1.

Importance of chemical processes in the pharmaceutical

industries.
2. The key step in building complex molecules from simple
precursors.

sp3

C-C Cross Coupling Reactions in Organic chemistry by Anthony crasto

1. 1. (With examples of Pharmaceuticals) by DR ANTHONY MELVIN

CRASTO Principal Scientist INDIA MAR 2016
2. 2. This is a vast topic and a short overview is given and in no way
complete justice can be done for this
1
3. 3. Prof. Akira Suzuki Prof. Richard F. Heck Prof. Ei-ichi Negishi
4. 4. The Nobel Prize was awarded jointly to Richard F. Heck, Ei- ichi
Negishi and Akira Suzuki for Palladium- catalyzed C-C cross
coupling reaction in 2010. The Nobel Prize was awarded jointly to
Richard F. Heck, Ei-ichi Negishi and Akira Suzuki for Palladium-
catalyzed C-C cross coupling reaction in 2010. 1. Importance of
chemical processes in the pharmaceutical and industries. 2. The
key steps in building complex molecules from simple precursors.

5. Coupling reactions occur between organometallic with organic

halide with the aid of a metal containing catalyst.
Coupling reactions can be divided into two main classes, cross
couplings in which two different molecules react to form one new
molecule.
The other type of coupling is homocoupling, in this reaction two
similar molecules coupling together to form a new molecule.
Coupling Reactions

6. 6. The C-C bond formation between an organic electrophile (RX)

and a nucleophile (Organometallic RM or R-C=C) in the presence
2
 of a transition metal catalyst, usually Pd (even Cu, Ni, Fe etc. are
also used).

7. Common metal used in this field is Pd, in addition to Zn, Ni, Cu,
B, and Sn. Most of coupling reactions are air and water
sensitive ?? But, some coupling reactions can be carried out in
aqueous solutions. Main features
8. 8. Some thing about Palladium
9. 9. 5. HECK (1972) 4. SONOGASHIRA (1975) 3. NEGISHI (1977)
2. STILLE (1978) 1. SUZUKI- MIYAURA (1979)
10. 10. Negishi- M= Organiozincompound Suzuki- M=
Organoboran compound Stille-M= organotin compound Heck-
Mizoroki Negishi R1-M= Organozinc compound Stille- R1-M =
Organotin compound Suzuki- R1-M = Organoborane compound
11. 11. CuI can increase the reaction rate and ability to scavenge
the free ligand.
12. 12. Variable oxidation states and coordination number
Metals are Lewis acid (electron deficient):- origin of Chemical
reactivity. There are some other type of lewis acid. One way
interaction only.
13. 13. RepulsionTwo major reasons are:- 1. Simultaneous
availability of empty and filled non bonding orbitals , because of
that Synergic bonding occurres. 2. Ready and reversible oxidation
and reduction under one set of reaction condition. Charge
polarization can be cancelled. Hence required very less energy
barrier. Two way interaction

3
14. 14. Palladium is a d-block transition metal. Pd favours the
formation of tetrahedral d10 and square planar d8 complexes of
low oxidation states (0 and II respectively). This feature affords
Pd good electron-donating and electron- accepting capabilities,
allowing fine-tuning by altering the electronic properties of its
ligands. Pd may easily participate in concerted processes due to
its closely lying HOMO and LUMO energies. Pd complexes tend
to be less sensitive to oxygen and are less toxic.
15. 15. The oxidative addition of organic electrophiles (halides,
sulfonates, and related activated compounds) to Pd(0) is the first
step in cross- coupling. Increases both the oxidation state and
coordination number of a metal centre. In order for the oxidative
addition to succeed, the formation of a low- coordinate Pd(0)-
species is required (e.g. the formation of 14-electron Pd-species,
L2Pd(0)). Oxidative additions may proceed via two major
pathways that depend on the metal center and the substrates (also
any added additives, metal-bound ligands and solvent).
16. 16. Concerted Mechanism : Normally found in addition of
non- polar reagents and aryl halides. Retention of configuration is
in case of chiral A-B reagents. SN2 Mechanism : Its an associative
bimolecular process. Often found in oxidative additions of polar
reagents and in polar solvents. Oxidative addition of C(sp3)-X
electrophiles to Pd(0) complexes PdL4 (L =phosphine) takes place
usually by this mechanism. Results in inversion of configuration
17. 17. Predominant retention in noncoordinating solvents as
benzene, CH2Cl2, tetrahydrofuran (THF), or acetone. On the
other hand, in coordinating solvents such as MeCN or
dimethylsulfoxide (DMSO), complete or near-complete inversion
was observed . Electron-withdrawing substituents on aryl
electrophiles led to rate acceleration. Higher the electron density
on metal , more favours the oxidative addition. Electron rich and
bulky phosphine ligands, enhances reactivity of transition metal
18. 18. Transmetallation reactions involve the transfer of an
organic group R from one metal M to another one M.
Transmetallation in the Suzuki Reaction: Due to the low
nucleophilicity of the borane reagents (compared with
organostannanes, for example), the Suzuki reaction requires the
use of base in order to take place. The main role of base is to
generate a more reactive borate by coordination of hydroxide to
boron, which will react with the intermediate R-Pd(II)-X complex.
4
19. 19. It is the reverse of oxidative addition. Reductive
elimination involves the elimination or expulsion of a molecule from
a transition metal complex. In the process of this elimination, the
metal centre is reduced by two electrons. The groups being
eliminated must be in a mutually cis orientation
20. 20. A carbometallation reaction is defined by the addition of
a carbon-metal bond of an organometallic 1 across a carbon-
carbon multiple bond 2, leading to a new organometallic 3, in
which the newly formed carbon-metal bond can be used for further
transformations. This step is subsequently followed by a syn-
insertion process .(resulting in a -organopalladium intermediate ).
This process is sensitive not only to steric but also electronic
factors, which in turn influences the regiochemical outcome of the
reaction.
21. 21. - The beta-hydride elimination can either be a vital step
in a reaction or an unproductive side reaction. .
22. 22. -Hydride elimination may occur if a -hydrogen is
accessible. C-C bond rotation of intermediate D is required, as
well as a coordination vacancy on the metal centre. Then cis -
hydrogen elimination takes place, generating a coordinated
palladium hydride complex E. The hydridopalladium species is
subsequently liberated from E, producing complex F and the free
Mizoroki-Heck product G
23. 23. Reaction Year Reactant 1 Reactant 2 Catalyst Kumada
1972 R-MgBr RX Pd or Ni Heck 1972 Alkene RX Pd Sonogashira
1973 Alkyne RX Pd or Cu Nigishi 1977 R-Zn-X RX Pd or Ni Stille
1977 R-Sn-R3` RX Pd Suzuki 1979 R-B(OR)2 RX Pd Hyiama
1988 R-Si-R3 RX Pd Buchwald-Hartwig 1994 R2-N-R RX Pd
Important coupling reactions
24. 24. Cross coupling between aryl or alkyl Grignard with aryl
or vinyl halocarbon. The first Pd or Ni catalysed coupling reaction
Kumada coupling reaction
25. 25. Kumada coupling
26. 26. Kumada coupling
27. 27. Example of an iron-catalyzed Kumada reaction in the
synthesis of 122. Tetrahedron Lett.201460. , 5560. , 1376. J. Med.
Chem.200561. , 4861. , 6887. J. Org. Chem.201062. , 7562. ,
5398.
28. 28. The coupling of organomagnesium compounds and
organic electrophiles is known as the Kumada reaction and is
5
 normally catalyzed by palladium or nickel complexes.ST1535 (122)
is a highly selective adenosine A2Areceptor ligand antagonist with
good pharmacological properties, which might be considered a
potential new drug for the treatment of Parkinson's disease.
Previous approaches for its synthesis explored Stille or Suzuki
couplings for the installation of the alkyl side chain present in the
final target.Despite the good yields observed, both approaches
suffered from major drawbacks such as drastic reaction conditions,
low turnover number and frequency for the palladium catalysts
employed, the need to prepare organoboron or tin reagents and
the toxicity of starting materials and by-products in the special
case of Stille reaction. In this context, in 2014, the authors
described a new approach exploring the Kumada coupling of a
Grignard reagent, one of the cheapest organometallic reagents
available, catalyzed by Fe(acac)3, where acac = acetylacetonate,
which is also a low-cost and easily removable catalyst. Besides the
advantages regarding the cost of reagents and catalysts, the new
procedure also generates less waste, due to the intrinsic higher
atom-economy and also by not requiring an excess base, as seen
for the Suzuki coupling approach. This procedure was successfully
employed in the preparation of 38.5 g of 123, which could be
converted to 122 through bromination and bromine displacement
with triazole followed by benzyl protecting group removal, as
previously described in the literature
29. 29. Pd catalyzed coupling between aryl or vinyl halides with
activated alkene in basic media. Heck coupling
30. 30. Broadly defined as the palladium-catalyzed coupling of
alkenyl or aryl (sp2) halides or triflates with alkenes to yield
products which formally result from the substitution of a hydrogen
atom in the alkene coupling partner. First discovered by Mizoroki,
though developed and applied more thoroughly by Richard F. Heck
in the early 1970s.[3] Generally thought of as the original
palladium catalysed cross-coupling, and probably the best
evolved, including a multitude of asymmetric varients.[4] The Heck
Reaction 3. R. F. Heck, J. P. Nolley, Jr., J. Org. Chem. 1972, 37,
2320 4. Review on asymmetric Heck reactions: A. B. Dounay, L. E.
Overman, Chem. Rev. 2003, 103, 2945 2963 H R1 R2 R3 R4 X
R4 R1 R2 R3 cat. [Pd0 Ln] base R4 = aryl, benzyl, vinyl X = Cl, Br,
I, OTf

6
31. 31. Mechanism of the Heck Reaction neutral PPh3 Pd Ph3P
PPh3 Ph3P PPh3 Pd Ph3P Ph3P PPh3 Pd Ph3P PPh3 - PPh3 -
PPh3 Pd0 Pd0 Pd0 Br Pd Ph3P Br PPh3 PdII O O Pd Ph3P Br
PPh3 O O PdII -Complex Pd Ph3P Br O O H H PdII -
Intermediate Pd Ph3P H Br PPh3 O O PdII -Complex Pd Ph3P H
Br PPh3 B HBr / B PdIIO O Oxidative Addition -hydride
Elimination Reductive Elimination
32. 32. Mechanism of the Heck Reaction cationic PPh3 Pd Ph3P
PPh3 Ph3P PPh3 Pd Ph3P Ph3P PPh3 Pd Ph3P PPh3 - PPh3 -
PPh3 Pd0 Pd0 Pd0 Br Pd Ph3P Br PPh3 PdII O O Pd Ph3P PPh3
O O PdII -Complex Pd Ph3P O O H H PdII -Intermediate Pd
Ph3P H PPh3 O O PdII -Complex Pd Ph3P H PPh3 B PdIIO O
Oxidative Addition -hydride Elimination Reductive Elimination
BrAg HB Ag Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem.
1987, 52, 41334135.
33. 33. The type of mechanism in action is incredibly important,
as it can manifest itself in a variety of ways, especially the
regioselectivity. In the neutral catalytic cycle, the regioselectivity
is governed by steric factors generally addition occurs to the
terminal end of the alkene. However, in the cationic cycle,
regiochemistry is affected by electronics. The cationic Pd complex
increases the polarization of the alkene favouring transfer of the
vinyl or aryl group to the site of least electron density. The type of
mechanism in effect is generally controlled by choice of
halide/pseudohalide acting as a leaving group in the cationic cycle;
triflate promotes, whereas bromide detracts. Regioselectivity in the
Heck Reaction a) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995,
28, 27. b) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi,
R. J. Org. Chem. 1992, 57, 14811486. Ph Y N CH3 OH O OH
100 90 100 10 100 60 80 40 20 Y = CO2R CN CONH2 Ph Y N
CH3 OH O OH 60 5 95 100 10 100 90 Y = CO2R CN CONH2 40
100 Neutral Catalytic Cycle Cationic Catalytic Cycle
34. 34. The Heck Reaction: Dehydrotubifoline a) V. H. Rawal, C.
Michoud, R. F. Monestel, J. Am. Chem. Soc. 1993, 115, 3030
3031 b) V. H. Rawal, C. Michoud, J. Org. Chem. 1993, 58, 5583
5584. N R H N I Me H N N Me H H N N Me H PdII Ln OMeO H N
N H H MeO2C PdII Ln Me H N N H H MeO2C PdII Ln second 1,2-
insertion -hydride elimination bond rotation, rearrangement
Pd(OAc)2, K2CO3 nBu4NCl, DMF, 60 C N N Me H H MeO2C

7
 Heck Cyclisation 3: ()-dehydrotubifoline dehydrotubifoline 1: R=H
2: R=CO2Me 4 5 6 7
35. 35. The Heck Reaction: Capnellene a) K. Kagechika, M.
Shibasaki, J. Org. Chem. 1991, 56, 4093 4094 b) K. Kagechika,
T. Ohshima, M. Shibasaki, Tetrahedron, 1993, 49, 1773 1782.
TfO Me Me Pd P P * Me Pd P P * Pd(OAc)2 (1.7 mol%) (S)-binap
(2.1 mol%) nBu4NOAc DMSO, 20 C major minor OTf OTf 14 15
18 catalysic asymmetric Heck Cyclisation P P * H Me Pd AcO OAc
(89% yield, 80% ee) anion capture 16 H Me OAc 17 MeHO Me H
OH H HOMe MeHO H OH H HOMe HO capnellene 9(12)-
capnellene- 3,8,10-triol 9(12)-capnellene- 3,8,10,14-
tetraol H Me OAc 19 PPh2 PPh2 P P * = (S)-binap
36. 36. The Heck Reaction: Taxol a) S. J. Danishefsky, J. J.
Masters, W. B. Young, J. T. Link, L. B. Snyder, T. V. Magee, D. K.
Jung, R. C. A. Isaacs, W. G. Bornmann, C. A. Alaimo, C. A.
Coburn, M. J. Di Grandi, J. Am. Chem. Soc. 1996, 118, 2843
2859 b) J. J. Masters, J. T. Link, L. B. Snyder, W. B. Young, S. J.
Danishefsky, Angew. Chem. Int. Ed. Engl. 1995, 34, 1723 1726.
O O O OTf Me H BnO O OTBS Me O O O Me H BnO O OTBS Me
HO BzO Me H AcO O OH Me AcO O O BzHN OH Ph O taxol
[Pd(PPh3)4] (110 mol%) M. S. (4 A) K2CO3, MeCN, 90 C (49%)
Intramolecular Heck Reaction 22 23 24: taxol
37. 37. The Heck Reaction: Estrone L. F. Tietze, T. NVbel, M.
Spescha, J. Am. Chem. Soc. 1998, 120, 8971 8977. MeO Br Br
Me Ot Bu Pd(OAc)2, PPh3 nBu4NOAc DMF/MeCN/H2O 70 C
Intermolecular Heck Reaction MeO Br PdLn Br Me Ot Bu H 5 4
MeO Br H Me Ot Bu H MeO H Me Ot Bu HH HO H Me O HHA D
29, nBu4NOAc DMF/MeCN/H2O 115 C (99%) (50%)
Intramolecular Heck Reaction 25 26 27 26 28 30 30: estrone
estroneP Pd o-Tol o-Tol O O P Pd o-Tolo-Tol O O Me Me
38. 38. Domino Heck Reactions Y. Zhang, G.Wu, G. Angel, E.
Negishi, J. Am. Chem. Soc. 1990, 112, 8590 8592. Me EtO2C
EtO2C I Me EtO2C EtO2C I Me EtO2C EtO2C [Pd(PPh3)4] (3 mol
%) Et3N (2 eq.) MeCN, 85 C (76%) Intramolecular Domino Heck
Cyclisation32 33
39. 39. Domino Heck Reactions a) L. E. Overman, D. J. Ricca, V.
D. Tran, J. Am. Chem. Soc. 1993, 115, 2042 2044 b) D. J.
Kucera, S. J. OIConnor, L. E. Overman, J. Org. Chem. 1993, 58,
5304 5306. O O I TBSO Me H Pd(OAc)2 (10 mol%) PPh3 (20
mol%) Ag2CO3 THF, 70 C Oxidative Addition PdLn TBSO Me H I
1,2-insertion OO TBSO Me H PdLn I 1,2-insertion TBSO Me Ln Pd
8
 H OO I TBSO Me Ln Pd H OO I OBz Me H -Hydride Elimination
scopadulic acid O HO2C Me H HO 42: Scopadulic Acid B 4140 39
3837 (82% overall) OO Intramolecular Heck Cascade
40. 40. Heck coupling
41. 41. Synthesis of idebenone (124) based on Heck reaction of
2- bromo-3,4,5-trimethoxy-1-methylbenzene with dec-9-en-1-ol
under microwave irradiation. Org. Process Res. Dev.201165. ,
1565. , 673.
42. 42. The palladium-catalyzed olefination of a sp or benzylic
carbon attached to a (pseudo)halogen is known as the Heck
reaction. It is a powerful tool, mainly used for the synthesis of
vinylarenes, and it has also been employed for the construction of
conjugated double bonds. The widespread application of this
reaction can be illustrated by numerous examples in both
academia small-scale and industrial syntheses.As an example, in
2011, a idebenone (124) total synthesis based on a Heck reaction
was described . This compound, initially designed for the treatment
of Alzheimer's and Parkinson's diseases, presented a plethora of
other interesting activities, such as free radical scavenging and
action against some muscular illnesses. The key step in the
synthesis was the coupling of 2-bromo-3,4,5-trimethoxy-1-
methylbenzene (125) with dec-9-en-1-ol affording products 126.
Under non-optimized conditions (Pd(OAc)2, PPh3, Et3N, 120 C),
a mixture composed of 60% linear olefins 126 and 15% of the
undesired branched product 127 was obtained after three days of
reaction. Therefore, the conditions were optimized, allowing the
preparation of 126 in 67% yield with no detection of 127 after only
30 min of reaction employing DMF, Pd(PPh3)4, iPr2NEt under
microwave heating. To conclude the synthesis, the Heck adducts
were submitted to hydroxyl protection/deprotection, hydrogenation,
and ring oxidation. After these reactions, idebenone was obtained
with 20% overall yield over 6 steps.
43. 43. J. Agric. Food Chem.201366. , 6166. , 5347. Synthesis of
the ginkgolic acid based on the Heck reaction of aryl triflate 130
44. 44. A similar strategy to link an aryl and an alkyl group by
means of a Heck reaction was applied in 2013 in the synthesis of
ginkgolic acid (13:0) (128), a tyrosinase inhibitor, as shown in
SCHEME Benzoic acid 88 was used as starting material in order to
obtain the triflate 130. This intermediate and the 1-tridecene were
employed as coupling partners in the Heck reaction to obtain 131.
The system used was based on PdCl2(dppf) and K2CO3, affording
9
 the coupling product in 78% yield after 12 h with 3.2 mol% of
palladium. An alternative pathway to link the alkyl and aryl
fragments was also tested: the coupling was performed in the
presence of 9-borabicyclo(3,3,1)-nonane (9- BBN) to generate an
alkylborane in situ from olefin 132 and achieve Suzuki coupling.
However, this methodology was not productive. Once the Heck
reaction was performed, 128 was obtained with 34% overall yield
after the reduction of the double bond and the hydrolysis of the
acetal protecting group.
45. 45. J. Org. Chem.201267. , 7767. , 6340. Heck reaction in
synthesis of olopatadine (133) and trans-olopatadine (134).
46. 46. An intramolecular Heck-based cyclization was used as a
key step for commendable synthesis of the antihistaminic drug
olopatadine (133) and its trans isomer (134). Besides the Heck
reaction, another vital step in this route was a stereoselective
Wittig olefination using a non-stabilized phosphorus ylide that
afforded the olefins 135 and 136 (E:Z ratio = 9:1 for 135, for
instance). Concerning the Heck reaction, Pd(OAc)2, K2CO3, and
NBu4Cl (TBAC) were allowed to react with 135 and 136 at 60 C
during 24 h, providing the cyclic adducts 137 and 138 with
reasonable 60% and 55% yields, respectively. However, it is
important to note that in catalytic terms, the results were not
encouraging, considering that 20 mol% of palladium was used and
a disappointing turnover number (TON) of 3 was observed
47. 47. Synthesis of (R)-tolterodine based on a Heck-Matsuda
reaction and enantioselective reduction of compound 152.
48. 48. A variation of the Heck reaction that has attracted
considerable attention in recent years is the so-called Heck-
Matsuda arylation, which is based on the use of aryldiazonium
salts as electrophiles. These compounds have the advantages of
lower cost and improved reactivity in comparison to more
traditional electrophiles like aryl halides.As an example, a Heck-
Matsuda based strategy via aryl-coumarins was used in the
synthesis of (R)-tolterodine (149), a drug that is employed in
urinary incontinence treatment. The coupling was employed in the
first step of the route between the ortho- substituted cinnamate
150 and the 4-bromo substituted arenediazonium salt 151, using
10 mol% of Pd(OAc)2 as a pre-catalyst and CaCO3 as base. It is
important to note that the target molecule tolterodine contains no
bromine substituents, for this reason, after completion of the Heck
reaction, the product was not isolated, being directly submitted to
10
 debromination under H2 atmosphere and subsequently isolated as
152 with 63% over two steps . The employment of the bromo-
substituted aryldiazonium salt instead of phenyldiazonium salt was
justified by the lower yield of the Heck reaction using PhN2BF4
(only 41% yield). Nonetheless, compound 152 had already been
synthesized via a Heck reaction with 77% yield without
requirement of the debromination step. With the desired coumarin
152 in hands, the synthesis was accomplished by a copper-
catalyzed enantioselective conjugate reduction, furnishing153,
followed by reductive amination. With this methodology, (R)-
tolterodine was obtained in 30% overall yield and 98% ee after four
steps.
49. 49. Mizoroki-Heck Reaction
50. 50. The Mizoroki-Heck reaction between alkenyl bromide and
methyl acrylate. Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40,
1083. DOI: 10.1021/jo00896a020
51. 51. Terminal alkynes with aryl or vinyl halides (triflate). Pd
as a catalyst, Cu as co-catalyst and an amine as a base.
Sonogashira coupling
52. 52. Sonogashira coupling
53. 53. Sonogashira coupling
54. 54. The coupling of terminal alkynes with vinyl or aryl
halides via palladium catalysis was first reported independently
and simultaneously by the groups of Cassar[16] and Heck[17] in
1975. A few months later, Sonogashira and co-workers
demonstrated that, in many cases, this cross-coupling reaction
could be accelerated by the addition of cocatalytic CuI salts to the
reaction mixture.[18,19] This protocol, which has become known
as the Sonogashira reaction, can be viewed as both an alkyne
version of the Heck reaction and an application of palladium
catalysis to the venerable StephensCastro reaction (the coupling
of vinyl or aryl halides with stoichiometric amounts of copper(I)
acetylides).[20] Interestingly, the utility of the copperfree
Sonogashira protocol (i.e. the original CassarHeck version of this
reaction) has subsequently been rediscovered independently by
a number of other researchers in recent years.[21] The
Sonogashira Coupling 16. L. Cassar, J. Organomet. Chem. 1975,
93, 253 259. 17. H. A. Dieck, F. R. Heck, J. Organomet. Chem.
1975, 93, 259 263. 18. K. Sonogashira, Y. Tohda, N. Hagihara,
Tetrahedron Lett. 1975, 16, 4467 4470. 19. For a brief historical
11
 overview of the development of the Sonogashira reaction, see: K.
Sonogashira, J. Organomet. Chem. 2002, 653, 46 49. 20. R. D.
Stephens, C. E. Castro, J. Org. Chem. 1963, 28, 3313 3315. 21.
a) M. Alami, F. Ferri, G. Linstrumelle, Tetrahedron Lett. 1993, 34,
6403 6406; b) J.-P. Genet, E. Blart, M. Savignac, Synlett 1992,
715 717; c) C. Xu, E. Negishi, Tetrahedron Lett. 1999, 40, 431
434; R2 X cat. [Pd0 Ln] base R1 = alkyl, aryl, vinyl R2 = alkyl,
benzyl, vinyl X = Br, Cl, I, OTf R2 R1 H R2
55. 55. Mechanism of the Sonogashira Coupling Pd Ph3P PPh3
Ph3P PPh3 Pd Ph3P Ph3P PPh3 Pd Ph3P Ph3P - PPh3 - PPh3
Pd0 Pd0 Pd0 Br Pd Ph3P Br PPh3 PdII Pd Ph3P PPh3 R1 R1 Cu
CuBr H R1 NEt3 Pd Ph3P Ph3P R1 R1 R1 NEt3H PdII PdII
56. 56. K. C. Nicolaou, S. E. Webber, J. Am. Chem. Soc. 1984,
106, 5734 5736 The Sonogashira Coupling: Eicosanoid 212
MeBr OTBS TMS Sonogashira Coupling [Pd(PPh3)4] (4 mol%)
CuI (16 mol%) nPrNH2, C6H6, 25 C R Me OTBS AgNO3, KCN
208: R = TMS 209: R = H 210, [Pd(PPh3)4] (4 mol%) CuI (16 mol
%) nPrNH2, C6H6, 25 C 76% Overall from 208 Br CO2Me OTBS
Me OTBS CO2Me OTBS Me OH CO2H OH Sonogashira Coupling
206 207 210 211212
57. 57. P. Wipf, T. H. Graham, J. Am. Chem. Soc. 2004, 126,
15346 15347. The Sonogashira Coupling: Disorazole C1 Me
PMBO Me OH Me Me PMBO Me OH Me MeO O N CO2Me
Sonogashira Coupling 218 [Pd(PPh3)2Cl2] (4 mol%) CuI (30 mol
%), Et3N MeCN, -20 C, 94% 220, DCC, DMAP 80% Me PMBO
Me O Me MeO O N CO2Me O N O I OMe 218 [Pd(PPh3)2Cl2] (5
mol%) CuI (20 mol%), Et3N MeCN, -20 C, 94% Sonogashira
Coupling Me PMBO Me O Me MeO O N CO2Me O N O OMe OH
Me Me OPMB Me Me OH Me O Me MeO O N O N O OMe O Me
Me OH Me O disorazole N O RO O I OMe 218: R = Me 220: R = H
217 219 221 222223: Disorazole C1
58. 58. The Sonogashira Coupling: Dynemicin MeO2CN OMe Me
O O Br MeO2CN OMe Me O OIntramolecular Sonogashira
Coupling [Pd(PPh3)4] (2 mol%) CuI (20 mol%) toluene, 25 C 243
244 MeO2CN OMe Me O O 244 H H H H MeO2CN OMe Me OH
246 [Pd(PPh3)4] (2 mol %) CuI (20 mol %) toluene, 25 C Br
CO2Me 1) 2) LiOH, THF/H2O 65% overall Sonogashira Coupling
MeO2CN OMe Me OH CO2H Diels- Alder 2,4,6-Cl3C2H2COCl
DMAP, toluene, 25 C 50% 248 247 Yamaguchi
Macrolactonisation/ Diels-Alder HN OMe Me H O O O OMe OMe
OMe CO2Me dynemicin 249: tri-O- methyl dynemicin A methyl
12
 ester a) J. Taunton, J. L. Wood, S. L. Schreiber, J. Am. Chem. Soc.
1993, 115, 10 378 10379 b) J. L. Wood, J. A. Porco, Jr., J.
Taunton, A. Y. Lee, J. Clardy, S. L. Schreiber, J. Am. Chem. Soc.
1992, 114, 5898 5900 c) H. Chikashita, J. A. Porco, Jr., T. J.
Stout, J. Clardy, S. L. Schreiber, J. Org. Chem. 1991, 56, 1692
1694 d) J. A. Porco, Jr., F. J. Schoenen, T. J. Stout, J. Clardy, S. L.
Schreiber, J. Am. Chem. Soc. 1990, 112, 7410 7411.
59. 59. Nishimura, K.; Kinugawa, M.; Org. Process Res.
Dev.201251. , 1651. , 225 Olopatadine hydrochloride
60. 60. The construction of a new bond between sp2- and sp-
hybridized carbons is known as the Sonogashira reaction,and it is
nowadays a widely employed methodology for the construction of
arylacetylenes. For example, a Sonogashira coupling was
employed by the research and development group of Kyowa
Hakko Kirin in a new and concise synthetic route for olopatadine
hydrochloride (92), a commercial anti-allergic drug that was
previously developed by the same company. The reported
synthesis goes through the Sonogashira reaction between the
easy accessible aryl halide 93 and alkyne 94 leading to adduct 95
in 94% yield. This adduct is then subjected to a second metal-
catalyzed transformation, a stereospecific palladium- catalyzed
intramolecular cyclization, whose optimum conditions were
identified based on an elegant and comprehensive Design of
Experiments (DoE) investigation to provide 96 Elaboration of the
cyclization product 96 through aminomethylation and ester
hydrolysis followed by acid work-up completes the synthesis of the
final target. Although the presented synthetic route is very
promising and concise, providing olopatadine hydrochloride in 54%
overall yield for 6 steps from commercially available materials, it
has so far been reported only on a laboratory scale (5 g for the
Sonogashira coupling and 200 mg for the cyclization step).
61. 61. GRN-529 Sperry, J. B.; ET AL Org. Process Res.
Dev.201252. , 1652. , 1854.
62. 62. In 2012, in order to obtain necessary quantities for
preclinical and phase 1 clinical studies, investigators at Wyeth
Research reported the process implementation for the multi-
kilogram preparation of GRN-529 (97), a highly selective mGluR5
negative allosteric modulator that was previously identified by the
same company. The authors opted for the development of the
synthetic route initially presented by the medicinal chemistry
group, which featured a Sonogashira coupling as one of the key
13
 steps. Despite the good yield observed for this transformation, the
conditions originally employed were not amenable for the scale-up
of the reaction, requiring high loadings of metallic catalysts and
drastic reaction conditions, as well as chromatographic purification
of the product. During the developmental work, process friendly
conditions were identified for the effective coupling between aryl
halide 98 and alkyne 99, resulting in at least 10-fold reduction of
metal catalyst loadings and considerably lower reaction
temperatures
63. 63. A purification process involving the treatment of the crude
reaction with an aqueous cysteine and ammonia solution followed
by crystallization of the product afforded the coupling adduct 100
with high purity, acceptable levels of residual palladium and
copper, and an even higher yield (86%). Elaboration of the
coupling product100 through ester hydrolysis followed by
amidation furnished the final API, which was further purified via
crystallization, leading to even lower residual levels of palladium
and copper (< 1 and 15 ppm, respectively). This process was
successfully employed in the preparation of 5.5 kg of 97.
64. 64. MK-1220 Org. Process Res. Dev.201453. , 1853. , 423.
ACS Med. Chem. Lett.201154. , 254. , 207.
65. 65. Process chemistry researchers from Merck recently
employed Heck and Sonogashira reactions in the multi-gram
preparation of the macrocyclic compound MK-1220 (101), a potent
hepatitis C virus (HCV) protease inhibitor with good therapeutic
profile which has been evaluated as a potential new drug for the
treatment of hepatitis C. As an early synthetic step, a Heck
reaction was used to introduce the nitrogen and two carbon atoms
of the isoquinoline moiety present in the final target. The presence
of a bulky substituent in the olefin 102 allowed the achievement of
a 90:10 regioselectivity favouring the arylation of the terminal
carbon, leading to adduct 103 in 76% isolated yield A Sonogashira
reaction was employed at a later stage of the synthesis, allowing
the coupling of the advanced fragments 104 and 105 in 90% yield.
The reaction conditions for this coupling were chosen based on a
high throughput screening (HTS) study, which evaluated, among
other factors, the use of 12 distinct ligands. Among them, only
PtBu3.HBF4 led to a clean reaction and satisfactory conversion.
The triple bond reduction of the coupling adduct 106 with
concomitant removal of carboxybenzyl (CBz) protecting group led
directly to the substrate for the key macrocyclization step (107).
14
 The side chain installation in 107 completed the total synthesis of
MK-1220. According to the authors, this synthetic sequence could
be successfully scaled-up to produce kilograms of the final API.
66. 66. FILIBUVIR Org. Process Res. Dev.201455. , 1855. , 26.
67. 67. The Sonogashira reaction has also recently been used in
the synthesis of Filibuvir (108), a potential drug for hepatitis C
treatment, which acts as an inhibitor of RNA polymerase and has
been evaluated by clinical and toxicological studies. The coupling
between the alkyne 109 and aryl bromide 110 , employed to
introduce the pyridine moiety present in the final target, required
the careful exclusion of oxygen from the reaction medium and
addition of the palladium source prior to the copper catalyst, taking
special care to avoid the formation of by-products through the
oxidative coupling of the alkyne coupling partner The coupling
adduct 111 was then subjected to an acylation reaction followed by
reduction of the triple bond to afford 112. One of the drawbacks
initially observed in this sequence was the high catalyst loading
required for the hydrogenation step, which was attributed to
poisoning of the metallic catalyst by residues of copper and
phosphine derived from the initial Sonogashira coupling. Thus,
previous purification of the acylated coupling product by washes
with aqueous ethylenediaminetetraacetic acid (EDTA) followed by
filtration through activated charcoal was necessary. This sequence
of reactions was carried out on a pilot scale, producing 11.95 kg of
the advanced intermediate 112. It should be mentioned that alkyne
109 is prepared by an aldol addition to the ketone 113 which, in
turn, may also be prepared through a Sonogashira-type reaction
involving the acid chloride 114 followed by desilylation. Although
the authors present alternative and possibly more suitable
synthetic routes for the preparation of this alkynyl ketone, the
procedure based on the coupling between 109 and 110 could be
successfully employed in the preparation of 100 kg of this material.
68. 68. Pd or Ni catalyzed coupling organozinc compounds with
aryl, vinyl, benzyl halids. Nigishi coupling
69. 69. The use of organozinc reagents as the nucleophilic
component in palladium-catalyzed cross-coupling reactions, known
as the Negishi coupling, actually predates both the Stille and
Suzuki processes, with the first examples published in the 1970s.
[25] However, the stunning progress in the latter procedures left
the Negishi process behind, underappreciated and underutilised.

15
 Organozinc reagents exhibit a very high intrinsic reactivity in
palladium-catalyzed cross-coupling reactions, which combined
with the availability of a number of procedures for their preparation
and their relatively low toxicity, makes the Negishi coupling an
exceedingly useful alternative to other cross-coupling procedures,
as well as constituting an important method for carboncarbon
bond formation in its own right.[26] The Negishi Coupling R1 R3 X
cat. [Pd0 Ln] R1 = alkyl, alkynyl, aryl, vinyl R3 = acyl, aryl, benzyl,
vinyl X = Br, I, OTf, OTs ZnR2 R1 R3
70. 70. 25.a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem.
1977, 42, 1821 1823; for a discussion, see: b) E. Negishi, Acc.
Chem. Res. 1982, 15, 340 348. 26.a) E. Erdik, Tetrahedron
1992, 48, 9577 9648; b) E. Negishi, T. Takahashi, S. Babu,D. E.
Van Horn, N. Okukado, J. Am. Chem. Soc. 1987, 109, 2393
2401.
71. 71. Mechanism of the Negishi Coupling Pd Ph3P PPh3 Ph3P
PPh3 Pd Ph3P Ph3P PPh3 Pd Ph3P PPh3 - PPh3 - PPh3 Pd0
Pd0 Pd0 I Pd Ph3P PPh3I PdII Pd Ph3P PPh3 PdII -Complex R1
R2 ZnBr R3 Pd Ph3P Ph3P PdII R3 R2 R1 R3 R2 R1 R3 R2 R1
Zn (dust) 1.5 eq I2 (5 mol %) DMA, 80 C ZnBrI R1 R2 Br R3 Pd
Ph3P PPh3 R3 R2 R1 PdII
72. 72. The Negishi Coupling: Discodermolide a) A. B. Smith III,
T. J. Beauchamp, M. J. LaMarche, M. D. Kaufman, Y. Qiu, H.
Arimoto, D. R. Jones, K. Kobayashi, J. Am. Chem. Soc. 2000, 122,
8654 8664; b) A. B. Smith III, M. D. Kaufman, T. J.
Beauchamp,M. J. LaMarche, H. Arimoto, Org. Lett. 1999, 1, 1823
1826. c) For a review of the chemistry and biology of
discodermolide, see: M. Kalesse, ChemBioChem 2000, 1, 171
175 d) For examples of other approaches to discodermolide, see:
I. Paterson, G. J. Florence, Eur. J. Org. Chem. 2003, 2193 2208.
e) In the synthesis of discodermolide by the Marshall group, a B-
alkyl SuzukiMiyarua fragment-coupling strategy was employed to
form the C14C15 bond, in which 2.2 equivalents of an alkyl iodide
structurally related to 309 was required: J. A. Marshall, B. A.
Johns, J. Org. Chem. 1998, 63, 7885 7892. I Me Me TBSO O O
PMP Me t BuLi, ZnCl2 Et2O -78 C Zn Me Me TBSO O O PMP Me
[Pd(PPh3)4] (5 mol%) 311 Et2O, 25 C, 66% Negishi Coupling Me
Me OTBS O O PMP Me Me PMBO Me OTBS Me I PMBO Me
OTBS Me Me = 311 Me Me OH O Me MeMe OH Me NH2 OO O
HO HO Me HO discodermolide 313: discodermolide 312310309
1515 15 14 14 15 14
16
73. 73. The Negishi Coupling: Amphidinolide T1 a) C. Assa, R.
Riveiros, J. Ragot, A. Frstner, J. Am. Chem. Soc. 2003, 125, 15
512 15520. O Me R OMOM TBDPSO Me 314: R = ZnI (315: R =
I) (316: R = H) [Pd2(dba)3] (3 mol%) 285 P(2-furyl)3 (6 mol %)
toluene/DMA, 25 C, 50% Negishi Coupling O O Me Me Cl O O
Me OMOM TBDPSO Me O O Me Me O O Me OMOM TBDPSO
Me O O Me Me O 317 318 319: Amphidinolide T1 amphidinolide
74. 74. Nigishi coupling The Negishi reaction is the coupling
between an aryl (or vinyl) halide and an organozinc compound.
This coupling presents a greater tolerance towards sensitive
groups like esters or amides when compared to organomagnesium
or organolithium-based reactions; moreover, the enhanced
reactivity of organozinc compounds allows this reaction to be
performed at or even below room temperature, while boron or tin
coupling partners demand harsher conditions.
75. 75. BMS-599793 See description in next slide Pikul, S et al
Org. Process Res. Dev.201346. , 1746. , 907.
76. 76. In 2013, a Negishi coupling was employed as one of the
key steps in a new synthetic approach to BMS-599793 (84), an
HIV entry inhibitor licensed from Bristol-Myers Squibb (BMS) by
the International Partnership for Microbicides aiming towards its
further development as a topical microbicide candidate for use in
underdeveloped countries. While the original medicinal chemistry
route employed a Stille coupling as the last step of the sequence,
this new synthetic approach anticipates the metal-catalyzed C-C
bond forming reaction using a Negishi coupling as the first step,
which eliminated the inconvenience of high levels of toxic tin
residues previously observed in the final product. The coupling
between diarylzinc reagent 85 and azaindol 86 led to adduct 87,
obtained in 41 to 59% yield for several batches of 400 g each. A
single experiment carried out at a 1.5 kg scale afforded 87 in 54%
yield and 99.6% HPLC purity
77. 77. Synthesis of 88 with low loadings of Pd in a Negishi
coupling. Shu, L.; Org. Process Res. Dev.201347. , 1747. , 651.
78. 78. Acylation of the adduct's azaindole moiety with methyl
chlorooxalate followed by ester hydrolysis and amidation afforded
the final product which, however, still exhibited a high residual
content of palladium (16 ppm) and zinc (100 ppm), requiring
additional purification steps. At the end of the synthetic sequence,
product treatment with activated charcoal followed by several
washes, a precipitation step and polymorphic conversions led to
17
 the final active pharmaceutical ingredient (API) with Pd and Zn
contents of only 1 ppm each. A Negishi reaction was also used in a
multi-gram synthesis of compound 88, a CHRT2 receptor
antagonist with good pharmacological profile that was previously
identified by Roche. Since it is believed that CHTR2 plays a pro-
inflammatory role in allergic processes, its antagonists are viewed
as potential new drugs for the treatment of asthma, allergic rhinitis,
chronic obstructive pulmonary disease (COPD) and atopic
dermatitis, among other diseases. En route to 88, the Negishi
coupling between benzylzinc reagent 89 and aryl triflate 90
represented a major challenge. According to the previously
developed medicinal chemistry synthetic route, the arylzinc
preparation required a highly exothermic zinc activation process
and the subsequent coupling step employed very high catalyst
loadings, both of which are serious drawbacks for the scaling-up of
the synthesis .
79. 79. During the process development, a traditional zinc
activation approach was found to be effective, and by using
trimethylchlorosilane in DMF, 237 g of zinc dust could be activated
with only a 5 C temperature increase over a 30 min period.
Regarding the proper Negishi coupling step, in a first moment, the
authors were able to perform a 20-fold reduction in both palladium
and phosphine quantities; however, the high cost of SPhos ligand
was still prohibitive for large-scale production, even at 1 mol%
loading. Fortunately, the inexpensive PdCl2(PPh3)2complex was
equally effective when employed as the sole catalyst at 0.5 mol%
loading. Due to safety reasons associated with transferring a high
reactive zinc reagent, the coupling reaction was performed at the
same pot of zincate formation by the sequential addition of the Pd
source and aryl triflate followed by heating to 60-65 C, which
initiated the reaction. Without further heating, a temperature
increase of up to 30 C in a 10 min period was observed for
batches involving 500 g of trifate 90, which should be bypassed for
further scale-up. Filtration of the reaction crude trough Celite and
treatment with N-acetyl-L- cysteine followed by crystallization
afforded the coupling product 91 in 95% yield and > 99% HPLC
purity. The final hydrolysis step afforded the desired API, which
displayed well- controlled levels of residual palladium and zinc (6
and 20 ppm, respectively).
80. 80. Using tin (stannes) alkyl compounds, wide range of R
groups, but????? Less polar, more toxic??? Stille coupling
18
81. 81. Originally discovered by Kosugi et al[5] in the late
1970s, the Stille Coupling was later developed as a tool for organic
transformations by the late Professor J. K. Stille.[6] Milder than
the older Heck reaction, and more functional-group tolerant, the
Stille coupling remains popular in organic synthesis. A close
relative of the Stille coupling is the Hiyama; this involves the
palladium catalysed reaction of a organosilicon with organic
halides/triflates et c., but requires activation with fluoride (TBAF) or
hydroxide.[7] It is possible to couple bis-aryl halides using R3Sn-
SnR3, in a varient known as a Stille-Kelly reaction, but the toxicity
of these species is a somewhat limiting factor.[8] The Stille
Coupling 5. Original Report; a) M. Kosugi, K. Sasazawa, Y.
Shimizu, T. Migita, Chem. Lett. 1977, 301 302; b) M. Kosugi, K.
Sasazawa, T. Migita, Chem. Lett. 1977, 1423 1424. 6. a) D.
Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636 3638; b)
D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4992 4998;
c) For a review of Stille Reactions, see; V. Farina, V.
Krishnamurthy,W. J. Scott, Org. React. 1997, 50, 1 652 7. T.
Hiyama, Y. Hatanaka, Pure Appl. Chem. 1994, 66, 1471 8. T. R.
Kelly, Tetrahedron Lett. 1990, 31, 161 R1 R2 X cat. [Pd0 Ln] base
R1 = alkyl, alkynyl, aryl, vinyl R2 = acyl, alkynyl, allyl, aryl, benzyl,
vinyl X = Br, Cl, I, OAc, OP(=O)(OR)2, OTf SnR3 R1 R3
82. 82. Mechanism of the Stille Coupling Pd Ph3P PPh3 Ph3P
PPh3 Pd Ph3P Ph3P PPh3 Pd Ph3P Ph3P - PPh3 - PPh3 Pd0
Pd0 Pd0 Br Pd Ph3P Br PPh3 PdII Pd Ph3P PPh3 Pd Ph3P Ph3P
BrSnBu3 SnBu3 R2 R1 R3 R2 R3 R1 R2 R1 PdII PdII R1 R1 R2
R1
83. 83. The Stille Coupling: Rapamycin a) K. C. Nicolaou, T. K.
Chakraborty, A. D. Piscopio, N. Minowa, P. Bertinato, J. Am. Chem.
Soc. 1993, 115, 4419 4420; K. C. Nicolaou, A. D. Piscopio, P.
Bertinato, T. K. Chakraborty, , N. Minowa, K. Koide, Chem. Eur. J.
1995, 1, 318 333. b) A. B. Smith III, S. M. Condon, J. A.
McCauley, J. L. Leazer, Jr.,J. W. Leahy, R. E. Maleczka, Jr., J. Am.
Chem. Soc. 1995, 117, 5407 5408. O O NO I Me I O Me O O O
H OH H Me Me OH MeOMe Me H OH Me OMe OMe Bu3Snn Snn
Bu3 [PdCl2(MeCN)2] (20 mol%) iPr2NEt, DMF, THF, 25C
Intermolecular Stille Coupling O O NO I Me O Me O O O H OH H
Me Me OH MeOMe Me H OH Me OMe OMe Snn Bu3
Intramolecular Stille Coupling O O NO Me O Me O O O H OH H
Me Me OH MeOMe Me H OH Me OMe OMe O O NO Me O Me O
19
 O O H OTIPS H Me Me OTBS MeOMe Me H TESO Me OMe OMe
Snn Bu3 I 1. [PdCl2(MeCN)2] (20 mol%) iPr2NEt, DMF, THF, 25C
(74%) Intramolecular Stille Coupling 2. Deprotection (61%) 27%
Overall rapamycin 76: Rapamycin75 7472 "Stitching Cyclisation"
84. 84. The Stille Coupling: Dynamycin a) M. D. Shair, T.-Y. Yoon,
K. K. Mosny, T. C. Chou, S. J. Danishefsky, J. Am. Chem. Soc.
1996, 118, 9509 9525; b) M. D. Shair, T.-Y. Yoon, S. J.
Danishefsky, Angew. Chem. 1995, 107, 1883 1885; Angew.
Chem. Int. Ed. Engl. 1995, 34, 1721 1723; c) M. D. Shair, T.
Yoon, S. J. Danishefsky, J. Org. Chem. 1994, 59, 3755 3757.
TeocN O OH OH H Me I I OTBS Me3Sn SnMe3 [Pd(PPh3)4] (5
mol%) DMF, 75 C 81% Tandem Intermolecular Stille Coupling
TeocN O OH OH H Me OTBS HN O CO2H OMe H Me OH O O
OH OH 79 dynemicin 81: () Dynamycin77 Teoc = 2-
(trimethylsilyl)ethoxycarbonyl
85. 85. The Stille Coupling: Sanglifehrin a) K. C. Nicolaou, J. Xu,
F. Murphy, S. Barluenga, O. Baudoin, H.-X.Wei, D. L. F. Gray, T.
Ohshima, Angew. Chem. Int. Ed. 1999, 38, 2447 2451; b) K. C.
Nicolaou, F. Murphy, S. Barluenga, T. Ohshima, H. Wei, J. Xu, D.
L. F. Gray, O. Baudoin, J. Am. Chem. Soc. 2000, 122, 3830
3838. N NH OO O NH O OH HN O Me Me O Me O Me Snn Bu3
Me I I [Pd2(dba)3]CHCl3 AsPh3, i Pr2NEt DMF, 25 C, 62%
Chemoselective Intramolecular Stille macrocyclisation N NH OO O
NH O OH HN O Me Me O Me O Me Me I 1. [Pd2(dba)3]CHCl3
AsPh3, i Pr2NEt DMF, 40C, 45% 2. aq. H2SO4 THF/H2O (33%)
Intermolecular Stille Coupling N NH OO O NH O OH HN O Me Me
O Me O Me MeMe NH O O Me OH Me Me Me Me Me NH O O Me
OH Me Me Me Me 88 86 87 87: sanglifehrin A sanglifehrin Snn
Bu3 23 22
86. 86. The Stille Coupling: Manzamine A a) S. F. Martin, J. M.
Humphrey, A. Ali, M. C. Hillier, J. Am. Chem. Soc. 1999, 121, 866
867; b) J. M. Humphrey, Y. Liao, A. Ali, T. Rein, Y.-L. Wong, H.-J.
Chen, A. K. Courtney, S. F. Martin, J. Am. Chem. Soc. 2002, 124,
8584 8592. NBoc OTBDPS O N TBDPSO Br CO2Me Snn Bu3
[Pd(PPh3)4)] (4 mol%) toluene, 120 C Intermolecular Stille
Coupling 109 NBoc OTBDPS O N TBDPSO CO2Me N O TBDPSO
N OTBDPS H Boc E 110 N O OTBDPS CO2Me NBoc OTBDPS H
H 111 endo-intramolecular Diels-Alder Reaction (68% Overall) N N
H N N H H OH H A B C D 112: Manzamine A manzamine
87. 87. The Carbonylative Stille Coupling: Jatrophone A. C.
Gyorkos, J. K. Stille, L. S. Hegedus, J. Am. Chem. Soc. 1990, 112,
20
 8465 8472. O O Me Me O Me Me Me O O Me Me Me Me Me O
O Me Me Me Me Me [PdCl2(MeCN)2] LiCl, CO (50 psi) DMF, 25
C Intermolecular Carbonylative Stille CouplingSnn Bu3 OTf Snn
Bu3 PdLn Cl O O Me Me Me Me Me Snn Bu3 53% Overall 8382
8485: ()-2-epi-jatrophone jatrophone PdLn O Cl Carbonyl
Insertion
88. 88. Org. Biomol. Chem.201358. , 1158. , 7852. Total
synthesis of the HIV-1 integrase inhibitor 119 using a Stille reaction
to append the carbonylated side-chain to the central pyridine ring.
89. 89. In 2013, the total synthesis of the HIV-1 integrase inhibitor
119 was described in a nine step route . The authors employed the
bromopyridine120 as starting material and the target compound
was obtained with 18% overall yield. In the insertion of a side chain
in the pyridinone central ring, the Stille cross-coupling of a vinyl
stannane was applied and led to the product 121 with 83% yield
after 1 h of reaction in DMF. A large amount (10 mol%) of the pre-
catalyst PdCl2(PPh3)2 in combination with a 20% excess of the tin
reagent was necessary to provide high yields. It must be
mentioned that the iodinated substrate was also applied in the
cross-coupling; however, according to the authors, the bromo
derivative was preferred due to a simpler chromatographic
purification.
90. 90. Using boronic acids or esters B(OR)3 . Needs base to
activate boron species Suzuki coupling
91. 91. The Suzuki reaction was formally developed by Suzuki
Group in 1979[9], although the inspiration for this work can be
traced back to publications by Heck[10] and Negishi,[11] and their
earlier presentation of these papers at conferences. The
popularity of this reaction can be partially attributed to the ease of
preparation of the organoboron reagents required, their general
stability, and the lack of toxic by-products. Progress in the last
quarter-century has shown that the Suzuki reaction is incredibly
powerful, with examples of C(sp2)C(sp3) and even C(sp3)
C(sp3) now well documented.[12] The Suzuki Coupling 9. Original
Report; a) N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett.
1979, 20, 3437 3440; b) N. Miyaura, A. Suzuki, J. Chem. Soc.
Chem. Commun. 1979, 866 867 10. a) R. F. Heck in
Proceedings of the Robert A. Welch Foundation Conferences on
Chemical Research XVII. Organic-Inorganic Reagents in Synthetic
Chemistry (Ed.W. O. Milligan), 1974, p. 5398; b) H. A. Dieck, R. F.
21
 Heck, J. Org. Chem. 1975, 40, 1083 1090. 11. E. Negishi in
Aspects of Mechanism and Organometallic Chemistry (Ed.: J. H.
Brewster), Plenum, New York, 1978, p. 285. 12. a) T. Ishiyama, S.
Abe, N. Miyaura, A. Suzuki, Chem. Lett. 1992, 691 694. b) J.
Zhou, G.C. Fu, J. Am. Chem. Soc. 2004, 126, 1340 1341, and
references therein. c) A. C. Frisch, M. Beller, Angew. Chem. Int.
Ed. 2005, 44, 674 688. d) For a relatively recent review, see N.
Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457. R1 R2 X cat. [Pd0
Ln] base R1 = alkyl, alkynyl, aryl, vinyl R2 = alkyl, alkynyl, aryl,
benzyl, vinyl X = Br, Cl, I, OAc, OP(=O)(OR)2, OTf BY2 R1 R2
92. 92. Mechanism of the Suzuki Coupling Pd Ph3P PPh3 Ph3P
PPh3 Pd Ph3P Ph3P PPh3 Pd Ph3P PPh3 - PPh3 - PPh3 Pd0
Pd0 Pd0 I Pd Ph3P IPh3P PdII Pd Ph3P PPh3 PdII -Complex
NaOEtNaI Pd Ph3P OEtPh3P PdII R1 R2 BF3 R3 K BF3OEt Pd
Ph3P Ph3P PdII R3 R2 R1 R3 R2 R1 R3 R2 R1
93. 93. The Suzuki Coupling: Palytoxin O O OTBS NHTeoc O Me
Me O TBSO OTBS OTBS B OTBS TBSO TBSO OTBS TBSO
OTBS HO OH O IOAc OTBS OTBS TBSO OTBS OTBSO CO2Me
TBSO TBSO H OTBS OTBS [Pd(PPh3)4] (40 mol%) TlOH,
THF/H2O, 25 C (70%) Intermolecular Suzuki Coupling O O OTBS
TeocHN O Me Me O TBSO OTBSTBSO OTBS TBSO TBSO
OTBS OTBS OTBS O OAc OTBS OTBS OTBS OTBS TBSO O
MeO2C OTBS OTBS HTBSO OTBS a) R.W. Armstrong, J.-M.
Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D.
Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli, W. J.
McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas,
M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M.
Yonaga, J. Am. Chem. Soc. 1989, 111, 7525 7530; b) R.W.
Armstrong, J.-M. Beau, S. H.Cheon,W. J. Christ, H. Fujioka,W.-H.
Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,W.
J. McWhorter, Jr.,M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas,
M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White,
M.Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 7533; c) E. M.
Suh, Y. Kishi, J. Am. Chem. Soc. 1994, 116, 11205 11206.
94. 94. The Suzuki Coupling: Palytoxin a) R.W. Armstrong, J.-M.
Beau, S. H. Cheon, W. J. Christ, H. Fujioka, W.-H. Ham, L. D.
Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli, W. J.
McWhorter, Jr., M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas,
M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White, M.
Yonaga, J. Am. Chem. Soc. 1989, 111, 7525 7530; b) R.W.
Armstrong, J.-M. Beau, S. H.Cheon,W. J. Christ, H. Fujioka,W.-H.
22
 Ham, L. D. Hawkins, H. Jin, S. H. Kang, Y. Kishi, M. J. Martinelli,W.
J. McWhorter, Jr.,M. Mizuno, M. Nakata, A. E. Stutz, F. X. Talamas,
M. Taniguchi, J. A. Tino, K. Ueda, J.-I. Uenishi, J. B. White,
M.Yonaga, J. Am. Chem. Soc. 1989, 111, 7530 7533; c) E. M.
Suh, Y. Kishi, J. Am. Chem. Soc. 1994, 116, 11205 11206. O O
OH NH2 O Me Me O HO OH OH OH HO OH OH OH OH O OH O
OH OH OH HO O OH OH H HO OH OH O OH HO OH OH HO O
O Me OH OH OH HO OH O HO OH OH H HN OHMeOHMe OH O
HN O OH palytoxin
95. 95. a) D. A. Evans, J. T. Starr, J. Am. Chem. Soc. 2003, 125,
13531 13540 b) D. A. Evans, J. T. Starr, Angew. Chem. 2002,
114, 1865 1868; Angew. Chem. Int. Ed. 2002, 41, 1787 1790.
The Suzuki Coupling: FR182887 MeO Me O Br BrMeMe OTBS
TBDPSO B OTBS OTBS Me HO OH [Pd(PPh3)4)] (5 mol%)
Tl2CO3, THF/H2O, 23 C (84%) Intermolecular Suzuki Coupling
TBDPSO OTBS OTBS Me MeO Me O BrMeMe OTBS O HO OH H
Me Br H H H CO2Et H HO Me Me H B O B O B O Me Me Me
[PdCl2(dppf))] (10 mol%) Cs2CO3, DMF/H2O, 100 C (71%) O HO
OH H Me Me H H H CO2Et H HO Me Me H O HO OH H Me Me H
H H H O Me Me H O fr182887 132: FR182887131 130 129 128
127126 Intermolecular Suzuki Coupling
96. 96. a) N. K. Garg, D. D. Capsi, B. M. Stoltz, J. Am. Chem.
Soc. 2004, 126, 9552 9553. b) For a failed alternative route
without Pd Catalysis: N. K. Garg, R. Sarpong, B. M. Stoltz, J. Am.
Chem. Soc. 2002, 124, 13179 13184. The Suzuki Coupling:
DragmacidinMe TBSO HO O N SEM Br [Pd(PPh3)4] (10 mol%)
toluene/MeOH/H2O, 23 C Intermolecular Heck Reaction Me
TBSO HO O N SEM PdOAc TBSO HO O N SEM H (74%) TBSO
MeO O N SEM H B O O [Pd(PPh3)4] (10 mol%) 161,
toluene/MeOH/H2O NaCO3, 50 C, 77% Intermolecular Suzuki
Reaction TBSO MeO O N SEM H NTs Br N N OMe 167 165166
162 164 HO O N H H Me NH Br N H N O N N H2N dragmacidin
168: dragmacidin Ts N B Br OH HO N N I Br OMe [Pd(PPh3)4] (10
mol%) toluene/MeOH/H2O, 23 C (71%) Intermolecular Suzuki
Coupling NTs Br N N Br OMe 161 160159
97. 97. 13) a) N. Miyaura, T. Ishiyama, M. Ishikawa, A. Suzuki,
Tetrahedron Lett. 1986, 27, 6369 6372; b) not to be confused
with the Miyaura boration, in which an aryl halide is converted to
an aryl boronate via palladium catalysis and a diboron reagent.
However, this is a useful preparation of the organoboron reagents
required for the Suzuki reaction. See: T. Ishiyama, M. Murata, N.
23
 Miyuara. J. Org. Chem. 1995, 60, 7508. 14) Review of the
development, mechanistic background, and applications of the B-
alkyl Suzuki-Miyaura cross-coupling reaction, see S. R. Chemler,
D. Trauner, S. J. Danishefsky, Angew. Chem. Int. Ed. 2001, 40,
4544 4568. 15) Q. Tan, S. J. Danishefsky, Angew. Chem. Int. Ed.
2000, 39, 4509 4511. An important trend in Suzuki chemistry is
the development of a C(sp3)C(sp2) methodology, which has
become known as the Suzuki-Miyaura B-Alkyl varient.[13-15]
Often used as an alternative to RCM, leaving a single isolated
double bond, rather than the conjugated systems produced by a
regular Suzuki coupling. The Suzuki-Miyaura B-Alkyl Coupling:
CP-236,114 O ITBS O TBSO H O TBS O H OTBS O TBS OTBS H
OTBS I O TBS OTBS H OTBS OBn 6 O O O O O O CO2H H Me
O H Me [Pd(OAc)2(PPh3)2] Et3N, THF, 65 C (92%)
Intermolecular Heck Reaction B{(CH2)6OBn}3 [PdCl2(dppf)]
CsCO3, AsPh3, H2O, 25 C (70%) Suzuki-Miyaura B-Alkyl
Reaction 174: CP-263,114 169 170 171173 CP-263,114
98. 98. a) P. J. Mohr, R. L. Halcomb, J. Am. Chem. Soc. 2003,
125, 1712 1713 b) N. C. Callan, R. L. Halcomb, Org. Lett. 2000,
2, 2687 2690. The Suzuki Coupling: Phomactin A O O H Me Me
OTMS OTES Me I 9-BBN THF, 40 C O O H Me Me OTMS OTES
Me I B O O H Me OTMS OTES Me Me Me O O H Me OH OH Me
Me Me TBAF (78%) Suzuki-Miyaura B-Alkyl Macrocyclisation
[PdCl2(dppf)] (100 mol%) AsPh3(200 mol%), Tl2CO3
THF/DMF/H2O, 25 C (37%) 200: phomactin A phomactin
99. 99. M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles, 2000,
53, 553 556 The Suzuki Coupling: Yuehhukene N O O Directed
o-Metallation tBuLi, THF, then BEt3 N Boc BEt3 Li Me TfO Me Me
[PdCl2(PPh3)2 CO (10 atm) THF, 60 C 75% Carbonylative Suzuki
Coupling N Boc O Me Me Me HN Me H H MeMe NH yuehchukene
205: yuehhukene 204 202 201 203
100. 100. M. Ishikura, K. Imaizumi, N. Katagiri, Heterocycles,
2000, 53, 553 556 The Suzuki Coupling: Yuehhukene N O O
Directed o-Metallation t BuLi, THF, then BEt3 N Boc BEt3 Li Me
TfO Me Me [PdCl2(PPh3)2 CO (10 atm) THF, 60 C 75%
Carbonylative Suzuki Coupling N Boc O Me Me Me HN Me H H
MeMe NH yuehchukene 205: yuehhukene 204 202 201 203
101. 101. Suzuki coupling
102. 102. Suzuki coupling
103. 103. Suzuki-Miyaura Reactions Dalby, A.; ET AL Tetrahedron
Lett.201324. , 5424. , 2737. and WO2010059838-A2,
24
 WO2010059838-A3,200925. . The more reactive benzyl bromide
moiety of dibromide 2 was coupled with a pinacol arylboronic ester,
providing diarylmethane 3 in 66% yield. Activation of the remaining
bromide in 3 was carried out using the same conditions, only
changing the temperature and reaction time, and furnishing 1 at a
yield of 71%.
104. 104. Suzuki reaction for the synthesis of PF-01367338
Contd.. Gillmore, A. T.; et al Org. Process Res. Dev.201228. ,
1628. , 1897
105. 105. Gillmore et al. developed a multi-kilogram preparation of
PF-01367338 (14), a drug candidate for the treatment of breast
and ovarian cancers.It is an inhibitor of poly(ADP ribose)
polymerase (PARP), an enzyme that is responsible for repairing
damaged DNA in normal and tumour cells.The described synthetic
route delivered 2 kg of the salt 14, and the authors described how
they had to overcome some synthetic challenges in order to scale
up the synthesis to multi-kilogram scale. The overcome problems
include: understanding of the thermal hazards of the Leimgruber-
Batcho indole synthesis, installation of the side chain through a
reductive alkylation procedure, improvements in the robustness of
the Suzuki coupling, removal of hydrogen cyanide generation
during a reductive amination reaction, and reliable generation of
good-quality free base for the final salt formation step. The Suzuki
reaction between the tricyclic bromide 15 and 4-
formylphenylboronic acid was first carried out in multi-kilogram
scale using by Pd(PPh3)4 as catalyst. The reaction did not reach
completion requiring an additional catalyst charge. In the
sequence, the Suzuki reaction was performed with
[PdCl2(dppf)CH2Cl2] as a pre-catalyst, and full conversion was
obtained after 2 h at 90 C , providing 16 with yield of 92%.
Contd..
106. 106. Synthesis of GDC-0941 (24) through a Suzuki reaction
of THP-protected boronic acid 26. Tian, Q.; Cheng, Z.;et al Org.
Process Res. Dev.201330. , 1730. , 97.
107. 107. Tian et al. described a convergent synthesis for GDC-
0941(24), a phosphatidylinositol 3-kinase (PI3K) inhibitor . The
PI3K pathway is frequently activated in tumours and its inhibition
has a role in human cancers. The indazole-derived boronic acid 26
was employed as its tetrahydropyran- protected derivative due to
solubility issues and to render an easier purification. Previous
studies identified Pd- or Ni-catalyzed systems for this Suzuki
25
 reaction. The first employed PdCl2(PPh3)2 with Na2CO3 as base
and 1,4- dioxane as solvent; regarding the economically more
attractive nickel, Ni(NO3)2.6H2O/PPh3 was identified as an
optimal pre-catalyst, with K3PO4 as base and acetonitrile as
solvent. In the Ni-catalyzed reaction, boronic acid 26 performed
better than the corresponding boronate ester. The yield of the Pd-
catalyzed reaction was 60%, whereas the Ni-catalyzed reaction
provided 27 in 79% yield. Mild removal of the THP-protecting
group then provided 24. Regarding purification after the Suzuki
reaction, residual Ni was easily removed through an aqueous
ammonia wash followed by crystallization, while the removal of
residual Pd demanded expensive scavengers and a large volume
of solvents. The easy removal of nickel traces compensated for the
high loadings of its pre-catalyst (30 mol%); Pd loadings were lower
(4.5 mol%), however the lower yield and difficult purification
impaired the use of this noble metal. GDC-0941
108. 108. En route to producing large quantities of Crizotinib (62),
a c- Met/anaplastic lymphoma kinase (ALK) inhibitor in advanced
clinical tests, De Koning et al. employed a Suzuki reaction in order
to generate an advanced intermediate. However, before describing
the large-scale synthesis itself, it is worth noting some aspects of
the initial medicinal chemistry screening: compounds with the
basic structure 63 were obtained through a sequence of protection,
palladium- catalyzed borylation, deprotection and Suzuki reactions
in order to allow for late-stage functionalization with substituted
bromopyrazoles. De Koning, P. D.; ET AL Org. Process Res.
Dev.201137. , 1537. , 1018. Crizotinib Casestudy suzuki
109. 109. Then, once crizotinib (and its R isomer) had been
identified as the most promising candidate, the Suzuki cross-
coupling was performed in an inverse way: the pyrazol moiety was
employed as its boron pinacolate derivative (64, ). Even though 64
was obtained in a moderate 40% yield, its Suzuki reaction
furnished the desired product in excellent quantities, thus allowing
a better use of the valuable chiral intermediate 65
110. 110. The large-scale synthesis demanded further
modifications: the preparation of multi- kilogram amounts of
imidazole 64 presented high levels of dimerization; therefore, the
palladium-catalyzed borylation was abandoned in favour of a
Knochel-type procedure.The Suzuki cross-coupling was performed
in a different solvent system: in order to avoid the undesirable
DME, toluene and water were employed together with the phase-
26
 transfer catalyst tetrabutylammonium bromide (TBAB). This new
procedure allowed the catalyst loading to be reduced to 0.9 mol%
with a significant simplification of the purification procedure, once
the cross-coupling product was soluble in toluene and hence easily
separated from the water layer Baron, O.; Knochel, P.; Angew.
Chem., Int. Ed.200538. , 4438. , 3133.
111. 111. Organosilanes (Si), with organohalids. Needs base or
fluoride ion to activate Fluorinated, methoxyleted silanes more
reactive than alkyl ones. Hyiama coupling
112. 112. Hiyama coupling with a copper co-catalyst Nakao, Y.;
Takeda, M.; Matsumoto, T.; Hiyama, T. (2010), "Cross-Coupling
Reactions through the Intramolecular Activation of
Alkyl(triorgano)silanes", Angewandte Chemie 122: 4549,
doi:10.1002/ange.201000816
113. 113. Hyiama coupling Denmark, S. E.; Yang, S.-M. (2002),
"Intramolecular Silicon-Assisted Cross-Coupling Reactions:
General Synthesis of Medium-Sized Rings Containing a 1,3-cis-cis
Diene Unit",Journal of the American Chemical Society 124: 2102,
doi:10.1021/ja0178158 Hiyama coupling as a ring-closing reaction[
114. 114. Pd catalyzed synthesis of aryl secondry or tertiary
amines. Using primary or secondry amins and aryl halides (or
triflates) Buchwald-Hartwig coupling
115. 115. Buchwald-Hartwig coupling
116. 116. Pd catalyzed synthesis of aryl secondry or tertiary
amines. Using primary or secondry amins and aryl halides (or
triflates) Buchwald-Hartwig coupling
117. 117. Buchwald-Hartwig coupling
118. 118. An example of the reaction using relatively unreactive
aryl chlorides. 1 The large scale synthesis of BINAP: Under similar
reaction conditions, phosphorus- and sulfur-based groups can be
introduced. Strong bases are unnecessary in those cases.2 1 Zim,
D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413. DOI:
10.1021/ol034561h 2 Org. Synth. 2000, 76, 6.
119. 119. The Fukuyama Coupling is a modification of the
Negishi Coupling, in which the electrophilic component is a
thioester. The product of the coupling with a Negishi-type
organozinc reagent is carbonyl compound, thus negating the need
for a carbon monoxide atmosphere. The Fukuyama Coupling 27)
H. Tokuyama, S. Yokoshima, T. Yamashita, S.-C. Lin, L. Li, T.
Fukuyama, J. Braz. Chem. Soc., 1998, 9, 381-387. R1 R3 cat.
27
 [Pd0 Ln] R1 = alkyl, alkynyl, aryl, vinyl R3 = acyl, aryl, benzyl, vinyl
R4 = Me, Et, et c. ZnR2 R1 R3 O SR4 O MeO SEt O ZnI
[PdCl2(PPh3)2] (10 mol%) toluene, 25 C, 5 min, 87% Fukuyama
Coupling MeO O
120. 120. Pd catalyzed coupling of organozinc with thioesters to
form ketones. Fukuyama Coupling*
121. 121. The Fukuyama coupling is a coupling reaction taking
place between a thioester and an organozinc halide in the
presence of a palladium catalyst. The reaction product is aketone.
This reaction was discovered by Tohru Fukuyama et al. in 1998.
Advantages are high chemoselectivity, mild reaction conditions
and the use of less-toxic reagents. One advantage of this method
is that the reaction stops at the ketone and does not proceed to a
tertiary alcohol. In addition, the protocol is compatible with
functional groupssuch as ketones, acetates, sulfides, aromatic
bromides, chlorides and aldehydes.
122. 122. Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama,
T. (1998). "A novel ketone synthesis by a palladium-catalyzed
reaction of thiol esters and organozinc reagents". Tetrahedron
Letters 39 (20): 31893192. doi:10.1016/S0040- 4039(98)00456-0.
Jump up^ Mori, Y.; Seki, M. (2007). "SYNTHESIS OF MULTI-
FUNCTIONALIZED KETONES THROUGH THE FUKUYAMA
COUPLING REACTION CATALYZED BY PEARLMANS
CATALYST: PREPARATION OF ETHYL 6-OXOTRIDECANOATE
(Tridecanoic acid, 6-oxo-, ethyl ester)" (PDF). Org. Synth. 84: 285
294.; Coll. Vol. 11, pp. 281288 Jump up^ Shimizu, T.; Seki, M.
(2000). "Facile synthesis of (+)-biotin via Fukuyama coupling
reaction". Tetrahedron Letters 41 (26): 50995101.
doi:10.1016/S0040-4039(00)00781-4.
123. 123. The palladium catalysed nucleophilic substitution of
allylic compounds was discovered independently by Trost and
Tsuji, and represents the first example of a metalated species
acting as an electrophile.[22] Originally developed as a
stoichiometric process, Trost succeeded in transforming the
allylation of enolates with p-allylpalladium complexes into the
catalytic process of renown.[23,24] A wide range of allylic
substrates undergo this reaction with a correspondingly wide range
of carbanions, making this a versatile and important process for
the formation of carboncarbon bonds. Whilst the most
commonly employed substrates for palladium-catalyzed allylic
28
 alkylation are allylic acetates, a variety of leaving groups also
function effectivelythese include halides, sulfonates, carbonates,
carbamates, epoxides, and phosphates. The Tsuji-Trost Reaction
22. For early reviews of the Tsuji-Trost reaction, see a) B. M. Trost,
Acc. Chem. Res. 1980, 13, 385 393; b) J. Tsuji, Tetrahedron
1986, 42, 4361 4401. 23. J. Tsuji, H. Takahashi, Tetrahedron
Lett. 1965, 6, 4387 4388. 24. For recent reviews of the
palladium-catalyzed asymmetric alkylation reaction, see: a) B. M.
Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921 2943; b) B. M.
Trost, J. Org. Chem. 2004, 69, 5813 5837. cat. [Pd0 Ln] base X
= Br, Cl, OCOR, OCO2R, CO2R, P(=O)(OR)2 NuH = -
dicarbonyls, -ketosulfones, enamines, enolates X NuH Nu
124. 124. Mechanism of the Tsuji-Trost Reaction Pd Ph3P PPh3
Ph3P PPh3 Pd Ph3P Ph3P PPh3 Pd Ph3P PPh3 - PPh3 - PPh3
Pd PPh3Ph3P R1 OAc R2 R1 OAc R2 Pd PPh3Ph3P R1 R2 Pd
PPh3Ph3P R1 R2 Pd PPh3Ph3P R1 R2 Pd PPh3Ph3P R1 R2 Nu
Nu Nu * * R1 R2 Nu * R1 R2 Nu * or or
125. 125. The Tsuji-Trost Reaction: Strychnine a) S. D. Knight, L.
E. Overman, G. Pairaudeau, J. Am. Chem. Soc. 1993, 115, 9293
9294 b) S. D. Knight, L. E. Overman, G. Pairaudeau, J. Am. Chem.
Soc. 1995, 117, 5776 5788. PdLn OAcO OMe O O t BuO CO2Et
[Pd2(dba)3] (1 mol%) PPh3 (15 mol%) NaH, THF, 23 C [-CO2,
-MeO ] Tsuji-Trost Reaction AcO O t BuO CO2Et AcO Ot Bu O
CO2Et H 91% Me3Sn TIPSO Ot Bu [Pd2(dba)3] (3 mol%) AsPh3
(22 mol%), CO (50 psi) LiCl, NMP, 70 C 80% Carbonylative Stille
Coupling TIPSO Ot Bu O N Me N MeN O N OO H H H H
strychnine 250 251 252 253 MeN N NMe O I 254256: Strychnine
255
126. 126. OTBS MeO2C PhO2S O [Pd2(dba)3] (1 mol%) PPh3
(15 mol%) NaH, THF, 23 C Tsuji-Trost Macrocyclisation TBSO
MeO2C PhO2S OLnPd TBSO MeO2C PhO2S OHLnPd O O O
PhO2S PhO2S HOMeO2C OTBS -[Pd0 Ln] 85% BnNH2
[Pd(PPh3)4] (15 %) THF, 35 C, 70% Tsuji-Trost ReactionO
PhO2S NBn HO N O NHCl MeO Me Me Roseophilin 263 264 265
266267268 269: Roseophilin The Tsuji-Trost Reaction: Roseophilin
a) A. Frstner, H. Weintritt, J. Am. Chem. Soc. 1998, 120, 2817
2825; b) A. Frstner, T. Gastner, H. Weintritt, J. Org. Chem. 1999,
64, 2361 2366.
127. 127. The Tsuji-Trost Reaction: Hamigeran B B. M. Trost, C.
Pissot-Soldermann, I. Chen, G.M. Schroeder, J. Am. Chem. Soc.
2004, 126, 4480 4481. Pd Me O Ot Bu OAc [{3 -C3H5PdCl}2]
29
 (1 mol%) ligand 285 (2 mol%) LDA, t BuOH, Me3SnCl DME, 25 C
Asymmetric Allylic Alkylation Me O t BuO P P Pd PP a b * * O Ot
Bu Me 77%, 93% ee OOMe Me OTf Me Me Me Pd(OAc) (10 mol
%) dppb (20 mol%) K2CO3 toluene, 110 C, 58% Intramolecular
Heck Reaction OOMe Me H Me Me Me OOMe Me H Me Me Me
NH O P Ph Ph HN O P Ph Ph hamigeran B 285 284 286 287 288
289290: hamigeran
128. 128. The Tsuji-Trost Reaction: (+)-g-lycorane H. Yoshizaki, H.
Satoh, Y. Sato, S. Nukui, M. Shibasaki, M. Mori, J. Org. Chem.
1995, 60, 2016 2021. OBz OBzBzO O O Br NH MeO2C O
[Pd2(OAc)3] (5 mol%) 293 (10 mol%) LDA THF/MeCN, 0 C
Asymmetric Allylic Alkylation O O Br NH MeO2C O Pd PP * 66%,
54% ee O O Br NH MeO2C O OBz Pd(OAc) (5 mol%) dppb (20
mol%) NaH DMF, 50 C Intramolecular Allylic Alkylation/ Heck
Reaction Cascade O O Br N MeO2C O PdLn O O Br N MeO2C O
H H i Pr2NEt, 100 C O O N CO2Me O H H H O O N H HH
lycorane 299: (+)-g-lycorane 298 297 296 295294 292 291 O O
PPh2 PPh2 293
129. 129. HARD NUCLEOPHILE INVERSION,SOFT ONE GIVES
RETENTION
130. 130. MIGITA COUPLING Recently, Pfizer researchers
described an efficient Heck- and Migita-based multi- kilogram
process for the vascular endothelial growth factor (VEGF) inhibitor
axitinib (147) A Migita coupling was used in the first step of the
synthesis in order to assemble the mercaptobenzamide moiety of
147. In the last step of the route, a Heck reaction between 148 and
2-vinyl-piridine was designed. However, the free NH of
148impaired the reaction. Therefore, the authors decided to
acylate the indazole for both protecting the NH group and
rendering the oxidative addition to palladium easier. The protection
was achieved in situ with Ac2O and when no more than 2% of 148
was present, the Heck reaction was started using 4 mol% of
Pd(OAc)2, 4 mol% of XantPhos and six equivalents of 2-vinyl-
pyridine. When the reaction was completed, 1,2-diaminopropane
(DAP) was added in THF for removal of the protective group and
to chelate the palladium before product crystallization. With this
strategy, 29 kg of axitinib could be obtained with 50% overall yield
in a six steps route.
131. 131. Process for axitinib based on palladium catalyzed Migita
C-S coupling and Heck reaction.Org. Process Res. Dev.2014, 70. ,
1870. , 266.
30
132. 132. This review has highlighted only a small number of
applications of palladium catalysis in organic synthesis, but new
examples are published every month. Each example pushes the
field forwards, towards universal conditions, where application of
them results in a useful yield without prior optimisation. However,
palladium is only one metal; the breadth of catalysis available from
rhodium,[28] ruthenium[29] and platinum based systems extend far
further, and into the realms of metathesis.[30] Frstner has shown
analogous procedures using Iron catalysts,[31] with obvious
economic and toxicity benefits. Palladium Catalysis: Outlook And
Summary 28) For an example of palladium-mimicking rhodium
catalysis, see: M. Lautens and J. Mancuso, Org. Lett. 2002, 4,
2105 29) For a recent review of "atom ecconomic" ruthenium
catalysis, see: B. M. Trost, M. U. Frederiksen, M. T. Rudd, Angew.
Chem. Int. Ed., 2005, 41, 6630 6666. 30) For the complementary
review on Metathesis Reactions in Total Synthesis, see: K. C.
Nicolaou, P. G. Bulger, D. Sarlah , Angew. Chem. Int. Ed., 2005,
41, 4490-4527. 31) A. Frstner, R. Martin, Chem. Lett. 2005, 34,
624-629.
133. 133. All the C-C cross-couplings reaction broadly follow the
same catalytic cycle, which involves number of processes. Heck
reaction follows a slightly different pathway from other C-C
couplings. Rate-determining step depends on the nature of the
electrophile, nucleophile, and the ligands on palladium.
134. 134. The ongoing efforts towards the use of Pd-catalyzed C-C
cross-coupling reactions for the synthesis of drug components or
drug candidates highlighted in this review demonstrated how
powerful these methodologies are. The Suzuki reaction is the most
exploited cross-coupling reactions, especially when the creation of
a biaryl motif is involved. One of the main advantages of this
methodology is the use of air- and water-stable, non-toxic and
ease to manipulate organoboronic acid and its derivatives. Heck
reactions are also intensely exploited for inter or intramolecular
coupling involving Csp double bonds. Despite the success of the
coupling reactions, several challenges need to be overcome in
order to have an economic, robust and reliable industrial process.
Scale-up from the small (medicinal chemistry synthesis) to large
scale usually requires new Pd catalyst precursors and several
modifications to the reaction parameters. From the economic
standpoint, in some cases, the cost of the precious metal
palladium, as well as the ligand itself, can be a problem. There is a
31
 plethora of palladium catalyst precursors described in the literature
that promote the C-C cross-coupling reactions.
135. 135. However, when these reactions need to be applied for
the synthesis of complex molecules such as drug components or
drug candidates, a few simple catalyst precursors are usually the
first choice: Pd(OAc)2, Pd2(dba)3, Pd/C, PdCl2L2, Pd(PPh3)4. For
aryl iodides or some very activated aryl bromides, ligand-free Pd
catalysts can be used. However, in most of the reactions involving
the synthesis of drugs, a phosphine ligand is necessary and
triphenylphosphine is the most frequently used ligand. This cheap
and stable phosphine is usually used already complexed in the Pd
precursor (PdCl2(PPh3)2 and Pd(PPh3)4) or in association with a
simple Pd precursor (Pd(OAc)2 or Pd2(dba)3). When a bidentated
ligand is necessary, dppf or other ferrocenil-based bidentated
phosphine ligands are used, with PdCl2(dppf)2 being the catalyst
precursor of choice. Economically more attractive aryl chlorides
have been used in some cases due to the development of
electron-rich- and steric demanding phosphine ligands. However,
the quest for precursor catalyst and ligands that allow high TON
and turnover frequency (TOF), that would make the process
economically attractive is still a challenge. Another important point
that needs to be taken in account is the contamination of the
product with palladium and the need for further purification steps.
Therefore, practical and feasible catalytic systems that allow the
easy recovery of palladium or coupling reactions involving cheaper
transition metals are welcomed.
136. 136. Recently many C-C coupling reactions catalyzed by
Ni(0), Pt(0), or Cu(I) also. May follow the similar reaction schemes.
Future scope is that various transition metals are available, you
can try some other organic reaction with some other metal and can
lead to be a new Nobel prizes pathway.
137. 137. Metal-Catalyzed Cross-Coupling Reactions, 2nd Edition.
Wiley -Edited by Armin de Meijere, Franois Diederich
https://www.youtube.com/watch?v=B3Oz90EfNO0(Nobel Prize
Lectures in Uppsala 2010 - Chemistry Laureate Ei-ichi Negishi)
138. 138. To take full advantage of Chemical Web content, it is
essential to use several Software:Winzip,Chemscape Chime,
Shockwave, Adobe Acrobat, Cosmo Player, Web Lab Viewer, Paint
Shop Pro, Rasmol, ChemOffice, Quick Time,etc
139. 139. LIONEL MY SON He was only in first standard in school
when I was hit by a deadly one in a million spine stroke called
32
 acute transverse mylitis, it made me 90% paralysed and bound to
a wheel chair, He cried bitterly and we had never seen him so
depressed Now I keep Lionel as my source of inspiration and
helping millions, thanks to millions of my readers who keep me
going and help me to keep my son and family happy. I will live and
die for my family.
140. 140. SUCCESS FORMULA

Transition metals extend the range of organic reactions

Some of the most exciting reactions in organic chemistry make use of

transition metals, and in recent years three Nobel prizes have been
awarded for work in this area.

Just a catalytic amount of palladium is needed to make the reaction go:

the most useful organometallic reactions are those in which the metal
acts catalytically.

Reagents and complexes containing transition metals are important in

modern organic synthesis because they allow apparently impossible
reactions to occur easily.

The 18 electron rule

A simple guide to the stability of transition metal complexes: the 18

electron rule.

There is a simple guide to the stability of transition metal

complexes: the 18 electron rule:
The rule states that thermodynamically
stable transition metal organometalliccompounds are formed whe
n the sum of the metal d eectrons and the electrons conventionally

33
considered as being supplied by the surrounding ligands equals 1
8.

Chromium, for example, forms stable complexes with a benzene

ring, giving it six electrons, and three molecules of carbon
monoxide, giving it two each: 6 + 6 + 2 + 2 + 2 = 18.

Palladium is happy with just four triphenylphosphines (Ph3P:)

giving it two each: 10 + 2 + 2 + 2 + 2 = 18.

There are exceptions to the 18-electron rule, particularly among

complexes of Ti, Zr, Ni, Pd, and Pt, which can all form stable 16-
electron complexes.

The important 16-electron Pd(II) complex with two chlorides and

two acetonitriles (MeCN) is PdCl2(MeCN)2.

Representing bonds in transition metal complexes

34
Ligands can be attached in many different ways

Neutral ligands can also bond in a variety of ways.

Cyclooctatetraene can act as an alkene (2), a diene (4), a triene (6), or a
tetraene (8), and the reactivity of the ligand changes accordingly.

Hapto number: The number of carbon atoms on a group that are attached to the
metal is indicated by the superscript in n.

35
Bonding and reactions in transition metal complexes

36
Oxidative addition inserts metal atoms into single
bonds

Potential ligands that do not have a lone pair or filled -type orbital are
still able to interact with transition metal complexes but only by breaking
a bond. This is the first step in a wide variety of processes and is
described as oxidative addition because the formal oxidation state
of the transition metal is raised by two, for example M(0) to M(II), in the
process. This is the result of having two extra ligands bearing a formal
negative charge. You have seen this process in the formation of
Grignard reagents (Chapter 9).

Oxidative addition of Pd(0) to aryl iodides

Activation of Wilkinsons catalyst for hydrogenation in solution by

oxidative addition to a hydrogen molecule.
37
Vaskas complex

There are a number of possible mechanisms for oxidative addition

and the precise one followed depends on the nature of the reacting
partners.
Vaskas complex [Ir(PPh3)2COCl] has been extensively studied and
it reacts differently with hydrogen and methyl iodide.
Hydrogen is added in a cis fashion, consistent with concerted
formation of the two new iridiumhydrogen bonds. The 16e (count
them!), d8, Ir(I) complex becomes a new 18e, d6, Ir(III) species.
With methyl iodide the kinetic product is that of trans addition,
which is geometrically impossible from a concerted process.
Instead, an SN2-like mechanism is followed involving nucleophilic
displacement of iodide followed by ionic recombination.

The number of co-ordinated ligands also increases by two so the

starting complex is usually in low oxidation state (0 or 1; the
diagram shows 0) and co-ordinatively unsaturated, that is,
it has an empty site for a ligand and, say, only 16 electrons, like
(MeCN)2PdCl2, whereas the product is usually co-ordinatively
saturated, that is, it cannot accept another ligand unless it
loses one first.

SN2
Reductive elimination removes metal atoms and forms new single
bonds

38
Our general reaction shows M(II) going to M(0), releasing XY. These
two ligands were separate in the complex but are bound together in the
product. A new XY bond has been formed.

The ligands to be eliminated must be cis to one another for reductive

elimination to occur. This is because the process is concerted.

Two examples from palladium chemistry make this point clear.

An indole synthesis that depends on a reductive elimination at

palladium as a last step. In the starting material, palladium has two
bonds sharing electrons with C, and is Pd(II). In the reaction the two C
substituents bond together to form the indole ring and a Pd(0) species
is eliminated.

Migratory insertion builds ligand structure

This process involves migration of one of the ligands from the metal to
the other ligand, and insertion of one of the ligands into the other metal
ligand bond. It is known as migratory insertion.
The insertion process is reversible and, as the metal effectively loses a
ligand in the process, the overall insertion may be driven by the addition
of extra external ligands (L) to produce a co-ordinatively saturated
complex.
39
Migration normally occurs with retention; As with reductive
elimination, a cis arrangement of the ligands is required and the
migrating group (X) retains its stereochemistry (if it has any) during the
migration.

Migratory insertion is the principal way of building up the chain

of an organic ligand before elimination. The group to be
inserted must be unsaturated in order to accommodate the
additional bonds and common examples include carbon
monoxide, alkenes, and alkynes, producing metalacyl, metal
alkyl, and metalalkenyl complexes, respectively.
In each case the insertion is driven by additional external ligands, which
may be an increased pressure of carbon monoxide in the case of
carbonylation or simply excess phosphine for alkene and alkyne
insertions

40
This iron anion is a good soft nucleophile for alkyl halides and can be
used twice over to produce first a monoanion with one alkyl group and
then a neutral complex with two alkyl groups and four CO ligands.
Each of these complexes has 18 electrons. If extra CO is added by
increasing the pressure, CO inserts into one FeC bond to form an iron
acyl complex.
Finally,reductive elimination couples the acyl group to the other alkyl
group.

Ph3P is often used instead of an increased CO pressure. The phosphine adds to

the iron and pushes out the poorest ligand (one of the alkyl groups) on to a CO
ligand in a process of ligand migration.

Carbon monoxide incorporation extends the carbon chain

The OXO process is the hydroformylation of alkenes such as propene
and uses two migratory insertions to make higher value aldehydes.

41
Insertion reactions are reversible

The reverse process, decarbonylation, is also fast but can be arrested

by maintaining a pressure of carbon monoxide above the reaction
mixture.
The reverse of hydrometallation involves the elimination of a hydride
from the adjacent carbon of a metal alkyl to form an alkene complex.
This process is known as hydride elimination or simply
elimination. It requires a vacant site on the metal as the number of
ligands increases in the process and so is favoured by the shortage of
ligands in 16-electron complexes.
In more complex structures, the metal and the hydride must be syn to
each other on the carbon chain for the elimination to be possible.

Palladium is a d-block transition metal.

Pd favours the formation of tetrahedral d10 and square planar d8
complexes of low oxidation states (0 and II respectively).
This feature affords Pd good electron-donating and electron-
accepting capabilities, allowing fine-tuning by altering the
electronic properties of its ligands.
Pd may easily participate in concerted processes due to its closely
lying HOMO and LUMO energies.
Pd complexes tend to be less sensitive to oxygen and are less
toxic.

42
 The variety of reactions that can be catalysed by Pd together with
the range of functional groups tolerated, and usually with excellent
chemo- and regioselectivity.

Choice of palladium complex

There are many available complexes of palladium(0) and

palladium(II).
i) Tetrakis(triphenylphosphine)palladium(0),Pd(PPh3)4,
and tris(dibenzylidene-acetone)dipalladium(0), Pd2(dba)3, or
the chloroform complex, Pd2(dba)3CHCl3, which is air-stable, are the
most common sources of palladium(0).
Palladium(II) complexes are generally more stable than their
palladium(0) counterparts. The dichloride PdCl2 exists as a polymer
and is relatively insoluble in most organic solvents. However,
(PhCN)2PdCl2 and (MeCN)2PdCl2 (both easily prepared from PdCl2)
are soluble forms of PdCl2, as the nitrile ligands are readily displaced
in solution. Bis(phosphine)palladium(II) chloride complexes are also
air-stable and readily prepared from PdCl2. Palladium is, of course,
an expensive metalthese complexes cost about 50100 per gram
but very little is needed for a catalytic reaction.

Palladium chemistry is dominated by two oxidation states. The lower,

palladium(0), present in tetrakis(triphenylphosphine)palladium,
for example, is nominally electron-rich, and will undergo oxidative
addition with suitable substrates such as organic halides, resulting in a
palladium(II) complex.
Oxidative addition is thought to occur on the coordinatively unsaturated
14-electron species, formed by ligand dissociation in solution.

43
Carbopalladation (carbon and palladium become attached to the ends
of the alkene system): The resulting PdR bond in such complexes is
very reactive, especially towards carboncarbon bonds. Thus an
alkene in the reacting system will lead to coordination followed by
migratory insertion into the palladiumcarbon bond.
-
With some metals the process of olefin coordination and insertion may
continue, leading to polymerization, but with palladium the metal is
expelled from the molecule by a -hydride elimination reaction and the
product is an alkene, plus a Pd(II) complex.
For the whole process to be catalytic, this Pd(II) product of -hydride
elimination must be converted to a Pd(0).
This occurs in the presence of base, which removes HX from the
palladium(II) species. This is another example of reductive elimination:
one that forms a hydrogen halide rather than a carboncarbon or
carbonhydrogen bond, as you saw earlier.

The speed of the -hydride elimination (which is intramolecular and very

fast) means that the original substrate for the oxidative addition reaction
must be chosen with carethe presence of hydrogen at an sp3 carbon
in the position must be avoided. Thus, substrates for oxidative
addition reactions in palladium chemistry are frequently vinylic, allylic, or
aromatic and never ethyl or n-propyl.
The Heck reaction couples together an organic halide
or trifl ate and an alkene

44
The Heck reaction couples an alkene with an organic halide or triflate
R1X to form a new alkene.

The R1 group in R1X can be aryl, vinyl, or any alkyl group without
hydrogens on an sp3 carbon atom.
The group X can be a halogen (Br or I) or triflate (OSO2CF3).
The alkene can be mono- or disubstituted and can be electron-rich,
-poor, or neutral.
The base need not be at all strong and can be Et3N, NaOAc, or
aqueous Na2CO3.
Trifl ates
Triflates: The triflate (trifluoromethanesulfonate) anion, CF3SO3, or
TfO, is an excellent, non-basic leaving group. It is often used as an
oxygen-based alternative to halides, and metals will insert into the C
OSO2CF3 bond. Triflates, particularly aryl and vinyl triflates, can be
made conveniently with Comins reagent.

The mechanism involves the oxidative addition of the halide, insertion of

the olefin, and elimination of the product by a -hydride elimination
process. A base then regenerates the palladium(0) catalyst. The whole
process is a catalytic cycle.
Organometallic Nobels
Organometallic chemistry has been a popular subject for the
Nobel prize committee. In 1912 Grignard (Mg) won the award, in 1973
Wilkinson and Fischer for sandwich compounds (such as ferrocene), in
2005 Chauvin, Grubbs, and Schrock for alkene metathesis, and in 2010
45
Heck, Negishi, and Suzuki (Stille had died in 1989) for transitionmetal
catalysed couplings.
Ph3P
The Heck coupling between two heterocyclic substrates.
Easy chemistry to do, but impossible without a Pd catalyst.

Notice the regioselectivity: the Heck reaction favours one isomer,

and when the alkene is polarized by an electron-withdrawing group
the new CC bond forms at the other end of the alkene. Notice also
in this example and those below that the Pd is added as Pd(II), not
Pd(0).

The mild conditions of the Heck reaction mean that protected

amino acids can be made without any racemization.
A more hindered analogue of triphenylphosphine is used, but the
mechanism is the same.

In situ formation of Pd(0) by reduction of Pd(II):

In reactions requiring palladium(0), formation of the active complex may
be achieved more conveniently by reduction of a palladium(II) complex,
for example Pd(OAc)2. Any phosphine may then be used in the reaction,
without the need to synthesize and isolate the corresponding
palladium(0)phosphine complex. The reduction of palladium(II) to
palladium(0) can be achieved with amines, phosphines, alkenes, and
organometallics such as DIBAL-H, butyl lithium, or trialkylaluminium.

46
In contrast, electron-donating groups such as ethers lead to attack at
the end of the alkene substituted by oxygen to produce the 1,1-
disubstituted product. These reactions must be dominated
by the interaction of the filled orbital of the alkene with an empty d
orbital on Pd.
In the example below, the Heck reaction works even in the absence of a
phosphine ligand.

Because -hydride elimination is reversible, when there is a choice the

more stable of the possible alkenes usually results. The reaction of
allylic alcohols is particularly important as the more stable of the two
alkenes is the enol and a carbonyl compound is formed.

In the 1990s by Buchwald and Hartwig has shown that Pd can be used

47
to promote nucleophilic substitution at a vinylic or aromatic centrea
reaction which would not normally be possible.
For example, aromatic amines can be prepared directly from the
corresponding bromides, iodides, or triflates and the required amine in
the presence of palladium(0) and a strong alkoxide base.

The mechanisms and catalysts used in this BuchwaldHartwig

chemistry mirror those of coupling reactions involving oxidative addition,
transmetallation, and reductive elimination.
The first step, as usual, is oxidative insertion of Pd(0) into the aryl
halogen bond. The Pd(II) complex now adds the amine so that both
coupling partners fi nd themselves bonded to the same palladium atom.
The base eliminates HI from the complex and reductive elimination
forms the ArN bond.

Various bases, such as t-BuONa, MeONa, LiN(TMS)2, or K2CO3, have

been successful and
some of the most successful ligands (coordinating groups shown in
brown) are shown below.
The fourth structure is a preformed complex used in catalytic amounts.

LiN(TMS)2, or K2CO3,

48
The range of compounds which can be made is very great: both
electron-withdrawing and electron-donating substituents are acceptable;
hindered compounds or those with acidic hydrogens such as phenols
are tolerated. Even aryl chlorides, which are much cheaper than
bromides or iodides, can also be successful.

Aromatic heterocyclic halides also work well whether they are electron-
deficient or electron-rich. These couplings use the more hindered ligand
shown in the margin.

It is tempting to view the amine as the nucleophile in these reactions

but it is clear that nucleophilicity has little to do with it as amides also
couple to aromatic rings under similar conditions. The ability to act as a
ligand for palladium is the important thing. The ligand xantphos is used
in these reactions and again the nature of the substituents on the
benzene ring is of little account. Even strained azetidines react well.

49
Sepracor wanted to make their anti-fungal compound itraconazole,
it was obvious that they should make the two ends with
stereochemistry and join them together with a central achiral
section

The preparation of left hand end part:

The right-hand end of the molecule (we shall call this R2) was coupled
as its bromide to the free NH group by a second BuchwaldHartwig
amination reaction process.

Nucleophilic aromatic substitution and palladium

catalysis compared
You will have noticed that BuchwaldHartwig chemistry accomplishes
the same as nucleophilic aromatic substitution (SNAr): the replacement
of a halogen by a nucleophile.
50
So what are the differences?

The synthesis of a drug to control blood clotting gives us the opportunity

to review both methods. This compound also has a central piperazine
ring and disconnection of the righthand side chain reveals an amine that
could be functionalized by alkylation with a suitable benzylic halide or
reductive amination.
Palladium-catalysed amination of aromatic rings

51
52
18-Electron Rule: In mononuclear, diamagnetic complexes, the
total number of electrons never exceeds 18 (noble gas

53
configuration). The total number of electrons is equal to the sum
of d-electrons plus those contributed by the ligands.

18 electrons = coordinatively saturated

< 18 electrons = coordinatively unsaturated.

General Considerations

Oxidative Addition
54
Originally restricted to aryl and alkenyl halide (Br and I) and sulfonates
(OTf), or substrates without -hydrogens. -hydride elimination is fast
above 20 C. New catalysts systems have allowed chloride substrates
and those with -hydrogens to be used. Stereochemistry conserved
with alkenyl halides.
Order of reactivity: I > OTf > Br >> Cl

alkenylOTf >> arylOTf

Transmetallation & Reductive Elimination

Most always the rate-limiting step. If the coupling does not work well, it
is this step that is likely to blame.
Exact mechanism is poorly understood. Both metals must benefit
energetically from this step. Additives are often required to promote.
Metals used: Li, Mg, Zn, Zr, B, Al, Sn, Si, Ge, Hg, Tl, Cu, In, Bi, Ga, Ti,
Ag, Mn, Sb, Te, Ni

Reductive elimination is faster than -hydride elimination so sp2 and sp3

organometallics are compatible.

Usually proceeds with retention of stereochemisty on both organic

partners.

Catalysts
Wide range of ligands have been used, but phosphines are generally
required for the oxidative addition step. Both bidentate and
monodentate ligands can be used. Influence can be profound.
Experimentation is often required. Pd(0) is required for O.A., but these
catalysts can be quite air sensitive. Fortunately, Pd(+2) is easily
reduced to Pd(0) by CO, ROH, R3N, alkenes, phosphines, and main
group organometallics. Pd(PPh3)4 ("tetrakis") is commonly used along
with Pd2(dba)3/phosphine.

"Polarity" of components
The electronics of the aryl halide and organometallic partner are
important as well.
The aryl halide can be considered to be an "electrophile", while the
organometallic can be considered to be a "nucleophile".

55
Oxidative addition into electron-deficient aryl halides is faster than
electron-rich.
If one component must be electron-rch, consider using that as the
organometallic, or use very electronrich ligands to make the catalyst
more nucleophilic.

The mechanism of palladium-catalysed cross-coupling starts, as in the

Heck reaction, with oxidative addition of the halide or trifl ate to the
initial palladium(0) phosphine complex to form a palladium(II) species.
But the next step is new: it is a transmetallation, so called
because the nucleophile (R1) is transferred from the metal in the
organometallic reagent to the palladium and the counterion (X=halide or
trifl ate) moves in the opposite direction. The new palladium(II) complex
with two organic ligands undergoes reductive elimination to give the
coupled product and the palladium(0) catalyst, ready for another
cycle.

The halide partner (R2X) must be chosen with care, as -hydride

elimination would decompose the first intermediate during the slow
transmetallation step.

The choice for R2 is restricted to substituents without -hydrogen atoms

on sp3 carbon atoms: vinyl, allyl, benzyl, and polyfluoroalkyl halides,
triflates, and phosphates have all been coupled successfully.

The organometallic reagent (R1M) can be based on magnesium, zinc,

copper, tin, silicon, zirconium, aluminium, or boron and the organic
fragment can have a wide variety of structures as coupling is faster than
-hydride elimination.

(R2X) R1-M or R1-C=C)

56
Organometallics 1 and 2: Oxford Primers, OUP, Oxford,1994. A book
that does contain mechanisms of a number of the
reactions in this book, as well as others, is
P. Wyatt and S. Warren, Organic Synthesis: Strategy and Control,
Wiley, Chichester, 2007.
Probably the best comprehensive account is
J. Hartwig, Organotransition Metal Chemistry, University Science
Books, New York, 2010.
The Ullmann reaction or Ullmann coupling is a coupling
reaction between aryl halides and copper.

A typical example is the coupling of 2 o-chloronitrobenzene reactants to form 2,2'-

dinitrobiphenyl with a copper - bronze alloy.

The traditional version of the Ullmann reaction requires:

i) harsh reaction conditions,
ii) reaction is limited to electron deficient aryl halides
iii) the reaction has a reputation for erratic yields.
Since its discovery some improvements and alternative procedures
have been introduced.
The reaction probably involves the formation of an organocopper
compound (RCuX) which reacts with the other aryl reactant in a nucleophilic
aromatic substitution.
57
 Wurtz-Fittig reaction, a similar reaction useful for alkylbenzenes synthesis

Theory-III

1-Bromo-4-chloro-2-nitrobenzene

58
59
Dominic Chan; Patrick Lam

60
The large scale synthesis of BINAP.

Ref.: Org. Synth. 2000, 76, 6.

61
62
63
64
65
Bombykol is a sex pheromone secreted by the female silkworm moth Bombyx
mori to attract mates. Bombykols structure was elucidated in 1959 using 6.4 mg
of material obtained from 500,000 silkworm moths. One step in an effi cient
synthesis of bombykol is the Suzuki reaction, a stereospecific carboncarbon
bond-forming reaction between a vinylborane and a vinyl halide to form a
conjugated diene.

References:
i) J. Hartwig, Organotransition Metal Chemistry, University Science
Books, New York, 2010.
66
 ii) M. Bockmann, Organometallics 1 and 2: Oxford Primers, OUP,
Oxford, 1994.
iii) P. Wyatt and S. Warren, Organic Synthesis: Strategy and
Control, Wiley, Chichester, 2007.
iv) Leading references for the Buchwald and Hartwig chemistry:
a) J. F. Hartwig and group, Angew. Chem. Int. Ed., 2005, 44,
1371;
b) S. L. Buchwald and group, Organic Letters, 2005, 7, 3965.

to

67