Baran Group Meeting 1/31/2007

Fischer Carbene Complexes in Organic Synthesis

Ernst Otto Fischer (1918 - ) German inorganic chemist. Born in Munich on November 10, 1918. Studied at Munich Technical University and spent his career there. Became director of the inorganic chemistry institute in 1964. In the 1960s, discovered a metal alkylidene and alkylidyne complexes, referred to as Fischer carbenes and Fischer carbynes. Shared the Nobel Prize in Chemistry with Geoffery Wilkinson in 1973, for the pioneering work on the chemistry of organometallic compounds. Other Types of Stabilized Carbenes:

Ke Chen

Schrock carbene, named after Richard R. Schrock, is nucleophilic at the carbene carbon atom in an unpaired triplet state. Comparision of Fisher Carbene and Schrock carbene:

Schrock carbenes are found with: Isolation of first transition-metal carbene complex:
LiMe
(CO)5W CO (CO)5W O
E. O. Fischer, A. Maasbol, Angew. Chem. Int. Ed., 1964, 3, 580.

Representatives:
CH2 Cp2Ta CH3

Me

CH2N2

Me (CO)5W OMe

high oxidation states early transition metals Ti(IV), Ta(V) non pi-acceptor ligands non pi-donor substituents
A.B. Charette J. Am. Chem. Soc. 2001, 123, 11829.

Persistent carbenes, isolated as a crystalline solid by Anthony J. Arduengo in 1991, can exist in the singlet state or the triplet state.

Representative Fischer Carbenes:

W(CO)5 Me OMe Ph Cr(CO)5 Ph Ph Fe(CO)4 NEt2 Ph Mn(CO)2(MeCp) OTiCp2Cl Me Co(CO)3SnPh3 OMe

Fischer carbenes are found with : low oxidation state metals; middle and late transition metals Fe(0), Mo(0), Cr(0), W(0); pi-electron acceptor metal ligands; pi-donor substituents on methylene group such as alkoxy and amino groups.

Foiled carbenes were defined as "systems where stabilization is obtained by the inception of the facile reaction which is foiled by the impossibility of attaining the final product geometry". They only exist in the singlet state.
Rolf Gleiter, Ronald Hoffman J. Am. Chem. Soc. 1968, 90, 5457 - 5460. Jean-Luc Mieusset and Udo H. Brinker J. Am. Chem. Soc. 2006, 128, 15843 - 15850.

Baran Group Meeting 1/31/2007

Fischer Carbene Complexes in Organic Synthesis

Ke Chen

Advantages over regular carbenes - From fleeting intermediates to powerful reagents 1. Improved stability Typical carbenes such as diphenyl carbene have lifetimes in the nanosecond regime.

2. Excellent functional group compatibility - serving as blocking groups in organic synthesis.

OTMS OMe [Cr] Ph OMe Ph H O

BuLi, THF, -78 oC

Et

[Cr] Et

75 %

Most Fischer carbene complexes are stable to air and water and to dilute acids and bases. Despite the high dipole moment of these complexes (~ 4 - 5 Debye), most complexes can be purified by chromatography on silica gel with hexane as eluent and are usually the first compounds to elute. Identification of the fractions from the column containing the carbene complex can simply be done by eye on the basis of their color. The colors of complexes bearing alkoxy groups as the heteroatom-stabilizing group tend to correlate with the hybridzation of the carbon substituent of the carbene carbon. Those with sp3 carbons usually are yellow, those with sp2 carbons are normally red and those with sp hybridized carbon substituents are invariably an intense purple/black color.

3 equiv of CH2CHCH2Li, THF -78 oC to RT, then SiO2 71 %

[Cr]

Ph

Et

J. Barluenga. J. Am. Chem. Soc. 2002, 124, 9056 -9057.

3. Improved reactivity and selectivity

Cr(CO)5 MeO Cr(CO)5 Cr(CO)5 MeO

RT, 3 h 70 %

MeO

92
O MeO MeO O

:
O MeO

thermal conditions: RT, 7 months, 54 % AlCl3, 0.5 h , 50 %

http://www.chemistry.msu.edu/faculty/wulff/myweb26/research/carbenes.htm

70 95

: :

30 5

W. Wulff. J. Am. Chem. Soc. 1990, 112, 3642.

Baran Group Meeting 1/31/2007

Fischer Carbene Complexes in Organic Synthesis

Ke Chen

Synthesis of Fischer carbene complexes: 1. Standard Fischer route

M(CO)6 R1Li
OLi (OC)5M R1 HS R3 HN R4 SR3 (OC)5M R1 (OC)5M R1 NR3R4

2. Hegedus-Semmelhack approach
O

RX

OR2 (OC)5M R1 R3

M(CO)6

C8K

K2[M(CO)5]
O R1

R1

Cl

OK (OC)5M R1

R2X

OR2 (OC)5M R1

M = Cr, Mo, W R1 = alkyl, aryl, vinyl RX = R23O+BF4-, R2OSO3F R3, R4 = H, alkyl

NR3R4

O(OC)5M NR3R4 R1

TMSCl

NR3R4 (OC)5M R1

This is the most direct and general approach to Fischer carbene complexes; Limitations are the availability of organolithium compound and the alkylation reagent.
O OLi (OC)5M R1 R2 O X R2 (OC)5M R1 O

M = Cr, W R1 = alkyl, aryl, vinyl R2X = R23O+BF4-, R2OSO3F R3, R4 = H, alkyl

Me4N+Br-

O-NMe4+ (OC)5M R1

This strategy combining an organoelectrophile and a metal nucleophile can be extended to the synthesis of aminocarbene complexes.

M = Cr, W R1 = alkyl, aryl, vinyl R2 = Me, tBu X = Br, Cl R3 = terpene, sugar skeletons
(OC)5M

Recent reviews:
W. D. Wulff, in Comprehensive Organometallic Chemistry II, ed. A. W. Abel, F. G. A. Stone and G. Wilkinson, pergamon Press, Oxford, 1995, vol. 12, p. 469 L. S. Hegedus, ibid., vol. 12, p. 549.

R3OH
OR3 R1

This is the standard approach to optically active Fischer carbene complexes bearing alkoxy substituents.

Baran Group Meeting 1/31/2007

Fischer Carbene Complexes in Organic Synthesis

Ke Chen

Reaction pattern of carbene complexes: Part I: Ligand-centered

(OC)5M R OR (OC)5M R OR

Pattern B: Bond formation via metal carbene anions

OMe (OC)5Cr O OMe

C
OC CO OC Cr OC CO O R

pKa = 12
H3C N O N (OC)4Cr CH3 Ph CH3

pKa = 25
OH O N Ph O N CH3

E Nu

CR2 H

1. nBuLi 2. PhCHO 3. HOAc / Ce(IV) 60 %, > 96 % de

Ph

CH3

W. Wulff, J. Org. Chem., 1994, 6882.

Pattern A: Addition of nucleophiles

OMe (OC)5Cr Ph

OMe OMe - MeOH H (OC)5Cr NHR Ph O NHR Ph (OC)5Cr

1. nBuLi 2.
O

OMe (OC)5Cr OLi (OC)5Cr

NH2R

(OC)5Cr

OMe (OC)5Cr O Ph OLi Li

B. A. Anderson, J. Am. Chem. Soc., 1993, 115, 4602.

THF, -80 oC to RT Ph 50 %
O Cr(CO)5

Pattern C: Transformation of metal carbenes to metal carbynes

J. Barluengal, J. Chem. Soc., Chem. Commun. 1993, 1068

OMe (OC)5Cr Ph N

?
MeO

Ph N Cr(CO)5
H. Fischer, Chem. Ber. 1980, 113, 193 For reviews on reaction pattern of carbene complexes, see "Carbene Chemistry : From Fleeting Intermediates to Powerful Reagents", chapter 8.

Baran Group Meeting 1/31/2007

Fischer Carbene Complexes in Organic Synthesis

Diels-Alder reaction of boroxycarbene complexes:
Br CH3 N

Ke Chen

Reaction pattern of carbene complexes: Part I: Ligand-centered Cycloaddition reactions:

[2 + 2]
(OC)5W OMe OMe

OMe

1. t-BuLi, Et2O (OC)5Cr 2. Cr(CO)6, Et2O 3. BF3 Et2O, RT

.

F B N F

Ph

N Me

RT, 12 h 87 %

(OC)5W H3CO

CH3

K. L. Faron, J. Am. Chem. Soc. 1988, 110, 8727 -8729.

[3 + 2]
OMe (OC)5W

1.THF, -78 oC to RT 85% 2. 3N HCl, THF, RT 95 %

CHO N O (OC)5Cr O F B N O
J. Barluenga. J. Am. Chem. Soc. 1998, 120, 2514 -2522.

TMSCHN2 hexanes, RT 4.5 h, 87 %

OMe (OC)5W NH H3C N

HBr, DCM, RT 85 %

CH3

[4 + 2]
H 3C N O N (OC)4Cr Ph CH3 TBSO

W. D. Wulff, J. Am. Chem. Soc. 1986, 108, 5229 -5236.

H3C N O OCH3 N (OC)4Cr CH3O OTBS

W. D. Wulff, J. Am. Chem. Soc. 1997, 119, 6438 -6439.

CH3 Ph CH3

Miscellaneous cases
Ipc OLi (OC)5W Ph

(-) -Ipc2BCl, Et2O -78 oC to RT

Ph

DCM, RT, 12 h 80 %,single isomer

CH3

J. Barluenga, J. Am. Chem. Soc,, 1996, 118, 6090 -6091.

Intramolecular Pauson -Khand reaction:

NH (OC)5W

H2O2, NaOH 83 %, > 99 % de

OH OH

[Co2(CO)8] 75 %
Ph

(OC)5W

Ph O Ph

J. M. Moreto. Angew. Chem. Int. Engl. 1991, 11,1470.

Baran Group Meeting 1/31/2007

Fischer Carbene Complexes in Organic Synthesis

OMe (OC)5Cr

Ke Chen

Reaction pattern of carbene complexes: Part II: Metal-centered 1. Reaction with olefins
OR1 (OC)5Cr R2 (OC)4Cr R2 OR1 (OC)4Cr OR1 R2

DMF, 152 oC Fe 88 %, 97 % de

OMe H

Fe

"The functionalized Ru Fischer-type complexes are active in a variety of olefin metathesis reactions, although with significantly lower rates than the corresponding carbon analogues."
R, H. Grubbs, Organometallics. 2002, 21, 2153 -2164.

Cr(CO)5

THF, 100oC
Et

Me MeO H Et MeO R

H Et

Olefin Metathesis

Cyclopropanation

Me

OMe

55 %

favored

H Et MeO Cr (CO)4 H OMe MeO Et Cr (CO)4 R MeO Et R Cr(CO)4 H R

General carbene complexes used in cyclopropanation reactions:

R*Ph2P OC Cp Fe Me W(CO)5 Ph OMe Ph W(CO)5 H Bu Mo(CO)5 OMe H OC OC Cp Fe CH2 Me Cr(CO)5 OMe Ph Cr(CO)5 OMe Cr(CO)5

Cr(CO)4 Me MeO H Et

disfavored

J. Am. Chem. Soc. , 113, 23, 1991, 8916-8921

(leads to olefin metathesis product) Suitable olefins:

(less stable )
O Cr(CO)5 Alkyl R1 R1 R2 R2 O Cl OMe
o intermediate 85 C,12 h A 85 %

O O O

EWG R1 R3 R2

Alkyl

EWG

EWG

R1, R2 and R3 = alkyl requires stronger electrophilic metal carbenes

R1, R2 = akyl, aryl

Chemtracts - Organic Chemistry. 17, 67 -71, 2004

Baran Group Meeting 1/31/2007

Reaction pattern of carbene complexes: Part II: Metal-centered
2. Benzannulation (Dotz reaction)
Cr(CO)5 OMe

Fischer Carbene Complexes in Organic Synthesis

Ke Chen

OMe O

O Cr(CO)5

ether, reflux 51 %

OMe O

OH nPr

Cr(CO)4

- CO + CO

OMe

M. F. Semmelhack, Tetrahedron, 1985, 5803.

RS RL RS O Cr(CO)3 OMe RL OC OC CO RL O RS Cr(CO)3 OMe HO RL RS Cr(CO)3 OMe OMe RS Cr CO RL

RL RS Cr(CO)4
W. D. Wulff, J. Am. Chem. Soc,, 1994, 116, 6449.

OTBS OCPh3 OMe (OC)5Cr OCPh3

TBSCl, hunig base > 92 % d. e.

OMe Cr(CO)3

OMe OTBS

minimization of interaction

O MeO

OMe Cr(CO)5 TBSO BnO OMe OTBS EtO N

35 %

O MeO

Suitable metal: Cr (metal of choice) Mo ( furan formation occasionally) W (favor 3 + 2 cycloaddtion) Mg (low yields)

Compatible substitution pattern: Aryl carbenes with various substituents Naphthyl and heteroaryl carbenes Vinyl carbenes bearing alkyl substituents Electron - neutral alkynes with various substituents
O O OH OTBS BnO EtO N

fredericamycin A

D. L. Boger, J. Am. Chem. Soc,, 1995, 11839.

Baran Group Meeting 1/31/2007

Reaction pattern of carbene complexes: Part II: Metal-centered

Fischer Carbene Complexes in Organic Synthesis

Me OMe (OC)5Cr CH3
Organometallics, 1990, 9, 3014 - 3015

Ke Chen

MeO

Me

OMe

3. General Annulation of Fischer carbenes with alkynes and alkenes:

13 %
OMe (OC)5Cr CO2Et CH3 H

10 %

CO2Et OMe Bu

66 %
J. Am. Chem. Soc. 1994, 116, 6719 - 6732

OMe (OC)5Cr Ph O OMe (OC)5Cr CH3 C 3H 7

o

O O

THF, 70 oC, 24 h CO, 73 %, d. r. = 3 :1

H

O O OMe

O O Ph

CH3

O O

CH3

J. Am. Chem. Soc. 1992, 114, 10665 - 10666

Ph O O CH3OMe

Ph

THF, 105 C, 15h

CH3 OMe

Ph

CH3 OMe

OMe (OC)5Mo

Ph CH3

48 %
J. Am. Chem. Soc. 1991, 113, 5459 - 5461

18 %

THF, 70 oC, 14 h, 40 %
Me

Ph CH3

Ph OMe (OC)5Cr Ph Me Me

J. Am. Chem. Soc. 1990, 112, 1645 - 1647

THF, 90 oC 71 %
MeO

O Me Me (OC)5Cr

OEt NMe2 SiMe3

Angew. Chem. 1999, 111, 1369

Ph

Ph Ph EtO Ph

3 Ph THF

EtO

TMSO

OTMS

Ph
J. Barluenga, Org. Lett., 2006, 8, 2703 -2706.

Ph

NMe2

Ph

NMe2

64

36

Baran Group Meeting 1/31/2007

State of art:

Fischer Carbene Complexes in Organic Synthesis

Ke Chen

Group 6 metal carbenes in catalytic carbene transfer reactions

OMe (OC)5M R L nM R OMe

multi-faced chemistry

M = Cr, W stable, storable, less reactive

NMe2 (OC)5Cr

M = Pd, Cu, Rh reactive, unstable

O CO2Me Br

CO2Me

2 mol %Pd(OAc)2, Et3N THF, reflux, 8 h, 80 %

Br
M. A. Sierra, J. Am. Chem. Soc., 2001, 123, 851 -861.

Daniel F. Harvey

Jose Barluenga

O (OC)5Cr O

1. [Cu(MeCN)4][PF6], DCM 2. DCM, Et2O

J. Barluenga, Angew. Chem. Int. Ed., 2001, 40, 3392.

MeCN Cu Et2O

PF6
O

William D. Wulff Louis S. Hegedus