Baran Group Meeting
1/31/2007
Fischer Carbene Complexes in Organic Synthesis
Ernst Otto Fischer (1918 - )
Other Types of Stabilized Carbenes:
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.
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
Ke Chen
Me
CH2N2
(CO)5W
Me
(CO)5W
OMe
O
high oxidation states
early transition metals Ti(IV), Ta(V)
non pi-acceptor ligands
non pi-donor substituents
Representatives:
CH2
Cp2Ta
CH3
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.
E. O. Fischer, A. Maasbol, Angew. Chem. Int. Ed., 1964, 3, 580.
Representative Fischer Carbenes:
W(CO)5
Me
OMe
Cr(CO)5
Ph
Ph
Fe(CO)4
Ph
NEt2
Mn(CO)2(MeCp)
Ph
OTiCp2Cl
Co(CO)3SnPh3
Me
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.
1
Baran Group Meeting
1/31/2007
Fischer Carbene Complexes in Organic Synthesis
Advantages over regular carbenes
- From fleeting intermediates to powerful reagents
2. Excellent functional group compatibility - serving as blocking groups
in organic synthesis.
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 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.
Ke Chen
OMe
OTMS
OMe
[Cr]
BuLi, THF, -78 oC
Ph
3 equiv of CH2CHCH2Li, THF
-78 oC to RT, then SiO2
[Cr]
O
Et
O
71 %
Ph
H
Et
J. Barluenga. J. Am. Chem. Soc. 2002, 124, 9056 -9057.
3. Improved reactivity and selectivity
Cr(CO)5
Cr(CO)5
RT, 3 h
MeO
Cr(CO)5
MeO
MeO
70 %
92
:
O
MeO
MeO
thermal conditions: RT, 7 months, 54 %
AlCl3, 0.5 h , 50 %
8
O
O
http://www.chemistry.msu.edu/faculty/wulff/myweb26/research/carbenes.htm
H
[Cr]
75 %
Et
Ph
MeO
70
:
30
95
:
5
W. Wulff. J. Am. Chem. Soc. 1990, 112, 3642.
2
Baran Group Meeting
1/31/2007
Fischer Carbene Complexes in Organic Synthesis
Synthesis of Fischer carbene complexes:
2. Hegedus-Semmelhack approach
1. Standard Fischer route
M(CO)6
R1Li
O
OLi
OR2
RX
(OC)5M
(OC)5M
R1
M = Cr, Mo, W
R1 = alkyl, aryl, vinyl
RX = R23O+BF4-, R2OSO3F
R3, R4 = H, alkyl
M(CO)6
C8K
K2[M(CO)5]
R1
HS
NR3R4
(OC)5M
R1
R1
OK
(OC)5M
R2X
OR2
(OC)5M
R1
R1
NR3R4
O(OC)5M
R2
O
O-NMe4+
(OC)5M
R1
R1
O
X
R2
NR3R4
TMSCl
NR3R4
(OC)5M
R1
R1
This is the most direct and general approach to Fischer carbene
complexes;
Limitations are the availability of organolithium compound
and the alkylation reagent.
(OC)5M
Cl
R4
(OC)5M
Me4N+Br-
R1
O
R3
HN
R3
SR3
OLi
Ke Chen
R1
M = Cr, W
R1 = alkyl, aryl, vinyl
R2X = R23O+BF4-, R2OSO3F
R3, R4 = H, alkyl
This strategy combining an organoelectrophile and a metal nucleophile
can be extended to the synthesis of aminocarbene complexes.
O
(OC)5M
R1
M = Cr, W
R1 = alkyl, aryl, vinyl
R2 = Me, tBu
X = Br, Cl
R3 = terpene, sugar skeletons
R3OH
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.
OR3
(OC)5M
R1
This is the standard approach to optically active Fischer carbene
complexes bearing alkoxy substituents.
3
Baran Group Meeting
1/31/2007
Fischer Carbene Complexes in Organic Synthesis
Reaction pattern of carbene complexes:
Part I: Ligand-centered
Pattern B: Bond formation via metal carbene anions
OR
OR
(OC)5M
OMe
(OC)5M
R
O
R
OMe
(OC)5Cr
R
O
pKa = 12
C
OC
CO
OC Cr
OC
CO
A
N
B
OH
CH3
1. nBuLi
2. PhCHO
3. HOAc / Ce(IV)
O
Nu
H
pKa = 25
H3C
E
CR2
Ke Chen
N
(OC)4Cr
B
Ph
Ph
O
N
Ph
60 %, > 96 % de
CH3
O
N
CH3
CH3
W. Wulff, J. Org. Chem., 1994, 6882.
Pattern A: Addition of nucleophiles
OMe
OMe
NH2R
(OC)5Cr
(OC)5Cr
Ph
OMe
- MeOH
H
(OC)5Cr
NHR
Ph
NHR
Ph
(OC)5Cr
1. nBuLi
2.
OMe
O
(OC)5Cr
(OC)5Cr
O
OLi
B. A. Anderson, J. Am. Chem. Soc., 1993, 115, 4602.
OMe
O
OLi
(OC)5Cr
O
Ph
THF, -80 oC to RT Ph
Li
50 %
Pattern C: Transformation of metal carbenes to metal carbynes
O
Cr(CO)5
J. Barluengal, J. Chem. Soc., Chem. Commun. 1993, 1068
OMe
N
(OC)5Cr
Ph
Ph
?
MeO
N
Cr(CO)5
For reviews on reaction pattern of carbene complexes, see "Carbene Chemistry : From Fleeting
Intermediates to Powerful Reagents", chapter 8.
H. Fischer, Chem. Ber. 1980, 113, 193
4
Baran Group Meeting
1/31/2007
Reaction pattern of carbene complexes:
Diels-Alder reaction of boroxycarbene complexes:
Part I: Ligand-centered
Cycloaddition reactions:
OMe
RT, 12 h
(OC)5W
CH3
N
CH3
(OC)5W
87 %
1. t-BuLi, Et2O
(OC)5Cr
2. Cr(CO)6, Et2O
Br
OMe
OMe
[2 + 2]
Ke Chen
Fischer Carbene Complexes in Organic Synthesis
O
F
B
Ph
F
N
.
3. BF3 Et2O, RT
H3CO
1.THF, -78 oC to RT
85%
2. 3N HCl, THF, RT
95 %
K. L. Faron, J. Am. Chem. Soc. 1988, 110, 8727 -8729.
[3 + 2]
TMSCHN2
hexanes, RT
OMe
(OC)5W
OMe
CH3
N
NH
O
HBr, DCM, RT
F
B
F
N
85 %
N
H3C
(OC)5Cr
CHO
(OC)5W
4.5 h, 87 %
N
Me
O
O
W. D. Wulff, J. Am. Chem. Soc. 1986, 108, 5229 -5236.
[4 + 2]
H 3C
CH3 TBSO
N
J. Barluenga. J. Am. Chem. Soc. 1998, 120, 2514 -2522.
H3C
CH3
N
O
O
N
Ph
(OC)4Cr
OCH3
DCM, RT, 12 h
80 %,single isomer
N
(OC)4Cr
Miscellaneous cases
Ipc
Ph
CH3
OLi
(OC)5W
(-) -Ipc2BCl, Et2O
Ph
O
B
H
-78 oC to RT
CH3O
Ph
CH3
OTBS
W. D. Wulff, J. Am. Chem. Soc. 1997, 119, 6438 -6439.
H2O2, NaOH
83 %, > 99 % de
J. Barluenga, J. Am. Chem. Soc,, 1996, 118, 6090 -6091.
Intramolecular Pauson -Khand reaction:
NH
(OC)5W
[Co2(CO)8]
75 %
(OC)5W
Ph
OH
O
OH
Ph
Ph
J. M. Moreto. Angew. Chem. Int. Engl. 1991, 11,1470.
5
Baran Group Meeting
1/31/2007
Reaction pattern of carbene complexes:
OMe
Part II: Metal-centered
(OC)5Cr
(OC)4Cr
R2
R2
"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."
Cr(CO)5
Olefin Metathesis
Cyclopropanation
Me
Et
OMe
R, H. Grubbs, Organometallics. 2002, 21, 2153 -2164.
OC
Cp
Fe
OC
H
OC
Cp
Fe
Cr(CO)5
CH2
Me
OMe
Ph
Cr(CO)5
Cr(CO)5
OMe
OMe
Et
MeO
Ph
W(CO)5
OMe
Ph
H
(leads to olefin
metathesis product)
Me
55 %
MeO
Et
favored
Et
MeO
R
(CO)4
R
Cr(CO)4
H
H
Me
MeO
Et
Cr
(CO)4
Mo(CO)5
Bu
Cr
H
H
H
Me
W(CO)5
THF, 100oC
H
General carbene complexes used in cyclopropanation reactions:
R*Ph2P
Fe
OR1
OR1
(OC)4Cr
R2
H
88 %, 97 % de
Fe
OR1
OMe
DMF, 152 oC
1. Reaction with olefins
(OC)5Cr
Ke Chen
Fischer Carbene Complexes in Organic Synthesis
R
MeO
R
Et
Cr(CO)4
MeO
disfavored
J. Am. Chem. Soc. , 113, 23, 1991, 8916-8921
OMe
(less stable )
O
O
Cr(CO)5
Suitable olefins:
Alkyl
R1
R3
R2
EWG
EWG
R1, R2 and R3 = alkyl
requires stronger
electrophilic metal carbenes
Cl
R1
Alkyl
EWG
Et
R1
R2
OMe
R2
O
o
intermediate 85 C,12 h
A
85 %
O
O
R1, R2 = akyl, aryl
Chemtracts - Organic Chemistry. 17, 67 -71, 2004
6
Baran Group Meeting
1/31/2007
Ke Chen
Fischer Carbene Complexes in Organic Synthesis
Reaction pattern of carbene complexes:
Part II: Metal-centered
OMe O
2. Benzannulation (Dotz reaction)
O
Cr(CO)5
Cr(CO)5
OMe O
ether, reflux
OH
O
nPr
51 %
Cr(CO)4
- CO
OMe
OMe
O
M. F. Semmelhack, Tetrahedron, 1985, 5803.
+ CO
RS
RL
RS
RL
OCPh3
TBSCl, hunig base
(OC)5Cr
Cr(CO)3
> 92 % d. e.
RS
O
OTBS OCPh3
OMe
RL
OMe
Cr(CO)3
OMe
RS
RL
OC
Cr(CO)4
OTBS
Cr CO
OC CO
OMe
W. D. Wulff, J. Am. Chem. Soc,, 1994, 116, 6449.
OMe
minimization
of interaction
O
O
OMe
MeO
Cr(CO)5
35 %
RL
O
RL
RS
Cr(CO)3
OMe
HO
RS
O
TBSO
O
BnO
Cr(CO)3
OMe
O
O
EtO
OMe OTBS
N
MeO
Suitable metal:
Compatible substitution pattern:
Cr (metal of choice)
Mo ( furan formation occasionally)
W (favor 3 + 2 cycloaddtion)
Mg (low yields)
Aryl carbenes with various substituents
Naphthyl and heteroaryl carbenes
Vinyl carbenes bearing alkyl substituents
Electron - neutral alkynes with various
substituents
fredericamycin A
O
O
OH
OTBS
BnO
EtO
N
D. L. Boger, J. Am. Chem. Soc,, 1995, 11839.
7
Baran Group Meeting
1/31/2007
Ke Chen
Fischer Carbene Complexes in Organic Synthesis
Me
Reaction pattern of carbene complexes:
OMe
Part II: Metal-centered
MeO
(OC)5Cr
O
O
Me
OMe
CH3
3. General Annulation of Fischer carbenes with alkynes and alkenes:
13 %
Organometallics, 1990, 9, 3014 - 3015
10 %
OMe
(OC)5Cr
H
CO2Et
CH3
CO2Et
66 %
OMe
Bu
J. Am. Chem. Soc. 1994, 116, 6719 - 6732
OMe
O
Ph
O
OMe
(OC)5Cr
CH3
C 3H 7
Ph
CH3
O
CH3
O
THF, 105 C, 15h
CH3
OMe
Ph
CH3
OMe
THF, 70 oC, 14 h, 40 %
18 %
Me
Me
Ph
TMSO
Me
OTMS
THF, 90 oC
71 %
O
O
Me
MeO
Ph
CH3
(OC)5Cr
Ph
Ph
OEt
NMe2
Me
Ph
J. Barluenga, Org. Lett., 2006, 8, 2703 -2706.
CH3OMe
J. Am. Chem. Soc. 1990, 112, 1645 - 1647
Ph
OMe
O
O
CH3
(OC)5Mo
J. Am. Chem. Soc. 1991, 113, 5459 - 5461
(OC)5Cr
Ph
Ph
OMe
OMe
H
J. Am. Chem. Soc. 1992, 114, 10665 - 10666
O
Ph
48 %
O
CO, 73 %, d. r. = 3 :1
O
O
O
o
O
THF, 70 oC, 24 h
(OC)5Cr
SiMe3
Angew. Chem. 1999, 111, 1369
3 Ph
EtO
Ph
THF
EtO
NMe2
Ph
64
Ph
Ph
:
NMe2
36
8
Baran Group Meeting
1/31/2007
Fischer Carbene Complexes in Organic Synthesis
Ke Chen
State of art:
Group 6 metal carbenes in catalytic carbene transfer reactions
OMe
OMe
(OC)5M
multi-faced
chemistry
L nM
R
R
M = Pd, Cu, Rh
M = Cr, W
stable, storable, less reactive
NMe2
reactive, unstable
O
CO2Me
(OC)5Cr
2 mol %Pd(OAc)2, Et3N
THF, reflux, 8 h, 80 %
CO2Me
Daniel F. Harvey
Br
Jose Barluenga
Br
M. A. Sierra, J. Am. Chem. Soc., 2001, 123, 851 -861.
1. [Cu(MeCN)4][PF6], DCM
2. DCM, Et2O
O
(OC)5Cr
O
J. Barluenga, Angew. Chem. Int. Ed., 2001, 40, 3392.
MeCN
O
PF6
Cu
Et2O
William D. Wulff
O
Louis S. Hegedus
9