Fischer Carbene Complexes in Organic Synthesis
1
A.B. Charette J. Am. Chem. Soc. 2001, 123, 11829.
Baran Group Meeting1/31/2007
Ke Chen
German inorganic chemist. Born in Munichon November 10, 1918. Studied at MunichTechnical University and spent his careerthere. Became director of the inorganicchemistry institute in 1964. In the 1960s,discovered a metal alkylidene and alkylidynecomplexes, referred to as Fischer carbenesand Fischer carbynes. Shared the Nobel Prizein Chemistry with Geoffery Wilkinson in 1973,for the pioneering work on the chemistry oforganometallic compounds.
Ernst Otto Fischer (1918 - )
Isolation of first transition-metal carbene complex:
(CO)5W CO
LiMe
(CO)5W
Me
O
CH2N2(CO)5W
Me
OMe
E. O. Fischer, A. Maasbol, Angew. Chem. Int. Ed., 1964, 3, 580.
Representative Fischer Carbenes:
Me OMe
W(CO)5
Ph Ph
Cr(CO)5
Ph NEt2
Fe(CO)4
Ph OTiCp2Cl
Mn(CO)2(MeCp)
Me OMe
Co(CO)3SnPh3
Comparision of Fisher Carbene and Schrock carbene:
Schrock carbenes are found with:
high oxidation states early transition metals Ti(IV), Ta(V) non pi-acceptor ligands non pi-donor substituents
Schrock carbene, named after Richard R. Schrock, is nucleophilic at the carbene carbon atom in an unpaired triplet state.
Representatives:
Cp2Ta
CH2
CH3
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.
Persistent carbenes, isolated as a crystalline solid by Anthony J. Arduengo in 1991, can exist in the singlet state or the triplet state.
Foiled carbenes were defined as "systems where stabilization isobtained 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.
Other Types of Stabilized Carbenes:
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.
Fischer Carbene Complexes in Organic Synthesis
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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.
Most Fischer carbene complexes are stable to air and water and todilute acids and bases. Despite the high dipole moment of thesecomplexes (~ 4 - 5 Debye), most complexes can be purified bychromatography on silica gel with hexane as eluent and are usuallythe first compounds to elute. Identification of the fractions from thecolumn containing the carbene complex can simply be done by eyeon the basis of their color. The colors of complexes bearing alkoxygroups as the heteroatom-stabilizing group tend to correlate with the hybridzation of the carbon substituent of the carbene carbon. Thosewith sp3 carbons usually are yellow, those with sp2 carbons arenormally red and those with sp hybridized carbon substituents areinvariably an intense purple/black color.
2. Excellent functional group compatibility - serving as blocking groups in organic synthesis.
J. Barluenga. J. Am. Chem. Soc. 2002, 124, 9056 -9057.
3. Improved reactivity and selectivity
MeO
Cr(CO)5
RT, 3 h
70 %
MeO
Cr(CO)5
MeO
Cr(CO)5
MeO
O
thermal conditions: RT, 7 months, 54 %
MeO
O
MeO
O
92 : 8
70 : 30
W. Wulff. J. Am. Chem. Soc. 1990, 112, 3642.http://www.chemistry.msu.edu/faculty/wulff/myweb26/research/carbenes.htm
AlCl3, 0.5 h , 50 % 95 : 5
[Cr]
OMe
Ph
OTMS
Et
Ph O
[Cr]
OMe
Et
O[Cr]
Ph EtH
H
BuLi, THF, -78 oC
75 %
3 equiv of CH2CHCH2Li, THF
-78 oC to RT, then SiO2
71 %
Fischer Carbene Complexes in Organic Synthesis
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Ke Chen
Synthesis of Fischer carbene complexes:
1. Standard Fischer route
M(CO)6
R1Li(OC)5M
OLi
R1
RX(OC)5M
OR2
R1
HNR3
R4
HS R3
(OC)5M
SR3
R1
(OC)5M
NR3R4
R1
M = Cr, Mo, W
R1 = alkyl, aryl, vinyl
RX = R23O+BF4
-, R2OSO3F
R3, R4 = H, alkyl
(OC)5M
OLi
R1
Me4N+Br-
(OC)5M
O-NMe4+
R1
X R2
O
(OC)5M
O
R1
R2
O
R3OH
(OC)5M
OR3
R1
M = Cr, W
R1 = alkyl, aryl, vinyl
R2 = Me, tBu
X = Br, Cl
R3 = terpene, sugar skeletons
2. Hegedus-Semmelhack approach
M(CO)6
C8KK2[M(CO)5]
R1 Cl
O
(OC)5M
OK
R1
R2X(OC)5M
OR2
R1
(OC)5M
O-
R1
R1 NR3R4
O
NR3R4
TMSCl(OC)5M
NR3R4
R1
M = Cr, WR1 = alkyl, aryl, vinyl
This is the most direct and general approach to Fischer carbenecomplexes;Limitations are the availability of organolithium compoundand the alkylation reagent.
This is the standard approach to optically active Fischer carbenecomplexes bearing alkoxy substituents.
R2X = R23O+BF4
-, R2OSO3F
R3, R4 = H, alkyl
This strategy combining an organoelectrophile and a metal nucleophilecan be extended to the synthesis of aminocarbene complexes.
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. 469L. S. Hegedus, ibid., vol. 12, p. 549.
Fischer Carbene Complexes in Organic Synthesis
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Ke Chen
Reaction pattern of carbene complexes:
OC
Cr
CO
OC
OC CO CR2
O R
H
E
Nu
B
C
A
B
(OC)5M
OR
R
(OC)5M
OR
R
Part I: Ligand-centered
Pattern A: Addition of nucleophiles
(OC)5Cr
OMe
Ph
NH2R(OC)5Cr
OMe
PhNHR
H(OC)5Cr
NHR
Ph
- MeOH
(OC)5Cr
OMe
Ph
NMeO
Ph
Cr(CO)5
N
?
(OC)5Cr
OMe
OPh
OLi
Li
O
O
Ph
Cr(CO)5
THF, -80 oC to RT
50 %
J. Barluengal, J. Chem. Soc., Chem. Commun. 1993, 1068
H. Fischer, Chem. Ber. 1980, 113, 193
Pattern B: Bond formation via metal carbene anions
(OC)5Cr
OMe 1. nBuLi
2. O
(OC)5Cr
OMe
OLi
(OC)5Cr
O
(OC)5Cr
OMe
O
OMe
pKa = 12 pKa = 25
(OC)4Cr
N
CH3
N
O
H3C
Ph
CH31. nBuLi2. PhCHO3. HOAc / Ce(IV)
60 %, > 96 % de
N
O
N
O
Ph
OH
Ph CH3
CH3
Pattern C: Transformation of metal carbenes to metal carbynes
W. Wulff, J. Org. Chem., 1994, 6882.
B. A. Anderson, J. Am. Chem. Soc., 1993, 115, 4602.
For reviews on reaction pattern of carbene complexes, see "Carbene Chemistry : From Fleeting Intermediates to Powerful Reagents", chapter 8.
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Ke Chen
Reaction pattern of carbene complexes:
Part I: Ligand-centered
Cycloaddition reactions:
[2 + 2]
(OC)5W
OMe
CH3
OMe
RT, 12 h
87 %
CH3
OMe
(OC)5W
H3CO
[3 + 2]
K. L. Faron, J. Am. Chem. Soc. 1988, 110, 8727 -8729.
(OC)5W
OMe
CH3
TMSCHN2
hexanes, RT
4.5 h, 87 %
(OC)5W
OMe
N
NH
H3C
W. D. Wulff, J. Am. Chem. Soc. 1986, 108, 5229 -5236.[4 + 2]
(OC)4Cr
N
N
O
H3C
Ph
CH3
DCM, RT, 12 h80 %,single isomer
CH3
OCH3
TBSO
(OC)4Cr
N
N
O
H3C
Ph
CH3
OTBS
CH3
CH3O
W. D. Wulff, J. Am. Chem. Soc. 1997, 119, 6438 -6439.
Diels-Alder reaction of boroxycarbene complexes:
Br
N
1. t-BuLi, Et2O
2. Cr(CO)6, Et2O
3. BF3. Et2O, RT
N
BO
F
F(OC)5Cr
N
Me
Ph
1.THF, -78 oC to RT
85%
2. 3N HCl, THF, RT
95 %
N
BO
F
F(OC)5Cr
O
HBr, DCM, RT
85 %
CHO
N
O
J. Barluenga. J. Am. Chem. Soc. 1998, 120, 2514 -2522.
Intramolecular Pauson -Khand reaction:
(OC)5W
NH
Ph
[Co2(CO)8]
75 %
(OC)5W Ph
O
J. M. Moreto. Angew. Chem. Int. Engl. 1991, 11,1470.
Fischer Carbene Complexes in Organic Synthesis
Miscellaneous cases
(OC)5W
OLi (-) -Ipc2BCl, Et2O
-78 oC to RT
BOH
Ipc
H2O2, NaOH83 %, > 99 % de
Ph
Ph
OHOH
Ph
J. Barluenga, J. Am. Chem. Soc,, 1996, 118, 6090 -6091.
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Ke Chen
Reaction pattern of carbene complexes:
Part II: Metal-centered
(OC)5Cr
OR1
R2
(OC)4Cr
OR1
R2
(OC)4Cr R2
OR1
Olefin MetathesisCyclopropanation
1. Reaction with olefins
"The functionalized Ru Fischer-typecomplexes are active in a variety ofolefin metathesis reactions, althoughwith significantly lower rates than the corresponding carbon analogues."
General carbene complexes used in cyclopropanation reactions:
Fe
Cp
OC
R*Ph2PH
Me
Fe
Cp
CH2OC
OCCr(CO)5
Me OMe
W(CO)5
Ph OMe
W(CO)5
Ph H
Mo(CO)5
Bu OMe
Cr(CO)5
Ph OMe
Cr(CO)5
OMe
(leads to olefinmetathesis product)
(less stable )
Suitable olefins:
EWG EWGAlkyl
EWG
Alkyl
R2
R1R2
R1
R1, R2 = akyl, aryl
R2
R1
R3
R1, R2 and R3 = alkylrequires stronger
electrophilic metal carbenes
R, H. Grubbs, Organometallics. 2002, 21, 2153 -2164.
Cr(CO)5
Me OMeEt
THF, 100oC
55 %
Me
MeO
H
Et
CrEt
MeO
H
R
(CO)4
H
REt
MeOCr(CO)4
CrMeO
Et
H
R
(CO)4
H
RMeO
EtCr(CO)4
Me
MeO
H
Et
J. Am. Chem. Soc. , 113, 23, 1991, 8916-8921
(OC)5Cr
OMe
Fe
DMF, 152 oC
88 %, 97 % de Fe
H
OMe
Cr(CO)5
OMe
O
Cl 85oC,12 hO
O
O
Chemtracts - Organic Chemistry. 17, 67 -71, 2004
Fischer Carbene Complexes in Organic Synthesis
85 %
intermediate A
favored
disfavored
O
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Ke Chen
D. L. Boger, J. Am. Chem. Soc,, 1995, 11839.
Fischer Carbene Complexes in Organic Synthesis
2. Benzannulation (Dotz reaction)
OMe
Cr(CO)5
OMe
Cr(CO)4
RS RL
OMe
Cr(CO)4
RS
RLOMe
RSRL
CrOC CO
OC CO minimizationof interaction
OMe
RS
O
RL
O
RL
RS
OMe
Cr(CO)3
Cr(CO)3HO
RL
RS
OMe
Cr(CO)3
Reaction pattern of carbene complexes:
Part II: Metal-centered
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 substituentsNaphthyl and heteroaryl carbenesVinyl carbenes bearing alkyl substituents
Electron - neutral alkynes with varioussubstituents
OMe
Cr(CO)5
O Oether, reflux
OMe O
O
nPr
O OH
51 %
(OC)5Cr
OMe OCPh3 TBSCl, hunig base
OTBS OCPh3
Cr(CO)3> 92 % d. e.
MeO
OO
Cr(CO)5
OMe
OO
NEtO
TBSO
OTBS
OO
MeO
OO
OMe
OH
OTBS
N
OTBSBnO
EtO
fredericamycin A
OMe
BnO
35 %
M. F. Semmelhack, Tetrahedron, 1985, 5803.
W. D. Wulff, J. Am. Chem. Soc,, 1994, 116, 6449.
- CO
+ CO
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Baran Group Meeting1/31/2007
Ke ChenFischer Carbene Complexes in Organic Synthesis
3. General Annulation of Fischer carbenes with alkynes and alkenes:
Reaction pattern of carbene complexes:
Part II: Metal-centered
(OC)5Cr
CH3
OMe
O
PhC3H7
THF, 105 oC, 15h
O
CH3
OMeCH3
Ph
O
O
CH3
OMeCH3
Ph
O
48 % 18 %
J. Am. Chem. Soc. 1991, 113, 5459 - 5461
(OC)5Cr
CH3
OMe
O
Me
MeOO
OMeMe
13 % 10 %Organometallics, 1990, 9, 3014 - 3015
CO2Et
(OC)5Cr
CH3
OMe H
Bu
OMe
CO2Et
66 %
J. Am. Chem. Soc. 1994, 116, 6719 - 6732
(OC)5Cr
Ph
OMe
O
O THF, 70 oC, 24 h
CO, 73 %, d. r. = 3 :1
O
O OMe
Ph
H
J. Am. Chem. Soc. 1992, 114, 10665 - 10666
(OC)5Mo
OMe
Me
Ph
O
CH3
THF, 70 oC, 14 h, 40 %
O
CH3
Ph
O
CH3OMe
J. Am. Chem. Soc. 1990, 112, 1645 - 1647
(OC)5Cr
OEt
SiMe3
NMe2Ph
THF
3EtO
Ph
Ph
Ph
NMe2
EtO
Ph
Ph
Ph
NMe2
64 : 36Angew. Chem. 1999, 111, 1369
(OC)5Cr
OMe
Ph
MeMe
TMSO OTMS
THF, 90 oC
71 %
O O
Ph
Ph
MeO Me
Me
J. Barluenga, Org. Lett., 2006, 8, 2703 -2706.
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Ke ChenFischer Carbene Complexes in Organic Synthesis
State of art:
Group 6 metal carbenes in catalytic carbene transfer reactions
(OC)5M
R
OMe
M = Cr, W
stable, storable, less reactive
LnM
R
OMe
M = Pd, Cu, Rh
reactive, unstable
multi-faced chemistry
(OC)5Cr
O
O
1. [Cu(MeCN)4][PF6], DCM2. DCM, Et2O
Cu
O
O
Et2O
MeCN
PF6J. Barluenga, Angew. Chem. Int. Ed., 2001, 40, 3392.
(OC)5Cr
NMe2
Br
CO2Me
2 mol %Pd(OAc)2, Et3N
THF, reflux, 8 h, 80 %
O
CO2Me
Br
M. A. Sierra, J. Am. Chem. Soc., 2001, 123, 851 -861.
Louis S. Hegedus
William D. Wulff
Daniel F. Harvey Jose Barluenga