtain full conversion and to isolate ethyl 4-allylbenzoate in 65 % yield (entry 1). A similar result was given by the dibutyl cuprate (entry 2) although only one equivalent of cuprate was used in this case. Much better results were observed when the steric bulk of the non-transferable group was increased. The neopentyl group proved to be the best: the exchange was complete within three hours (using 1 equiv of cuprate) and the allylated compound was recovered in 95 % yield (entry 3). The related neophyl group appeared to be slightly less reactive, requiring a longer reaction time and higher temperature (entry 5). Finally, the secondary alkyl group also furnished the expected product in good yield, but warming to rt overnight was necessary to complete the exchange (entry 4). A non-transferable ligand containing a silyl group was also tested, since t proved to be i advantageous for organozinc chemistry.6b,
19

It showed a moderate efficiency (entry 6), and its

reactivity, comparable with that of other alkyl groups, suggests that no -silyl effect88 is present.

4.5

Neopentyl and neophyl group as non-transferable ligands

After these encouraging results, neopentyl and neophyl groups were the ligands of choice for performing an iodine-copper exchange on various functionalised substrates. Lithium

dineopentylcuprate (Np2 CuLi) 33 was readily prepared starting from commercially available neopentyl iodide, which was converted into the lithium species 32 by reaction with t-BuLi, according to the procedure of Negishi,89 and then transmetalated to copper to give the higher order cyanocuprate (Scheme 41).

t-BuLi (2.1 equiv) Et2O -78 C to rt, 1.5 h 32

Li

CuCN (0.5 equiv) THF, 0 C, 10 min

Cu(CN)Li2

33

Scheme 41

88

Bertz has prepared and investigated the reactivity of alkyl (trimethylsilylmethyl)cuprates and argues the involvement of -silyl effect. Bertz, S. H.; Eriksson, M.; Miao, G.; Snyder, J. P. J. Am. Chem. Soc. 1996, 118, 10906 and references therein. 89 Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55, 5406.

42 Similarly, lithium dineophylcuprate was prepared from the starting chloride which, upon refluxing overnight with metallic lithium in hexane, reacted to give the lithium compound 34.

Reaction of this with CuCN at rt gave the expected cuprate 35 (Scheme 42).

Cl Ph

Li, Hexane reflux, 12 h Ph 34

Li

CuCN (0.5 equiv) THF, rt, 10 min Ph 35

2

Cu(CN)Li2

Scheme 42 Neophyllithium is obtained as an ethereal solution, according to the procedure of Cano et al.,90 and is titrated before use with menthol in the presence of o-phenanthroline as indicator. The solution can be stored for several days at -30 C without loosing its reactivity. These two lithium dialkylcuprates exhibit different thermal stability:91 dineopentylcuprate is stable at 0 C in THF for a few hours but decomposes rapidly if warmed to rt, while dineophylcuprate retains its reactivity in the same solvent for up to three hours at rt.

4.6

Halogen-copper exchange on functionalised arylic compounds

Having established an easy method for the preparation of lthium dineopentylcuprate Np2 CuLi 33 i and lithium dineophylcuprate Nphyl2 CuLi 35, these were employed to perform a chemoselective halogen-copper exchange on a variety of functionalised arylic systems. Np2 CuLi, 33 and Nphyl2 CuLi 35 rapidly reacted with various fictionalized halogenides of type 36, leading to mixed organocuprates of type 37, which selectively transferred the aryl group in the reaction with electrophiles (E+) leading to products of type 38 (Scheme 43).

90

Cano, A.; Cuenca, T.; Galakov, M.; Rodrguez, G. M.; Royo, P.; Cardin, C. J.; Convery, M. A. J. Organomet. Chem. 1995, 493, 17. 91 Higher order cuprates have a similar stability to heterocuprate reagents. Bertz, S. H.; Dabbagh, G. J. Chem. Soc. Chem. Commun. 1982, 18, 1030.

43

X FG 36: X= Br,I

R2 CuLi (33 or 35) THF FG

CuR Li

E+ FG

37

38

FG = ester, ketone, aldehyde; R= Me3CCH2 (33) or Me2 PhCCH2 (35)

Scheme 43 This approach allows a general preparation of polyfunctional organocuprates.92 The steric hindrance at the copper centre of 33 and 35 is essential for ensuring the chemoselectivity of the iodine-copper exchange 93 and the large bulk of the non-transferable group serves to orientate the neophyl or neopentyl ligand far away from the incoming electrophile, thereby placing the second organic residue in closer proximity to the electrophilic reaction partner.

4.6.1 Reactions of lithium dineopentylcuprate

Lithium neopentylcuprate has proved to be more reactive than the neophyl reagent. Its exchange reaction with various fictionalized arylic substrates occurred in THF within 3 h at a temperature between -78 C and -30 C, in good to excellent yield (Table 6). Quenching with 0.9-1 equiv. of electrophile furnished the expected products normally without detection of neopentyl transfer or partial attack at the functional group present. Thus, ethyl 4-iodobenzoate 36a underwent a smooth iodine-copper exchange with Np2 CuLi (1.1 equiv, -30 C, 2 h), affording the desired mixed cuprate 37a, which reacted with electrophiles like allyl bromide, acid chlorides or 2cyclohexen-1-one to afford the desired products 38a-f in 60 %-95 % yield (entries 1 -5). Since arylic iodides are expensive and sometimes difficult to synthesize, it was interesting to observe that the functionalised aromatic bromide diethyl 2-bromoterephthalate smoothly underwent a bromine-copper exchange with Np2 CuLi (THF, -40 C, 30 min), leading to the lithium cuprate 37b, allylation of which furnished the diester 38e in 76 % yield (entry 6). Remarkably, ketone functions are compatible with the iodine-copper exchange reaction. The treatment of 292

For the preparation of functionalized cuprates see: a) Taylor, R. J. K. Organocopper Reagents, Oxford Unversity Press, Oxford, 1994. b) Krause, N. Modern Organocopper Chemistry, Wiley-VCH, Weinheim, 2002. 93 For a chemoselective halogen-lithium exchange, see: Kondo, Y.; Asai, M.; Uchiyama, T.; Sakamoto, T. Org. Lett. 2001, 3, 13.

44 iodobenzophenone with 33 (-40 C to 0 C, 30 min) led to the desired mixed cuprate 37c. After allylation or methylation with methyl iodide the products 38f and 38g were obtained in 80 % yield (entries 7 and 8). Similarly, 4-iodophenyl tert-butyl ketone was converted into the cuprate 37d and allylated in 93 % yield (entry 9), while its reaction with 2-cyclohexen-1-one gave the 1,4-adduct in 60 % yield (entry 10). Interestingly, electron-rich substrates are also susceptible to iodine-copper exchange, even if higher temperature and longer reaction times are required. Thus, [4-(1,3-dithiolan-2-yl)-2-iodo-6-methoxyphenoxy](triisopropyl)silane gave after treatment with

Np2 CuLi (1.1 equiv, rt, 7 h) the expected mixed cuprate 37e which was allylated in 61 % yield (entry 11). Finally, a halogen-copper exchange reaction was performed on a polyhalogenated system (entry 11), to investigate the selectivity of the method. Ethyl 2-bromo-3,5-diiodobenzoate was treated with Np2 CuLi and at -50 C a rapid and selective exchange reaction took place (45 min) in 3-position, giving, after quenching with allyl bromide, ethyl 3-allyl-2-bromo-5iodobenzoate as the sole product in 76 % yield (entry 12). No bromine-copper exchange was detected.

45 Table 6. Products of type 38 obtained by the reaction of mixed functionalised lithium neopentylcuprate of type 37 with electrophiles.

Entry

Cuprate of type 37 a

Electrophile

Product of type 38

Yield (%)b

Cu(R )Li

1
CO2Et

allyl bromide
CO2Et

38a

95 90c

37a
O R

37a

PhCOCl
CO2 Et

R = Ph

38b

87 95c 83

37a

t-BuCOCl

R = t-Bu

38c

37a

COCl

38d R=
O

60

37a

cyclohexenone

38e

70

CO2Et
CO2Et Cu(R1)Li

CO 2Et

6
CO2Et

allyl bromide
CO 2Et

38f

76

37b

46

Cu(R1)Li
Ph

Ph

37c 37c
Cu(R )Li
1

allyl bromide methyl iodide

R = allyl R = methyl

38g 38h

80 80

9
COt-Bu

allyl bromide
COt-Bu

38i

93

37d
O

11

37d

cyclohexenone

38j

60

COt-Bu

12
Li(R )Cu
1

allyl bromide
OMe OTIPS
OMe OTIPS

38k

61

37e
CO2Et Br
CO 2Et

11
I Cu(R )Li
1

allyl bromide
I

Br

38l

76

37f
a b c

R1 = neopentyl; R2 = neophyl. Isolated yield of analytically pure product.

Yields obtained by performing the I/Cu exchange with the reagent 35.

47 4.6.2 Aldehydes and ketones: reactions of neophylcuprate

Recently, Knochel et al. showed that iodine-magnesium exchange allows the preparation of polyfunctional arylmagnesium reagents94 bearing ester, nitrile, amino or nitro groups, but more sensitive functionalities like a ketone or an aldehyde are not usually compatible with the presence of a carbon-magnesium bond. For this reason, a methodology that could tolerate the presence of these important moieties would mean a considerable improvement of this branch of organometallic chemistry. The performance of an iodine-copper exchange on 2-

iodobenzaldehyde was therefore attempted. The treatment of this substrate with Np2 CuLi (1.1 equiv, -40 C to -20 C, 4 h) provided the cuprate 37g, the allylation of which gave 2allylbenzaldehyde 38m in 80 % yield (Scheme 44 and Table 7).

CHO I

H Np2CuLi -40 C to -20 C THF, 4 h

Li Cu Np

Br

CHO

39

37g

38m : 80 %

Scheme 44

Similarly, acylation gave the expected product in 75 % yield, demonstrating that an aldehyde group is compatible with an iodine-copper exchange. The reaction is sensitive towards steric effects: quenching with bulky electrophiles like benzoyl chloride, pivaloyl chloride or ethyl propiolate did not furnish the desired products.

The proximity of the carbonyl group to the iodine seems to be essential for the success of the exchange reaction. In fact, attempts to obtain the mixed cuprate starting from meta- or paraiodobenzaldehyde did not lead to any ligand exchange product and when the temperature was increased, attack of the aldehyde was observed.

The use of Np2 CuLi for the conversion of 4 -iodoacetophenone into the corresponding cuprate led to extensive deprotonation to the carbonyl. However, the use of Nphyl2 CuLi 35 allowed the preparation of the corresponding cuprate 37h, which was allylated in 71 % yield (Scheme 45).
94

Jensen, A. E.; Dohle, W.; Sapountzis, J.; Lindsay, D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 565.

48

Np2CuLi

Li H2 COC

I H3 COC Nphyl2 CuLi -30 C to rt THF, 30 min H 3COC 37h Cu Nphyl Li Br H3 COC 38o : 71 %

Scheme 45

The exchange reaction proceeded relatively fast, requiring just 30 min at rt for complete conversion of 4-iodoacetophenone into the mixed cuprate 37h, which could also be acylated in 89 % yield (Table 7, entry 4) and underwent Michael additions with 2-cyclohexen-1-one and ethyl propiolate leading to the expected products in 68 and 78 % yield respectively (entries 5 and 6). In contrast to the aldehydic substrate, here the success of the exchange reaction is not dependent on the position of the carbonyl group.

49

Table 7. Reaction of functionalised lithium cuprates 37g-h with electrophiles to give 38m-s.

Entry

Cuprate of type 37a

CHO

Electrophile

Product of type 38
CHO

Yield (%)b

Cu(R )Li

allyl bromide

38m

80

37g
CHO O

37g
Cu(R )Li
2

CH3 COCl

38n

75

3
COCH3

allyl bromide 37h

COCH3

38o

71

37h

Br

38p
COCH3

65

COPh

37h

PhCOCl
COCH3
O

38q

77

37h

cyclohexenone

38r

68

COCH3

50
CO2Et

37h

ethyl propiolate
COCH3

38s

78

a b

R1 = neopentyl; R2 = neophyl. Isolated yield of analytically pure product.

As already mentioned, neophylcuprate proved to be slightly less reactive than the neopentyl reagent. On the other hand, its low reactivity becomes an advantage when very sensitive functional groups are involved in the exchange. Furthermore, its straightforward and inexpensive preparation makes it a very attractive reagent, particularly for industrial applications.

4.7

Regioselective functionalisation of polyiodinated arylic substrates

Having two lithium alkylcuprates with complementary reactivity and functional group tolerance, it should in principle be possible to perform a halogen-copper exchange on a polyiodinated system to selectively introduce different functionalities. For example, starting from the triiodoester 40 a polyfunctionalised molecule of type 43 could be synthesized (Scheme 46).
CO2Et I I 40 CO2Et FG 1 R = Np or Nphyl FG
3

1) R2CuLi or i-PrMgCl 2) FG
1

CO2Et 1 FG I 41 I

3) R2CuLi 4) FG
2

CO2Et FG1 I 42 FG2

5) R2CuLi 6) FG
3

FG 43

Scheme 46

Combining neopentyl and neophyl cuprates with Grignard reagents, three organometallic reagents of decreasing reactivity are now at our disposal, and a large variety of

51 polyfunctionalised compounds can thereby be prepared.95 The first exchange can be performed either with Grignard or with organocopper reagents however, in order to obtain complete selectivity, the reaction conditions had to be optimised. The importance of the solvent was soon recognized. In the allylation reaction of ethyl 2,3,5-triiodobenzoate all three possible

regioisomers were detected by GC-MS when THF was chosen as solvent, probably because the strong solvating medium minimizes the ortho-directing effect of the ester group, making all the three positions susceptible to exchange, regardless of which copper reagent was used. Switching to diethyl ether resulted in a considerable improvement, a clean and selective iodine-copper exchange took place and the desired product was isolated in 62 % yield. Similarly, a selective iodine-magnesium exchange was achieved, leading, upon reaction with immonium

trifluoroacetate 1, to the aminomethylation product 40c in 85 % yield (Scheme 47).

CO2Et 40d : 62 % I I

Np2CuLi CO2Et I I 39 I i-PrMgCl Et2O, -50 C 1h N Et2O, -50 C 20 min

Br

CO2Et N I I 40c : 85 %

Scheme 47

The selectivity of the reaction was determined by HMBC/HSQC-NMR. Applying these optimised conditions, a variety of products substituted in the 2-position were obtained (Table 8).

95

Rotter, T. Diplomarbeit, LMU Universitt Mnchen, 2002.

52 Table 8. Selective iodine-metal exchange in the 2-position on ethyl 2,3,5-triiodobenzoate.

Entry

Reagent

Electrophile

Product of type 41

Yield (%)a

O O

i-PrMgCl

PhCHO
I O O I

Ph

41a

77

i-PrMgCl

CHO
I
CO 2Et

41b
I

83

i-PrMgCl

N
I I

41c

85

CO 2Et

Np2 CuLi

Br

41d
I CO 2Et I COCH3

62

Np2 CuLi

Cl

41e

60

I
a

Isolated yield of analytically pure product

A second exchange was then performed on e thyl 2-acetyl-3,5-diiodobenzoate (Table 8, entry 5), using lithium dineophylcuprate. At -78 C a smooth reaction with propanoyl chloride occurred in 1 hour to give the expected product 42 of acylation in position 3, in 66 % yield (Scheme 48). The regioselectivity was determined by a NOESY-NMR experiment.

53
1) Nphyl2CuLi -78 C, 1 h 2) O Cl 41e I O 42 : 66 % CO2Et COCH3

CO2Et COCH3 I I

Scheme 48

Finally even a third exchange was achieved on the diacylated substrate 42 at -78 C in 1.5 h. The allylated product was isolated in 61 % yield (Scheme 49).

CO2Et COCH3 I O 42

1) Nphyl2CuLi -78 C, 1.5 h 2) Br

CO2Et COCH3

O 43a : 61 %

Scheme 49

The reactivity of the system decreased slightly from the first to the third exchange, depending of course also on the functional groups introduced. For the substitution in the 5-position, where no ortho-effect is possible, reaction times are significantly longer and sometimes an excess of cuprate is required to bring the exchange reaction to completion. Using this efficient protocol, a variety of polysubstituted aryl compounds can be prepared. Particularly interesting are polyacylated molecules like 43b which are not easy to obtain by other methods and can serve as useful building blocks for more complex systems (Figure 1).
CO2Et N

CO2Et COCH3

O 43b : 63 % 43c : 60 %

54

Figure 1

4.8

The role of copper cyanide

For industrial application the use of other copper salts instead of the relatively unfriendly cyanide would be desirable. The possibility of preparing homocuprate reagents of the type R CuLi for use 2 in the exchange reaction of ethyl 4-iodobenzoate was then examined (Scheme 50).
R Cu CO2Et Li

I CuX (0.5 equiv) RLi R2CuLi LiX

CO2Et

Scheme 50

Two of the most common sources of Cu(I), the salts CuI and CuBrSMe2 , were employed in the reaction with neophyllithium. In both cases no exchange was observed and the unreacted iodobenzoate was recovered. This result underlines the different reactivity of the higher order cuprates compared to the Gilman reagents, despite the fact that the role of the cyanide is still not clearly understood.

4.9

Substitution reactions with functionalised mixed cuprates

The regio- and stereochemical outcomes of the reactions of organocopper reagents with allylic esters,96 halides,97 sulfonates,98 phosphonates,99 carbamates,100 alcohols and ethers,101 ammonium

96

a) Underiner, T. L.; Goering, H. L. J. Org. Chem. 1991, 56, 2563. b) Belelie, J. L.; Chong, J. M. J. Org. Chem. 2002, 67, 3000. c) Agami, C.; Couty, F.; Evano, G.; Mathieu, H. Tetrahedron, 2000, 56, 367. 97 Arai, M.; Nakamura, E.; Lipshutz, B. H. J. Org. Chem. 1991, 56, 5489. 98 a) Ibuka, T.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Am. Chem. Soc. 1989, 111, 4864. b) Ibuka, T.; Akimoto, N.; Tanaka, M.; Nishii, S.; Yamamoto, Y. J. Org. Chem. 1989, 54, 4055. 99 a) Yanagisawa, A.; Noritake, Y.; Nomura, N.; Yamamoto, H. Synlett 1991, 251. b) Belelie, J. L.; Chong, J. M. J. Org. Chem. 2001, 66, 5552. 100 Denmark, S. E.; Marble, L. K. J. Org. Chem. 1990, 55, 1984. 101 Goering, H. L.; Kantner, S. S. J. Org. Chem. 1981, 46, 2144.

55 salts,102 and oxiranes,103 as well as with propargylic104 and allenic105 substrates, are well documented.106 Organocopper-Lewis acid complexes are one of the reagents of choice in (E)stereoselective and SN2-selective reactions. Preliminary experiments performed with mixed lithium neopentylcuprate showed that the reaction between the mixed organocuprate 37a and 2iodo-2-cyclohexen-1-yl acetate proceeded at -20 C in 30 min to give the substitution product 56 in 64 % yield and without loss of stereochemical information (Scheme 51).

OAc I I EtO2C Np2CuLi -78 C to -30 C 2h EtO2C 37a Np Cu Li 93 % ee -10 C, 10 min CO2Et 56 : 64 % 92 % ee I

Scheme 51

This interesting result suggests the potential for the regio- and stereoselective introduction of moieties bearing very sensitive functionalities which are normally not tolerated by magnesium or zinc cuprates.

4.10 Summary

In summary, it has been shown that sterically hindered cuprates 33 and 35 allow a highly chemoselective halogen-copper exchange. With this method, new functionalised cuprates bearing ester, ketone, or even aldehyde functions can be prepared and used in synthesis. Moreover, an efficient method for the selective functionalisation of polyiodoarylic substrates was developed. The possibility of employing three different organometallic reagents allows the synthesis of a potentially vast range of complex molecules bearing very sensitive functional groups at any position of the benzene ring. Finally, preliminary experiments on the use of these mixed cuprates

102 103

Pan, Y.; Hutchinson, D. K.; Nantz, M. H.; Fuchs, P. L. Tetrahedron Lett. 1989, 45, 467. Marino, J.P.; Kelly, M. G. J. Org. Chem. 1981, 46, 4389. 104 Alexakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. Tetrahedron Lett. 1989, 30, 2387. 105 Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3059. 106 Marshall, J. A. Chem. Rev. 1989, 89, 1503.

56 in substitution reactions with optically active substrates, indicated their possible application in the preparation of a broad variety of functionalised enantiomerically pure products.

57

Iodine-Copper Exchange on Vinylic Substrates

Numerous methods for the preparation of vinylic transition metal complexes are known and have been used frequently in organic synthesis.107 An efficient method is the addition of organocopper reagents to terminal alkynes and to acetylene.54,63 An alternative route is the transmetalation of a variety of organometallic intermediates mediated by preformed higher order cuprates. As already mentioned, vinylic stannanes,59 tellurides,60,
108

and zirconates61,

109

readily exchange their vinylic

ligands for alkyl groups on copper. Vinylic alanes, formed via Negishi carbometalations with Me3 Al/catalytic Cp2 ZrCl2 ,62 have also been converted into mixed higher order cyanocuprates. No example of halogen-copper exchange for the formation of vinylic cuprates has appeared until now in the literature. In order to extend the scope of our new method, its application to the selective transfer of vinylic substrates was studied. Generally, the transferability of organic ligands decreases in the order alkenyl > alkyl > methyl > alkynyl110 but changes in this order are not unusual, depending on the type of system studied. The iodine-copper exchange was then studied on the following ,-unsaturated ketone which possesses acidic -hydrogens (Scheme 52).

O I Np2CuLi -30 C, 3 h

Li Cu Np Br

44a

45a : 74 %

Scheme 52 Probably thanks to the chelating effect of the carbonyl group, -deprotonation was minimized and a smooth iodine-copper exchange occurred (Np2 CuLi, -30 C, 3 h), to give the allylated product 45a in good yield.

107

For a recent review see: a) Frstner, A. Active Metals, Wiley-VCH, Weinheim, 1996. b) Negishi, E. Organometallics in Organic Synthesis, Wiley-Interscience, New York, 1980. 108 a) Tucci, F.; Chieffi, A.; Comasseto, J. V. J. Org. Chem. 1996, 61, 4975. 109 a) Lipshutz, B. H. Acc. Chem. Res. 1997, 30, 277. b) Farhat, S.; Marek, I. Angew. Chem. Int. Ed. 2002, 114, 1468. 110 a) Corey, E. J.; Beames, D. J. J. Am. Chem. Soc. 1972, 94, 7210. b) Alexakis, A.; Hanaizi, J.; Jachiet, D.; Normant, J. F. Tetrahedron Lett. 1990, 31, 1271. c) Mandeville, W. H.; Whitesides,G. M. J. Org. Chem. 1974, 39, 400.

58 After this promising result, another two ,-unsaturated open-chain substrates were tested. Ethyl (2Z) 3-iodo-3-phenylpropenoate was reacted with lithium dineopentylcuprate at -50 C but the major product observed was ethyl (2E)-5,5-dimethyl-3-phenyl-2-hexenoate, derived from addition-elimination reaction. The use of the less reactive neophylcuprate solved the problem: a very fast exchange took place ( -78 C, 3 min) and the allylated product 45b could be isolated in 88 % yield as a single stereoisomer (Scheme 53 and Table 9).
CO2Et Ph Cu Nphyl Li 44b CO2Et Ph I CO2Et Ph Cu Nphyl Li 44b 45b : 50 %

CO2Et Ph I

Nphyl2 CuLi -78 C, 3 min THF / HMPA

Br Ph

CO2Et

45b : 88 % CO2Et Ph

Nphyl2CuLi -50 C, 20 min THF

Br

Scheme 53

Table 9. Reaction of functionalised lithium vinyl cuprates 44 with electrophiles to give 45.

Entry

Cuprate of type 44a

Electrophile

Product of type 45
O

Yield (%)b

Cu(R )Li

allyl bromide

45a

74

44a
CO2Et
CO 2Et

2
Ph Cu(R )Li
2

allyl bromide

45b
Ph

88 50c 60d

44b

59

CO2Et

44b

1-Br-hexyne
Ph Bu

45c

63

44b

PhCOCl
Ph

CO2Et

45d
COPh
CO2Et

56

44b

cyclohexenone

45e
Ph

48

6
MeO

Cu(R2)Li

COPh

PhCOCl
MeO

45f

72

44c
O
O

Li(R1)Cu

allyl bromide

45g

55

44d
O O N

44d

CH3 COCl

45h

72

Bu

O N

44d

1-Br-hexyne

45i

58

a 1 b c

R = neopentyl; R2 = neophyl Isolated yield of analytically pure product.

d

Yield in THF

Yield in THF/DMPU 1:1

The reaction seemed to be very sensitive to the solvent system. Poor yields and selectivities were observed in THF alone as solvent (entry 2). Addition of HMPA had a great impact on the reaction. Not only were the yields improved, but the (Z)-products were obtained exclusively in presence of nine equivalent of HMPA64 (entry 2). The use of DMPU as cosolvent was also

60 effective but yields were generally lower. This result suggests that the additive stabilizes vinylcopper intermediate,111 avoiding isomerization to the (E) cuprate. The cuprate 44b could be allylated (entries 2) and acylated with benzoyl chloride in reasonable yield (entry 4). Remarkably, a cross-coupling reaction with 1-bromohexyne also furnished the desired product in acceptable yield, always with complete retention of the double bond geometry (entry 3). Alkenylcopper reagents are considerably less reactive than alkylcopper derivatives and undergo 1,4-additions less efficiently than their alkyl-counterparts.56 Vinylic copper compounds prepared by the addition of alkylcoppers to terminal alkynes in diethyl ether are especially unreactive towards Michael acceptors. On the other hand, vinyl copper reagents prepared by lithium-copper or magnesium-copper exchange react with enones to give conjugate addition products in good yields.112 In our case, probably due also to a steric effect, the mixed vinylic cuprate 44b underwent a 1,4-addition reaction with 2-cyclohexen-1-one (entry 5) in moderate yield. Non-activated vinylic iodides like 44c could also be acylated in good yield, even if the exchange reaction was slower (2.5 h at 0 C, entry 6). Surprisingly, functionalised vinylic bromides were also susceptible to halogen-copper exchange with neophylcuprate, although the yields of these reactions tended to be lower. Complete exchange occurred in 30 min at 0 C and allylation, acylation and coupling products were isolated in acceptable yields (entries 7-9).

5.1

Summary

In conclusion, the halogen-copper exchange on vinylic substrates is a suitable method for the preparation of tri- or tetrasubstituted alkenes. The cuprate stability is dependent on the solvent system and best results are obtained in more polar systems. The exchange reaction occurs very fast in the case of activated vinylic substrates and leads to the desired products in good yields with no isomerisation of the double bond. The procedure is also applicable to non-activated substrates and even to vinylic bromides, although moderate yields are obtained in this case. Further studies should be made on the performance of iodine-copper exchange on linear vinylic halides bearing other functional groups such as aldehydes.

111 112

Piers, E.; Chong, J. M.; Keay, B. A. Tetrahedron Lett. 1985, 26, 6265. a) Funk, R. L.; Vollhardt, K. P.C. J. Am. Chem. Soc. 1980, 102, 5253. b) Leonard, J.; Ryan, G. Tetrahedron Lett. 1987, 28, 2525.

61

Halogen-Copper Exchange on Heterocycles

Heterocycles are fundamental constituents of most biologically active compounds. The preparation of polyfunctional heterocycles has been recently studied.113 Moreover, the halogenmagnesium exchange has already been established as a very efficient tool for the synthesis of substituted indoles114 or quinoline derivatives115 (Scheme 54).
Ph N I 1) i-PrMgBr (2 equiv) THF, -10 C, 3 h 2) CuCN N Ph 3) OMe Br (2 equiv) Ph 68 %
O HN Tf2 O (1.2 equiv) pyridine (3 equiv) CH2 Cl2 , 0 C to rt, 16 h N

Ph N OMe H2SO4 (cat.) MeOH, rt, 30 sec N H2N N H

2LiCl

-10 C to rt, 16 h
Ph N I 1) i-PrMgBr (1.3 equiv) THF, -10 C, 1 h 2) ZnBr2 (1 equiv) -10 C, 30 min 3) Pd(dba)2 (10 mol%) tpf (20 mol%) TBAI (3 equiv) OTf CO2Et (0.7 equiv) rt, 16 h

71 %
OTf

CO2 Et

CO2 Et 74 %

CO2Et 62 %

Scheme 54

A similar approach was adopted for the preparation of heterocyclic copper reagents. The readily prepared dibromopyridine 47 smoothly underwent to a bromine-copper exchange in presence of two equivalents of Np2 CuLi at 0 C in 1 h, affording the corresponding cuprate 48a which was allylated in 73 % yield. As in the case of magnesium exchange, the first equivalent is probably partially chelated by the amidine moiety and the second performs a selective exchange in the 3 position (Scheme 55 and Table 10, entry 1).

113 114

Neumann, H.; Wangelin, A. J. v.; Grdes, D.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc. 2001, 123, 8398. Dohle, W. Ph.D. Thesis LMU Universitt Mnchen, 2002. 115 Jensen, A. E. Ph.D. Thesis LMU Universitt Mnchen, 2001.

62

Br N

Br N N

Np2CuLi (2 equiv) 0 C, 1 h THF

Br N

Cu Np N N

Li Br

Br N N N

47

48a

49a : 73 %

Scheme 55

Acylation of the cuprate 48a with benzoyl chloride yielded the expected product in only 30 % yield (entry 2) and the hydrolysed bromopyridine was also recovered. This seems to indicate that the reaction is quite sensitive to steric effects, which was confirmed by the unsuccessful 1,4addition to 2-cyclohexen-1-one (entry 3).

More interesting is the imidazole system. Generally, the acidic hydrogen in the 2-position of an imidazole ring can be abstracted by a base at low temperature.116 For this reason, the carbon in the 2-position has to be protected if a halogen-lithium exchange is attempted, however this precaution is not necessary when magnesium reagents are used. Starting from commercially available N-methylimidazole, bromination furnished the imidazole derivatives 50, which was treated with n-BuLi to give the protected substrate 52. Similarly, iodination and subsequent methylation yielded the diiodomethyl imidazole 51, which upon iodine-magnesium exchange and quenching with DMF, furnished the unprotected substrate in the 2-position 53 (Scheme 56).
1) BuLi, -78 C, 5 min PhSSPh THF 2) BuLi, -78 C, 15 min DMF

N N

AcONa AcOH, Br 2

Br N

Br

PhS N

CHO

Br 50 : 50 %

Br 52 : 60 %

H N N

1) I2, KI, NaOH 2) NaOH Me2SO4 N

I I

1) EtMgCl, rt, 30 min 2) DMF N

CHO I 53 : 67 %

51 : 67 %

116

For review on imidazole chemistry see: a) Grimmett, M. R. Adv. Heterocyc. Chem. 1980, 27, 241. b) Grimmett, M. R. Comprehensive Heterocyclic Chemistry (Ed. A. R. Katrizsky and C. W. Rees), Pergamon Press, Oxford, 1984, Vol.4, p.345.

63

Scheme 56

For the bromine-copper exchange the more reactive Np2 CuLi was employed. In this case only one equivalent was necessary for the reaction to take place and after quenching with allyl bromide the desired product 49d was obtained in 61 % yield. When non-protected imidazole was used, neopentyl cuprate had to be replaced by Nphyl2 CuLi in order to avoid deprotonation, and the reaction proceeded smoothly at -78 C to give 4-allyl-1-methyl-1H-imidazole-5-carbaldehyde 49e in 67 % yield (Scheme 57 and Table 10).

PhS N

CHO Br

Np2CuLi 0 C, 4 h

PhS N

CHO Li Cu Np

Br

PhS N

CHO

52

48b

49d : 61 %

N N I 53

CHO

Nphyl2 CuLi -78 C, 1 h N

CHO Li Cu Nphyl 48c

Br N

CHO

49e : 67 %

Scheme 57

64 Table 10. Reaction of functionalised lithium heterocyclic cuprates 48 with electrophiles to give 49. Entry Cuprate of type 48a Electrophile Product of type 49 Yield (%)b

Br

Cu(R )Li

Br

1
N N N

allyl bromide
N N N

49a

73

48a
O

48a

PhCOCl

Br N N

Ph N
O

49b

30

48a

cyclohexenone
Br N N N

49c

trace

PhS N

CHO Cu(R )Li

1

allyl bromide

PhS N

CHO

49d

61

48b 5
N N

CHO Cu(R )Li

2

allyl bromide
N

CHO

49e

67

48c
OEt OEt

6
N

allyl bromide
Cu(R )Li N I
2

49f

91

48d
OEt
OEt

7
N

allyl bromide
CHO Cu(R )Li
2

N N

49g
CHO

46

48e

65

a 1 b

R = neopentyl; R2 = neophyl Isolated yield of analytically pure product.

Similarly,

1-ethoxymethyl-4,5-diiodoimidazole

smoothly

underwent

iodine-copper

exchange

with Nphyl2 CuLi (-78 C, 1 h), furnishing after quenching with allyl bromide the expected product in 91 % yield (entry 6).117 The related derivative functionalised in the 5 -position with an aldehyde group was allylated in 46 % yield (entry 7). Interestingly, it was also possible to achieve a double iodine-copper exchange in situ in the presence of 2 equiv of Nphyl2 CuLi at -78 C, whereby the double acylated product 55 was obtained in 28 % overall yield (Scheme 58).

OEt N N I 54 I 1) Nphyl2CuLi -78 C, 1 h 2) CH3CH2COCl N N

OEt O 3) Nphyl2CuLi -78 C, 1 h N I 4) CH3CH2COCl N

OEt O

O 55 : 28 %

Scheme 58

6.1

Summary

These results demonstrate that halogen-copper exchange on functionalised heterocycles is a method with a vast range of substrate applicability. Pyridine and imidazole derivatives react smoothly and furnish a variety of mono- and disubstituted products. Moreover, fast exchange rates and high functional group tolerance make it a potentially very useful tool in natural product synthesis.

117

Matsuo, K. Unpublished results.

66

Summary and Outlook

This work has been focused on new methods for the synthesis of z and copper reagents, and inc their application in the preparation of polyfunctionalised molecules.

In the first part an aminomethylation reaction of various functionalised zinc and magnesium reagents has been described. The readily prepared immonium trifluoroacetates reacted with organometallic species to give the corresponding protected amines in good to excellent yields (Scheme 59).

R1ZnX or R12 Zn

THF, CH 2Cl2

H H

N
30 min

R1CH2N

OCOCF3
1 5a-f : 68-96 %

Ph
R1ZnX or R12 Zn THF, Et2O

Ph Ph
30 min

H H

R CH2N

Ph

OCOCF3
2 5g-h : 73-92 %

Scheme 59

The bis-allylated amines could then be deprotected to the primary amines. The reaction showed high tolerance towards functionalities like esters or nitriles (Scheme 60).

O R CH 2N
5a-h or 7a
1

O N O N Me

Pd(PPh3 )4 (2 mol%)

R1CH 2NH2
CH2 Cl2, 35 C, 1 to 3 h 8a-g : 57-80 %

Me

Scheme 60

67

An efficient protocol for the preparation of substituted benzylic zinc reagents has been developed. It is based on a fragmentation reaction of sterically hindered homobenzylic alcoholates and in this way avoids any formation of Wurtz-coupling side products. The fragmentation reaction leads to the formation of a benzylic zinc reagent, which reacts with various aldehydes, furnishing the desired substituted homobenzylic alcohols in good yields as a 1:1 mixture of diastereoisomers (Scheme 61).
OH Ph R
1 1 1

t-Bu t-Bu

1) n-BuLi, -78 C 2) ZnCl2, -78 C 3) R2CHO, -78 C to rt, 12 h

OH Ph R
1

9a : R = allyl 9b : R = methyl

13a-i : 46-80 %

Scheme 61

Further improvements to this procedure would allow the synthesis of functionalised secondary benzylic zinc reagents, which are still difficult to obtain by other methods.

A similar concept was applied for the preparation of substituted allylic zinc reagents, obtained by a cyclization-fragmentation reaction of sterically hindered ketones. A cyclic five-membered ring alcoholate was obtained after iodine-lithium exchange at low temperature, and transmetalation to zinc followed by fragmentation led to the substituted allylic zinc reagent which, upon reaction with aldehydes, yielded the expected homoallylic alcohols in good yields and excellent diastereoselectivities (Scheme 62).

68
1) n-BuLi -90 C to 0 C, 30 min THF / DMPU 1:1 F 18 2) ZnBr2 , 0 C, 15 min THF F 26 F R'CHO 0 C to r.t. ZnX O R R O ZnX

OH 68 - 96 % syn/anti up to > 98:2 R' R 27

Scheme 62

The reaction proceeds via a six-membered ring intermediate with a fixed geometry, thereby favouring the attack of the electrophile from only one side of the molecule. It was observed that the addition of a polar cosolvent such as DMPU brought a significant improvement in yield and reaction rate and the size of the substituent R also played an important role in the diastereoselectivity of the reaction, while the steric bulk of the aldehyde had a minor influence.

A further step in the development of this elegant procedure would be the preparation of functionalised allylic zinc reagents. Even if preliminary results were not satisfactory, due to difficulties in the synthesis of the starting material, it would be of interest to develop a more general protocol that allows the formation of highly functionalised allylic zinc reagents and to investigate their diastereoselective reaction with a broader range of electrophiles.

In the second part of this work the preparation of new sterically hindered lithium dialkylcuprates, Np2 CuLi and Nphyl2 CuLi, for the synthesis of highly functionalised mixed cuprates via halogencopper exchange was developed. This method has been applied to arylic, vinylic and heterocyclic substrates and exhibited very high functional group tolerance. For the first time, sensitive functionalities such as aldehydes or enolizable ketones were compatible with a halogen-metal exchange (Scheme 63).

69
H I Np2CuLi -40 C to -20 C THF, 4 h 39 37g 38m : 80 % O

CHO

Li Cu Np

Br

CHO

Scheme 63

Polyiodinated aryl reagents could be regioselectively functionalised combining the use of the two cuprates which possess different reactivity and, consequently, complementary functional group tolerance (Scheme 64).
CO2Et I I 40 CO2Et FG 1 R = Np or Nphyl FG
3

1) R2CuLi or i-PrMgCl 2) FG
1

CO2Et 1 FG I 41 I

3) R2CuLi 4) FG
2

CO2Et FG1 I 42 FG2

5) R2CuLi 6) FG
3

FG 43

Scheme 64

Preliminary studies on substitution reactions with mixed cuprates have shown that the reaction proceeds with high stereoselectivity (Scheme 65).
OAc I I EtO 2C Np2CuLi -78 C to -30 C 2h EtO2C 37a Np Cu Li 93 % ee -10 C, 10 min CO2 Et 56 : 64 % 92 % ee I

Scheme 65

70 Further investigations in this field could lead to very interesting applications, for example in the synthesis of ligands.

Vinylic substrates underwent halogen-copper exchange with retention of the configuration of the double bond. The exchange rate was very fast and allowed the preparation of various functionalised tri- and tetrasubstituted alkenes (Scheme 66).

CO2Et Ph I

Nphyl2 CuLi -78 C, 3 min THF / HMPA Ph

CO2Et Cu Nphyl Li 44b

Br Ph

CO2Et

45b : 88 %

Scheme 66

Finally, heterocycles have also proved to be suitable reagents for the halogen-copper exchange. Pyridine and imidazole systems bearing aldehydes or ketones were reacted with Np2 CuLi or Nphyl2 CuLi affording the expected products in reasonable to very good yield (Scheme 67).
OEt O 3) Nphyl2CuLi -78 C, 1 h N I 4) CH3CH2COCl O 55 : 28 % N O

OEt N N I 54 I 1) Nphyl2CuLi -78 C, 1 h 2) CH3CH2COCl N N

OEt

Scheme 67

The important role of heterocycles in biologically active compounds makes them especially interesting substrates that should be further investigated. A particularly stimulating task would be the application of this new and quite successful methodology in the synthesis of natural products.

71

Experimental Section

72

General Conditions

All reactions were carried out with magnetic stirring and, if air or moisture sensitive, in flamedried glassware under argon. Syringes which were used to transfer reagents and solvents were purged with argon prior to use.

Solvents Solvents were dried according to standard methods by distillation over drying agents as stated below and were stored under argon. CH2 Cl2 , DMF and pentane (CaH2 ), diethyl ether, hexane and THF (Na/benzophenone), pyridine and triethylamine (KOH), toluene (Na).

Reagents Reagents of >98 % purity were used as obtained. n-Butyllithium was used as 1.5 M solution in hexane. t-Butyllithium was used as 1.5 M solution in pentane. The following reagents were prepared according to literature procedures: ethyl bromomethylacrylate,118 ethyl(Z)-3-iodo-3-phenylpropenoate,119 2-iodo-3-methyl-2cyclohexen-1-one,120 4-iodo-7-methoxy-1,2-dihydronaphtalene, 121 3-chloro-2,4dimethylpentane. 122

Content determination of organometallic reagent Organolitium and organomagnesium solution were titrated using the method of Paquette.123 The concentrations of organozinc solutions were determined by back titration of iodine with an aqueous Na2 S2 O3 solution.

118 119

Villieras, J.; Rambaud, M. Synthesis 1982, 925. Piers, E.; Wong, T.; Coish, P. D.; Rogers, C. Can. J. Chem. 1994, 72, 1816. 120 Johnson, C. R.; Sakaguchi, H. Synlett, 1992, 813. 121 Lee, K.; Wiemer, D. E. Tetrahedron Lett. 1993, 34, 2433. 122 Metveeva, E. D. ;Yaloskaya, A. I.; Cherepanov, I. A.; Bundel, Y. G.; Kurts, A. L. J. Org. Chem. URSS 1989, 25, 587. 123 Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503.

73

Chromatography Thin layer chromatography (TLC) was performed using aluminium plates covered with SiO 2 (Merck 60, F-254). The chromatograms were viewed under UV light and /or by treatment of the TLC plate with one of the solutions below followed by heating with a heat gun: - KMnO 4 (0.3 g), K2 CO3 (20 g), KOH (0.3 g) in water (300 mL). - Phosphormolybdic acid (5.0 g), Ce(SO4 )2 (2.0 g), conc. H2 SO4 (12 mL) in water (230 mL). Flash column chromatography was performed using SiO 2 60 (0.040-0.063 mm) from Merck. Gas chromatography (GC): Hewlett-Packard 6890 - Column A: 5 % phenylmethylpolysiloxane (HP Ultra 2) 12 m x 0.2 mm - Column B: 5 % phenylmethylpolysiloxane (HP %) 5 m x 0.25 mm The compounds were detected with a flame ionisation detector.

Analytical data Melting points were determined on a Bchi B-540 apparatus and are uncorretted. NMR spectra were recorded on Brucker ARX 200, AC 300 or WH 400 instruments. Chemical shifts are reported as -values in ppm relative to the deuterated solvent peak: CDCl3 ( H: 7.27, C: 77.0). For the characterization of the observed signal multiplicities the following abbreviations were applied: s (singlet), d (doublet), dd (double doublet), dt (double triplet), h (heptet), t (triplet), q (quartet), m (multiplet), as well as br (broad).

Infrared spectra were recorded from 4000-400 cm-1 on a Nicolet 510 FT-IR or a PerkinElmer 281 IR spectrometer. Samples were measured either as a film between sodium chloride plates or (for solids) as potassium tablets. The absorption bands are reported in wave numbers (cm-1 ). For the band characterization the following abbreviations were applied: br (broad), s (strong), m (medium), vs (very strong), w (weak).

74 Electron impact mass (Ei, 70 eV) spectra were recorded on a Varian MAT CH 7A instrument. High resolution mass spectra (HRMS) were recorded on a Varian MAT 711 instrument. Additionally, for the combination of gas chromatography with mass spectroscopic detection, a GC/MS from Hewlwtt-Packard HP 6890/MSD 5973 was used. - Column C: 5% phenylmethylpolysiloxane (HP 5) 30m x 250 m x 0.25 m Elemental analysis was carried out on a Heraeus CHN-Rapid-Elementanalyzer in the microanalytical laboratories of the Department fr Chemie und Pharmazie, LudwigMaximilians Universitt Munich.

75

Typical Procedures (TP)

TP 1: Typical procedure for the aminomethylation of functionalised organozinc and Grignard reagents

A dried, argon flushed 100 mL flask was charged with the starting aminal (5.3 mmol) and CH2 Cl2 (10 mL), was added. The solution was cooled to 0 C and trifluoroaceticanhydride (0.74 mL, 5.3 mmol) was added dropwise. The mixture was kept at 0 C for 10 min and at rt for 0.5 h. Development of a yellow colour indicates the formation of the iminium. The immonium trifluoroacetate was then cooled to -78 C and a solution of the functionalised organometallic reagent (7.5 mmol) in THF was added. After stirring for the required time, the reaction was quenched with saturated, aqueous NH4 Cl and extracted with CH2 Cl2 or diethyl ether (4 x 30 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography yielded the desired product.

TP 2: Typical procedure for palladium-catalysed deprotection of allylamines

A solution of the allylamine (2.0 mmol) in dry degassed CH2 Cl2 (5 mL), was added with a syringe in a Schlenk tube containing the catalyst (Pd(PPh3 )4 , 69 mg, 5.9x10-5 mmol) and NDMBA (1.9 g, 11.9 mmol) under argon. The homogeneous mixture was stirred at 35 C for the required time. After cooling, the CH2 Cl2 was removed under vacuum and the residue dissolved in diethyl ether. Water was added and the mixture was acidified with 1 N HCl to pH 2, then the organic layer was separated. The aqueous layer was basified to pH 9 with saturated, aqueous Na2 CO3 and extracted with CH2 Cl2 (9 x 20 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography yielded the desired deprotected amine.

TP 3: Typical procedure for the preparation of benzylic alcohols via a fragmentation reaction

A solution of n-BuLi (8.4 mL, 12.3 mmol) was added at -78 C to a solution of the tertiary alcohol (1.1 mmol) in THF (3 mL). The reaction mixture was stirred at this temperature for 30

76 min and a solution of zinc chloride (115 mg, 0.8 mmol) in THF (2 mL) was added, followed by the aldehyde (0.67 mmol). The reaction was slowly warmed to rt overnight and quenched with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (3 x 15 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography yielded the desired product.

TP 4: Typical procedure for the generation of homoallylic zinc reagents via a cyclizationfragmentation reaction

A solution of n-BuLi (0.55 mL, 0.8 mmol) was added at -90 C to a solution of the starting ketone (0.8 mmol) in THF/DMPU 1:1 (2 mL). The reaction mixture was quickly warmed up to 0 C and after 30 min a 1.5 M solution of zinc bromide in THF (0.74 mL, 1.1 mmol) was added. After 15 min the aldehyde was added and the mixture was let warm up to rt overnight. The reaction mixture was then quenched with saturated, aqueous NH4 Cl and the aqueous phase was extracted with diethyl ether (3 x 15 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography yielded the desired product.

TP 5: Typical procedure for the halogen-copper exchange on arylic substrates

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with the aryl halide (1.0 mmol). Dry THF (2 mL) was added and the solution was added slowly into a dry and argon flushed 25 mL flask, containing the dialkyllithiumcuprate 33 or 35, previously prepared (1.2 mmol) and cooled to -78 C. The mixture was warmed quickly to the required temperature. The halogen-copper exchange was complete within 1 h (checked by GC -3 analysis of reaction aliquots) and the electrophile (0.9 mmol) was added to the mixed organocuprate (4), then the mixture was let warm up to rt. After 0.5 h of stirring at rt, the reaction mixture was quenched with saturated, aqueous NH4 Cl (2 mL) and poured into water (25 mL). The aqueous phase was extracted with diethyl ether (3 x 30 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography yielded the desired product.

77

TP 6: Typical procedure for the iodine-copper exchange on ethyl (2Z)-3-iodo-3phenylpropenoate

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with ethyl (2Z)-3-iodo-3-phenylpropenoate (302 mg, 1.0 mmol). THF (1 mL) and HMPA (1.6 mL, 9.0 mmol) were added and the solution was added slowly into a dry and argon flushed 25 mL flask, containing the dineophyllithiumcuprate 35, previously prepared (1.2 mmol) and cooled to -78 C. The iodine-copper exchange was complete within 3 min (checked by GC analysis of reaction aliquots) and the electrophile (0.9 mmol) was added to the mixed organocuprate, then the mixture was let warm up to rt. After 0.5 h of stirring at rt, the reaction mixture was quenched with saturated, aqueous NH4 Cl (2 mL) and poured into water (25 mL). The aqueous phase was extracted with diethyl ether (3 x 20 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography yielded the desired product.

TP 7: Typical procedure for the bromine-copper exchange on N,N-diallyl-2-bromo-3methyl-butenamide

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with N,N-diallyl-2-bromo-3-methyl-butenamide (258 mg, 1.0 mmol). THF (1 mL) was added and the solution was added slowly into a dry and argon flushed 25 mL flask, containing the dineophyllithiumcuprate 35, previously prepared (1.2 mmol) and cooled to -78 C. The reaction mixture was quickly warmed to 0 C. The bromine-copper exchange was complete within 30 min (checked by GC analysis of reaction aliquots) and the electrophile (2.0 mmol) was added to the mixed organocuprate, then the mixture was let warm up to rt. After 0.5 h of stirring at rt, the reaction mixture was quenched with saturated, aqueous NH4 Cl (2 mL) and poured into water (25 mL). The aqueous phase was extracted with diethyl ether (3 x 20 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography yielded the desired product.

78 TP 8: Typical procedure for the iodine-copper exchange on imidazole derivatives

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with 4-iodo-1-methyl-1H-imidazole-5-carbaldehyde 53 (236 mg, 1.0 mmol). THF (1 mL) was added and the solution was added slowly into a dry and argon flushed 25 mL flask, containing the dineophyllithiumcuprate 35, previously prepared (1.2 mmol) and cooled to -78 C. The iodine-copper exchange was complete within 1 h (checked by GC analysis of reaction aliquots) and the electrophile (1.0 mmol) was added to the mixed organocuprate, then the mixture was let warm up to rt. After 0.5 h of stirring at rt, the reaction mixture was quenched with saturated, aqueous NH4 Cl (2 mL) and poured into water (25 mL). The aqueous p hase was extracted with diethyl ether (3 x 20 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography yielded the desired product.

79

Synthesis of Organozinc and Organocopper Reagents

Synthesis of primary and secondary alkylzinc iodides29

A 250 mL two-necked flask equipped with a dropping funnel, a reflux condenser and a stirring bar was charged with zinc dust (8.6 g, 132 mmol, Aldrich, 325 mesh), flame d ried, and flushed with argon. THF (40 mL) and 1,2-dibromoethane (2.5 g, 13.3 mmol) were added and the zinc was activated by heating the solvent to reflux with a heat gun, then allowing the reaction mixture to cool. This procedure was repeated three times, then TMSCl (2.4 mL, 26.3 mmol) was added. The mixture was then heated to 50 C and an alkyl iodide (45.0 mmol) was added dropwise as a solution in THF (20 mL). The mixture was maintained at 50 C until the zinc insertion into the alkyl iodide was complete (checked bi GC analysis, approx. 4 h). The reagent was concentrated in vacuo and titrated before use.

Synthesis of benzylic zinc bromides124 A 250 mL two-necked flask equipped with a dropping funnel, a reflux condenser and a stirring bar was charged with zinc dust (8.6 g, 132 mmol, Aldrich, 325 mesh), flame dried, and flushed with argon. THF (40 mL) and 1,2-dibromoethane (2.5 g, 13.3 mmol) were added and the zinc was activated by heating the solvent to reflux with a heat gun, then allowing the reaction mixture to cool. This procedure was repeated three times, then TMSCl (2.4 mL, 26.3 mmol) was added. The mixture was cooled to 0 C before the benzylic zinc bromide (44.0 mmol) was added dropwise (1 drop/sec) as a solution in THF (20 ml). The temperature was m aintained at 0 C until the reaction was complete (checked by GC, approx. 2 h). The reagent was concentrated in vacuo and titrated before use.

124

Berk, S. C.; Yeh, M. C. P.; Jeong, N., Knochel, P. Organometallics 1990, 9, 3053

80
Synthesis of lithium dimethylcuprate 125

MeLi (2.25 mL, 4.0 mmol, 1.79 M in Et2 O) was added dropwise to a suspension of CuCN (0.2 g, 2.2 mmol) in THF (2 mL) at -78 C. The mixture was warmed quickly to -40 C till a clear colourless solution was obtained. Lithium dibutylcuprate and lithium trimethylsilylmethylcuprate were prepared by an analogous procedure.

Synthesis of lithium bis(1-isopropyl-2-methylpropyl)cuprate 126

A mixture of lithium metal (56 mg, 8.0 mmol) and 4,4 Di-tert-butylbiphenyl (2.4 g, 9.2 mmol) in THF (6 mL) was cooled to -4 C and stirred overnight at this temperature. In the morning the reaction mixture was cooled to -78 C and a solution of 3-chloro-2,4-dimethylpentane (540 mg, 4.0 mmol) in THF (4 mL) was added. The dark red solution obtained was then cannulated into a suspension of CuCN (190 mg, 2.1 mmol) in THF (2 mL). The mixture was then warmed to -20 C and stirred for 20 min, furnishing the expected dialkylcuprate ready to use.

Synthesis of lithium dineopentylcuprate 127

A 10 mL round-bottomed flask, flame dried and flushed with argon was charged with neopentyl iodide (0.3 mL, 2.2 mmol) and the compound dissolved in 2 mL of diethyl ether. The solution was cooled to -78 C and t-BuLi (3.1 mL, 4.6 mmol) was added dropwise. The reaction mixture was stirred for 1 h at -78 C and warmed to rt. After stirring for another hour the mixture was then cannulated into a suspension of CuCN (110 mg, 1.2 mmol) in THF (1 mL) cooled to -78 C. the reaction mixture was allowed to warm to 0 C, furnishing the expected dialkylcuprate ready to use.

125 126

Lipshutz, B. H.; Kozlowski, J. A.; Wilhelm, R. S. J. Org. Chem. 1983, 48, 546. Freeman, P. K.; Hutchinson, L. L.; J. Org. Chem. 1980, 45, 1924. 127 Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990, 55, 5406.

81 Synthesis of lithium dineophylcuprate 89

A 500 mL round-bottomed flask, flame dried and flushed with argon was charged with lithium metal (3.0 g, 432 mmol) and neophylchloride (14.0 mL, 86.9 mmol) in hexane (75 mL). The reaction mixture was heated under reflux overnight. After cooling to rt the mixture was cannulated into a flame dried Schlenk tube and the hexane removed in vacuo. Dry diethyl ether was added and the mixture was centrifuged (2000 rpm, 30 min). The clear solution of neophyllithium thus obtained was titrated before use with menthol using o-phenantroline as indicator and could be stored at -30 C for several days. A 25 mL round-bottomed flask, flame dried and flushed with argon was charged with CuCN (110 mg, 1.2 mmol). THF (1 mL) was added and the suspension cooled to 0 C. The freshly titrated solution of neophyllithium was then slowly added and the mixture quickly warmed to rt and stirred for 10 min, till a clear yellow solution of the desired cuprate was obtained.

82

4 Aminomethylation of Functionalised Organozinc Reagents and Grignard Reagent Using Immonium Trifluoroacetates

Synthesis of N,N,N,N-tetraallylmethanediamine (3)

A 100 mL round bottomed flask was charged with diallylamine (30 mL, 240 mmol). A solution of formaldehyde (12 mL, 320 mmol), was added slowly at 0 C and the mixture was heated at 100 C for 2 h. The formation of a biphasic system was observed, the upper layer was separated and dried over KOH pellets. After filtration the crude mixture was distilled under vacuum to give the desired product 3 as a colourless oil (18.3 g, 74 %).

Bp 90 C, 7 mbar ~ IR (film, cm-1 ): 3077 (w), 2805 (m), 1643 (m), 1417 (m), 1399 (m), 1161 (m), 994 (s), 916 (vs).
1

H NMR (CDCl3 , 300 MHz): d 5.82-5.68 (m, 4H), 5.09-4.98 (m, 8H), 3.09-3.06 (m, 8H), 3.03 C NMR (CDCl3 , 75 MHz): d 136.6, 117.5, 72.7, 54.7. HRMS Calcd. Found 205.1705 [MH]+ 205.1691 [MH]+

(s, 2H).
13

MS (EI, 70 eV): 205 ([MH]+, 1), 110 (100), 81 (4), 68 (3), 41 (13). C13 H22 N2

Synthesis of N,N,N,N-tetrabenzylmethanediamine (4)

Ph Ph N N

Ph Ph

A 100 mL round bottomed flask was charged with dibenzylamine (46 mL, 239 mmol). A solution of formaldehyde (13 mL, 350 mmol), was added slowly at 0 C and the mixture heated at 100 C for 2 h. The formation of a biphasic system was observed, the upper layer was

83 separated and dried over KOH pellets. After filtration and concentration in vacuo a yellow solid was obtained. Recrystallization from n-Hexane yielded the desired product 4 as a white crystalline solid (29.0 g, 30 %).

Mp 105 C

~ IR (KBr, cm-1 ): 3067 (w), 2815 (m), 1629 (m), 1427 (m), 1153 (m), 963 (s), 916 (vs), 791 (s),
750 (vs), 734 (vs), 696 (vs), 470 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.47-7.36 (m, 20H), 3.77 (s, 8H), 3.26 (s, 2H). C NMR (CDCl3 , 75 MHz): d 140.3, 129.5, 129.4, 129.1, 128.9, 128.7, 127.5, 127.3, 72.8, 56.7. Calcd. Found C, 85.67 C, 85.28 H, 7.43 H, 7.36 N, 6.89 N, 6.88

13

MS (EI, 70 eV): 406 ([MH]+,10), 210 (100), 91 (41). C29 H30 N2

Synthesis of 3-[2-diallylamino)ethyl]benzonitrile (5a)

CN

Prepared according to TP 1 from the corresponding benzylic zinc reagent (20.3 mL, 11.3 mmol, 0.56 M solution in THF) and immonium trifluoroacetate 1 (7.6 mmol) at -78 C. Reaction time: 30 min. Purification by flash chromatography (CH2 Cl2 /MeOH 99:1) yielded 5a as a colourless oil (1.6 g, 96 %).

~ IR (film, cm-1 ): 3077 (m), 2977 (m), 2927 (m), 2807 (s), 2229 (vs), 1642 (m), 1483 (m),
1418 (m), 1151 (m), 115 (m), 996 (s), 920 (vs), 797 (s), 691 (s).
1

H NMR (CDCl3 , 300MHz): d 7.28-7.41 (m, 4H), 5.67-5.78 (m, 2H), 5.05-5.13 (m, 4H), 3.07

(d, J = 6,4 Hz, 4H), 2.70 (t, J = 29.1 and 6.5 Hz, 2H), 2.61 (t, J = 29.1 and 6.5 Hz, 2H).
13

C NMR (CDCl3 , 75 MHz): d 142.5, 135.8, 133.8, 132.7, 130.1, 129.4, 119.4, 118.0, 112.6

57.3, 54.7,33.4. MS (EI, 70 eV): 226 (M+, 30), 199 (90), 110 (100), 41 (31). C15 H18 N2 Calcd. Found C, 79.21 C, 79.61 H, 7.88 H, 8.01 N, 12.26 N, 12.38

84 Synthesis of N-allyl-N-(cyclohexylmethyl)-2-propen-1-amine (5d)

Prepared according to TP 1 from the corresponding zinc reagent (30.0 mL, 30.7 mmol, 1 M solution in THF) and immonium trifluoroacetate 1 (20.0 mmol) at rt. Reaction time: 2 h. Purification by flash chromatography (CH2 Cl2 /MeOH 98:2) yielded 5d as a light yellow oil (3.2 g, 83 %).

~ IR (film, cm-1 ): 3400 (s, br), 2931 (vs), 2858 (vs), 1643 (w), 1448 (m), 1372 (m), 113 (vs),
952 (m).
1

H NMR (CDCl3 , 300 MHz): d 5.71-5.84 (m, 2H), 5.02-5.12 (m, 4H), 2.98 (d, J = 6.3 Hz, C NMR (CDCl3 , 75 MHz): d 135.2, 115.9, 59.5, 56.4, 34.9, 30.8, 26.2, 24.3. Calcd. Found C, 80.57 C, 80.76 H, 11.66 H, 11.99 N, 7.23 N, 7.24

4H), 2.12 (d, J = 6.9 Hz, 2H), 0.74-1.72 (m, 11H).

13

MS (EI, 70 eV): 193 (M+, 3), 135 (12), 110 (100), 73 (59), 55 (75). C13 H23 N

Synthesis of N-ally-N-[2-(6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethyl]-2-propen-1-amine (5e)

Prepared according to TP 1 from the corresponding zinc reagent (3.0 mL, 3.4 mmol, 1.2 M solution in THF) and immonium trifluoroacetate 1 (2.0 mmol) at rt. Reaction time: 1 h. Purification by flash chromatography (CH2 Cl2 /MeOH 98:2) yielded 5e as a light yellow oil (435 mg, 88 %).

~ IR (film, cm-1 ): 3077 (w), 2980 (m), 2934 (vs), 2799 (m), 1730 (w), 1642 (w), 1468 (m), 1270
(m), 995 (m9, 917 (vs).

85
1

H NMR (CDCl3 , 300 MHz): d 5.74-5.83 (m, 2H), 5.02-5.12 (m, 4H), 3.00 (d, J = 6.3 Hz, 4H), 1.10 (s,

3H), 0.93 (s, 3H), 0.74-2.37 (m, 13H).

13

C NMR (CDCl3 , 75 MHz): d 136.2, 117.6, 57.3, 52.4, 46.5, 41.4, 39.9, 35.0, 34.1, 28.6, 27.2,

23.4, 22.9. MS (EI, 70 eV): 247 (M+, 3) 206 (4), 178 (9), 110 (100), 81 (4), 41 (10). C17 H29 N Calcd. Found C, 81.52 C, 81.32 H, 11.81 H, 11.34 N, 5.66 N, 5.56

Synthesis of 4-[2-(diallylamino)methyl]benzonitrile (5f)

CN

Prepared according to TP 1 from the corresponding zinc reagent (17.0 mL, 13.4 mmol, 0.79 M solution in THF) and immonium trifluoroacetate 1 (5.2 mmol) at -78 C. Reaction time: 1 h. Purification by flash chromatography (CH2 Cl2 /MeOH 98:2) yielded 5f as a light yellow oil (0.8 g, 72 %).

~ IR (film, cm-1 ): 3400 (w, br), 2920 (m), 2810 (s), 2228 (vs), 1643 (s), 1608 (vs), 1447 (m),
1415 (s), 1366 (m), 1257 (m), 989 (s), 922 (vs), 816 (s), 548 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.49 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 5.68-5.79 (m, 2H), C NMR (CDCl3 , 75 MHz): d 146.1, 132.4, 135.7, 129.2, 119.4, 118.1, 111.0, 57.5, 57.0. Calcd. Found C, 79.20 C, 78.73 H, 7.59 H, 7.37 N, 13.19 N, 12.74

5.03-5.12 (m, 4H), 3.51 (s, 2H), 2.97 (d, J = 6.3 Hz, 4H).
13

MS (EI, 70 eV): 212 (M+, 24), 185 (52), 171 (24), 116 (100), 89 (23), 41 (26). C14 H16 N2

Synthesis of 3-[2-(dibenzylamino)ethyl]benzonitrile (5g)

86
Ph N Ph

CN

Prepared according to TP 1 from the corresponding zinc reagent (16.0 mL, 11.2 mmol., 0.69 M in THF) and immonium trifluoroacetate 2 (9.9 mmol) at -78 C. Reaction time: 1 h. Purification by flash chromatography (CH2 Cl2 ) yielded 5g as white crystalline solid (3.0 g, 92 %). Mp 60 C ~ IR (KBr, cm-1 ): 3436 (w, br), 2790 (vs), 2227 (s), 1492 (s), 1448 (s), 1374 (s), 1234 (m), 1128 (m), 1115 (m), 1026 (m), 791 (s), 750 (vs), 734 (vs), 696 (vs), 470 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.38-7.13 (m, 14H), 3.52 (s, 4H), 2.69 (t, J = 6.9 Hz, 2H), 2.61 (t, J = C NMR (CDCl3 , 75 MHz): d 141.0, 138.2, 126-132, 118.0, 111.1, 57.4, 53.1,32.1. Calcd. Found C, 84.62 C, 84.28 H, 6.79 H, 6.75 N, 8.58 N, 8.51

6.9 Hz, 2H).

13

MS (EI, 70 eV): 324 (38), 233 (40), 210 (92), 91 (100), 65 (10), 39 (2). C23 H22 N2

Synthesis of N,N-dibenzyl-2-(6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethanamine (5h)

Ph N Ph

Prepared according to TP 1 from the corresponding zinc reagent (4.6 mL, 4.1 mmol, 0.88 M in THF) and immonium trifluoroacetate 2 (3.6 mmol) at rt. Reaction time: 3 h. Purification by flash chromatography (pentane/diethyl ether 98:2) yielded 5h as a colourless oil (1.1 g, 86 %).

~ IR (film, cm-1 ): 3026 (s), 2936 (vs), 2793 (s), 1601 (w), 1494 (vs), 1452 (vs), 1382 (s), 1365
(vs), 1125 (m), 1028 (s), 744 (vs), 698 (vs).

87
1

H NMR (CDCl3 , 300 MHz): d 7.08-7.24 (m, 10H), 3.44 (s, 4H), 2.31 (t, J = 7.5 Hz, 4H), 1.04 (s, 3H),

0.89 (s, 3H), 0.69-2.15 (m, 9H).

13

C NMR (CDCl3 , 75 MHz): d 140.5, 129.3, 128.6, 127.2, 58.8, 52.4, 46.8, 42.0, 41.5, 39.5,

35.3, 34.1, 28.7, 27.1, 23.8, 23.0. MS (EI, 70 eV): 347 (M+, 4), 278 (20), 210 (100), 181 (1), 91 (75). C25 H33 N Calcd. Found C, 86.39 C, 86.11 H, 9.57 H, 9.49 N, 4.03 N, 3.99

Synthesis of ethyl 5-[(diallylamino)methyl]-2-thiophenecarboxylate (7a)

EtO 2C

N S

Ethyl 5-bromo-2-thiophenecarboxylate (1.8 g, 7.7 mmol) was dissolved in THF (10 mL) and cooled to -40 C. i-PrMgBr (11.0 mL, 8.8 mmol, 0.8 M solution in THF) was added dropwise over 15 min. After 1 h the solution of immonium trifluoroacetate 1 (4.9 mmol) in CH2 Cl2 was added at -40 C. After 3 h the reaction was quenched with saturated, aqueous Na2 CO3 . The aqueous phase was extracted with diethyl eher (3 x 30 mL) and the combined o rganic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (CH2 Cl2 ) yielded 7a as a light yellow oil (1.0 g, 77 %).

~ IR (film, cm-1 ): 2979 (m), 1710 (vs), 1541 (m), 1466 (s), 1366 (m), 1280 (vs), 1092 (vs), 922
(m), 751 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.55 (d, J = 3.8 Hz, 1H), 6.8 (d, J = 3.6 Hz, 1H), 5.73-5.82 (m, 2H),

5.05-5.20 (m, 4H), 4.24 (q, J = 7.2 Hz, 2H), 3.69 (s, 2H), 3.04 (d, J = 6.3 Hz, 4H), 1.28 (t, J = 10.9 Hz, 3H).
13

C NMR (CDCl3 , 75 MHz): d 162.8, 152.0, 135.7, 133.5, 131.3, 126.1, 118.2, 61.3, 56.7, 52.3,

14.7. MS (EI, 70 eV): 265 (M+, 23), 238 (15), 169 (100), 141 (34), 96 (21), 41 (18). C14 H19 NO2 S Calcd. Found C, 63.36 C, 63.03 H, 7.21 H, 6.97 N, 5.28 N, 5.13 S, 12.08 S, 12.43

88

Synthesis of 3-(2-aminoethyl)benzonitrile (8a)

NH2

CN

Prepared according to TP 2 from 5a (0.45 g, 2.0 mmol), Pd(PPh3 )4 (69 mg, 5.9x10-5 mmol) and NDMBA (1.86 g, 11.9 mmol). Reaction time: 1.5 h. Purification by flash chromatography (CH2 Cl2 /MeOH 99:1) yielded 8a as a red oil (182 mg, 63 %).

~ IR (film, cm-1 ): 3400 (vs, br), 2228 (vs), 1676 (vs), 1582 (vs), 1379 (s), 1119 (m), 798 (s), 722
(m), 691 (s), 541 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.54-7.39 (m, 4H), 3.01 (t, J = 6.5 Hz, 2H), 2.80 (t, J = 6.5 Hz, C NMR (CDCl3 , 75 MHz): d 140.4, 132.4, 131.3, 129.0, 128.2, 117.9, 111.4, 41.7, 38.5.

2H), 1.47 (s, br, 2H).

13

MS (EI, 70 eV): 145 ([MH]+, 10), 128 (21), 117 (100), 89 (85), 75 (17), 63 (39), 51 (22), 39 (36). C9 H10 N2 Calcd. Found C, 73.94 C, 73.87 H, 6.89 H, 6.46 N, 19.16 N, 19.17

Synthesis of 2-(6,6-dimethylbicyclo[3.1.1]hept-2-yl)ethanamine (8d)

NH2

Prepared according to TP 2 from 5e (395 mg, 1.6 mmol), Pd(PPh3 )4 (50 mg, 4.3x10-5 mmol) and NDMBA (1.6 g, 10.0 mmol). Reaction time: 3 h. Purification by flash chromatography (CH2 Cl2 /MeOH 98:2) yielded 8d as a light yellow oil (200 mg, 74 %).

~ IR (film, cm-1 ): 3271 (m, br), 2931 (vs), 2869 (vs), 1726 (vs), 1658 (vs), 1466 (s), 1383 (s),
1271 (vs), 1122 (vs), 1073 (s), 797 (m).

89
1

H NMR (CDCl3 , 300 MHz): d 2.63 (m, 4H), 1.11 (s, 3H), 0.94 (s, 3H), 0.80-2.37 (m, 13H). C NMR (CDCl3 , 75 MHz): d 131.5, 117.6, 67.1, 45.5, 40.5, 40.0, 39.6, 37.8, 37.7, 32.7, 29.4,

13

27.2, 23.4, 22.9. MS (EI, 70 eV): 167 (M+, 30), 135 (36), 107 (42), 82 (100), 69 (40). C11 H21 N Calcd. Found C, 78.48 C, 78.32 H, 12.69 H, 12.36 N, 8.37 N, 8.29

Synthesis of 4-(aminomethyl)benzonitrile (8e)

NH2

CN

Prepared according to TP 2 from 5f (0.4 g, 1.9 mmol), Pd(PPh3 )4 (46 mg, 3.9x10-5 mmol) and NDMBA (1.9 g, 11.9 mmol). Reaction time: 3 h. Purification by flash chromatography (CH2 Cl2 /MeOH 9:1) yielded 8e as a yellow oil (200 mg, 80 %).

~ IR (film, cm-1 ): 3380 (vs, br), 2230 (vs), 1668 (vs), 1575 (vs), 1344 (s), 1122 (m), 799 (s), 719
(m), 690 (s), 540 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.55-7.36 (m, 4H), 3.88 (s, 2H), 2.21 (s, br, 2H). C NMR (CDCl3 , 75 MHz): d 147.3, 130.9, 126.7, 117.9, 109.6, 44.9. Calcd. Found C, 72.70 C, 72.22 H, 6.10 H, 5.84 N, 21.19 N, 20.61

13

MS (EI, 70 eV): 132 (M+, 100), 104 (44), 77 (15). C8 H8 N2

Synthesis of ethyl 5-(aminomethyl)-2-thiphenecarboxylate (8f)

EtO 2C

NH 2 S

90 Prepared according to TP 2 from 8a (290 mg, 1.1 mmol), Pd(PPh3 )4 (30 mg, 2.6x10-5 mmol) and NDMBA (1.06 g, 6.8 mmol). Reaction time: 3 h. Purification by flash chromatography (CH2 Cl2 /MeOH 99:1) yielded 8f as a light yellow oil (122 mg, 60 %).

~ IR (film, cm-1 ): 3269 (m, br), 2979 (m), 1710 (vs), 1541 (m), 1466 (s), 1366 (m), 1280 (vs),
1092 (vs), 922 (m), 751 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.46 (d, J = 3.7 Hz, 1H), 6.83 (d, J = 3.7 Hz, 1H), 4.26 (q, J = C NMR (CDCl3 , 75 MHz): d 161.3, 154.0, 133.9, 131.3, 129.2, 60.0, 14.7.

7.2 Hz, 2H), 4.00 (s, 2H), 1.31 (t, J = 10.9 Hz, 3H).
13

MS (EI, 70 eV): 185 (M+, 42), 155 (29), 140 (15), 112 (100), 78 (24). C8 H11 NO2 S Calcd. Found C, 51.96 C, 51.63 H, 5.99 H, 5.46 N, 7.57 N, 7.17 S, 17.30 S, 16.85

91

Preparation of Benzylic Zinc Reagents via a Fragmentation Reaction

Synthesis of 3,3-dimethyl-1-phenyl-butan-2-one (11)128

O Ph t-Bu

A solution of t-BuMgCl (65 mL, 0.11 mol, 1.7 M in THF was added dropwise over 1 h at 0 C to a stirred suspension of copper(I) bromide (14.3 g, 0.10 mol) in THF (30 mL) containing phenylacetyl chloride (15.5 g, 0.10 mol). After complete addition the black reaction mixture was stirred at rt for 1 h and poured into ice (200 mL). The mixture was then filtered over celite and acidified with 1N HCl. The yellow solution was extracted with diethyl ether (3 x 30 mL), and the combined organic layer was washed with water (2 x 30 mL) and brine, dried over MgSO4 and concentrated in vacuo. The crude material was distilled under vacuum to give 3,3-dimethyl-1phenyl-butan-2-one (11.9 g, 68 %) as a light yellow oil.

Bp 115 C, 0.1 mbar. ~ IR (film, cm-1 ): 2967 (m), 1711 (s), 1477 (m), 1060 (m), 724 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.24-7.08 (m, 5H), 3.71 (s, 2H), 1.11 (s, 9H). C NMR (CDCl3 , 75 MHz): d 212.8, 135.1, 129.7, 128.5. HRMS Calcd. Found 176.1201 176.1199

13

MS (EI, 70 eV): 91 (48), 85 (62), 57 (100). C12 H16 O

Synthesis of 2,2-dimethyl-4-phenylhept-6-en-3-one (12a)129

O Ph t-Bu

128 129

Chen, K.; Koser, F. J. Org. Chem. 1991, 56, 5764. De las Heras ; M. A., Vaquero, J. J. ; Garcia-Navio, J. L. ; Alvarez-Builla J. Tetrahedron 1996, 52, 14297.

92 A solution of 11 (6.3 g, 35.7 mmol) and allyl bromide (3.7 mL, 42.7 mmol) in THF (10 mL) was added at rt to a suspension of sodium hydride (2.7 g, 67.0 mmol, 60 % suspension in oil) in THF (40 mL). The reaction mixture was stirred for 3 h and a saturated aqueous solution of NH4 Cl was carefully added at 0 C. The aqueous layer was extracted with diethyl ether (3 x 30 mL). The combined organic layer was washed with water and brine, then dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (pentane/diethyl ether 9:1) to afford 12a as a colourless oil (7.6 g, 98 %).

~ IR (film, cm-1 ): 2967 (m), 1702 (s), 1477 (m), 1073 (m), 700 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.24-7.10 (m, 5H), 5.61-5.47 (m, 1H), 4.96-4.84 (m, 2H), 4.08-

4.04 (m, 1H), 2.68-2.58 (m, 1H), 2.38-2.28 (m, 1H), 0.99 (s, 9H).
13

C NMR (CDCl3 , 75 MHz): d 214.9, 139.6, 136.4, 129.0, 128.6, 127.3, 117.1, 53.3, 45.4, 40.2,

26.9. MS (EI, 70 eV): 216 (M+, 1), 159 (17), 131 (84), 115 (19), 103 (8), 91 (52), 85 (45), 77 (11), 57 (100). C15 H20 O Calcd. Found C, 83.28 C, 83.16 H, 9.32 H, 9.43

Synthesis of 2,2-dimethyl-4-phenylpentan-3-one (12b) 130

O Ph t-Bu

A solution of 11 (1.0 g, 5.7 mmol) and methyl iodide (0.8 mL, 12.0 mmol) in THF (5 mL) was added at rt to a suspension of sodium hydride (480 mg, 12.0 mmol, 60 % suspension in oil) in THF (5 mL). The reaction mixture was stirred for 3 h and a saturated aqueous solution of NH4 Cl was carefully added at 0 C. The aqueous layer was extracted with diethyl ether (3 x 30 mL). The combined organic layer was washed with water and brine, then dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (pentane/diethyl ether 125:1) to afford 12b as a light yellow oil (980 mg, 91 %).

130

Zushi, S.; Kodama, Y.; Nishihata, K.; Umomura, K.; Nishio, M.; Uzawa, J.; Hirota, M. Bull. Chem. Soc. Jpn. 1980, 53, 3631.

93

~ IR (film, cm-1 ): 2969 (m), 1703 (m), 1477 (m), 1367 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.21-7.17 (m, 5H), 4.18 (q, J = 6.9 Hz, 1H), 1.02 (s, 9H). C NMR (CDCl3 , 75 MHz): d 216.1, 141.6, 128.7, 128.0, 126.9, 46.5, 45.3, 26.7, 21.2. Calcd. Found C, 82.06 C, 81.76 H, 9.53 H, 9.63

13

MS (EI, 70 eV): 190 (M+, 14), 105 (93), 85 (69), 77 (35), 57 (100). C13 H18 O

Synthesis of 3-tert-butyl-2,2-dimethyl-4-phenylhept-6-en-3-ol (9a)

OH Ph t-Bu t-Bu

A solution of t-BuLi (18.5 mL, 27.7 mmol) was added at -78 C to a solution of the ketone 12a (5.0 g, 23.1 mmol) in diethyl ether (35 mL). The reaction mixture was stirred at this temperature for 1 h and quenched with a saturated aqueous solution of NH4 Cl. The aqueous layer was extracted with diethyl ether (3 x 30 mL). The combined organic layer was washed with brine, then dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (pentane/diethyl ether 9:1) to afford 9a as a colourless oil (5.9 g, 93 %).

~ IR (film, cm-1 ): 3592 (m), 2923 (s), 1491 (m), 1393 (m), 994 (m), 705 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.33-7.08 (m, 5H), 5.49-5.37 (m, 1H), 4.90 (d, J = 17.0 Hz, 1H),

4.83 (d, J = 14.1 Hz, 1H), 3.42 (d, J = 7.4 Hz, 1H), 3.10-2.87 (m,2H), 1.21 (s, 9H), 1.07 (s, 9H).
13

C NMR (CDCl3 , 75 MHz): d 140.0, 138.4, 132.5, 127.8, 126.7, 115.6, 81.9, 52.4, 44.2, 44.0,

35.6, 31.1, 30.0. MS (EI, 70 eV): 217 (5), 161 (2), 143 (21), 131 (39), 87 (54), 57 (100). C19 H30 O Calcd. Found C, 83.15 C, 83.28 H, 11.02 H, 11.21

Synthesis of 2,2,4,4-tetramethyl-3-(1-phenylethyl)-pentan-3-ol (9b)

94
OH Ph t-Bu t-Bu

A solution of t-BuLi (2.2 mL, 3.3 mmol) was added at -78 C to a solution of the ketone 8b (0.3 g, 1.6 mmol) in diethyl ether (2.5 mL). The reaction mixture was stirred at this temperature for 45 min and quenched with a saturated aqueous solution of NH4 Cl. The aqueous layer was extracted with diethyl ether (3 x 30 mL). The combined organic layer was washed with brine, then dried over MgSO4 and concentrated in vacuo. The resulting oil was purified by flash chromatography (pentane/diethyl ether 99:1) to afford 9b as a colourless oil (340 mg, 89 %).

~ IR (film, cm-1 ): 3595 (m), 2963 (s), 1393 (m), 988 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.37-7.33 (m, 2H), 7.20-7.10 (m, 3H), 3.55 (q, J = 7.4 Hz, 1H), C NMR (CDCl3 , 75 MHz): d 144.0, 131.6, 127.8, 126.5, 81.9, 45.7, 44.3, 43.8, 30.8, 30.4,

1.65 (d, J = 7.4 Hz, 3H), 1.20 (s, 9H).

13

27.0, 19.6. MS (EI, 70 eV): 191 (2), 143 (13), 105 (72), 87 (49), 57 (100). C17 H28 O Calcd. Found C, 82.20 C, 81.94 H, 11.36 H, 11.42

Synthesis of 1,2-diphenylpent-4-en-1-ol (13a)

OH Ph Ph

Prepared according to TP 3 from 9a (270 mg, 1.1 mmol), n-BuLi (0.56 mL, 0.84 mmol), zinc chloride (115 mg, 0.84 mmol) and benzaldehyde (68 L, 0.67 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 92:8) yielded 13a as a colourless oil (118 mg, 74 %).

~ IR (film, cm-1 ): 3436 (m), 1680 (s), 1494 (m), 698 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.33-7.05 (m, 10H), 5.72-5.41 (m, 1H), 4.99-4.77 (m, 3H), 3.13-

2.95 (m, 1H), 2.75-2.58 (m, 1H), 2.35-2.18 (m, 1H).

95
13

C NMR (CDCl3 , 75 MHz): d 143.0, 142.9, 141.3, 140.8, 137.3, 136.6, 130.6, 129.4, 129.3,

128.9, 128.7, 128.5, 128.4, 128.2, 127.7, 127.4, 127.3, 126.9, 126.2, 116.7, 116.5, 78.5, 78.3, 54.4, 53.7, 36.8, 34.8. MS (EI, 70 eV): 178 (5), 132 (62), 107 (100), 91 (55). C17 H16 HRMS Calcd. Found 220.1247 [M-H2 O]+ 220.1252

Synthesis of 1-(2-naphthyl)-2-phenylpent-4-en-1-ol (13b)

OH Ph 1-Napht

Prepared according to TP 3 from 9a (0.3 g, 1.1 mmol), n-BuLi (0.57 mL, 0.84 mmol), zinc chloride (115 mg, 0.84 mmol) and 1-naphthaldehyde (0.12 mL, 0.87 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 13b as a light yellow oil (158 mg, 63 %).

~ IR (film, cm-1 ): 3436 (m), 1730 (s), 1383 (s), 1112 (s), 911 (s), 734(s).
1

H NMR (CDCl3 , 300 MHz): d 7.95-6.97 (m, 12H), 5.44-5.36 (m, 2H), 4.78-4.64 (m, 2H), 3.34C NMR (CDCl3 , 75 MHz): d 141.2, 137.3, 135.9, 132.7, 129.3, 128.1, 127.9, 127.5, 127.3,

3.31 (m, 1H), 3.19-3.16 (m, 2H), 2.70-2.25 (m, 1H).

13

127.1, 127.0, 126.8, 125.8, 125.5, 124.9, 124.4, 124.3, 124.0, 123.8, 123.4, 123.3, 122.2, 122.1, 115.5, 114.9, 73.9, 72.7, 52.7, 51.6, 35.7, 31.8. MS (EI, 70 eV): 288 (M+, 5), 270 (7), 229 (8), 158 (29), 129 (100). C21 H20 O Calcd. Found C, 86.99 C, 86.88 H, 6.91 H, 7.07

Synthesis of 1-(2-furyl)-2-phenylpent-4-en-1-ol (13c)

OH Ph O

96

Prepared according to TP 3 from 9a (1.3 g, 4.7 mmol), n-BuLi (2.9 mL, 4.3 mmol), zinc chloride (600 mg, 4.4 mmol) and furfural (0.3 mL, 3.6 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 13c as a colourless oil (600 mg, 73 %).

~ IR (film, cm-1 ): 3398 (m), 1668 (s), 1475 (s), 703 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.30-7.01 (m, 6H), 6.22 (d, J = 3.1 Hz, 1H), 6.11 (d, J = 3.4 Hz,

1H), 5.70-5.30 (m, 1H), 4.85-4.72 (m, 3H), 3.15-3.08 (m, 1H), 2.60-2.40 (m, 1H), 2.97-2.24 (m, 1H).
13

C NMR (CDCl3 , 75 MHz): d 155.5, 142.3, 141.9, 141.1, 140.6, 137.0, 136.3, 129.2, 129,

128.9, 128.5, 127.5, 127.0, 126.2, 116.8, 116.7, 110.5, 107.9, 107.3, 72.3, 71.6, 66.2, 51.6, 51.4, 36.8, 35.5, 15.6. MS (EI, 70 eV): 228 (M+, 6), 210 (6), 170 (4), 141 (8), 132 (100), 115 (32), 104 (12). C15 H16 O2 Calcd. Found C, 78.92 C, 78.82 H, 7.06 H, 6.99

Synthesis of (1E)-1,4-diphenylhepta-1,6-dien-3-ol (13d)

OH Ph Ph

Prepared according to TP 3 from 9a (0.3 g, 1.1 mmol), n-BuLi (0.56 mL, 0.84 mmol), zinc chloride (115 mg, 0.84 mmol) and 3-phenyl-2-propenal (85 L, 0.67 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 88:12) yielded 13d as a colourless oil (80 mg, 46 %).

~ IR (film, cm-1 ): 3027 (s), 1640 (s), 1494 (s), 700 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.36-7.20 (m, 10H), 6.51 and 6.57 (2d, J = 21.0 Hz, 1H), 6.15

(dd, J = 21.0 and 6.6 Hz, 1H), 6.08 (dd, J = 21.0 and 6.6 Hz, 1H), 5.78-5.55 (m, 1H), 5.06-4.85 (m, 2H), 4.52-4.40 (m, 1H), 3.02-2.83 (m, 1H), 2.73-2.38 (m, 2H).

97
13

C NMR (CDCl3 , 75 MHz): d 141.0, 140.8, 137.2, 137.1, 136.8, 134.9, 132.4, 131.4, 130.8,

130.5, 129.4, 129.0, 128.8, 128.7, 128.2, 128.0, 127.4, 127.2, 127.0, 126.9, 126.2, 125.9, 116.8, 116.7, 76.5, 76.3, 52.8, 52.4, 36.6, 35.6. MS (EI, 70 eV): 205 (2), 133 (100), 115 (23), 91 (32), 77 (14). C19 H18 HRMS Calcd. Found 246.1409 [M-H2 O]+ 246.1402

Synthesis of 1-(4-isopropenylcyclohex-1-en-1-yl)-2-phenylpent-4-en-1-ol (13e)

OH Ph

Prepared according to TP 3 from 9a (1.3 g, 4.6 mmol), n-BuLi (3.3 mL, 4.9 mmol,), zinc chloride (690 mg, 5.0 mmol) and L-perillaldehyde (0.26 mL, 1.7 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 95:5) yielded 13e as a colourless oil (340 mg, 70 %).
~ IR (film, cm-1 ): 3435 (s), 2921 (s), 1642 (s), 1453 (m), 700 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.26-7.06 (m, 5H), 5.70-5.46 (m, 2H), 4.87-4.56 (m, 4H), 4.06C NMR (CDCl3 , 75 MHz): d 150.2, 149.9, 142.3, 141.3, 138.5, 138.0, 137.6, 136.9, 136.8,

4.02 (m, 1H), 2.80-1.97 (m, 7H), 1.68 (s, 3H), 1.60 (s, 3H), 1.44 (s, 1H).
13

129.2, 128.5, 127.3, 126.2, 116.4, 109.1, 80.5, 50.2, 41.4, 37.3, 31.1, 27.9, 25.4, 24.8, 23.9, 21.3, 21.1. MS (EI, 70 eV): 282 (M+, 1), 241 (37), 223 (12), 157 (16), 131 (45), 117 (19), 91 (100). C20 H26 O Calcd. Found C, 85.86 C, 85.85 H, 9.28 H, 9.33

Synthesis of 1-cyclohexyl-2-phenylpent-4-en-1-ol (13f)

98
OH Ph

Prepared according to TP 3 from 9a (1.5 g, 5.4 mmol), n-BuLi (3.4 mL, 5.1 mmol), zinc chloride (700 mg, 5.1 mmol) and cyclohexanecarboxaldehyde (0.49 mL, 4.1 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/ diethyl ether 95:5) yielded 13f as a light yellow oil (600 mg, 60 %).
~ IR (film, cm-1 ): 3400 (m), 2913 (s), 1640 (s), 701 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.23-7.06 (m, 5H), 5.52 (m, 1H), 4.94-4.80 (m, 2H), 3.42-3.38 C NMR (CDCl3 , 75 MHz): d 143.1, 141.6, 137.7, 137.3, 129.5, 128.8, 127.0, 126.7, 116.5,

(m, 1H), 2.3-2.40 (m, 2H), 1.64-0.97 (m, 11H).

13

116.2, 80.4, 78.6, 66.2, 49.1, 48.2, 40.9, 40.4, 37.7, 35.5, 30.8, 30.6, 27.9, 27.0, 26.9, 26.7, 26.6, 26.4, 15.7. MS (EI, 70 eV): 226 (M+-H2 O, 4), 185 (4), 132 (100), 117 (37), 91 (74). C17 H24 O Calcd. Found C, 83.55 C, 83.53 H, 9.89 H, 9.99

Synthesis of 1,2-diphenylpropan-1-ol (13g)131

OH Ph Ph

Prepared according to TP 3 from 9b (250 mg, 1.0 mmol) n-BuLi (0.6 mL, 0.9 mmol), zinc chloride (115 mg, 0.8 mmol) and benzaldehyde (0.068 mL, 0.7 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 88:12) yielded 13g as a colourless oil (104 mg, 73 %).
~ IR (film, cm-1 ): 3436 (m), 2259 (s), 1681 (s), 1494 (m), 700 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.30-7.05 (m, 10H), 4.73 (d, J = 6.0 Hz, 1H), 2.97 (m, 1H), 1.22

(d, J = 7.0 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H).

131

Diaz, A. F.; Cheng, Y. Y.; Ochoa, M. J. Am. Chem. Soc. 1977, 99, 6319.

99
13

C NMR (CDCl3 , 75 MHz): d 143.7, 143.6, 143.1, 142.7, 128.8, 128.4, 128.2, 128.1, 128.0,

127.4, 127.2, 127.1, 126.6, 126.5, 79.9, 78.9, 48.3, 47.4, 18.5, 15.1. MS (EI, 70 eV): 107 (100), 106 (81), 105 (38), 91 (45), 79 (54). C15 H16 O Calcd. Found C, 84.87 C, 84.67 H, 7.60 H, 7.65

Synthesis of 1-(2-naphthyl)-2-phenylpropan-1-ol (13h)

OH 1-Napht Ph

Prepared according to TP 3 from 9b (0.3 g, 1.1 mmol), n-BuLi (0.56 mL, 0.84 mmol), zinc chloride (115 mg, 0.84 mmol) and benzaldehyde (68 L, 0.67 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 92:8) yielded 13h as a light yellow oil (140 mg, 80 %).
~ IR (film, cm-1 ): 3428 (m), 2919 (s), 1678 (s), 1489 (m), 700 (s).
1

H NMR (CDCl3 , 300 MHz): d 8.03-7.12 (m, 12H), 5.55 (d, J = 5.7 Hz, 1H), 5.45 (d, J = 8.7 Hz, C NMR (CDCl3 , 75 MHz): d 143.7, 137.4, 132.7, 129.2, 128.0, 127.5, 126.7, 125.5, 124.9,

1H), 3.30 (m, 2H), 1.85 (s, 2H), 1.16 (d, J = 7.1 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H).
13

124.3, 124. 2, 123.0, 122.0, 75.6, 73.9, 44.1, 43.8, 12.6, 11.5. MS (EI, 70 eV): 262 (M+, 4), 233 (7), 158 (45), 128 (100), 105 (23). C19 H18 O Calcd. Found C, 86.99 C, 86.78 H, 6.91 H, 7.17

Synthesis of 1-(2-furyl)-2-phenylpropan-1-ol (13i)132

OH Ph O

132

Molander, G. A.; Estevez-Braun, A. M. Bull. Soc. Chim. Fr. 1997, 134, 275.

100 Prepared according to TP 3 from 9b (0.3 g, 1.1 mmol), n-BuLi (0.73 mL, 1.1 mmol), zinc chloride (180 mg, 1.3 mmol) and furfural (75 l, 0.9 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 13i as a red oil (120 mg, 66 %).
~ IR (film, cm-1 ): 3400 (m), 2963 (s), 1675 (s), 1478 (s), 711 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.32-7.06 (m, 6H), 6.18-6.14 (dt, J = 3.1 and 0.8 Hz, 1H), 5.96

(dd, J = 3.1 and 2.6 Hz, 1H), 4.15 (d, J = 4.8, 1H), 3.18 (q, J = 4.8 Hz, 1H), 1.9 (bs, 1H), 1.29 (d, J = 13.1 Hz, 3H).
13

C NMR (CDCl3 , 75 MHz): d 155.8, 155.4, 147.7, 143.6, 143.2, 142.4, 141.9, 129.1, 128.7,

128.3, 128.8, 127.4, 126.9, 110.6, 110.5, 107.9, 107.0, 77.9, 77.4, 77.0, 73.3, 73.2, 46.0, 45.3, 18.5, 16.4. MS (EI, 70 eV): 202 (M+, 3), 185 (2), 105 (21), 97 (100), 91 (25), 77 (19). C13 H14 O2 Calcd. Found C, 77.72 C, 77.67 H, 6.97 H, 7.10

101

Preparation of Allylic Zinc Reagents via a Cyclization-Fragmentation Reaction

Synthesis of 1-(bromomethyl)-4-fluoro-2-iodobenzene (25)133

Br I

A mixture of N-bromosuccinimide (2.2 g, 12.4 mmol), 4-fluoro-2-iodotoluene (5 g, 20.8 mmol), and benzoyl peroxide (0.1 g, 0.4 mmol), in tetrachloromethane (200 mL), was refluxed overnight. After cooling to rt, the succinimide was filtered and the resulting light red solution was concentrated in vacuo. Purification by flash chromatography (hexane) yielded 25 as a white solid (3.5 g, 90 %).

Mp 75 C
~ IR (KBr, cm-1 ): 3067 (br, s,), 1694 (vs), 1590 (vs), 1479 (vs), 1415 (m), 1291 (s), 1228 (vs),

1028 (s), 866 (vs), 822 (m), 713 (s), 608 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.50 (dd, J = 8.7 and 2.7 Hz, 1H), 7.37 (dd, J = 8.7 and 5.7 Hz, C NMR (CDCl3 , 75 MHz): d 163.6, 160.3, 136.8, 131.7, 131.6, 127.5, 127.2, 116.5, 116.2,

1H) 6.98 (td, J = 8.2 and 2.6 Hz, 1H), 4.5 (s, 2H).
13

99.9, 99.8, 38.0. MS (EI, 70 eV): 314 (M+, 2), 235 (100), 108 (29), 81 (4). C7 H5 BrFI Calcd. Found C, 26.69 C, 26.59 H, 1.78 H, 1.75 Br, 25.37 Br, 25.33 F, 6.03 F, 5.99 I, 40.30 I, 40.22

133

Kesteleyn, B.; De Kimpe, N.; Van Puyvelde, L. Synthesis 1999, 11, 1881.

102 Synthesis of ethyl-1-methyl-2-cyclohexene -1-carboxylate (20a)134

CO 2Et

n-BuLi (150 mL, 225 mmol) was added dropwise to a solution of diisopropylamine (33.0 mL, 230 mmol) in THF (200 mL), at -78 C. The mixture was stirred at 0 C for 5 min, then cooled back to -78 C. HMPA (44.0 mL, 252 mmol) was added and after 30 m ethyl 1-cyclohexenein 1carboxylate (35.0 g, 230 mmol). The mixture was stirred at this temperature for 1 h and then methyliodide (17.2 mL, 276 mmol) was added. After 1 h the reaction was quenched with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 200 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Distillation under reduced pressure yielded 20a as a light yellow oil (25.0 g, 65 %).

Bp 89 C, 18 mbar ~ IR (film, cm-1 ): 2935 (s), 1730 (vs), 1453 (m), 1224 (s), 1181 (s), 1110 (s), 1033 (m), 727 (m).
1

H NMR (CDCl3 , 300 MHz): d 5.66-5.62 (m, 2H), 4.05 (qd, J = 7.2 and 2.3 Hz, 2H), 2.02-1.55 C NMR (CDCl3 , 75 MHz): d 177.3, 131.2, 128.1, 60.8, 43.3, 33.3, 26.7, 24.5, 20.0, 14.5. Calcd. Found C, 71.39 C, 71.42 H, 9.59 H, 9.48

(m, 6H), 1.2 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H).
13

MS (EI, 70 eV): 168 (M+, 10), 122 (15), 95 (100), 79 (11), 67 (20). C10 H16 O2

Synthesis of ethyl 1-benzyl-2-cyclohexene -1-carboxylate (20b)

CO2Et

n-BuLi (150 mL, 225 mmol) was added dropwise to a solution of diisopropylamine (17.0 mL, 120 mmol) in THF (50 mL), at -78 C. The mixture was stirred at 0 C for 5 min, then cooled to 50 C. DMPU (30 mL) was added and after 30 min ethyl 1 -cyclohexene-1carboxylate (35.0 g, 230 mmol). The mixture was stirred at this temperature for 2 h and then benzyl bromide (18.0

134

Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H. Tetrahedron Lett. 1973, 26, 2436.

103 mL, 150 mmol) was addded. After 1 h the reaction was quenched with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 200 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Distillation under reduced pressure yielded 20b as a yellow oil (18 g, 74 %).

Bp 99 C, 6 mbar ~ IR (film, cm-1 ): 2936 (s), 1727 (vs), 1495 (m), 1454, (m), 1220 (s), 1182 (vs), 1089 (s), 1029 (m), 730 (m), 701 (vs).
1

H NMR (CDCl3 , 300 MHz): d 5.64 (m, 2H), 5.96 (dd, J = 3.1 and 2.6 Hz, 1H), 4.15 (d, J = 4.8, C NMR (CDCl3 , 75 MHz): d 175.9, 139.6, 131.4, 130.9, 130.4, 126.9, 126.3, 61.0, 48.6, 46.4,

1H), 3.18 (q, J = 4.8 Hz, 1H), 1.9 (s, br, 1H), 1.29 (d, J = 13.1 Hz, 3H).
13

31.4, 26.8, 21.4, 14.5. MS (EI, 70 eV): 244 (M+, 25), 171 (27), 152 (50), 140 (11), 91 (100), 79 (28). C16 H20 O2 Calcd. Found C, 78.65 C, 78.45 H, 8.25 H, 8.70

Synthesis of 1-methyl-2-cyclohexene -1-carboxylic acid (21a)135

CO2H

A solution of 20a (1.7 g, 10.0 mmol) and KOH (850 mg, 15.0 mmol) in ethanol (21 mL) and water (7 mL), was heated to reflux for 1 h, concentrated in vacuo and the residue dissolved in diethyl ether (50 mL). The mixture was acidified with 1N HCl solution at 0 C and the aqueous phase was extracted with diethyl ether (3 x 30 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo, to give 1.4 g of 21a as a yellow oil, used for the next step without further purification.

Synthesis of 1-benzyl-2-cyclohexene -1-carboxylic acid (21b)

135

Schultz, A. G.; Macielag, M.; Podhorez, D. E.; Suhadolnik, J. C.; Kullnig, R. K. J. Org. Chem. 1988, 53, 2456.

104
COOH

A solution of 20b (4.6 g, 19.0 mmol) and KOH (4.5 g, 80.0 mmol) in ethanol (30 mL) and water (5 mL), was heated to reflux for 1 h, concentrated in vacuo and the residue dissolved in diethyl ether (70 mL). The mixture was acidified with 1N HCl solution at 0 C and the aqueous phase was extracted with diethyl ether (3 x 40 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo, to give 3.9 g of 21b as a yellow oil, used for the next step without further purification.

Synthesis of 1-methyl-2-cyclohexene -1-carbonyl chloride (22a)136

COCl

Thionly chloride (3.6 mL, 50.0 mmol) was added slowly to 21a and the mixture stirred overnight at rt. Distillation of the thionyl chloride yielded 11.4 g of the desired product as a dark yellow oil, used for the next step without further purification.

Synthesis of 1-benzyl-2-cyclohexene -1-carbonyl chloride (22b)

COCl

Thionly chloride (8 mL, 100 mmol) was added slowly to 21b and the mixture stirred overnight at rt. Distillation of the thionyl chloride yielded 3.5 g of the desired crude product as a dark yellow oil, used for the next step without further purification.

136

Klein, J. Tetrahedron 1964, 20, 465.

105 Synthesis of 2-methyl-1-(1-methyl-2-cyclohexen-1-yl)-1-propanone (23a)

To a suspension of the starting 22a (1.4 g, 8.4 mmol) and CuBr (1.4 g, 9.5 mmol) in THF (10 mL), i-PrMgBr (16.6 mL, 9.5 mmol, 0.57 M solution in THF), was added slowly at -20 C. After 1 h the reaction was quenched with with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 20 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Distillation under reduced pressure yielded the desired product as a light yellow oil (7.0 g, 56 %).

Bp 107 C, 23 mbar ~ IR (film, cm-1 ): 2965 (s), 2934 (vs), 1707 (vs), 1460 (m), 1006 (m), 727 (m).
1

H NMR (CDCl3 , 300 MHz): d 5.75 (dt, J = 10.1 and 3.5 Hz, 1H), 5.63 (d, J = 10.2 Hz, 1H),

3.00 (h, J = 6.7 Hz, 1H), 1.94-1.30 (m, 6H), 1.23 (s, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H).
13

C NMR (CDCl3 , 75 MHz): d 217.0, 129.4, 128.2, 48.5, 36.5, 33.5, 30.8, 24.0, 18.5, 17.9. Calcd. Found C, 79.46 C, 79.19 H, 10.91 H, 10.84

MS (EI, 70 eV): 166 (M+, 3), 95 (100), 67 (20). C11 H18 O2

Synthesis of 1-(1-benzyl-2-cyclohexen-1-yl)-2-methyl-1-propanone (23b)

Ph

To a suspension of the starting 22b (12.1 g, 51.4 mmol) and CuBr (9.0 g, 62.7 mmol) in THF (30 mL), i-PrMgBr (45.0 mL, 58.0 mmol, 1.3 M solution in THF), was added slowly at -20 C. After 2 h the reaction was quenched with with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 30 mL). The organic fractions were washed with brine, dried

106 over MgSO4 and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 99:1) yielded 23b as a yellow oil (5.0 g, 40 %).
~ IR (film, cm-1 ): 2932 (s), 1702 (vs), 1495 (w), 1454 (m), 1380 (w), 736 (m), 702 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.14-6.98 (m, 5H), 5.77-5.74 (m, 2H), 2.96 (d, J = 12.8 Hz, 1H),

2.75 (h, J = 6.7 Hz, 1H), 2.56 (d, J = 12.9 Hz, 1H), 1.95-1.30 (m, 6H), 0.89 (d, J = 6.7 Hz, 3H), 0.75 (d, J = 6.6 Hz, 3H).
13

C NMR (CDCl3 , 75 MHz): d 218.0, 137.8, 130.9, 130.5, 129.4, 128.7, 128.2, 126.7, 121.3,

54.5, 45.0, 37.2, 31.8, 25.4, 23.5, 20.3, 19.1. MS (EI, 70 eV): 242 (M+, 2), 199 (2), 171 (95), 129 (24), 91 (100), 71 (20), 67 (22), 42 (34). C17 H22 O Calcd. Found C, 84.25 C, 84.45 H, 9.15 H, 9.41

Synthesis (18a)

of

3-(4-fluoro-2-iodophenyl)-2,2-dimethyl-1-(1-methyl-2-cyclohexen-1-yl)-1-propanone

n-BuLi (8 mL, 12 mmol) was added dropwise to a solution of diisopropylamine (1.7 mL, 12.0 mmol) in THF (15 mL), at -78 C. The mixture was stirred at 0 C for 5 min, then cooled to -10 C. 23a (16.6 g, 10.0 mmol) was added and after 2 h at -10 C a solution of 25 (3.5 g, 11.0 mmol) in THF (10 mL) was added and the mixture was let warm up to rt. After 1 h the reaction was quenched with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 25 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 99:1) yielded 18a as a yellow oil (2.4 g, 69 %).
~ IR (film, cm-1 ): 3067 (s, br), 2965 (s), 2934 (vs), 1707 (vs), 1590 (s), 1479 (s), 1415 (m), 1291

(s), 1228 (vs), 1028 (s), 1006 (m), 866 (vs), 822 (m), 727 (m), 713 (s), 608 (m).

107
1

H NMR (CDCl3 , 300 MHz): d 7.46 (dd, J = 8.7 and 2.6 Hz, 1H), 7.00 (dd, J = 8.8 and 6.2 Hz,

1H), 6.87 (td, J = 8.4 and 2.8 Hz, 1H), 5.79 (d, J = 10.4 Hz, 1H), 5.66 (dt, J = 10.1 and 3.8 Hz, 1H), 3.06 (d, J = 2.7 Hz, 2H), 2.18-1.31 (m, 6H), 1.20 (d, J = 3.9 Hz, 6H), 1.10 (s, 3H).
13

C NMR (CDCl3 , 75 MHz): d 220.3, 162.4, 159.1, 138.2, 131.9, 131.7, 131.6, 128.5, .127.0,

126.7, 115.3, 115.1, 102.7, 102.6, 52.1, 50.9, 47.9, 34.2, 27.3, 25.1, 25.1, 20.0. MS (EI, 70 eV): 305 (25), 277 (100), 235 (80), 133 (20), 95 (50). C18 H22 FIO HRMS Calcd. Found 400.0699 400.0695

Synthesis

of

1-(1-benzyl-2-cyclohexen-1-yl)-3-(4-fluoro-2-iodophenyl)-2,2-dimethyl-1-

propanone (18b)
Ph O I

n-BuLi (16.0 mL, 24.0 mmol) was added dropwise to a solution of diisopropylamine (3.5 mL, 25.0 mmol) in THF (20 mL), at -78 C. The mixture was stirred at 0 C for 5 min, then 23b (4.8 g, 20.0 mmol) was added. After 1.5 h at 0 C a solution of 25 (8.8 g, 28.0 mmol) in THF (10 mL) was added and the mixture was let warm to rt overnight. The reaction was quenched with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 25 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 98:2) yielded 18b as a yellow oil (3.8 g, 40 %).
~ IR (film, cm-1 ): 3067 (s, br), 2932 (s), 1702 (vs), 1590 (vs), 1495 (w), 1479 (vs), 1454 (m),

1415 (m), 1380 (w), 1291 (s), 1228 (vs), 1028 (s), 866 (vs), 736 (m), 713 (s), 702 (s), 608 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.46 (dd, J = 8.7 and 2.6 Hz, 1H), 7.14-6.98 (m, 5H), 7.00 (dd, J

= 8.8 and 6.2 Hz, 1H), 6.87 (td, J = 8.4 and 2.8 Hz, 1H), 5.79 (d, J = 10.4 Hz, 1H), 5.66 (dt, J = 10.1 and 3.8 Hz, 1H), 3.06 (d, J = 2.7 Hz, 2H), 2.96 (d, J = 12.8 Hz, 1H), 2.56 (d, J = 12.9 Hz, 1H), 2.18-1.31 (m, 6H), 1.20 (d, J = 3.9 Hz, 6H).

108
13

C NMR (CDCl3 , 75 MHz): d 220.3, 162.4, 159.1, 139.4, 138.2, 131.9, 131.7, 131.6, 128.5,

128.3, 127.0, 126.7, 125.7, 115.3, 115.1, 102.7, 102.6, 52.1, 50.9, 47.9, 38.1, 34.2, 27.3, 25.1, 25.1. MS (EI, 70 eV): 305 (25), 277 (100), 235 (80), 133 (20), 95 (50), 91 (85). C24 H26 FIO HRMS Calcd. Found 476.1012 476.1009

Synthesis of benzenemethanol, -(1-methyl-2-cyclohexen-1-yl) (27a)

OH Ph

Prepared according to TP 4 from 18a (331 mg, 0.8 mmol), n-BuLi (0.6 mL, 0.9 mmol), zinc bromide (0.6 mL, 0.9 mmol, 1.5 M solution in THF) and benzaldehyde (0.1 mL, 1.0 mmol). Reaction time: 45 min. Purification by flash chromatography (pentane/diethyl ether 97:3) yielded 27a as a light yellow oil (114 mg, 68 %). dr: 97:3
~ IR (film, cm-1 ): 3390 (m), 2972 (s), 1668 (s), 1448 (s), 700 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.38-7.18 (m, 5H), 5.78 (dt, J = 10.1 and 4.2 Hz, 1H), 5.33 (dd, J

= 10.1 and 1.0 Hz, 1H), 4.39 (s, 1H), 1.9 (s, br, 1H), 1.89 (m, 2H), 1.78 (td, J = 12.1 and 3.3 Hz, 2H), (1,60-0.90, m, 2H), 0.85 (s, 3H).
13

C NMR (CDCl3 , 75 MHz): d 139.6, 132.8, 128.5, 127.0, 126.5, 126.3, 79.9, 73.3, 73.2, 39.5,

28.7, 24.1, 22.8, 17.8. MS (EI, 70 eV): 107 (100), 96 (53), 79 (26), 67 (9), 55 (4). C14 H18 O Calcd. Found C, 83.12 C, 82.91 H, 8.97 H, 9.01

Synthesis of 1-naphthalenemethanol, -(1-methyl-2-cyclohexen-1-yl) (27b)

OH 1-Napht

109

Prepared according to TP 4 from 18a (400 mg, 1.0 mmol), n-BuLi (0.6 mL, 0.9 mmol), zinc bromide (0.8 mL, 1.2 mmol, 1.5 M solution in THF) and 1 -naphtylaldehyde (0.2 mL, 1.4 mmol). Reaction time: 45 min. Purification by flash chromatography (pentane/diethyl ether 92:8) yielded 27b as a yellow oil (201 mg, 80 %). dr: 88:12
~ IR (film, cm-1 ): 3436 (m), 1730 (s), 1383 (s), 1112 (s), 911 (s), 734(s).
1

H NMR (CDCl3 , 300 MHz): d 9.30-7.49 (m, 7H), 5.82 (dt, J = 10.1 and 4.2 Hz, 1H), 5.55 (s, C NMR (CDCl3 , 75 MHz): d 136.4, 133.0, 132.4, 130.9, 127.7, 127.0, 126.9, 126.5, 124.8,

1H), 5.43 (d, J = 10.1 Hz, 1H), 2.04-1.64 (m, 6H), 1.04 (s, 3H).
13

124.6, 124.4, 123.1, 79.9, 40.4, 32.6, 24.2, 22.8, 18.0, 14.2. MS (EI, 70 eV): 252 (M+, 14), 157 (100), 129 (33), 101 (21). C18 H20 O Calcd. Found C, 85.67 C, 85.74 H, 7.99 H, 8.02

Synthesis of 2-furanmethanol, -(1-methyl-2-cyclohexen-1-yl) (27c)

OH O

Prepared according to TP 4 from 18a (400 mg, 1.0 mmol), n-BuLi (0.6 mL, 0.9 mmol), zinc bromide (0.8 mL, 1.2 mmol, 1.5 M solution in THF) and furfural (0.12 mL, 1.4 mmol). Reaction time: 45 min. Purification by flash chromatography (pentane/diethyl ether 95:5) yielded 27c as a yellow oil (184 mg, 96 %). dr: 97:3
~ IR (film, cm-1 ): 3398 (m), 1668 (s), 1475 (s), 703 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.19 (m, 1H), 6.27 (m, 1H), 6.19 (m, 1H), 5.78 (dt, J = 10.1 and

4.2 Hz, 1H), 5.33 (d, J = 10.1 Hz, 1H), 4.42 (s, 1H), 2.09 (s (br), 1H), 1.90 (td, J = 12.2 and 3.1 Hz, 2H), 1.78-1.50 (m, 4H), 0.93 (s, 3H).
13

C NMR (CDCl3 , 75 MHz): d 153.6, 140.5, 131.9, 128.5, 109.0, 106.6, 74.0, 39.4, 29.2, 24.0,

17.9. MS (EI, 70 eV): 192 (M+, 10), 159 (12), 115 (30), 97 (100).

110 C12 H16 O2 Calcd. Found C, 74.97 C, 74.83 H, 8.39 H, 8.25

Synthesis of 1-naphthalenemethanol, -[1-(phenylmethyl)-2-cyclohexen-1-yl] (27d)

OH 1-Napht Ph

Prepared according to TP 4 from 18b (370 mg, 0.8 mmol), n-BuLi (0.54 mL, 0.8 mmol), zinc bromide (0.7 mL, 1.0 mmol, 1.5 M solution in THF) and 1-naphthaldehyde (0.12 mL, 0.9 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 96:4) yielded 27d as a white solid (220 mg, 87 %). dr > 98:2

Mp 50 C
~ IR (KBr, cm-1 ): 3436 (br, m), 2933 (vs), 2865 (s), 1689 (vs), 1632 (vs), 1450 (vs), 1403 (s),

1317 (vs), 1217 (vs), 1170 (m), 1056 (s), 885 (m), 806 (vs), 774 (vs).
1

H NMR (CDCl3 , 300 MHz): d 7.74-7.13 (m, 12H), 5.71 (m, 2H), 5.46 (s, 1H), 2.99 (d, J = 13.1 C NMR (CDCl3 , 75 MHz): d 137.8, 137.1, 132.3, 131.0, 130.5, 129.8, 128.7, 128.0, 127.7,

Hz, 1H), 2.73 (d, J = 13.0 Hz, 1H), 1.63 (s, br, 1H), 1.43-1.19 (m, 6H).
13

126.9, 126.8, 125.1, 125.0, 124.6, 124.1, 122.6, 71.1, 44.2, 41.0, 26.9, 23.8, 17.4. MS (EI, 70 eV): 310 (M+-H2 O, 16), 219 (15), 172 (20), 157 (100), 129 (70), 115 (12), 91 (30). C24 H24 O Calcd. Found C, 87.76 C, 87.73 H, 7.37 H, 7.16

Synthesis of 2-cyclohexene -1-methanol, -cyclohexyl-1-(phenylmethyl)- (27e)

OH

Ph

Prepared according to TP 4 from 18b (470 mg, 1.0 mmol), n-BuLi (0.8 mL, 1.0 mmol), zinc bromide (0.9 mL, 1.3 mmol, 1.5 M solution in THF) and cyclohexancarboxaldehyde (0.13 mL,

111 1.2 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 93:7) yielded 27e as a colourless oil (227 mg, 80 %). dr > 98:2
~ IR (film, cm-1 ): 3495 (m, br), 2925 (vs), 2851 (vs), 1667 (w), 1494 (m), 1450 (s), 1261 (w),

1079 (m), 701 (s).

1

H NMR (CDCl3 , 300 MHz): d 7.20-7.09 (m, 5H), 5.77 (dt, J = 10 and 4 Hz, 1H), 5.46 (d, J = 10 C NMR (CDCl3 , 75 MHz): d 139.1, 133.0, 131.1, 129.8, 128.1, 126.3, 79.8, 53.8, 45.0, 43.6,

Hz, 1H), 3.10 (s, 1H), 2.77 (d, J = 14 Hz, 1H), 2.60 (d, J = 14 Hz, 1H), 1.83-1.14 (m, 17H).
13

39.2, 34.0, 28.4, 27.7, 27.4, 26.9, 26.8,. 25.3, 19.3. MS (EI, 70 eV): 284 (M+, 1), 267 (1), 193 (4), 172 (100), 143 (3), 129 (10), 111 (35), 91 (50), 82 (60). C20 H20 O HRMS Calcd. Found 284.2140 284.2114

Synthesis of 2-cyclohexene -1-methanol, -[(1E)-1-butenyl]-1-(phenylmethyl)- (27f)

OH

Ph

Prepared according to TP 4 from 18b (470 mg, 1.0 mmol), n-BuLi (0.8 mL, 1.0 mmol), zinc bromide (0.9 mL, 1.3 mmol, 1.5 M solution in THF) and trans-2-penten-1-al (0.1 mL, 1.0 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 96:4) yielded 27f as a colourless oil (198 mg, 79 %). dr: 91:9
~ IR (film, cm-1 ): 3485 (m, br), 2913 (vs), 2860 (vs), 1672 (w), 1484 (m), 1447 (s), 1260 (w),

1069 (m), 700 (s).

1

H NMR (CDCl3 , 300 MHz): d 7.18-7.09 (m, 5H), 5.83 (dt, J = 3.1 and 2.6 Hz, 1H), 5.67 (dt, J =

15.2 and 7.0 Hz, 1H), 5.52-5.42 (m, 2H), 3.75 (d, J = 8.1 Hz, 1H), 2.74 (d, J = 13.1 Hz, 1H), 2.53 (d, J = 13.2 Hz, 1H), 2.03 (qd, J = 8.1 and 1.0 Hz, 2H), 1.83-1.49 (m, 6H), 0.95 (t, J = 7.0 Hz, 3H).
13

C NMR (CDCl3 , 75 MHz): d 139.0, 137.4, 132.1, 131.2, 130.9, 128.6, 128.2, 126.3, 43.9, 42.9,

27.8, 25.9, 25.3, 19.1, 14.0.

112 MS (EI, 70 eV): 238 (M+-H2 O, 5), 172 (25), 147 (48), 129 (30), 105 (40), 91 (100), 79 (35). C18 H24 O HRMS Calcd. Found 256.1827 256.1824

Synthesis of me thyl 1-(4-cyanobenzyl)-2-cyclohexene -1-carboxylate (20c)

CO2Me

CN

n-BuLi (150 mL, 225 mmol) was added dropwise to a solution of diisopropylamine (17.0 mL, 120 mmol) in THF (50 mL), at -78 C. The mixture was stirred at 0 C for 5 min, then cooled to 50 C. HMPA (11 mL) was added and after 30 min methyl 1 -cyclohexene-1-carboxylate (7.7 g, 55.0 mmol). The mixture was stirred at this temperature for 3 h, then 4-

(bromomethyl)benzonitrile (10.0 g, 51.0 mmol) was addded and the mixture was let warm to rt. After 3 h the reaction was quenched with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 200 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 95:5) yielded 20c as a light yellow oil (10.0 g, 77 %).
~ IR (film, cm-1 ): 3435 (s), 2933 (s), 2228 (s), 1493 (m), 1451, (m), 1261 (m), 1043 (m), 801 (s),

780 (vs), 713 (m), 702 (s).

1

H NMR (CDCl3 , 300 MHz): d 7.48 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.3 Hz, 2H), 5.77 (m, 1H), C NMR (CDCl3 , 75 MHz): d 174.4, 141.9, 130.8, 129.7, 128.7, 127.4, 117.9, 109.6, 50.9, 47.2,

5.59 (d, J = 10.3 Hz, 1H), 3.57 (s, 3H), 2.91 (s, 2H), 1.98-1.35 (m, 6H).
13

44.8, 30.1, 23.8, 18.4. MS (EI, 70 eV): 256 ([M+H]+, 4), 196 (26), 154 (9), 139 (100), 116 (31), 106 (20). C16 H17 NO2 HRMS Calcd. Found 256.1338 [M+H]+ 256.1334

Synthesis of 1-(4-cyanobenzyl)-2-cyclohexene -1-carboxylic acid (21c)

113
CO2H

CN

A solution of 20c (4.8 g, 19.0 mmol) and KOH (4.5 g, 80.0 mmol) in ethanol (30 mL) and water (5 mL), was heated to reflux for 1 h, concentrated in vacuo and the residue dissolved in diethyl ether (70 mL). The mixture was acidified with 1N HCl solution at 0 C and the aqueous phase was extracted with diethyl ether (3 x 40 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo, to give 3.9 g of 21b as a yellow oil, used for the next step without further purification.

Synthesis of 1-(4-cyanobenzyl)-2-cyclohexene -1-carbonyl chloride (22c)

COCl

CN

Thionly chloride (4 mL, 50 mmol) was added slowly to 21c and the mixture stirred overnight at rt. Distillation of the thionyl chloride yielded 3.5 g of the desired crude product as a dark yellow oil, used for the next step without further purification.

Synthesis of 4-[(1-isobutyryl-2-cyclohexen-1-yl)methyl]benzonitrile (23c)

CN

To a suspension of 22c (240 mg, 0.9 mmol) and CuI (300 mg, 2.0 mmol) in THF (2 mL), iPrMgBr (0.9 mL, 1.2 mmol, 1.3 M in THF), was added slowly at -20 C. After 2 h the reaction was quenched with with saturated, aqueous NH4 Cl. The aqueous phase was extracted with diethyl ether (4 x 30 mL). The organic fractions were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 98:2) yielded 23c as a yellow oil (96 mg, 40 %).

114

~ IR (film, cm-1 ): 2966 (s), 2933 (vs), 2228 (s), 1702 (vs), 1607 (m), 1447 (m), 1095 (m), 1022

(w), 854 (w).

1

H NMR (CDCl3 , 300 MHz): d 7.45 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 5.87 (m, 1H),

5.58 (d, J = 10.3 Hz, 1H), 3.11 (d, J = 12.8 Hz, 1H), 2.83 (h, J = 6.7 Hz, 1H), 2.65 (d, J = 12.8 Hz, 1H), 1.95-1.39 (m, 6H), 0.94 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H).
13

C NMR (CDCl3 , 75 MHz): d 216.2, 142.5, 130.6, 130.4, 130.1, 128.7, 128.1, 126.9, 118.0,

109.2, 53.2, 42.8, 38.9, 35.4, 30.3, 25.7, 18.8, 18.1, 17.8. MS (EI, 70 eV): 268 (M+, 46), 196 (100), 168 (9), 154 (29), 142 (13), 116 (66). C18 H21 NO HRMS Calcd. Found 267.1623 267.1621

Synthesis of 6-fluoro-2,2-dimethyl-1-(1-methyl-2-cyclohexen-1-yl)-1-indanol (28)

HO

The starting ketone 18a (400 mg, 1.0 mmol) was dissolved in THF (1 mL) and DMPU (1 mL) and cooled to -30 C. i-PrMgBr (3.3 mL, 2.0 mmol, 0.6 M solution in THF) was added dropwise and the mixture was let warm to 0 C. A solution of ZnBr2 (1.2 mL, 1.7 mmol, 1.5 M in THF) was added and the mixture was let warm to rt and stirred for 15 min. Benzaldehyde (0.15 mL, 2.0 mmol) was then added and the mixture was stirred for 1 h and quenched with saturated, aqueous NH4 Cl and extracted with diethyl ether (4 x 30 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 95:5) yielded the cyclized alcohol 28 as a colourless oil (265 mg, 97 %).
~ IR (film, cm-1 ): 3390 (m), 2972 (s), 1668 (s), 1448 (s), 700 (s).
1

H NMR (CDCl3 , 300 MHz): d 6.99-6.81 (m, 3H), 5.55 (m, br, 2H), 2.98 (d, br, J = 1.2 Hz, 1H), C NMR (CDCl3 , 75 MHz): d 161.9, 158.7, 147.4, 136.3, 131.6, 124.4, 124.3, 113.5, 113.2,

2.30 (d, br, J = 1.2 Hz, 1H), 1.77 (s, br, 1H), 1.72-0.86 (m, 6H), 1.33 (s, 6H), 0.81 (s, 3H).
13

113.1, 112.8, 87.9, 49.7, 44.9, 43.4, 29.2, 27.4, 23.6, 21.3, 18.4, 13.0.

115 MS (EI, 70 eV): 274 (M+, 1), 256 (26), 213 (36), 179 (100), 161 (18), 146 (6), 133 (3), 95 (3), 67 (1), 42 (3). C18 H23 FO Calcd. Found C, 78.80 C, 78.73 H, 8.45 H, 8.39 F, 6.92 F, 6.87

116

Preparation of Highly Functionalized Organocuprates via HalogenCopper Exchange

Synthesis of ethyl 4-allylbenzoate (38a)

CO2Et

Prepared

according

to

TP

from

ethyl

4-iodobenzoate (276 mg, 1.0 mmol), lithium

neopentylcuprate 33 (1.2 mmol) and allyl bromide (110 mg, 0.9 mmol). Reaction time: 2.5 h at 50 C. Purification by flash chromatography (pentane/diethyl ether 99:1) yielded 38a as a colourless oil (180 mg, 95 %).

~ IR (film, cm-1 ): 2980 (s), 1716 (vs), 1640 (m), 1611 (vs), 1575 (m), 1433 (s), 1367 (s), 1316
(s), 1276 (vs), 1177 (vs), 1105 (vs), 1022 (s), 917 (m), 758 (s).
1

H NMR (CDCl3 , 300 MHz,): d 7.90 (dd, J = 8.3 and 1.7 Hz, 2H), 7.79 (dd, J = 8.0 and 1.7 Hz,

2H), 5.95-5.82 (m, 1H), 5.05-4.99 (m, 2H), 4.29 (q, J = 7.0 Hz, 2H), 3.60 (d, J = 6.6 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).
13

C-NMR (CDCl3 , 75 MHz): d 165.6, 144.3, 135.4, 128.7, 127.6, 115.5, 59.8, 39.1, 13.3. Calcd. Found C, 75.46 C, 76.10 H, 7.42 H, 7.55

MS (EI, 70 eV): 190 (M+, 26), 162 (14), 145 (100), 117 (51), 115 (29), 101 (1). C12 H14 O2

Synthesis of ethyl 4-benzoyl-benzoate (38b)

O

CO 2Et

117 Prepared according to TP 5 from ethyl 4-iodobenzoate (276 mg, 1.0 mmol), lithium

neopentylcuprate 33 (1.2 mmol) and benzoyl chloride (0.1 mL, 0.9 mmol). Reaction time: 2.5 h at -50 C. Purification by flash chromatography (pentane/diethyl ether 95:5) 38b as a light yellow oil (400 mg, 87 %).

~ IR (film, cm-1 ): 3402 (m, br), 2982 (m), 1720 (vs), 1661 (vs), 1597 (m), 1579 (w), 1448 (m),
1405 (s), 1356 (s), 1369 (s), 1317 (s), 1275 (vs), 1105 (vs), 1020 (m), 939 (m), 927 (m), 851 (w), 769 (w), 715 (s), 698 (m), 657 (m).
1

H NMR (CDCl3 , 300 MHz,): d 8.07 (dd, J = 8.4 and 1.8 Hz, 2H), 7.74 (dd, J = 8.1 and 1.8 Hz,

2H), 7.73 (m, 2H), 7.53 (dt, J = 8.0 and 1.4 Hz, 1H), 7.40 (t, J = 8.0 Hz, 2H), 4.34 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).
13

C-NMR (CDCl3 , 75 MHz): d 195.0, 164.8, 140.2, 136.0, 132.6, 131.9, 129.1, 128.7, 128.4,

127.4, 126.2, 60.4, 13.3. MS (EI, 70 eV): 254 (M+, 48), 226 (14), 209 (45), 181 (18), 177 (57), 152 (10), 149 (14), 130 (20), 118 (17), 104 (100). C16 H14 O3 Calcd. Found C, 75.57 C, 75.41 H, 5.55 H, 5.54

Synthesis of ethyl 4-(2,2-dimethyl-1-oxopropyl)-benzoate (38c)

O t-Bu CO 2Et

Prepared

according

to

TP

from

ethyl

4-iodobenzoate (276 mg, 1.0 mmol), lithium

neopentylcuprate 33 (1.2 mmol) and pivaloyl chloride (108 mg, 0.9 mmol). Reaction time: 1.5 h at -50 C Purification by flash chromatography (pentane/diethyl ether 95:5) yielded 38c as a light yellow oil (350 mg, 83 %).

~ IR (film, cm-1 ): 3435 (vs, br), 1689 (vs), 1657 (vs), 1597 (m), 1579 (w), 1447 (s), 1402 (s),
1356 (s), 1316 (s), 1277 (vs), 1180 (w), 1072 (s), 939 (m), 928 (m), 850 (m), 794 (m), 736 (m), 699 (vs), 674 (m).

118
1

H NMR (CDCl3 , 300 MHz,): d 7.99 (dd, J = 8.7 and 1.8 Hz, 2H), 7.58 (dd, J = 8.7 and 1.8 Hz,

2H), 4.32 (q, J = 11.0 and 7.1 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H), 1.26 (s, 9H).
13

C-NMR (CDCl3 , 75 MHz): d 209.8, 166.2, 143.2, 132.4, 129.6, 127.7, 61.6, 44.7, 28.0, 14.6. HRMS Calcd. Found 235.1334 [M+H]+ 235.1352 [M+H]+

MS (EI, 70 eV): 235 ([M+H]+, 3), 189 (8), 177 (100), 149 (20), 121 (5), 103 (6). C14 H18 O3

Synthesis of 4-[(1-phenylcyclopentyl)carbonyl]benzoate (38d)

COOEt

Prepared

according

to

TP

from ethyl 4-iodobenzoate (552 mg, 2.0 mmol), lithium

neopentylcuprate 33 (2.2 mmol) and 1-phenylcyclopentanecarbonylchloride (375 mg, 1.8 mmol). Reaction time: 1.5 h at -50 C. Purification by flash chromatography (pentane/diethyl ether 95:5) yielded 38d as a colourless oil (350 mg, 60 %).

~ IR (film, cm-1 ): 3432 (m, br), 2956 (m), 1715 (vs), 1667 (s), 1366 (w), 1282 (vs), 1235 (s),
1129 (m), 1110 (s), 1019 (w), 724 (w), 705 (w).
1

H NMR (CDCl3 , 300 MHz): d 7.84 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.25-7.15 (m, C-NMR (CDCl3 , 75 MHz): d 202.2, 166.2, 144.3, 140.3, 133.2, 129.9, 129.5, 127.2, 126.5,

5H), 4.27 (q, J = 7.1 Hz, 2H), 2.42 (m, 2H), 2.03 (m, 2H), 1.66 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H).
13

64.0, 31.6, 37.5, 25.0, 14.6. MS (EI, 70 eV): 323 (M+, 1), 177 (24), 145 (100), 115 (2). C21 H22 O3 HRMS Calcd. Found 322.1569 [M-H]+ 322.1565

119 Synthesis of ethyl 4-(3-oxocyclohexyl)-benzoate (38e)

CO2Et

Prepared

according

to

TP

from

ethyl

4-iodobenzoate (552 mg, 2.0 mmol), lithium

neopentylcuprate 33 (2.2 mmol), 2-cyclohexen-1-one (0.16 mL, 1.6 mmol) and trimethylsilyl chloride (0.4 mL, 3.2 mmol). Reaction time: 1.5 h at -50 C. Purification by flash chromatography (pentane/diethyl ether 95:5) yielded ethyl 4-(3-oxocyclohexyl)-benzoate 5d as a light yellow oil (113 mg, 70 %).

~ IR (film, cm-1 ): 2977 (vs), 2934 (s), 2864 (vs), 1719 (m), 1444 (m), 1382 (s), 1350 (m), 1277
(m), 1261 (m), 1123 (vs), 1077 (s), 1043 (m), 1023 (m), 845 (w), 797 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.93 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 4.30 (q, J C-NMR (CDCl3 , 75 MHz): d 209.3, 165.4, 148.3, 129.0, 128.1, 125.6, 59.9, 47.5, 43.7, 40.1,

= 11.1 and 7.2 Hz, 2H), 3.05-2.95 (m, 1H), 2.56-1.50 (m, 8H), 1.32 (t, J = 7.1 Hz, 3H).
13

31.5, 24.4, 13.3. MS (EI, 70 eV): 246 (M+, 94), 218 (2), 201 (100), 189 (9), 177 (17), 148 (14), 145 (49), 131 (89), 117 (50), 102 (22). C15 H18 O3 Calcd. Found C, 73.15 C, 73.44 H, 7.37 H, 7.40

Synthesis of diethyl 2-allylterephtalate (38f)

CO2Et

CO2Et

Prepared according to TP 5 from diethyl 2-bromoterephtalate (630 mg, 2.1 mmol), lithium neopentylcuprate 33 (2.2 mmol) and allyl bromide (242 mg, 2.0 mmol). Reaction time: 1h at -40

120 C. Purification by flash chromatography (pentane/diethyl ether 99:1) yielded 38f as a light yellow oil (400 mg, 76 %).

~ IR (film, cm-1 ): 2980 (s), 2907 (m), 1722 (vs), 1638 (w), 1477 (m), 1407 (m), 1366 (s), 1269
(vs), 1188 (m), 1110 (vs), 1070 (m), 1021 (m), 915 (m), 753 (m), 732 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.87-7.82 (m, 3H), 5.99-5.86 (m, 1H), 5.00-4.97 (m, 2H), 4.36C-NMR (CDCl3 , 75 MHz): d 167.5, 166.3, 141.7, 137.1, 134.5, 133.6, 132.3, 130.8, 128.7,

4.27 (m, 4H), 3.60 (d, J = 6.6 Hz, 2H), 1.37-1.30 (m, 3H).
13

116.5, 62.0, 61.7, 38.6, 14.7, 14.6. MS (EI, 70 eV): 262 (M+, 62), 247 (91), 217 (100), 205 (14), 189 (20), 177 (34), 171 (25), 161 (9), 143 (22), 117 (49), 115 (62). C15 H18 O4 HRMS Calcd. Found 262.1205 262.1210

Synthesis of 2-allylbenzophenone (38g)

Prepared

according

to

TP

from

2-iodobenzophenone

(830 mg,

2.7 mmol),

lithium

neopentylcuprate 33 (2.8 mmol) and allyl bromide (302 mg, 2.5 mmol). Reaction time: 1h at -60 C. Purification by flash chromatography (pentane) yielded 38g as a light yellow oil (480 mg, 80 %).

~ IR (film, cm-1 ): 3511 (w, br), 3062 (m), 2956(vs), 2926 (vs), 2855 (s), 1666 (vs), 1598 (vs),
1580 (s), 1477 (s), 1465 (s), 1448 (vs), 1364 (s), 1315 (vs), 1269 (vs), 1154 (m), 999 (m), 928 (vs), 762 (vs), 702 (vs), 639 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.88-7.80 (m, 3H), 7.60-7.28 (m, 6H), 6.01-5.81 (m, 1H), 5.06C-NMR (CDCl3 , 75 MHz): d 196.9, 136.6, 136.2, 134.5, 132.5, 131.6, 130.4, 129.6, 128.3,

4.96 (m, 2H), 4.36-4.27 (m, 4H), 3.46 (d, J = 6.6 Hz, 2H).
13

127.9, 116.0, 39.6.

121 MS (EI, 70 eV): 222 (40), 207 (100), 178 (10), 165 (15), 145 (22), 115 (30), 105 (9), 91 (5), 77 (27). C16 H14 O HRMS Calcd. Found 222.1045 224.1036

Synthesis of 2-methylbenzophenone (38h)

O

Prepared

according

to

TP

from

2-iodobenzophenone

(620 mg,

2.0 mmol),

lithium

neopentylcuprate 33 (2.2 mmol) and methyl iodide (0.12 mL, 1.9 mmol). Reaction time: 1 h at 60 C. Purification by flash chromatography (pentane/diethyl ether gradient) yielded 38h as a light yellow oil (300 mg, 80 %).

~ IR (film, cm-1 ): 3511 (w, br), 3062 (m), 2936(vs), 2855 (w), 1676 (vs), 1562 (s), 1470 (s),
1458 (s), 1384 (m), 1315 (s), 1134 (w), 902 (m), 757 (vs), 701 (s).
1

H NMR (CDCl3 , 300 MHz,): d 7.74-7.71 (m, 3H), 7.50 (tt, J = 7.3 and 1.3 Hz, 1H), 7.40-7.14 C-NMR (CDCl3 , 75 MHz): d 199.0, 139.0, 138.1, 137.1, 133.5, 130.6, 130.5, 128.9, 128.8,

(m, 5H), 2.25 (s, 3H).

13

125.8, 113.9, 20.4. MS (EI, 70 eV): 195 (M+, 100), 178 (15), 165 (10), 152 (8), 119 (34), 105 (30), 91 (55), 77 (45), 65 (20), 51 (15), 39 (10). C14 H12 O HRMS Calcd. Found 196.0888 196.0881

Synthesis of 2,2-dimethyl-1-[4-(2-propenyl)phenyl]-1-propanone (38i):

COt-Bu

122

Prepared according to TP 5 from 4-iodophenyl t-butyl ketone (290 mg, 1.0 mmol), lithium neopentylcuprate 33 (1.2 mmol) and allyl bromide (109 mg , 0.9 mmol). Reaction time: 1.5 h at 0 C. Purification by flash chromatography (pentane/diethyl ether 100:1) yielded 38i as a light yellow oil (170 mg, 93 %).

~ IR (film, cm-1 ): 2968 (s), 2906 (s), 1672 (vs), 1606 (vs), 1477 (m), 1402 (s), 1366 (m), 1277
(s), 1171 (s), 962 (s), 916 (m), 824 (m), 759 (m), 560 (w).
1

H NMR (CDCl3 , 300 MHz): d 7.60 (d, J = 8.3 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 5.94-5.80 (m, C-NMR (CDCl3 , 75 MHz,): d 208.7, 143.8, 136.9, 136.5, 128.8, 128.6, 116.8, 44.5, 40.4, 28.5. HRMS Calcd. Found 202.1358 202.1330

1H), 5.04-4.98 (m, 2H), 3.33 (d, J = 6.6 Hz, 2H), 1.26 (s, 9H).
13

MS (EI, 70 eV): 202 (M+, 1), 145 (100), 115 (18), 101 (2). C14 H18 O

Synthesis of 3-[4-(2,2-dimethylpropanoyl)phenyl]cyclohexanone (38j)

O

COt-Bu

Prepared according to TP 5 from 4-iodophenyl t-butyl ketone (290 mg, 1.0 mmol), lithium neopentylcuprate 33 (1.2 mmol), 2-cyclohexen-1-one (0.12 mL, 1.2 mmol) and trimethylsilyl chloride (0.3 mL, 2.4 mmol). Reaction time: 2 h at 0 C. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 38j as a light yellow oil (150 mg, 60 %).

~ IR (film, cm-1 ): 3413 (m, br), 2935 (vs), 2870 (s), 1712 (vs), 1671 (vs), 1606 (s), 1477 (s),
1448 (m), 1414 (m), 1395 (m), 1366 (s), 1276 (s), 1198 (m), 1172 (vs), 962 (vs), 842 (m), 768 (m), 710 (w).
1

H NMR (CDCl3 , 300 MHz): d 7.63 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.3 Hz, 2H), 3.03-2.93 (m,

1H), 2.56-1.49 (m, 8H), 1.27 (s, 9H).

123
13

C-NMR (CDCl3 , 75 MHz) d 210.8, 208.7, 147.7, 137.1, 129.0, 127.4, 126.7, 48.9, 44.9, 44.5,

41.5, 32.9, 28.5, 25.8. MS (EI, 70 eV): 258 (M+, 1), 201 (100), 144 (1), 131 (3), 115 (4), 103 (2). C17 H22 O2 HRMS Calcd. Found 258.1620 258.1629

Synthesis of [2-allyl-4-(1,3-dithiolan-2-yl)-6-methoxyphenoxy](triisopropyl)silane (38k)

OMe OTIPS

Prepared

according

to

TP (505 mg,

5 0.9

from mmol),

[4-(1,3-dithiolan-2-yl)-2-iodo-6lithium neopentylcuprate 33

methoxyphenoxy](triisopropyl)silane

(12.1 mmol) and allyl bromide (490 mg, 4.0 mmol). Reaction time: 7h at rt. Purification by flash chromatography (pentane/diethyl ether 98:2) yielded 38k as a yellow oil (250 mg, 60 %).

~ IR (film, cm-1 ): 2945 (vs), 2865 (vs), 1585 (m), 1490 (vs), 1465 (vs), 1423 (m), 1311 (s), 1150
(s), 1077 (m), 917 (s), 884 (s), 680 (s).
1

H NMR (CDCl3 , 300 MHz): d 6.88 (d, J = 2.2 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 5.88 (m, 1H),

5.54 (s, 1H), 5.01 (m, 2H), 3.71 (s, 3H), 3.41 (m, 2H), 3.31 (d, J = 6.6 Hz, 2H), 3.25 (m, 2H), 1.18 (m, 3H), 0.99 (d, J = 7.1 Hz, 18H).
13

C-NMR (CDCl3 , 75 MHz): d 148.4, 142.2, 133.3, 129.8, 129.3, 120.5, 116.2, 107.6, 55.9, 53.7,

39.1, 33.8, 17.2, 13.2. MS (EI, 70 eV): 401 (4), 381 (100), 366 (45), 338 (24), 297 (51), 235 (9), 207 (27), 193 (12), 73 (13). C22 H36 O2 S2 Si HRMS Calcd. Found 424.1926 424.1920

124

Synthesis of ethyl 2,3,5-triiodobenzoate (40)

CO2Et I I I

A mixture of 2,3,5-triiodobenzoic acid (10.0 g, 20.0 mmol), EtOH (60 mL), and conc. H SO4 (3 2 mL), was heated to reflux for 14 h. After cooling to rt, the reaction mixture was dissolved in CH2 Cl2 (300 mL) and washed with saturated, aqueous NaHCO3 (till pH 5) and with brine, dried over MgSO4 and concentrated in vacuo. The crude solid was recrystallized from pentane to give the desired product 40 as a white crystalline solid (9.8 g, 93 %).

Mp 92 C

~ IR (KBr, cm-1 ): 2978 (w), 1736 (vs), 1271 (vs), 1184 (vs), 774 (w).
1

H NMR (CDCl3 , 300 MHz): d 8.29 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 4.39 (q, J = C-NMR (CDCl3 , 75 MHz): d 166.1, 148.6, 141.8, 136.8, 113.2, 106.5, 93.6, 62.5, 14.1.

7.1 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).

13

MS (EI, 70 eV): 528 (M+, 100), 500 (23), 483 (54), 455 (18), 373 (10), 218 (16), 201 (32), 74 (35). C9 H7 I3 O2 Calcd. Found C, 20.48 C, 20.43 H, 1.34 H, 1.40 I, 72.12 I, 72.05

Synthesis of ethyl 2-bromo-3,5-diiodobenzoate (41f)

CO2Et Br I I

i-PrMgCl (1.1 mL, 2.2 mmol, 2 M solution in THF) was added slowly to a solution of 40 (1.1 g, 2.1 mmol) in THF (2 mL), at -78 C. The reaction mixture was warmed to -50 C and after 1 h a solution of 1,2-dibromotetrachloroethane (0.8 g, 2.4 mmol) in THF (2 mL) was added. After 1 h the reaction was quenched with saturated, aqueous NH4 Cl. The aqueous phase was extracted with

125 diethyl ether (3 x 15 mL). The organic fractions were washed with brine, dried over and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 96:4) yielded 41f as a light red oil (850 mg, 85 %).

~ IR (film, cm-1 ): 3436 (s, br), 1731 (vs), 1527 (m), 1402 (m), 1374 (m), 1275 (vs), 1237 (s),
1191 (vs), 1108 (m), 1012 (m), 775 (w).
1

H NMR (CDCl3 , 300 MHz): d 7.95 (d, J = 2.0 Hz, 2H), 7.65 (d, J = 2.0 Hz, 2H), 4.30 (q, J = C-NMR (CDCl3 , 75 MHz): d 166.2, 150.2, 138.6, 132.9, 128.0, 106.2, 93.7, 62.9, 14.6. HRMS Calcd. Found 479.7719 479.7745

7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).

13

MS (EI, 70 eV): 479 (M+, 100), 453 (27), 436 (59), 406 (9), 352 (4), 279 (6), 152 (7). C9 H7 BrI2 O2

Synthesis of ethyl 3-allyl-2-bromo-5-iodobenzoate (38l)

CO 2Et Br I

Prepared according to TP 5 from 41f (400 mg, 0.8 mmol), lithium neopentylcuprate 33 (2.1 mmol) and allyl bromide (0.1 mL, 1.1 mmol). Reaction time: 45 min. Purification by flash chromatography (pentane/diethyl ether 100:1) yielded 38l as a colourless oil (250 mg, 76 %).

~ IR (film, cm-1 ): 2980 (m), 2925 (m), 1732 (vs), 1422 (m), 1281 (vs), 1155 (s), 1024 (vs), 919
(m), 775 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.69 (d, J = 2.1 Hz, 2H), 7.56 (d, J = 2.1 Hz, 2H), 5.83 (m, 1H), C-NMR (CDCl3 , 75 MHz): d 166.1, 143.7, 141.4, 136.8, 134.7, 123.0, 118.1, 92.3, 62.5, 40.7,

5.12-5.01 (m, 2H), 4.31 (q, J = 7.5 Hz, 2H), 3.44 (d, J = 6.5 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).
13

14.5. MS (EI, 70 eV): 393 (M+, 100), 350 (60), 287 (6), 241 (4), 160 (15), 115 (45). C12 H12 BrIO2 HRMS Calcd. Found 393.9065 393.9074

126

Synthesis of 2-iodobenzaldehyde 137 (39)

CHO I

A solution of oxalyl chloride (1.0 mL, 11.0 mmol) in dichloromethane (25 mL), was placed in a 100 mL two-necked argon flask equipped with two dropping funnels containing DMSO (1.7 mL, 22.0 mmol) dissolved in dichloromethane (5 mL), and 2-iodobenzylalcohol (2.34 g, 10.0 mmol) dissolved in 10 mL dichloromethane respectively. The DMSO was added to the stirred oxalyl chloride solution at -50 C. The reaction mixture was stirred for 2 min and the alcohol was added within 5 min; stirring was continued for additional 15 min.TEA (7.0 mL, 50.0 mmol) was added and the reaction mixture was stirred for 5 min and then allowed to warm to rt. Water (50 mL), was then added and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The crude yellow solid obtained was recrystallized from pentane to give 39 as a light yellow solid (1.9 g, 82 %).

Mp 36 C

~ IR (KBr, cm-1 ): 2851 (w), 1696 (vs), 1580 (s), 1437 (m), 1261 (s), 1199 (s), 1014 (s), 820 (m),
752 (s).
1

H NMR (CDCl3 , 300 MHz): d 9.98 (s, 1H), 7.87 (dd, J = 7.9 and 1.0 Hz, 1H), 7.80 (dd, J = 7.9 C-NMR (CDCl3 , 75 MHz): d 196.1, 141.0, 135.9, 135.5, 130.7, 129.1, 101.1. HRMS Calcd. Found 231.9385 231.9387

amd 1.8 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.23-7.18 (m, 1H).
13

MS (EI, 70 eV): 232 (M+, 100), 203 (16), 104 (78), 76 (31), 50 (16). C7 H5 IO

137

Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem., 1978, 43, 2480.

127 Synthesis of 2-allylbenzaldehyde (38m)

CHO

Prepared according to TP 5 from 39 (210 mg, 0.9 mmol), lithium neopentylcuprate 33 (1.2 mmol) and allyl bromide (110 mg, 0.9 mmol). Reaction time: 4.5 h at -40 C. Purification by flash chromatography (pentane/diethyl ether 98:2) yielded 38m as a colourless oil (100 mg, 80 %).

~ IR (film, cm-1 ): 2934 (vs, br), 2859 (vs, br), 1732 (vs), 1694 (vs), 1584 (w), 1579 (w), 1434
(m), 1368 (s), 1240 (vs), 1175 (w), 1112 (s), 1015 (s), 957 (m), 758 (s), 714 (m), 648 (w).
1

H NMR (CDCl3 , 300 MHz): d 10.20 (s, 1H), 7.77 (dd, J = 7.6 and 1.3 Hz, 1H), 7.46 (td, J = 7.5

and 1.4 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 6.03-5.90 (m, 1H), 5.04-4.88 (m, 2H), 3.75 (d, 3 J = 6.2 Hz, 2H).
13

C-NMR (CDCl3 , 75 MHz): d 191.3, 141.2, 135.9, 132.9, 130.6, 130.1, 125.9, 115.4, 35.5. HRMS Calcd. Found 146.0732 146.0729

MS (EI, 70 eV): 146 (M+, 19), 131 (100), 128 (39), 118 (47), 117 (63), 155 (80), 103 (48). C10 H10 O

Synthesis of 2-acetylbenzaldehyde (38n)

CHO O

Prepared according to TP 5 from 39 (230 mg, 1.0 mmol), lithium neopentylcuprate 33 (1.2 mmol) and acetyl chloride (70 L, 1.1 mmol). Reaction time: 4.5 h at -40 C. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 38n as a colourless oil (111 mg, 75 %).

~ IR (film, cm-1 ): 3379 (m, br), 2924 (m), 2856 (m), 1732 (vs), 1696 (vs), 1637 (w), 1599 (m),
1574 (w), 1434 (w), 1407 (w), 1286 (m), 1209 (m), 1175 (w), 1079 (w), 996 (m), 917 (m), 754 (s), 636 (w).

128
1

H NMR (CDCl3 , 300 MHz): d 10.19 (s, 1H), 7.92-7.72 (m, 2H), 7.64-7.55 (m, 2H), 2.69 (s,

3H).
13

C-NMR (CDCl3 , 75 MHz): d 193.9, 190.3, 140.0, 137.3, 133.4, 130.5, 130.4, 128.9, 28.3. HRMS Calcd. Found 148.0524 148.0538

MS (EI, 70 eV): 148 (M+, 3), 133 (4), 120 (2), 111 (1), 105 (100), 91 (8), 85 (3). C9 H8 O2

Synthesis of 4-allylacetophenone (38o)

COCH3

Prepared

according

to

TP

from

4-iodoacetophenone

(240 mg,

1.0 mmol),

lithium

neophylcuprate 35 (1.2 mmol) and allyl bromide (0.1 mL, 1.1 mmol). Reaction time: 30 min at rt.. Purification by flash chromatography (pentane/diethyl ether 99:1) yielded 38o as a colourless oil (112 mg, 71 %).

~ IR (film, cm-1 ): 2918 (w), 1682 (vs), 1605 (m), 1582 (m), 1357 (m), 1267 (vs), 1181 (m),
1005 (m), 917 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.81 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 5.87 (m, 1H), C-NMR (CDCl3 , 75 MHz): d 198.5, 146.1, 137.5, 136.7, 129.2, 129.0, 128.7, 128.4, 117.0,

5.05-4.98 (m, 2H), 3.35 (d, J = 6.6 Hz, 2H), 2.49 (s, 3H).
13

40.5, 15.7. MS (EI, 70 eV): 160 (M+, 15), 145 (100), 117 (21), 115 (38). C11 H12 O Calcd. Found C, 82.46 C, 82.69 H, 7.55 H, 7.72

129 Synthesis of 1-[4-(2-methyl-2-propenyl)phenyl]ethanone (38p)

COCH3

Prepared

according

to

TP

from

4-iodoacetophenone

(240 mg,

1.0 mmol),

lithium

neophylcuprate 35 (1.2 mmol) and 3-bromo-2-methyl-1-propene (0.1 mL, 1.0 mmol). Reaction time: 1 h at rt. Purification by flash chromatography (pentane/diethyl ether 97:3) yielded 38p as a light yellow oil (110 mg, 65 %).

~ IR (film, cm-1 ): 2919 (w), 1683 (vs), 1606 (m), 1430 (w), 1412 (w), 1357 (m), 1267 (vs), 1181
(w), 799 (w).
1

H NMR (CDCl3 , 300 MHz): d 7.82 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 5.86 (s, 1H), C-NMR (CDCl3 , 75 MHz): d 198.2, 145.9, 144.5, 135.7, 129.5, 128.9, 113.1, 44.9, 26.9, 22.5. HRMS Calcd. Found 174.1045 174.1038

5.65 (s, 1H), 3.29 (s, 2H), 2.50 (s, 3H), 1.60 (s, 3H).
13

MS (EI, 70 eV): 174 (M+, 11),159 (100), 131 (20), 116 (12), 105 (2). C12 H14 O

Synthesis of 4-acetylbenzophenone (38q)

COPh

COCH3

Prepared

according

to

TP

from

4-iodoacetophenone

(240 mg,

1.0 mmol),

lithium

neophylcuprate 35 (1.2 mmol) and benzoyl chloride (0.1 mL, 0.9 mmol). Reaction time: 1.5 h at rt. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 38q as a light yellow oil (155 mg, 77 %).

130

~ IR (film, cm-1 ): 3435 (vs, br), 1689 (vs), 1657 (vs), 1597 (m), 1579 (w), 1447 (s), 1402 (s),
1356 (s), 1316 (s), 1277 (vs), 1180 (w), 1072 (s), 939 (m), 928 (m), 850 (m), 794 (m), 736 (m), 699 (vs), 674 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.98 (dd, J = 8.0 and 1.8 Hz, 2H), 7.79 (dd, J = 8.1 and 1.8 Hz, C-NMR (CDCl3 , 75 MHz): d 197.9, 196.3, 141.7, 140.0, 137.3, 133.4, 130.5, 130.4, 129.2,

2H), 7.73 (m, 2H), 7.55 (dt, J = 8.1 and 1.4 Hz, 1H), 7.43 (t, J = 8.2 Hz, 2H), 2.59 (s, 3H).
13

128.9, 128.5, 27.3. MS (EI, 70 eV): 224 (M+, 29), 209 (90), 181 (8), 167 (100), 153 (11), 147 (20), 119 (3), 105 (34). C15 H12 O2 HRMS Calcd. Found 224.0837 224.0829

Synthesis of 3-(4-acetylphenyl)cyclohexanone (38r)

O

COCH3

Prepared

according

to

TP

from

4-iodoacetophenone

(240 mg,

1.0 mmol),

lithium

neophylcuprate 35 (1.2 mmol), 2-cyclohexen-1-one (0.12 mL, 1.2 mmol) and trimethylsilyl chloride (0.3 mL, 2.4 mmol). Reaction time: 2 h at rt. Purification by flash chromatography (pentane/diethyl ether 6:4) yielded 38r as a colourless oil (140 mg, 68 %).

~ IR (film, cm-1 ): 3430 (m, br), 2935 (vs), 2870 (s), 1712 (vs), 1657 (vs), 1606 (s), 1477 (s),
1448 (m), 1414 (m), 1395 (m), 1366 (s), 1276 (s), 1198 (m), 1172 (vs), 962 (vs), 842 (m), 768 (m), 710 (w).
1

H NMR (CDCl3 , 300 MHz): d 7.85 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 3.06-2.96 (m,

1H), 2.50 (s, 3H), 2.46-1.66 (m, 8H).

13

C-NMR (CDCl3 , 75 MHz): d 228.5, 210.6, 150.0, 136.2, 129.3, 127.2, 48.8, 45.0, 41.5, 32.8,

27.0, 25.8. MS (EI, 70 eV): 216 (M+, 27), 201 (100), 181 (11), 173 (8), 147 (3), 131 (16), 115 (4), 103 (4).

131 C14 H16 O2 Calcd. Found C, 77.75 C, 77.76 H, 7.46 H, 7.40

Synthesis of ethyl (2E)-3-(4-acetylphenyl)-2-propenoate (38s)

COOEt

COCH3

Prepared

according

to

TP

from

4-iodoacetophenone

(246 mg,

1.0 mmol),

lithium

neophylcuprate 35 (1.2 mmol) and ethyl propiolate (0.1 g, 1.0 mmol). Reaction time: 1.5 h at rt. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 38s as a light yellow oil (170 mg, 78 %).

~ IR (film, cm-1 ): 3487 (m, br), 2978 (m), 1717 (vs), 1683 (vs), 1637 (m), 1605 (m), 1365 (m),
1267 (vs), 1206 (s), 1177 (vs), 1031 (m), 828 (m), 700 (m).
1

H NMR (CDCl3 , 300 MHz): d 8.03 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 16.0 Hz, 1H), 7.67 (d, J =

8.3 Hz, 2H), 6.59 (d, J = 15.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).
13

C-NMR (CDCl3 , 75 MHz): d 197.7, 166.9, 143.4, 139.2, 138.4, 130.0, 129.2, 128.5, 128.3,

121.2, 61.1, 27.0, 14.7. MS (EI, 70 eV): 218 (M+, 24), 203 (100), 175 (16), 147 (7), 131 (10), 115 (3), 102 (12). C13 H14 O3 HRMS Calcd. Found 218.0943 218.0936

132 Synthesis of ethyl 4-(2-iodo-2-cyclohexen-1-yl)benzoate (56)

CO2Et

Prepared

according

to

TP

from

ethyl

4-iodobenzoate (265 mg, 1.0 mmol), lithium

neopentylcuprate 33 (1.2 mmol) and 2-iodo-2-cyclohexen-1-yl acetate (300 mg, 1.1 mmol, 93 % ee). Reaction time: 1 h at -40 C. Purification by flash chromatography (pentane/diethyl ether 95:5) yielded 56 as a light yellow oil (220 mg, 64 %). ee: 92 %

~ IR (film, cm-1 ): 2936 (vs), 1714 (vs), 1609 (s), 1416 (m), 1308 (s), 1275 (vs), 1178 (s), 1102
(vs), 1021 (s), 985 (m), 769 (m), 707 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.95 (dt, J = 8.4 and 1.9 Hz, 2H), 7.20 (dt, J = 8.4 and 1.9 Hz,

2H), 6.62 (td, J = 4.2 and 1.9 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 2.14-2.05 (m, 3H), 1.57-1.53 (m, 3H), 1.31 (t, J = 7.2 Hz, 3H).
13

C-NMR (CDCl3 , 75 MHz): d 166.9, 149.8, 141.2, 130.1, 129.4, 128.7, 100.2, 61.2, 53.0, 33.9,

30.4, 19.1, 14.8. MS (EI, 70 eV): 356 (M+, 82), 229 (82), 206 (47), 201 (21), 163 (41), 155 (53), 129 (100), 115 (53). C15 H17 IO2 HRMS Calcd. Found 356.0273 356.0265

133

Iodine-Copper Exchange on Vinylic Substrates

Synthesis of 2-allyl-3-methyl-2-cyclohexen-1-one (45a)

Prepared according to TP 5 from 2-iodo-3-methyl-cyclohexen-1-one (240 mg, 1 mmol), lithium neopentylcuprate 33 (1.2 mmol) and allyl bromide (110 mg, 0.9 mmol). Reaction time: 3.5 h at 30 C. Purification by flash chromatography (pentane/diethyl ether 96:4) yielded 45a as a colourless oil (100 mg, 74 %).

~ IR (film, cm-1 ): 2924 (m), 2868 (m), 1666 (vs), 1636 (s), 1430 (m), 1379 (m), 1360 (w), 1261
(w), 1191 (w), 1016 (w), 996 (w), 910 (m), 799 (w).
1

H NMR (CDCl3 , 300 MHz): d 5.73-5.64 (m, 1H), 4.90-4.84 (m, 2H), 2.99 (d, J = 6.2 Hz, 2H), C-NMR (CDCl3 , 75 MHz): d 198.6, 157.2, 136.2, 126.7, 114.7, 38.1, 33.3, 29.6, 22.6, 21.6. HRMS Calcd. Found 150.1045 150.1062

2.63-1.90 (m, 6H), 1.86 (s, 3H).

13

MS (EI, 70 eV): 150 (M+, 43), 135 (100), 131 (4), 122 (9), 119 (14), 117 (22), 107 (20). C10 H14 O

Synthesis of ethyl (2E)-3-phenyl-2,5-hexadienoate (45b)

CO 2Et Ph

Prepared according to TP 6 from ethyl (2Z)-3-iodo-3-phenylpropenoate (1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and allyl bromide (110 mg, 0.9 mmol). Reaction time: 20 min. Purification by flash chromatography (pentane/diethyl ether 99:1) yielded 45b as a light yellow oil (190 mg, 88 %).

134

~ IR (film, cm-1 ): 2976 (m), 1733 (vs), 1638 (w), 1445 (m), 1367 (m), 1253 (s), 1157 (s), 1032
(m), 907 (m), 764 (m), 699 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.42-7.17 (m, 5H), 5.78 (m, 1H), 5.06-4.92 (m, 2H), 4.14 (q, J = C-NMR (CDCl3 , 75 MHz): d 173.2, 166.7, 141.5, 139.7, 135.9, 134.4, 128.3, 118.6, 116.6,

7.1 Hz, 2H), 3.79 (d, J = 6.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H).
13

60.3, 35.9, 14.7. MS (EI, 70 eV): 216 (M+, 3), 187 (1), 170 (11), 141 (79), 128 (100), 115 (18), 102 (3). C14 H16 O2 HRMS Calcd. Found 216.1150 216.1128

Synthesis of ethyl (2Z)-3-phenyl-2-nonen-4-ynoate (45c)

CO2Et Ph Bu

Prepared according to TP 6 from ethyl (2Z)-3-iodo-3-phenylpropenoate (1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and benzoyl chloride (0.15 mL mg, 1.2 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 99:1) yielded 45c as a light yellow oil (161 mg, 63 %).

~ IR (film, cm-1 ): 2961 (s), 2873 (s), 1735 (vs), 1448 (m), 1370 (m), 1178 (s), 1098 (s), 1030
(m), 765 (w), 700 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.62 (m, 2H), 7.31 (m, 3H), 6.42 (s, 1H), 5.29 (q, J = 7.1 Hz, C-NMR (CDCl3 , 75 MHz): d 166.0, 138.3, 137.6, 130.0, 129.2, 128.6, 126.6, 118.5, 105.4,

2H), 2.49 (t, J = 7.1 Hz, 2H), 1.62-1.33 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H), 0.87 (t, J = 7.3 Hz, 3H).
13

60.6, 38.7, 26.3, 22.5, 20.2, 14.7, 14.0. MS (EI, 70 eV): 256 (M+, 10), 227 (100), 211 (64), 199 (40), 186 (99), 168 (60), 159 (61), 141 (95), 129 (76), 115 (83), 102 (25). C17 H20 O2 HRMS Calcd. Found 256.1463 256.1469

135

Synthesis of ethyl (2Z)-4-oxo-3,4-diphenyl-2-butenoate (45d)

CO2Et Ph COPh

Prepared according to TP 6 from ethyl (2Z)-3-iodo-3-phenylpropenoate (1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and benzoyl chloride (0.15 mL mg, 1.2 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 92:8) yielded 45d as a light yellow solid (186 mg, 69 %).

Mp 90 C

~ IR (film, cm-1 ): 3061 (m), 2980 (s), 1714 (vs), 1615 (vs), 1598 (vs), 1577 (vs), 1494 (s), 1448
(vs), 1369 (vs), 1346 (vs), 1276 (vs), 1218 (vs), 1182 (vs), 1096 (s), 1019 (s), 770 (vs), 698 (vs), 590 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.87 (m, 2H), 7.46-7.27 (m, 8H), 6.42 (s, 1H), 3.98 (q, J = 7.1 C-NMR (CDCl3 , 75 MHz): d 196.8, 165.4, 155.9, 136.5, 134.7, 133.9, 130.8, 129.5, 129.3,

Hz, 2H), 1.03 (t, J = 7.2 Hz, 3H).

13

129.1, 128.4, 127.3, 118.3, 61.3, 14.2. MS (EI, 70 eV): 280 (M+, 26), 252 (100), 235 (25), 206 (22), 111 (4), 105 (11). C18 H16 O3 Calcd. Found C, 77.12 C, 76.92 H, 5.75 H, 5.71

Synthesis of 3-[(1E)-3-oxo-1-phenyl-1-hexenyl]cyclohexanone (45e)

CO2Et Ph

Prepared according to TP 6 from ethyl (2Z)-3-iodo-3-phenylpropenoate (1.0 mmol), lithium neophylcuprate 35 (1.2 mmol), cyclohexen-1-one (0.15 mL, 1.5 mmol) and TMSCl (0.4 mL, 3.0

136 mmol). Reaction time: 3 min. Purification by flash chromatography (pentane/diethyl ether 1:1) yielded 45e as a light yellow oil (130 mg, 48 %).

~ IR (film, cm-1 ): 3443 (m, br), 2962 (s), 1713 (vs), 1630 (m), 1444 (m), 1371 (m), 1246 (m),
1176 (vs), 1030 (s), 765 (m), 700 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.28 (m, 2H), 7.11 (m, 3H), 5.69 (s, 1H), 4.12 (q, J = 7.1 Hz, C-NMR (CDCl3 , 75 MHz): d 210.6, 166.2, 162.4, 140.4, 128.5, 128.0, 120.4, 60.6, 46.2, 41.4,

2H), 2.30-1.52 (m, 9H), 1.23 (t, J = 7.2 Hz, 3H).

13

40.7, 30.4 ,25.9, 14.6. MS (EI, 70 eV): 272 (M+, 96), 243 (100), 226 (79), 199 (86), 171 (25), 141 (19), 128 (21), 85 (21), 71 (11), 44 (11). C17 H20 O3 HRMS Calcd. Found 272.1412 272.1421

Synthesis of (6-methoxy-3,4-dihydro-1-naphtalenyl)(phenyl)methanone (45f)

COPh

MeO

A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with 4-iodo-7-methoxy-1,2-dihydronaphtalene (260 mg, 0.9 mmol). THF (1 mL) was added and the solution was added slowly into a dry and argon flushed 25 mL flask, containing the lithium neophylcuprate 35, previously prepared (1.2 mmol) and cooled to -78 C. The reaction mixture was warmed to 0 C. The iodine-copper exchange was complete within 3 h (checked by GC analysis of reaction aliquots) and the mixture was cooled to -20 C. Benzoyl chloride (0.4 mL, 3.4 mmol) was added to the mixed organocuprate 44c. After 0.5 h of stirring at -20 C, the reaction mixture was quenched with saturated, aqueous NH4 Cl (2 mL) and poured into water (25 mL). The aqueous phase was extracted with diethyl ether (3 x 20 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 96:4) yielded 45f as a yellow oil (190 mg, 72 %).

137

~ IR (film, cm-1 ): 3057 (m), 2935 (s), 2834 (m), 1720 (m), 1657 (vs), 1605 (vs), 1499 (s), 1499
(vs), 1448 (s), 1304 (s), 1268 (vs), 1252 (vs), 1160 (m), 1136 (s), 1044 (s), 1029 (s), 779 (s), 708 (s).
1

H NMR (CDCl3 , 300 MHz): d 7.79 (dt, J = 7.0 and 1.4 Hz, 2H), 7.47 (tt, J = 7.4 and 1.3 Hz,

1H), 7.35 (tt, J = 7.3 and 1.2 Hz, 2H), 7.14 (m, 1H), 6.69-6.58 (m, 2H), 6.29 (t, J = 4.6 Hz, 1H), 3.72 (s, 3H), 2.78 (7, J = 8.1 Hz, 2H), 2.40 (m, 2H).
13

C-NMR (CDCl3 , 75 MHz): d 197.4, 159.3, 138.5, 138.3, 137.9, 134.5, 132.9, 131.1, 128.4,

127.2, 125.2, 114.1, 111.4, 55.4, 28.2, 23.4. MS (EI, 70 eV): 264 (M+, 100), 236 (27), 221 (16), 159 (57), 144 (30), 105 (45), 77 (16). C18 H16 O2 HRMS Calcd. Found 264.1150 264.1162

Synthesis of N,N-diallyl-2-(1-methylethylidene)-4-pentenamide (45g)

O N

Prepared according to TP 7 from N,N-diallyl-2-bromo-3-methyl-butenamide (1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and allyl bromide (0.2 mL, 2.3 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 45g as a colourless oil (120 mg, 55 %).

~ IR (film, cm-1 ): 3078 (w), 2921 (m), 1651 (vs), 1640 (vs), 1436 (m), 1413 (m), 1192 (m), 993
(w), 916 (m).
1

H NMR (CDCl3 , 300 MHz): d 5.66 (m, 1H), 5.14-4.84 (m, 2H), 4.25 (dd, J = 2.7 and 1.2 Hz,

2H), 4.20 (dd, J = 2.8 and 1.1 Hz, 2H), 3.69-3.53 (m, 2H), 2.56 (m, 2H), 2.24 (m, 2H), 1.67 (s, 6H).
13

C-NMR (CDCl3 , 75 MHz): d 172.3, 143.7, 136.9, 133.7, 117.3, 117.0, 116.5, 114.1, 50.9, 49.2,

48.3, 35.9, 20.3. MS (EI, 70 eV): 219 (M+, 2), 204 (15), 190 (11), 178 (100), 164 (5), 150 (5), 136 (10), 124 (39), 108 (4). C14 H21 NO HRMS Calcd. Found 219.1623 219.1608

138

Synthesis of 2-acetyl-N,N-diallyl-3-methyl-2-butenamide (45h)

O N

Prepared according to TP 7 from N,N-diallyl-2-bromo-3-methyl-butenamide (1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and acetyl chloride (0.1 mL, 1.4 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 45h as a colourless oil (160 mg, 72 %).

~ IR (film, cm-1 ): 2927 (s), 1715 (s), 1681 (vs), 1657 (vs), 1439 (vs), 1414 (vs), 1368 (s), 1282
(s), 1245 (m), 927 (m), 702 (w).
1

H NMR (CDCl3 , 300 MHz): d 5.73 (m, 2H), 5.19 (m, 4H), 3.90 (m, 4H), 2.27 (s, 3H), 2.17 s,

6H).
13

C-NMR (CDCl3 , 75 MHz): d 206.8, 167.6, 142.0, 131.9, 127.2, 117.4, 49.2, 47.9, 44.9, 30.6,

22.4, 18.6. MS (EI, 70 eV): 221 (M+, 16), 178 (7), 164 (100), 123 (10), 81 (12), 43 (18). C13 H19 NO2 HRMS Calcd. Found 221.1416 221.1404

Synthesis of N,N-diallyl-2-(1-methylethylidene)-3-octynamide (45i)

Bu

O N

Prepared according to TP 7 from N,N-diallyl-2-bromo-3-methyl-butenamide (1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and 1-bromohexyne (270 mg, 1.7 mmol). Reaction time: 30 min. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 45i as a colourless oil (150 mg, 58 %).

139

~ IR (film, cm-1 ): 3400 (s, br), 2959 (vs), 2930 (vs), 1677 (vs), 1650 (vs), 1442 (vs), 1415 (s),
1283 (s), 1048 (s), 1029 (s), 925 (m), 799 (m), 778 (s), 763 (s), 700 (s).
1

H NMR (CDCl3 , 300 MHz): d 5.74-5.60 (m, 2H), 5.17-5.02 (m, 4H), 3.86 (m, 4H), 2.49 (t, J = C-NMR (CDCl3 , 75 MHz): d 168.5, 143.6, 133.2, 128.4, 118.1, 81.8, 66.23, 48.9, 45.8, 31.4,

7.1 Hz, 2H), 1.80 (s, 6H), 1.62-1.33 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H).
13

24.7, 23.4, 19.6, 18.7, 15.64, 13.9. MS (EI, 70 eV): 259 (M+, 3), 231 (7), 216 (9), 190 (21), 164 (100), 136 (8), 94 (4), 81 (8), 41 (25) C17 H25 NO HRMS Calcd. Found 259.1936 259.1934

140

Halogen-Copper Exchange on Heterocycles

Synthesis of N-(3,5-dibromo-2-pyridinyl)-N,N-dimethylimidoformamide (47)

Br N

Br N N

3,5-dibromo-2-pyridinamine (15.0 g, 60.0 mmol) was dissolved in toluene (15 mL) and dimethoxy-N, N-dimethylmethanamine (15.9 mL, 120 mmol) was added. The reaction mixture was heated under reflux for 1 h. After cooling to rt, the toluene and excess reagent were distilled in vacuo. The crude product w recrystallized from EtOH to give 47 as a yellow crystalline solid as (14.5 g, 78 %).

Mp 76 C

~ IR (film, cm-1 ): 3435 (s, br), 1485 (vs), 1470 (s), 1438 (m), 1237 (vs), 1167 (s), 1083 (s), 942
(vs), 657 (m).
1

H NMR (CDCl3 , 300 MHz): d 8.39 (s, 1H), 8.18 (d, J = 2.2 Hz 1H), 7.72 (d, J = 2.2 Hz 1H), C-NMR (CDCl3 , 75 MHz): d 158.4, 156.0, 147.1, 143.1, 116.0, 112.0, 41.2, 35.2.

3.15 (s, 3H), 3.11 (s, 3H).

13

MS (EI, 70 eV): 305 (M+, 100), 291 (48), 251 (56), 228 (74), 155 (16), 57 (40). C8 H9 Br2 N3 Calcd. Found C, 31.30 C, 31.44 H, 2.96 H, 2.93 N, 13.69 N, 13.76 Br, 52.06 Br, 51.84

Synthesis of 1-methyl-2,4,5-tribromoimidazole138 (50)

Br N

Br Br

138

O Connell, J.; Parquette, J.; Yelle, W. E.; Wang, W.; Rapoport, H. Synthesis 1988, 767.

141

To a mixture of 1-methylimidazole (24.6 g, 300 mmol) and NaOAc (102 g, 1.2 mol) in glacial AcOH (500 mL), a solution of Br2 (146.0 g, 900 mmol) in glacial AcOH (50 mL) was added dropwise with vigorous stirring, and cooling to maintain the temperature below 60 C. After the addition the mixture was stirred at rt for 2 h, the poured into ice, stirred and filtered. Crystallization from AcOH/water afforded 50 as a light brown solid (48.7g, 50 %)

Mp 89 C (lit. 94 ) ~ IR (film, cm-1 ): 2960 (s, br), 1500 (vs), 1458 (m), 1366 (m), 1316 (s), 1221 (vs), 1134 (s), 1090 (s), 975 (vs).
1

H NMR (CDCl3 , 300 MHz): d 3.64 (s, 3H). C-NMR (CDCl3 , 75 MHz): d 150.7, 146.2, 106.9, 31.4. C, 15.07 C, 14.97 H, 0.95 H, 0.92 Br, 75.19 Br, 75, 12 N, 8.79 N, 8.73

13

C4 H3 Br3 N2 Calcd. Found

Synthesis of 4-bromo-1-methyl-2-(phenylsulfanyl)-1H-imidazole-5-carbaldehyde (52)

PhS N

CHO Br

Methyliodide (0.68 mL, 11.0 mmol) was added at rt to a solution of diphenylsufide (2.4 g, 11.0 mmol) in THF (10 mL) and the mixture was stirred for 1 h. n-BuLi (6.7 mL, 10.0 mmol) was added dropwise to a solution of 50 (3.2 g, 10.0 mmol) in THF (10 mL) at -78 C. After 5 min the solution of the disulfide was cannulated into the mixture and stirring was continued for further 5 min. A second equivalent of n-BuLi (6.7 mL, 10.0 mmol) was then added and after 15 min DMF (0.8 mL, 10.0 mmol) was added to the mixture. After 20 min the reaction was quenched with saturated, aqueous NH4 Cl (2 mL). The aqueous phase was extracted with diethyl ether (3 x 30 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 85:15) yielded 52 as a yellow crystalline solid (1.8 g, 60 %).

142 Mp 114 C

~ IR (KBr, cm-1 ): 3435 (w, br), 1665 (vs), 1631 (m), 1496 (s), 1457 (s), 1395 (s), 1327 (vs),
1265 (vs), 814 (s), 749 (s), 719 (s), 701 (m), 685 (m).
1

H NMR (CDCl3 , 300 MHz): d 9.60 (s, 1H), 7.26 (m, 5H), 3.80 (s, 3H). C-NMR (CDCl3 , 75 MHz): d 179.2, 149.0, 131.9, 131.6, 130.5, 130.2, 130.1, 129.2, 129.1,

13

34.1. MS (EI, 70 eV): 297 (M+, 100), 270 (12), 217 (15), 133 (9), 121 (26), 109 (14), 91 (52), 77 (21). C11 H9 BrN 2 OS Calcd. Found C, 44.46 C, 44.39 H, 3.05 H, 3.18 N, 9.43 N, 9.35 S, 10.79 S, 10.96

Synthesis of 4,5-diiodo-1-methyl-1H-imidazole (51)

N N I

Iodine (46.0 g, 181 mmol) and potassium iodide (30.0 g, 181 mmol) were dissolved in water (250 mL) and added with a dropping funnel to a solution of imidazole (3.4 g, 50.0 mmol) and sodium hydroxide (24 g, 600 mmol) in water (50 mL) at rt. After 3 h diluted acetic acid (200 mL) was added and the precipitate was filtered and washed many times with water and with 10 % sodiumthiosulfate aqueous solution. The light yellow solid obtained was dissolved in water (300 mL) and sodium hydroxide (ca 10.0 g) was added till a clear solution was obtained. Dimethyl sulfate (14.2 mL, 150 mmol) was added to the solution with a dropping funnel and in few minutes a white precipitate was formed. After stirring at rt for 30 min, the solid was filtered, washed with water and dried in the oven. The desired product 51 was obtained as a pale yellow solid (22.3 g, 67 %).

Mp 136 C

~ IR (KBr, cm-1 ): 3101 (w), 1485 (vs), 1470 (s), 1437 (m), 1237 (vs), 1167 (s), 1083 (s), 941
(vs), 657 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.66 (s, 1H), 3.63 (s, 3H). C-NMR (CDCl3 , 75 MHz): d 141.8, 95.3, 84.7, 36.6.

13

143 MS (EI, 70 eV): 333 (M+, 100), 206 (19), 166 (7), 126 (3), 79 (4). C4 H4 I2 N2 HRMS Calcd. Found 333.8464 333.8474

Synthesis of 4-iodo-1-methyl-1H-imidazole-5-carbaldehyde (53)

N N I

CHO

In a dried and argon flushed two necked 100 mL flask, equipped with a reflux condenser, 51 (5.0 g, 15.0 mmol) was dissolved in THF (50 mL) at rt. EtMgCl (9.0 mL, 18.0 mmol, 2 M solution in THF) was added slowly and the mixture was heated to reflux for 1 h. Dry DMF (2.2 mL, 22.0 mmol) was then added and after one additional hour the reaction was quenched with saturated, aqueous NH4 Cl (30 mL). The aqueous phase was extracted with EtOAc (6 x 30 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 53 as a pale yellow solid (1.4 g, 40 %).

Mp 129 C

~ IR (KBr, cm-1 ): 3099 (m), 1690 (vs), 1508 (w), 1449 (m), 1418 (s), 1387 (vs), 1334 (s), 944
(m), 784 (vs).
1

H NMR (CDCl3 , 300 MHz): d 9.74 (s, 1H), 7.19 (s, 1H), 4.01 (s, 3H). C-NMR (CDCl3 , 75 MHz): d 181.4, 145.9, 133.0, 85.0, 35.4.

13

MS (EI, 70 eV): 236 (M+, 100), 208 (36), 165 (4), 127 (9), 81(9), 66 (7), 54 (19), 42 (22). C5 H5 IN 2 O Calcd. Found C, 25.45 C, 25.56 H, 2.14 H, 2.13 N, 11.87 N, 11.83 I, 53.77 I, 53.76

144 Synthesis of 4,5-diiodo-1-ethoxymethyl-1H-imidazole (54)

OEt N N I I

Iodine (46.0 g, 181 mmol) and potassium iodide (30.0 g, 181 mmol) were dissolved in water (250 mL) and added with a dropping funnel to a solution of imidazole (3.4 g, 50.0 mmol) and sodium hydroxide (24.0 g, 600 mmol) in water (50 mL) at rt. After 3 h diluted AcOH (200 mL) was added and the precipitate was filtered and washed many times with water and with 10 % sodiumthiosulfate aqueous solution. The light yellow solid obtained (9.5 g, 29.7 mmol) was dissolved in DMF (89 mL) and NaH (1.25 g, 31.2 mmol) was added. The mixture was stirred at 0 C for 1 h, then chloromethyl ethyl ether (2.9 mL, 31.2 mmol) was added and the mixture was let warm to rt and stirred for additional 4 h. The reaction was quenched with brine and the aqueous phase extracted with EtOAc (6 x 30 mL). The organic fractions were washed with with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. The crude solid was recrystallized from pentane to give 54 as a light yellow solid (7.6 g, 78 %).

Mp 108 C

~ IR (KBr, cm-1 ): 3131 (w), 1495 (vs), 1478 (s), 1437 (m), 1250 (vs), 1171 (s), 1080 (s), 940
(vs), 655 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.74 (s, 1H), 5.33 (s, 2H), 3.51 (q, J = 7.0 Hz, 2H), 1.22 (t, J = C-NMR (CDCl3 , 75 MHz): d 142.0, 97.5, 82.2, 78.4, 65.0, 15.1. HRMS Calcd. Found 377.8726 377.8706

7.0 Hz, 3H).

13

MS (EI, 70 eV): 378 (M+, 100), 334, (18), 207 (40), 59 (55). C6 H8 I2 N2 O

145 Synthesis of 1-(ethoxymethyl)-4-iodo-1H-imidazole-5-carbaldehyde (56)

OEt N N I CHO

In a dried and argon flushed two necked 100 mL flask, equipped with a reflux condenser, 54 (3.5 g, 9.3 mmol) was dissolved in THF (10 mL) at rt. EtMgCl (5.4 mL, 10.7 mmol, 2 M solution in THF) was added slowly and the mixture was heated to reflux for 1 h. Dry DMF (1.0 mL, 11.0 mmol) was then added and after one additional hour the reaction was quenched with saturated, aqueous NH4 Cl (60 mL). The aqueous phase was extracted with EtOAc (6 x 30 mL). The organic fractions were washed with brine (30 mL), dried (MgSO4 ) and concentrated in vacuo. Purification by flash chromatography (penatne/diethyl ether 1:1) yielded 56 as a pale yellow oil (1.7 g, 66 %).

~ IR (film, cm-1 ): 3112 (m), 1698 (vs), 1528 (w), 1455 (m), 1427 (s), 1399 (vs), 1345 (s), 954
(m), 790 (vs).
1

H NMR (CDCl3 , 300 MHz): d 9.60 (s, 1H), 7.75 (s, 1H), 5.62 (s, 2H), 3.51 (q, J = 7.2 Hz, 1H),

3.41 (q, J = 7.2 Hz, 1H), 1.14 (t, J = 7.2 Hz, 3H).
13

C-NMR (CDCl3 , 75 MHz): d 181.5, 144.7, 129.7, 101.5, 76.2, 65.8, 15.2. HRMS Calcd. Found 279.9709 279.9685

MS (EI, 70 eV): 280 (M+, 30), 251 (100), 221 (10), 59 (25). C7 H9 IN 2 O2

Synthesis of N-(3-allyl-5-bromo-2-pyridinyl)-N,N-dimethylimidoformamide (49a)

Br N N N

Prepared according to TP 5 from 47 (0.3 g, 1.0 mmol), lithium neopentylcuprate 33 (2.2 mmol), and allyl bromide (0.2 mL, 2.3 mmol). Reaction time: 1 h at 0 C. Purification by flash chromatography (pentane/diethyl ether 1:1) yielded 49a as a yellow oil (190 mg, 73 %).

146

~ IR (film, cm-1 ): 2909 (m), 1624 (vs), 1563 (vs), 1441 (vs), 1415 (vs), 1384 (vs), 1347 (s),
1286 (m), 1239 (m), 1103 (vs), 913 (m).
1

H NMR (CDCl3 , 300 MHz): d 8.26 (s, 1H), 8.03 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), C-NMR (CDCl3 , 75 MHz): d 159.1, 154.8, 146.6, 139.6, 136.7, 130.7, 116.6, 113.3, 40.9, 35.8,

5.88 (m, 1H), 5.01 (m, 2H), 3.37 (d, J = 6.7 Hz, 2H).
13

34.9. MS (EI, 70 eV): 267 (M+, 92), 252 (100), 225 (38), 211 (16), 196 (22), 144 (48), 117 (26). C11 H14 BrN 3 HRMS Calcd. Found 267.0371 267.0347

Synthesis of N-(3-benzoyl-5-bromo-2-pyridinyl)-N,N-dimethylimidoformamide (49b)

O Br N N Ph N

Prepared according to TP 3 from 47 (0.3 g, 1.0 mmol), lithium neopentylcuprate 33 (2.2 mmol), and benzoyl chloride (0.4 mL, 3.4 mmol). Reaction time : 30 min at 0 C. Purification by flash chromatography (pentane/diethyl ether 1:1) yielded 49b as a yellow crystalline solid (100 mg, 30 %).

Mp 110 C

~ IR (film, cm-1 ): 3434 (m, br), 1666 (s), 1619 (vs), 1561 (vs), 1538 (s), 1448 (s), 1411 (s), 1374
(vs), 1338 (s), 1105 (vs), 955 (m), 709 (s).
1

H NMR (CDCl3 , 300 MHz): d 8.29 (d, J = 2.5 Hz, 1H), 8.26 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), C-NMR (CDCl3 , 75 MHz): d 196.7, 158.5, 154.5, 151.1, 139.9, 138.5, 132.9, 130.0, 129.2,

7.44-7.30 (m, 5H), 2.89 (s, 6H).

13

128.4, 112.7, 34.6 MS (EI, 70 eV): 331 (M+, 5), 304 (100), 259 (7), 193 (13), 153 (9), 105 (20), 77 (37). C15 H14 BrN 3 O HRMS Calcd. Found 331.0320 331.0290

147 Synthesis of 4-allyl-1-methyl-2-(phenylsulfanyl)-1H-imidazole-5-carbaldehyde (49d)

PhS N

CHO

Prepared according to TP 3 from 52 (296 mg, 1.0 mmol), lithium neopentylcuprate 33 (1.2 mmol) and allyl bromide (0.2 mL, 2.3 mmol). Reaction time: 3.5 h at -40 C. Purification by flash chromatography (pentane/diethyl ether 9:1) yielded 49d as a light yellow oil (157 mg, 61 %).

~ IR (film, cm-1 ): 3425 (w, br), 1659 (vs), 1633 (m), 1485 (s), 1461 (s), 1399 (s), 1330 (vs),
1270 (vs), 811 (s), 744 (s), 729 (s), 701 (m), 675 (m).
1

H NMR (CDCl3 , 300 MHz): d 9.60 (s, 1H), 7.26 (m, 5H), 6.40 (m, 1H), 5.17 (m, 2H), 3.80 (s, C-NMR (CDCl3 , 75 MHz): d 180.1, 149.0, 131.9, 131.6, 131.1, 130.5, 130.2, 130.1, 129.2,

3H), 3.37 (d, J = 6.7 Hz, 2H).

13

129.1, 120.5, 34.1, 33.2. MS (EI, 70 eV): 258 (M+, 100), 241 (47), 229 (26), 181 (17), 150 (10), 121 (15), 94 (16). C14 H14 N2 OS HRMS Calcd. Found 258.0827 258.0822

Synthesis of 4-allyl-1-methyl-1H-imidazole-5-carbaldehyde (49e)

N N

CHO

Prepared according to TP 8 from 53 (236 mg, 1 mmol), lithium neophylcuprate 35 (1.2 mmol) and allyl bromide (0.2 mL, 2.3 mmol). Reaction time: 1 h at -78 C. Purification by flash chromatography (CH2 Cl2 ) yielded 49e as a light yellow oil (100 mg, 67 %).

~ IR (film, cm-1 ): 3089 (m), 1688 (vs), 1513 (w), 1454 (m), 1411 (s), 1373 (vs), 1342 (s), 954
(m), 783 (vs).

148
1

H NMR (CDCl3 , 300 MHz): d 9.80 (s, 1H), 7.44 (s, 1H), 5.95 (m, 1H), 5.12-5.04 (m, 2H), 3.74

(s, 3H), 3.56 (dt, J = 6.2and 1.3 Hz, 2H).

13

C-NMR (CDCl3 , 75 MHz): d 179.4, 155.0, 143.1, 135.4, 126.2, 120.5, 34.8, 30.1. HRMS Calcd. Found 150.0793 150.0779

MS (EI, 70 eV): 150 (M+, 88), 133 (49), 122 (100), 94 (45), 81 (56), 67 (16), 53 (16), 41 (23). C8 H10 N2 O

Synthesis of 5-allyl-1-(ethoxymethyl)-4-iodo-1H-imidazole (49f)

OEt N N I

Prepared according to TP 8 from 54 (280 mg, 1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and allyl bromide (0.2 mL, 2.3 mmol). Reaction time: 20 min at -78 C. Purification by flash chromatography (pentane/diethyl ether 1:1) yielded 49f as a light yellow oil (266 mg, 91 %).

~ IR (film, cm-1 ): 3077 (m), 1509 (w), 1434 (m), 1411 (s), 1237 (vs), 1167 (s), 954 (m), 683
(m).
1

H NMR (CDCl3 , 300 MHz): d 7.48 (s, 1H), 5.82-5.59 (m, 1H), 5.16 (s, 2H), 5.04-4.91 (m, 2H), C-NMR (CDCl3 , 75 MHz): d 138.4, 132.5, 131.0, 115.7, 84.8, 74.1, 63.1, 27.8, 13.7. HRMS Calcd. Found 292.0073 292.0063

3.39 (d, J = 6.5 Hz, 2H), 3.35 (q, J = 7.0 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H).
13

C9 H13 IN 2 O

149 Synthesis of 4-allyl-1-(ethoxymethyl)-1H-imidazole-5-carbaldehyde (49g)

OEt N N CHO

Prepared according to TP 8 from 56 (280 mg, 1.0 mmol), lithium neophylcuprate 35 (1.2 mmol) and allyl bromide (0.2 mL, 2.3 mmol). Reaction time: 1 h at -78 C. Purification by flash chromatography (pentane/diethyl ether 1:1) yielded 49g as a light yellow oil (90 mg, 46 %).

~ IR (film, cm-1 ): 3083 (m), 1672 (vs), 1520 (w), 1463 (m), 1420 (s), 1385 (vs), 1350 (s), 966
(m), 790 (vs).
1

H NMR (CDCl3 , 300 MHz): d 9.83 (s, 1H), 7.70 (s, 1H), 6.03-5.90 (m, 1H), 5.66 (s, 2H), 5.10

(m, 2H), 3.59 (d, J = 6.2 Hz, 2H), 3.49 (q, J = 6.9 Hz, 2H), 1.13 (t, J = 6.9 Hz, 3H).
13

C-NMR (CDCl3 , 75 MHz): d 179.4, 155.0, 143.1, 135.4, 126.2, 121.2, 74.1, 64.0, 34.8, 13.9.

MS (EI, 70 eV): 194 (M+, 33), 165 (30), 149 (27), 135 (70), 120 (100), 107 (18), 80 (30), 59 (88), 53 (28). C10 H14 N2 O2 HRMS Calcd. Found 194.1055 194.1050

Synthesis of 1-[1-(ethoxymethyl)-4-propanoyl-1H-imidazol-5-yl]-1-propanone (55)

OEt O N N O

Prepared according to TP 3 from 54 (280 mg, 1.0 mmol), lithium neophylcuprate 35 (2.2 mmol) and propionyl chloride (0.2 mL, 2.3 mmol). Reaction time: 1 h at -78 C. Purification by flash chromatography (pentane/EtOAc 1:1) yielded 55 as a light yellow oil (67 mg, 28 %).

150

~ IR (film, cm-1 ): 3083 (m), 1730 (vs), 1725 (vs), 1580 (w), 1485 (m), 1434 (s), 1385 (vs), 1353
(s), 966 (m).
1

H NMR (CDCl3 , 300 MHz): d 7.58 (s, 1H), 5.36 (s, 2H), 3.42 (q, J = 7.2 Hz, 2H), 3.03 (q, J = C-NMR (CDCl3 , 75 MHz): d 197.4, 197.3, 141.3, 137.2, 137.1, 75.1, 64.1, 35.3, 32.2, 13.8,

6.9 Hz, 2H), 2.96 (q, J = 6.9 Hz, 2H), 1.19-1.09 (m, 9H).
13

7.2, 6.8. MS (EI, 70 eV): 238 (M+, 5), 209 (12), 192 (13), 181 (22), 151 (8), 95 (8), 59 (100), 41 (13). C12 H18 N2 O3 HRMS Calcd. Found 194.1317 194.1322

151

Abbreviations
Ac approx. Bn Bp br Bu c Calcd. cat. conc. d dr DBE DMF DMPU DMSO ee equiv EI Et EtOAc FG GC h HMPA HRMS i-Bu IR J LDA LDE M Me min Mp MS NDMBA NMP NMR Ph q quant. rt s s-Bu sec t t-Bu acetyl approximately benzyl boiling point broad butyl concentration calculated catalytic concentrated doublet diastereomeric ratio dibromoethane dimethylformamide 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone dimethylsulphoxide enantiomeric excess equivalent electron ionisation ethyl ethyl acetate functional group gas chromatography hour hexamethylphosphorous triamide high resolution mass spectroscopy isobutyl infrared spectroscopy coupling constant lithiumdiisopropylamine lithiumdiethylamine molar methyl minute melting point mass spectroscopy N,N-dimethylbarbituric acid N-methyl-pyrrolidone nuclear magnetic resonance phenyl quartet quantitative room temperature singlet secbutyl seconds triplet terbutyl

152 TEA TFA THF TIPS TLC TMS TMSCl TP UV triethylamine trifluoroacetic acid tetrahydrofuran triisopropylsilyl thin layer chromatography trimethylsilyl chlorotrimethylsilane typical procedure ultra-violet

153

Curriculum Vitae

Surname First name Date of birth Country of birth Nationality Marital status

: Piazza : Claudia : 24 December 1972 : Italy : Italian : Unmarried

Education 1986-1991 1991-1997 : Liceo Ginnasio A. Canova; Treviso (I). Certificate: July 1991. Mark: 60/60 : University of Padova, Biopolymer Research Centre, CNR; Padova (I). Chemistry Degree: December 1997. Mark:108/110. Specialization: Organic and Biological Chemistry. Thesis subject: Analogues of lipopeptaibol antibiotics Trikoningins KBI and KBII (Prof. C. Toniolo) : LMU University, Chemistry Department, Munich (D) Ph.D. in the group of Prof. P. Knochel Thesis subject: New Methods for the Synthesis of Organozinc and Organocopper Reagents

1999-2002

Work Experience June 1998-June 1999 : DSM Research, Section Fine Chemical-Organic Chemistry Biotechnology; Geleen (NL) (Dr. B. Kaptein). Stage, subject: Synthesis and enzymatic resolution of ,-disubstituted amino acid amides : Assistant at the Ludwig-Maximilians Universitt Mnchen: assistance of the students in organic chemistry laboratory courses.

2000-2002

Languages

: Italian English (fluent, written and spoken) German (Deutsche Zertifikat)

154 Publications 1. Piazza, C, Formaggio, F., Crisma, M., Toniolo, C., Kamphius, J. and Broxterman, Q.B. Total synthesis and membrane modifying properties of the lipopeptaibol Trikoningin KBII and its analogues with acyl chains of different length at the N- anc C-termini J. Peptide Sci. 1999, 5, 96. Peggion, C., Piazza, C., Formaggio., F., Crisma, M., Toniolo, C., Kaptein, B., Broxterman, Q.B. Total synthesis and membrane modifying properties of the Trikoningins KB lipopeptaibols: effect of hydrophobicity and chirality in position 1 Letters in Peptide Science 2000, 7, 9. Moretto, A., Peggion, C., Formaggio, F., Crisma, M., Toniolo, C., Piazza, C., Kaptein, B., Broxterman, Q.B., Ruiz, I., Diaz-De-Villegas, M.D., Galvez, J.A., Cativiela, C. (e)Nva: stereoselective synthesis and preferred conformations of selected model peptides Journal of Peptide Research 2000, 56, 283. Millot, N., Piazza, C., Avolio, S., Knochel, P. Aminomethylation of Functionalized Organozinc Reagents and Grignard Reagents using Imonium Trifluoroacetates Synthesis 2000, 7, 941. Piazza, C., Millot, N., Knochel, P. New preparation of Benzylic Zinc Reagents via a Fragmentation Reaction J. Organomet. Chem. 2001, 624, 88. Piazza, C., Knochel, P. New Sterically Hindered Lithium Dialkylcuprates for the Generation of Highly Functionalized Mixed Cuprates via a Halogen-Copper Exchange Angewandte Chem. Int. Ed. 2002, 41, 3263.

2.

3.

4.

5. 6.

Posters and Seminars June 2002 BASF A.-G. (Ludwigshafen, D) July 2002 XX ICOMC Corfu (G) October 2002 ISMOC Dortmund (G) October 2002 Roche Symposium Basel (CH)

The Halogen-Copper Exchange for the Synthesis of Functionalized Organocopper Reagents seminar New Synthesis of Functionalized Organocopper Reagents Via a Halogen-Copper Exchange poster Iodine-Copper Exchange for the Synthesis of Functionalized Organometallics seminar New Lithium Dialkylcuprates for the Generation of Highly Functionalized Mixed Cuprates seminar