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
