Chem 206

D. A. Evans
Introduction to Carbenes & Carbenoids-1
D. A. Evans
Friday
December 15 , 2006
Reading Assignment for this Lecture:
Chemistry 206
Advanced Organic Chemistry
Lecture Number 34
Introduction to Carbenes & Carbenoids-1
!Carbene Structure & Electronics
!Methods for Generating Carbenes
!Simmons-Smith Reaction
!Carbene-Olefin Insertions
!Carbene Rearrangements
Carey & Sundberg, Advanced Organic Chemistry, 4th Ed.
Part B Chapter 10, "Reactions Involving Highly Reactive
Electron-Deficient Intermediates", 595–680.
Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of
Lactones and Lactams, Aldrichchimica Acta. 1996, 29, 3 (handout)
McKervey, Organic Synthesis with !-Diazocarbonyl Compounds, Chem. Rev. 1994, 94,
1091-1160 (electronic handout)
Doyle, Catalytic Methods for Metal Carbene Transformations, Chem. Rev. 1986, 86,
919-939 (electronic handout)
Muller, Catalytic Enantioselective Aziridinations & Asymmetric Nitrene Insertions,
Chem. Rev. 2003, 103, 2905-2919 (electronic handout)
http://www.courses.fas.harvard.edu/colgsas/1063
Problems Database Keywords: Carbenes & Carbenes + rearrangements
Books: Modern Catalytic methods for Organic Synthesis with Diazo
Compounds; M. P. Doyle, Wiley, 1998.
Provide a mechanism for the following transformations.
Useful References to the Carbene Literature
Problem 410: Automerization of Naphthalene (The Cume Question from Hell!)
!–
13
C-labeled C
10
H
8
is isomerized into "–
13
C-labeled C
10
H
8
at 1035 °C
#
Rationalize
Scott, L.T., et. al., JACS 113 7082 (1991)
Corannulene 10%
! 10
-4
Torr
1000° C
L. T. Scott, JACS 1991, 113, 9692.
Problem 411: Provide a Mechanism for this Transformation
Problem 411: While investigating the reactivity of !-diazoketones, Padwa and
co-workers (Tetrahedron Lett. 1993, 49, 7853) discovered the interesting
reaction of diazoketone 1 under the conditions shown below. Provide a
detailed mechanism for the formation of spirocycle 2.
O
CHN
2
O
N
N
MeO
2
C
MeO
2
C
O
O
MeO
2
C CO
2
Me
1
Rh(II)octanoate
45-70%
1:1 mixture of
diastereomers
2
Br
Br
H
H
CH
3
Li
Et
2
O
Lechner and Christl described this interesting, albeit unintended degradation of 1 upon treatment with methyllithium
(Angew. Chem. Int. Ed. 1975, 765). These studies were undertaken en route to tetrahedrane, although the ultimate
goal was never realized.
Please provide a mechanism for this transformation.
Problem 405 Problem 405
Stoltz and co-workers recently reported the interesting rearrangement illustrated below (JACS 2003, 125, 13624).
MeO
Me
O
AgOBz, Et
3
N
THF, 45 °
N
2
Me
MeO
O
Please provide a mechanism for the illustrated transformation. Your answer should include clear 3-D drawings where
relevant and should provide the stereochemistry of the major product diastereoisomer.
H
95% yield
Problem Problem 332 332
Problem Problem 47 47
N
H
N
H
N
O
Bn
N N
H
N
O
O
Me
MeO
2
C
OH
N
O
O N
2
Bn
N
H
N
H
Wood recently reported a very clever approach to the synthesis of the indolocarbazole family of natural products
(JACS 1995, 117, 10413). His approach to the indolocarbazole core is the one-pot transformation outlined below.
pinacolone, 120 °C
58% yield
Provide a plausible mechanism for this multi-step transformation in the space below.
Rh
2
(OAc)
2
Chem 206 Carbenes: An Introduction
D. A. Evans
Suggested 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
H
H
Carbenes: Electronic Structure
Triplet (two unpaired e
-
)
Singlet (all e
-
paired)
p
! !
p
! Carbene Configuration: Triplet vs. Singlet
Often has radical-like character
Often has electrophilic or
nucleophilic character: A-type
(Ambiphilic)
1.078 Å
133.8˚
! Nitrene
R N
Singlet (all e
-
paired)
empty
filled
filled R N
H
empty
filled
! Nitrenium ion
H
p
E
n
e
r
g
y
!
Due to electron repulsion, there is an energy cost in pairing both electrons in the !
orbital. If a small energy difference between the ! and p orbitals exists, the electrons
will remain unpaired (triplet). If a large gap exists between the ! and p orbitals the
electrons will pair in the ! orbital (singlet).
singlet
8–10 kcal/mol
T
1
! Carbene Configuration: Triplet vs. Singlet
p !
triplet
S
1
! the History of the Singlet-Triplet Gap
Method
HCH Angle
S–T Splitting
kcal/mol
Author Year
Qual. 90-100° ––
Muliken
1932
Grnd State
singlet
Thermochem 180° small
Walsh
1947
triplet
160° 30
Gallup
1957
triplet
Qual. QM
138° >33
Harrison
1969
triplet
Ab initio
–– 8–9
Hase
1971
triplet
Kinetics
19
Pople
1971
triplet
SCF 132°
8.7 Dewar 1974 triplet MINDO 134°
19.5 Lineberger 1976 triplet Expt 138°
19.7 Schaeffer 1976 triplet An Initio –––
8.1 Zare 1978 triplet Expt –––
8.5 Haydon 1982 triplet Expt –––
(Wentrup)
Chem 206 Carbenes: Structure and Generation M. Shair, D. A. Evans
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 ! orbital energetically
favorable. As a result, these carbenes are often in the singlet state.
C
Cl
Cl
Heteroatom-Substituted Carbenes: Singlets
p
triplet
carbene
!
Energy
donor p
orbital
"-donor
heteroatom
Heteroatom-
substituted
carbene
Examples: Singlet
C
H
C
6
H
5
Singlet
C
Cl
Cl
Cl
H
C
Cl
Cl
C C O
R
R
! Alkyl Halides:
heat or h!
R
2
C
+
! ketenes
C
R
R
Cl
H
C
R
R
Methods of Synthesis
CO
OH
OH
Me
Me Me
N N
Ts
H
Me
Me Me
N N
Me
Me Me
N
N
Me
Me Me
H
Ts
Me Me
Me
! Bamford-Stevens Reaction: See Lecture 31 on Hydrazones
Shapiro Org. Rxns. 1976, 23, 405.
–Ts
–N
2
OR
R
1
R
2
N N
R
1
R
2
N N
R
1
C
R
2
! diazo compounds
h! or heat
+ N
2
N
N
R
2
R
1
diazirines
h! or heat
Chem. Soc. Rev. 1982, 11, 127.
R
1
R
2
N N
Rh
Rh
O
O
Me
Rh
Rh
O
O
Me
R
1
R
2
N
N
Rh
Rh
O
O
Me
R
1
R
2
Rh
Rh
O
O
Me
R
1
R
2
! metal-catalyzed decomposition Doyle Chem Rev. 1986, 86, 919 (handout)
carbenoid
(ligands omitted for
clarity)
–N
2
Rh
2
(OAc)
4
Chem 206 Carbenoids: Cyclopropanation
M. Shair, D. A. Evans
Carfbene–Olefin Cycloaddition: The FMO Analysis
See discussion in Fleming pp 95–96
C
H
R
LUMO
HOMO
C
H R
C C
LUMO
HOMO
C C
HOMO
C
H R
LUMO
Linear Approach
antibonding
antibonding
C
H
R
C C
HOMO
C
H
R
C C
LUMO
Non-linear Approach
LUMO
HOMO
O
THPO
O
N
2
CO
2
Me
THPO
O
CO
2
Me
O
THPO
O
CO
2
Me
O
Cu Powder
! Synthetic Applications
130˚C, Xylenes
CuLi
prostaglandins
2
Et
2
O, -12˚C
Corey and Fuchs JACS 1972, 94, 4014.
TBSO
Me O
O
N
2
TBSO
O
H
Me
O
H
H
TBSO
O
Me
O
H
H TBSO
O
Me
O
H
H
H
HO
Me
OH
CO
2
Me
O
O
H
1. Br
2
2. DBU
Antheridic Acid
Corey & Myers JACS 1985, 107, 5574.
Cu(I)
1,3-shift
Et
2
AlCl
Chem 206 Carbenoids: Cyclopropanation
D. A. Evans
The Simmons-Smith Reaction
OH OH
150:1 cis: trans
75% yield
Winstein et al.
JACS, 1961, 91,3235
Zn(Cu)
CH
2
I
2
OH
OH
OH
OH
OH
OH
> 99 : 1
> 99 : 1
Winstein, S. JACS 1969, 91, 6892
9 : 1
Me
OH
Me
Me Me
OH
OMe
OMe
Me
Me
OH
Me
Me
OH
>99:1
diastereoselectivity
Hydroxyl directivity is a powerful atribute of the S–S Rxn
no
diastereoselectivity
>99:1
diastereoselectivity
CH
2
I
2
Zn(Cu)
CH
2
I
2
Zn(Cu)
Zn(Cu)
CH
2
I
2
For an review of the directed Simmons-Smith, see:
Evans, D. A.; Hoveyda, A.; Fu, G. Chem. Rev. 1993, 93, 1307.
The Furakawa Simmons-Smith Variant
Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53
Et
2
Zn, CH
2
I
2
Solvent
Ph
Et
2
Zn, PhCHI
2
ether, rt 69%
syn : anti
94 : 6
Furukawa, J.; Kawabata, N.; Fujita, T. Tetrahedron, 1970, 26, 243
Et–Zn–Et I–CH
2
–I + 2 I–CH
2
–Zn–Et
For a recent general review of the Simmons-Smith reaction see:
Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001)
Hodgson and co-workers recently reported the highly diastereoselective
cyclopropanation illustrated below (JACS, 2004, 126, 8664).
This intramolecular cyclopropanation appears to be general for five- as well
as six-membered ring fomation.
O
t-BuLi or
LiTMP
OH
65%,
"single diastereomer"
Carbenes from Epoxides
O
H
Li
H
O
H
Li
H
+Li
Li
–Li
OH
Chem 206 D. A. Evans Carbenes: Enantioselective Cyclopropanation
N
2
CO
2
Et
Ph
Ph
CO
2
Et
Rh
2
(OAc)
4
cat.
For a detailed mechanistic study which provides supporting evidence for the
intermediacy of a Rh carbene, see: Kodakek, Science, 1992, 256, 1544.
"Copper(I) Carbenes: The Synthesis of Active Intermediates inCu-Catalyzed
Cyclopropanation" P. Hoffmann et al, Angew. Chem. Int. Ed. 2001, 40, 1288-1290
N
Cu
N
CH
2
CH
2
SiMe
3
SiMe
3
Me
3
C
Me
3
C
Ph
CO
2
Me
N
2
N
Cu
N
SiMe
3
SiMe
3
Me
3
C
Me
3
C
Ph
CO
2
Me
spectroscopically observed
Characterization of metal carbenoid intermediates: not much data!
N
2
CO
2
BHT
Ph
CO
2
BHT
Ph
N
O
N
O
Me Me
Me
3
C CMe
3
! Catalytic Asymmetric Variants:
Chiral Cu(I) Complexes
L
*
L
*
=
99% ee
94:6 trans/cis
Evans, et al. J. Am. Chem. Soc. 1991, 113, 726.
R
R
R
EtO
2
C N
2
R
CO
2
Et
ent-6b
a, R = Ph, >99% ee
b, R = Me, >99% ee
+
CuOTf
CuOTf
! Mechanism
There is no definitive evidence for metal-catalyzed cyclopropanation and the
possibility that metallacyclobutane intermediates are involved cannot be
ruled out.
N
O
N
O
Me
Me
Cu
Me
3
C
Me
3
C
N
O
N
O
Me
Me
Cu
Me
3
C
Me
3
C
CO
2
R
R R
+
+
+
R
Reductive
Elimination
H
H
R
H
CO
2
R
R
H
H
N
O
N
O
Me
Me
Cu
Me
3
C
Me
3
C
CO
2
R
H
H
N
2
CHCO
2
R

OTf

OTf

OTf
-N
2
O
O
N
2
nPr
O
O
nPr H
H
H
Rh Rh
O
N
N
Ph
O
CO
2
Me
H
(5 mol %)
95% ee
Doyle et al. Tetrahedron Lett. 1995, 36, 7579.
! Catalytic Asymmetric Variants:Chiral Rh(II) Complexes
How do these complexes really work??
CH
2
Cl
2
Chem 206
D. A. Evans
Carbenes: Enantioselective Cyclopropanation
O
O
N
2
nPr
O
O
nPr H
H
H
Rh Rh
O
N
N
Ph
O
CO
2
Me
H
(5 mol %)
95% ee
Doyle et al. Tetrahedron Lett. 1995, 36, 7579.
! Catalytic Asymmetric Variants: Chiral Rh(II) Complexes
CO
2
Me
Rh
Rh
O
N
N
O
H
CO
2
Me
CO
2
Me
H
O
N
H
O
N
H
MeO
2
C
CH
2
Cl
2
Doyle, JACS 1993, 115, 9968
Rh
N
O
O N
1
2
3
4
Numbers designate increasing steric
hindrance in each quadrant
! The Carbene Complex
Molecular mechanics: favored by 3 kcal/mol
CO
2
Me
Rh
Rh
O
N
N
O
H
CO
2
Me
CO
2
Me
H
O
N
H
O
N
H
MeO
2
C
C
H
CO
2
Me
variable ligand
Doyle, JACS 1993, 115, 9968
27A
CO
2
Me
H Ph
H
styrene
CO
2
Me
H H
Ph
48%ee
86%ee
27B
Chem 206 Carbenes: Rearrangements M. Shair, D. A. Evans
OMe
OMe
O
2
N
OMe
Me
O
N
2
OMe
OMe
O
2
N
CO
2
H
OMe
Me
! Wolff Rearrangement
Evans et al. J. Org. Chem. 1993, 58, 471. (+) Macbecin
retention
AgOBz
H
2
O
R
Me
O
N
2
AgX
R
C
Me
H
O
AgX
OH
2
R
Me
H
OH
OH
H
H
H
! Carbene-Carbene Rearrangements
Wu, Tetrahedron Lett. 1973, 3903.
C
Br
Br
C
C
13 [1,2]
! Skattebol Rearrangement
Tetrahedron Lett. 1973, 2283.
BuLi
! Other Rearrangements
O
H
O
H
N
2
150˚C
(71%)
Schecter, J. Am. Chem. Soc. 1971, 93, 5940.
O
H
O
H
!
O
O
N
2
O
O
Sammes, Chem. Comm. 1975, 328.
(92%)
200˚C
O
O
N
OTBS
TIPS
Teoc
Br
Br
O
O
Ph
Ph
N
OTBS
TIPS
Teoc
O
O
! Vinylidenes
Ph
Ph
Corey-Fuchs:
Danishefsky et al.
J. Am. Chem. Soc. 1996, 118, 9509.
2 eq. BuLi
-78˚C
(81%)
Br
Br H
R
BuLi
Li
Br H
R
C
H
R
Chem 206 Carbenes: Rearrangements M. Shair, D. A. Evans
! Carbene Rearrangements
P(OEt)
2
N
2
O
H
BuLi
–78 °C
C N
R
H
N
C
R
H
–N
2
R C C H
P(OEt)
2
N
2
O
R
OLi
vinylidene
carbene
RCHO
quite unstable
25˚C
Me
P(OEt)
2
O
N
2
O
CHO
OMOM
MeO
2
C
OMOM
MeO
2
C
+
(83%)
Bestmann, et al. Synlett 1996, 521.
K
2
CO
3
MeOH
H
Me
O
O
Me
Me
O
P(OEt)
2
N
2
O
H
–78 °C
KO-t-Bu
O
O
Me
Me
Me
68%
Gilbert, JOC 1983, 48, 5251
O
O
Me
Me
H
C
Me
stereospecific
C–H Insertion
N
O
I
+
Ph
N
O
I
+
Ph
SO
2
Ar
N
O
SO
2
Ar N
O
(63%)
CH
2
Cl
2
, 20˚C
Stang et al. J. Am. Chem. Soc. 1994, 116, 93.
OTf
NaSO
2
Ar
-PhI
Me
Me
O
H
Me
H
Me
Me
H
Me
O
Me
Me
H
Me
H
H
capnellene
620˚C
carbene intermediates are accessible at high
temperatures, more later!
Me
Me O
H
Me
H
H
620˚C
Me
Me
O
H
Me
H
H
CH insertion
Chem 206
D. A. Evans, D. Guterman
Thermal Generation of Carbene Intermediates
Carbenes are Accessible via Sigmatropic Rearrangement
O
H
O
H
H H
O
! [1,2] Shifts: Alpha-Alkynone Cyclizations
Conditions: 620° C, 12-16 Torr, Quartz filled Quartz Tube
[1,2]
• •
C-H
insertion
H
!
Karpf, M., Dreiding, A.S., Helv. Chim. Acta. 67 1963 (1984)
Clovene
80% (+ 19% isomers)
14 Torr
N
2
, 1 Hr
620° C
Me Me
O
H
H
Me
Me
Me
O
The Automerization of Naphthalene (The Cume Question from Hell!)
!–
13
C-labeled C
10
H
8
is isomerized into "–
13
C-labeled C
10
H
8
at 1035 °C
#
Rationalize
H
H
! Mechanism-2,3: L. T. Scott, JACS 1991, 113, 9692.
H
H
••
H
H
H
H ••
H H
••
H
H
H
H
X X
B A !(H
B
–H
A
) = –3.4 kcal/mol (MNDO)
BF
BF B A +
900 °C
21% 79% +
Option–2
Option–3
Scott, L.T., et. al., JACS 113 7082 (1991)
Corannulene 10%
! 10
-4
Torr
1000° C
Provide a Mechanism for this Transformation
C
C
! 10
-4
Torr
1000° C
H H
H
H
••
••
C–H Insertion
H
H
Chem 206
M. Shair, K. Beaver
Carbene Heteroatom Transformations: Sulfonium & Oxonium Ylids
Ylide Formation
R
N
2
OEt
O
catalyst
R
X
OEt
O
R R
X is generally S, O or N and can be sp
2
or sp
3
hybridized
Ylides often undergo sigmatropic rearrangements or cycloadditions
Reviews:
Barnes, Evening Seminar, March 16, 1993
Padwa, Chem. Rev. 1991 263
Padwa, Chem. Rev. 1996 223
R
2
X
[2,3]-Sigmatropic rearrangement:
Stevens Rearrangement ([1,2] alkyl shift):
R
2
N N
2
R
1
O
Rh
2
(OAc)
4
N
O
R
1 R
2
N
O
R
2
R
1
West, JACS 1993 1177
OMe
SPh
O
N
2
O
S
Ph
O
E
SPh
E
O Acorenone B
Kido and Kato, JCS Perkins 1 1992 229
Rh
2
(OAc)
4
Vedejs, JACS 1989, 111, 8430
Methynolide has been synthesized by Vedejs
using this ring-expansion methodology
72%
72%
50%
Methods based on sulfur ylides: (review) Vedejs, Accts. Chem. Res. 1984, 17, 358
Ring expansion reactions have been investigated
S
N
2
CO
2
Et
S
CO
2
Et
S
CO
2
Et
S S
Et O
Me
O
TfO CO
2
Et
S
EtO
2
C
Me
Me
OH
HO
Me
O
Cu(I)
DBU
KOt-Bu
OMe
Cl
MeO
CO
2
Me
O
N
2
O
Me Me
OMe
Cl
MeO
O Me
CO
2
Me
O
OMe
Cl
MeO
O
O
O
OH
Me
griseofulvin
Pirrung et al JACS, 1991, 113, 8561.
Me
O
H
AcO
H
Me
O
N
2
O
AcO
Me
O
O
AcO
Me
O
Cu
(I)
or Rh
(II)
Clark et al.
Tetrahedron Lett. 1996, 37, 5605.
Rh
2
(OAc)
4
Chem 206 Carbonyl Ylids: Dipolar Cycloaddition
D. A. Evans, D. Barnes
O
CHN
2
O
O
O
R
R
O NPh
R
O
O
O
H
H
O
CO
2
CH
3
CO
2
CH
3
R
O
O
N
CO
2
Et
R
O
O
O
R
N C CO
2
Et
R
O
NPh
H
O
O
Tandem Intramolecular Cyclization–Intermolecular
Cycloaddition (Lecture 18)
O
O
HOMO
LUMO
Dipolar-Dipolarophile Cycloadditions: HOMO–LUMO
Energies
Carbonyl Ylides have very small HOMO-LUMO gaps
Energy
ylide dipolarophile
Therefore, either raising the dipolarophile HOMO (electron-donating
substituents) or lowering the LUMO (electron-withdrawing) will accelerate
the reaction.
RCHO
DMAD
Rh
2
(OAc)
4
Carbenes: Reaction with Heteroatoms
Suggested Reading
Houk and Wu J. Org. Chem. 1991, 56, 5657.
Review Articles
Padwa and Hornbuckle Chem. Rev. 1991, 91, 263.
Padwa and Krumpe Tetrahedron 1992, 48, 5385.
Hoffman, R. W. Angew. Chem. Int. Ed. Engl. 1979, 18, 563.
McKervey et al. Chem. Rev. 1994, 94, 1091.
R
R R R
O
R O R
R R
Generally, the carbene precursor of choice is a diazoalkane or, more
frequently, an !-diazocarbonyl reagent. These can be decomposed via
thermolysis or photolysis. However, the most common method involves
catalytic amounts of
transition metals, such as copper or rhodium.
Ylide Formation by the Interaction of Carbeneoids
with Carbonyl Lone Pairs
••
R O R
R R
R O R
R R
X Y
R O R
R
R
X Y
Dipolar Cycloaddition (See Lecture 18)
Chem 206 Carbonyl Ylids: Dipolar Cycloaddition
D. A. Evans, D. Barnes
Reactions of Diazoimides: [3+2] addition
74%
Et
3
SiH / BF
3
•Et
2
O
CH
2
Cl
2
68%
Maier, M. E.; Evertz, K. Tetrahedron Lett. 1988, 29, 1677-1680.
O
N
O Bn
H
CH
3
N
Me
H
Me
OH
H
O
Bn
O
N Me
O O O
N
2
Bn
O
N
O Bn
COMe
H
Me
Me
PhCH
3
, 110 °C
O
N
O Bn
COMe
Me
Me
O
Rh
2
(OAc)
4
–N
2
Padwa et. al. Tetrahedron Lett. 1992, 33, 4731-4734.
"high yield"
Rh
2
(OAc)
4
PhH, reflux
N Me
O
O O
N
2
N
O
Me
H
H
O
O
N
O
N
Me
O O
N
2
N
N
O Me
O
O
H
H
H
88%
Cu(acac)
2
89%
CO
2
CH
3
O
O
O
O
N
2
CH
3
O
CO
2
CH
3
O
O
O
CH
3
O
HO
Can you propose a rational mechanism for this transformation?
Hildebrandt, Tetrahedron Lett. 1988, 29, 2045-2046.
O
O
O
O
CO
2
CH
3
CH
3
O
CO
2
CH
3
O
O
O
CH
3
O
O
N
N
OMe O
Me O
N
2
O
Bz
N
Bz
O
N
MeO
2
C
OM
Me
N
Bz
N
O
MeO
2
C
O
Me
H
H
Rh
2
(pfb)
4
Padwa, JOC 1995 2704
Lysergic Acid Skeleton
(93%)