Chem 206D. A. Evans
Matthew D. Shair Friday, December 13 , 2002
http://www.courses.fas.harvard.edu/~chem206/
Reading Assignment for this Lecture:
Introduction to Carbenes & Carbenoids-1
Chemistry 206
Advanced Organic Chemistry
Lecture Number 34
Introduction to Carbenes & Carbenoids-1
a73 Carbene Structure & Electronics a73 Methods for Generating Carbenes
a73 Simmons-Smith Reactiona73 Carbene-Olefin Insertions
a73 Carbene Rearrangements
Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of Lactones and Lactams, Aldrichchimica Acta. 1996, 29, 3
Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W., 1971.
Books:Modern Catalytic methods for Organic Synthesis with Diazo Compounds;
M. P. Doyle, Wiley, 1998.
Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 10, "Reactions Involving Highly Reactive
Electron-Deficient Intermediates", 595–680.
Provide a mechanism for the following transformations.
O
N
O N2
CO2EtCH
3 O
O
NH3C
EtO2C
CO2Me
CO2Me
MeO2C CO2Me
O
N
O N2
CO2EtCH
3 CO2MeMeO2C
OON
CH3EtO2C
1. Rh2(OAc)4
2.MeO2C CO2Me
JACS 1990 2037
O H OHN
2
150?C
(71%)
Useful References to the Carbene Literature
Lecture 09A Simmons-Smith Reaction: Enantioselective VariantsLecture 26B Synthetic Applications of α-Diazocarbonyl Compounds
Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 9, " C–C Bond Forming Rxns of Boron, Silicon
& Tin", 595–680.
Ligand Effects on the Chemoselectivity of Transition Metal Catalyzed Rxns of α-diazocarbonyl Compnds" Padwa et al.Angew Chem Int Ed. 1994, 33, 1797
"Stable Carbenes–Illusion or reality"? Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674
Rh2(OAc)4
Chem 206Carbenes: An IntroductionD. A. Evans
Mandatory Reading:
Doyle, Chem Rev. 1988, 86, 919.Kodadek, Science, 1992, 256, 1544.
Recent Review Article:Chemistry of Diazocarbonyls: McKervey et al. Chem Rev. 1994, 94, 1091.
Carbenes and Nitrenes in "Reactive Molecules: The Neutral Reactive Intermediates in Organic Chemistry", Wentrup, C. W. 1984, Wiley, p. 162.
Rearrangements of Carbenes and Nitrenes in Rearrangements in Ground & Excited States, Academic Press, DeMayo ed., Jones, W. M. 1980, p. 95.
Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W., 1971.
Books:Modern Catalytic methods for Organic Synthesis with Diazo Compounds;
M. P. Doyle, Wiley, 1998.
H
H HH
Carbenes: Electronic Structure
Triplet (two unpaired e-) Singlet (all e- paired)
p
σ σ
p
a73 Carbene Configuration: Triplet vs. Singlet
Often has radical-like character Often has electrophilic or nucleophilic character: A-type
(Ambiphilic)
p
Energ
y σ
Due to electron repulsion, there is an energy cost in pairing both electrons in the σ orbital. If a small energy difference between the σ and p orbitals exists, the electrons will
remain unpaired (triplet). If a large gap exists between the σ and p orbitals theelectrons will pair in the σ orbital (singlet).
singlet
1.078 ?
133.8?
8–10 kcal/mol
T1
S1
a73 Carbene Configuration: Triplet vs. Singlet
p σ
triplet
a73 the History of the Singlet-Triplet Gap
Method HCH Angle S–T Splittingkcal/molAuthorYear
Qual. 90-100° ––Muliken1932
Grnd State
singlet
Thermochem 180° smallWalsh1947 triplet
160° 30Gallup1957 tripletQual. QM
138° >33Harrison1969 tripletAb initio
–– 8–9Hase1971 tripletKinetics
19Pople1971 tripletSCF 132°
8.7Dewar1974 tripletMINDO 134°
19.5Lineberger1976 tripletExpt 138°
19.7Schaeffer1976 tripletAn Initio –––
8.1Zare1978 tripletExpt –––
8.5Haydon1982 tripletExpt –––
(Wentrup)
a73 Nitrene
R N
Singlet (all e- paired)
empty
filled
filled R N H
empty
filled
a73 Nitrenium ion
H
Chem 206Carbenes: Structure and Generation
C
Cl
Cl
Cl
H CClCl
C C ORR
Me
MeMe
N N
Ts
H Me
MeMe
N N Me
MeMe
N N
Me
MeMe
H
Ts
MeMe
Me
a73 Alkyl Halides:
heat or hν R2C +
a73 ketenes
a73 Bamford-Stevens Reaction: See Lecture 28 on HydrazonesShapiro Org. Rxns. 1976, 23, 405.
-Ts
R1
R2 N N
R1
R2 N N
R1C
R2
R1
R2 N N
Rh RhO
O
Me
Rh Rh
O O
Me
R1
R2 N
N
Rh RhO
O
Me
a73 diazo compounds hν or heat
R1
R2 Rh
RhO O
Me
+ N2
R1
R2
N
N
R2
R1
a73 metal-catalyzed decomposition Doyle Chem Rev. 1988, 86, 919.
diazirines
hν or heat
Chem. Soc. Rev. 1982, 11, 127.
carbenoid
(ligands omitted forclarity)C
R
R
Cl
H CRR
Methods of Synthesis
The p orbital of carbenes substituted with p-donor atoms (N, O, halogen) is raised high enough in energy to make the pairing of the electrons in the σ orbital energetically
favorable. As a result, these carbenes are often in the singlet state.
CClCl
Heteroatom-Substituted Carbenes: Singlets
p
tripletcarbene
σ
Energy
donor porbital
pi-donorheteroatomHeteroatom-substitutedcarbene
Examples: Singlet CHC
6H5
Singlet
M. Shair, D. A. Evans
CO
OH
OR
-N2
Rh2(OAc)4 -N2OH
Chem 206M. Shair, D. A. Evans Carbenes: Structure and Generation
N
N H
N
N
N
N
N
N
N
N
NaH, THF
cat. tBuOK
a73 "Stable Carbenes"
Arduengo et al. J. Am. Chem. Soc. 1991, 113, 361; 1992, 114, 5530.
(89%)
Arduengo et al. J. Am. Chem. Soc. 1994, 116, 6812, Neutron diffraction study:
Arduengo argues that these resonance structures are not players based on electron distribution from neutron diffraction.
For reviews on the subject, see: Regitz, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 725.
Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674.
These are nucleophilic carbenes which display high stability.
+
R
R
R
R
R
R H2C
R
R H2C
R
R
R
RH2C
R
R
a73 Cyclopropanation The Skell Rule:
H2C
R
R
+1
R
R
3
a73 Simmons-Smith Cyclopropanation (See Tedrow hanndout 09B)
OH
Triplet carbenes add non-stereospecifically
OH
>99:1 diastereoselectivity
Skell and Woodworth JACS, 1956, 78, 4496.
S
NMe Me
Au
F F
F
FF
H. G. Raubenheimer Chem. Comm. 1990, 1722.
X–ray Structure
Singlet carbenes add to olefins stereospecifically;
Simmons, H.; Smith, R. J. Am. Chem. Soc., 1958, 80, 5323.
The intermediate organometallic reagent: I–CH2–Zn–I
OH OH
150:1 cis : trans 75% yield
Winstein & Sonnenberg, JACS 1961, 91, 3235
Zn(Cu)
CH2I2
"Stable Carbenes–Illusion or reality"? Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674
Cl
ISC
ISC
CH2
CH2
CH2I2
Zn(Cu)
Chem 206M. Shair, D. A. Evans The Simmons-Smith Reaction
Me
OH
Me Me Me
OH
OMe OMe
For an review of the directed Simmons-Smith, see:with A. Hoveyda and G. Fu Chem. Rev. 1993, 93, 1307.
Me
Me
OH Me
Me
OH >99:1 diastereoselectivity
>50 : 1 diastereoselection
O Me OBnOBn
HOOMe
Me
O Me OBnOBn
HOOMe
Me
a73 Hydroxyl directivity is a powerful atribute of the S–S Rxn
Charette, A. B. JACS 1991, 113, 8166.
a73 The Furakawa Simmons-Smith Variant
Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53
Et2Zn, CH2I2
Solvent
PhEt2Zn, PhCHI2ether, rt 69% syn : anti 94 : 6
Furukawa, J.; Kawabata, N.; Fujita, T. Tetrahedron, 1970, 26, 243
Et–Zn–Et I–CH2–I+ 2 I–CH2–Zn–Et
OHR3R2
R1
OHR3R2
R1NHSO2R
NHSO2R(0.12 eq.)
ZnEt2, CH2I2
66-82 % ee
Kobayashi, et al. Tetrahedron Lett. 1994, 35, 7045.For a Lewis Acid catalyzed process in which the rate of the catalyzed process is
faster than the uncatalyzed, see: Charette, A. B. JACS 1995, 117, 11367.
a73 Catalytic Asymmetric Cyclopropanation:
Me R
O
N O
OH
OH
N
HNO O
NH
O
R =
Me
MeR =
Charrette, A. B.; J. Am. Chem. Soc.1996, 118, 10327. Falck J. Am. Chem. Soc.1996, 118, 6096.
Barrett, JOC, 1996, 61, 3280.
a73 Applications in Synthesis
no diastereoselectivity
>99:1 diastereoselectivity
O
O
Me Cl
OOH
OMe
HMeMeO
O
MeO NHOMe
Me
O
H
Calipeltoside A
Et2ZnCF3COOH
CH2I2
Cl
OO
Cl
OO 50:1 diastereoselectivity
New SS variant: see Shi, Tet. Lett 1998, 39,
8621
with Burch Org. Lett. 2001, 3, 503
For a recent general review of the Simmons-Smith reaction see: Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001)
CH2I2
Zn(Cu)
CH2I2
Zn(Cu)
Zn(Cu)
CH2I2
Et2Zn
CH2I2
H
FR-900848U-106305
Chem 206Carbenoids: Cyclopropanation
TBSO Me OO N2 TBSO
O
H
Me O
H H
TBSO
OMe O
H H TBSO
OMe OH
H H
HOMe
OH
CO2Me
O
O
H
1. Br2
2. DBU
Antheridic Acid
Corey & Myers JACS 1985, 107, 5574.
McKervey et al. JCS PTI, 1991, 2565.
N2
CO2Me CO2Me
Me
AcO Me
O
N2
Me
AcO Me O
O Me
Me
OTBS
H
Me
MeH
OH H
O
OMe
OMe
O2N OMe
Me
O N
2
a73 Buchner Reaction
OMe
OMe
O2N
cat.
confertin
CO2H
OMe
Me
(84%)
a73 Wolff Rearrangement
Evans et al. J. Org. Chem. 1993, 58, 471. (+) Macbecin
Cu(I)
O
THPO
O
N2
CO2Me
THPO
O CO2Me
O
THPO
O CO2Me
O
Cu Powder
a73 Synthetic Applications
130?C, Xylenes
CuLi prostaglandins2
Et2O, -12?C Corey and Fuchs JACS 1972, 94, 4014.
CO2Me
retention
1,3-shift
M. Shair, D. A. Evans
Et2AlCl Rh2(OAc)4
AgOBz
H2O
Chem 206D. A. Evans Carbenes: Enantioselective Cyclopropanation
N2
CO2Et
Ph Ph
N2
CO2BHT
Ph CO2BHT
CO2Et
Ph
N
O
N
OMe Me
Me3C CMe3
Rh2(OAc)4 cat.
For a detailed mechanistic study which provides supportingevidence for the intermediacy of a Rh carbene, see:
Kodakek, Science, 1992, 256, 1544.
a73 Catalytic Asymmetric Variants:Chiral Cu(I) Complexes
L*
L* =
99% ee94:6 trans/cis
Evans, et al. J. Am. Chem. Soc. 1991, 113, 726.
**
RR
R EtO
2C N2 R CO2Etent-6b a, R = Ph, >99% ee
b, R = Me, >99% ee
+
a73 Mechanism
There is no definitive evidence for metal-catalyzed cyclopropanation and the possibility that metallacyclobutane intermediates are involved cannot be
ruled out.
N ON
O Me
MeCu
Me3C
Me3C
N ON
O Me
MeCu
Me3C
Me3CCO
2R
R R+ +
+
R ReductiveElimination
H HR
HCO2RRH H
N ON
O Me
MeCu
Me3C
Me3CCO
2R
H H
O
O N2
nPr
O
O
nPrH
HH
Rh Rh
O N
NPh
O
CO2MeH
(5 mol %)
95% eeDoyle et al. Tetrahedron Lett. 1995, 36, 7579.
a73 Catalytic Asymmetric Variants:Chiral Rh(II) Complexes
How do these complexes really work??
CuOTf
CuOTf
N2CHCO2R
–OTf
–OTf
–OTf
-N2
CH2Cl2
Chem 206D. A. Evans Carbenes: Enantioselective Cyclopropanation
a73 The Carbene Complex
O
O N2
nPr
O
O
nPrH
HH
Rh RhO N
NPh
O
CO2MeH
(5 mol %)
95% eeDoyle et al. Tetrahedron Lett. 1995, 36, 7579.
a73 Catalytic Asymmetric Variants:Chiral Rh(II) Complexes
CO2Me
Doyle, JACS 1993, 115, 9968
Rh Rh
O N
NO HCO
2Me
CO2MeH
ONH
ON
H
MeO2C
Note N–O trans influence
Rh
N
O
O N12 34 Numbers designate increasing steric
hindrance in each quadrant
27B
favored by 3 kcal/mol
CO2Me
Rh Rh
O N
NO HCO
2Me
CO2MeH
ONH
ON
H
MeO2C C H
CO2Me
CO2Me
HPh
H
styrene
CO2Me
HH
Ph48%ee
86%ee
variable ligand
CH2Cl2
27A
Chem 206Carbenes: Rearrangements
H
HH
C BrBr C
C13
a73 Carbene-Carbene Rearrangements
Wu, Tetrahedron Lett. 1973, 3903.
C13
[1,2]
a73 Skattebol Rearrangement
Tetrahedron Lett. 1973, 2283.
a73 Other Rearrangements
Schecter, J. Am. Chem. Soc. 1971, 93, 5940.
O H OH
O
O
N2
O
O
N2
N
OTBS
TIPS
Teoc
Br
BrO
O Ph
Ph N
OTBS
TIPS
Sammes, Chem. Comm. 1975, 328.
Teoc
150?C
O
O
a73 Vinylidenes
Ph
Ph
Corey-Fuchs: Danishefsky et al. J. Am. Chem. Soc. 1996, 118, 9509.
2 eq. BuLi-78?C
(81%)
(71%)
(92%)
O H O H⊕
M. Shair, D. A. Evans
200?C O
O
BuLi
Chem 206Carbenes: Rearrangements
a73 Carbene Rearrangements
25?C
Me P(OEt)2
O
N2
O
CHO
OMOM
MeO2C
OMOM
MeO2C
N
O
I+Ph N
O
I+Ph
SO2Ar
N
O SO
2Ar N
O
+
(83%)
Bestmann, et al. Synlett 1996, 521.
(63%)
CH2Cl2, 20?C
-PhI
Stang et al. J. Am. Chem. Soc. 1994, 116, 93.
Me Me OH
Me H
Me MeH
Me
O Me MeH
Me H
H
capnellene
620?C
P(OEt)2
N2
OH BuLi
–78 °C C NR
H N
CRHR C C H
P(OEt)2
N2
O
R
OLi
H MeO
O MeMe
O
P(OEt)2
N2
OH
–78 °C
KO-t-Bu OO Me
Me
Me68%Gilbert, JOC 1983, 48, 5251
Me Me OH
Me H H
620?C Me
Me OH
Me H
H
carbene intermediates are accessible at high temperatures, more later!
CH insertion
M. Shair, D. A. Evans
vinylidenecarbene
K2CO3
MeOH
OTf NaSO2Ar
RCHO
–N2
Chem 206Carbenes: Rearrangements
a73 C–H Insertions continued...
Me
O N2
CO2Me
O
CO2Me
Me
N
CO2Me
N2
O
O
N
CO2Me
O
OH
O
O N
2 O OH
HRh RhO N
NPh
O
CO2MeH
(83%)
(75%)
Stork Tetrahedron Lett. 1988, 29, 2283.
Electrophilic carbenes are very sensitive to electronic effects
99%, 97% ee
Sulikowski, J. Org. Chem. 1995, 60, 2326.
(5 mol %)
Enantioselective C-H Insertion
Doyle, JACS 1994, 116, 4507
H H
N
H
O
Me H
HO
O
CO2PNB
N
H
O
Me H
HO
O
CO2PNB
N
H
O
Me H
HO
S
CO2
NH3
thienamycin
Salzmann, JACS, 1980, 102, 6163.
a73 N–H Insertions are also possible...
N–H
H
O
Me H
HO
CO2PNBO
N2
HR2
R1
R3 A
B
HR2
R1
R3 A
B
Insertions (X-H): Stereochemical outcome
R2 R1
R3 B A
H
Taber JACS, 1996, 107, 196.
O
CO2Me
Me PhMe Ph
MeO2C O
N2 H
M. Shair, D. A. Evans
δ+δ+ δ+δ+
Retention
Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of Lactones and Lactams, Aldrichchimica Acta. 1996, 29, 3
Rh2(OAc)4
CuOTf
CH2Cl2
Rh2(OAc)4
Rh2(OAc)4
Chem 206Carbenes: Rearrangements
hν
R O
H
H
N2O R
O
H
H C O
H
R CO2Et
OHH
N
S
CO2Me
H
O
O
N2
N
S
CO2Me
H
O
N H
O
Me
Me O N2
Me
OMe
(88%
hν
Tetrahedron Lett. 1990, 31, 6589.
iPr2NH
Moore et al. J. Org. Chem. 1983, 48, 3365.
Ring Contraction
Ring Opening
Wolff-[2+2]
hν
J. Org. Chem. 1980, 45, 2708. (74%)
(81%)
N2
Li TMS Br
N2
TMSR
TMSR
TMS
R
[1,2]-Rearrangements
Aoyama Chem. Pharm. Bull. 1989, 37, 2261.
Me
Me Me
N2O Cu(I)MeOH
Me Me
CO2Me
Vinylolgous Wolff Rearrangement Doyle pp520-521
Me
Me
Me Me O Me Me
CMe O
H
Me
Me C OH δ +
M. Shair, D. A. Evans
EtOH HOEt
Rh2(OPIV)4
CuOTf