Chem 206D. A. Evans
Matthew D. Shair Monday, December 16 , 2002
http://www.courses.fas.harvard.edu/~chem206/
Reading Assignment for this Lecture:
Introduction to Carbenes & Carbenoids-2
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.
Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 10, "Reactiona Involving Highly Reactive
Electron-Deficient Intermediates", 263-350 .
Useful References to the Carbene Literature
Lecture 09A Simmons-Smith Reaction: Enantioselective VariantsLecture 26B Synthetic Applications of α-Diazocarbonyl Compounds
Lecture 35A The Use of Fischer Carbenes in Organic SynthesisLecture 35B The Synthetic Applications of Carbonyl Ylides
Chemistry 206
Advanced Organic Chemistry
Lecture Number 35
Introduction to Carbenes & Carbenoids-2
a73 Thermally Induced Carbene Rearrangementsa73 Carbonyl Ylides and their Reactions
R C
R R R
O R O R
R R
R O R
R Ra73 Oxonium & Sulfonium Ylides and their Reactions
R C
R RX
R
RX
RCR
R
??
??
The Automerization of Naphthalene (The Cume Question from Hell!)
α–13C-labeled C10H8 is isomerized into β–13C-labeled C10H8 at 1035 °C
?Rationalize
Scott, L.T., et. al., JACS 113 7082 (1991)
Corannulene 10%≤ 10-4 Torr1000° C
Provide a Mechanism for this Transformation
L. T. Scott, JACS 1991, 113, 9692.
Chem 206D. A. Evans, D. Guterman
Carbenes are Accessible via Sigmatropic Rearrangement
O
H
O H
H H
O
O O O O
O
O
O O
O O
O O
O
Karpf, M., Dreiding, A.S., Helv. Chim. Acta. 67 1963 (1984)
Clovene80% (+ 19% isomers)
14 TorrN
2 , 1 Hr
620° CMe Me
OH H
Me
Me Me
a73 [1,2] Shifts: Alpha-Alkynone Cyclizations
Karpf, M., Dreiding, A., Helv. Chim. Acta. 65 13 (1982)
Conditions: 620° C, 12-16 Torr, Quartz filled Quartz Tube
[1,2] ? ?
90%892_
Recovery
89%_4654
78%13_87
80%
182260
_
1°2°3°S.M.
The Automerization of Naphthalene (The Cume Question from Hell!)
α–13C-labeled C10H8 is isomerized into β–13C-labeled C10H8 at 1035 °C
?
σ2s + σ2api2s + pi2a
pi2s + pi2aσ2s + σ2a
a73 For the azulene–naphthalene Isomerization: ?G° = –30.7 kcal/mol (298K)a73 The Activation energy for the isomerization: ?G± = +86 kcal/mol
H H
a73 Mechanism-1: L. T. Scott, JACS 1977, 99, 4506;
a73 Mechanism-2,3: L. T. Scott, JACS 1991, 113, 9692.
HH?? H H
HH??
H H
??
HH
H H
X X
B A?(HB–HA) = –3.4 kcal/mol (MNDO)
BF
BF B A+900 °C 21% 79%+
Rationalize
Thermal Generation of Carbene Intermediates
Option–2
Option–3O
C-Hinsertion
H
?
Chem 206Thermal Generation of Carbene Intermediates
Scott, L.T., et. al., JACS 113 7082 (1991)
Corannulene 10%≤ 10-4 Torr1000° C
Provide a Mechanism for this Transformation
Internal Ring: 6 e–External Ring: 14 e–
CC
≤ 10-4 Torr
1000° CH H
H H
????
C–H Insertion
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 α-diazocarbonyl reagent. These can be decomposed via thermolysis or
photolysis. However, the most common method involves catalytic amounts oftransition metals, such as copper or rhodium.
Ylide Formation by the Interaction of Carbeneoidswith Carbonyl Lone Pairs
?? R O RR R
R O R
R R X Y
R O RR
RX Y
Dipolar Cycloaddition
D. A. Evans, D. Guterman
H H
Chem 206Carbonyl Ylids: Dipolar CycloadditionD. A. Evans, D. Barnes
OCHN
2
O
O
O
R R
O NPh
R
O
O
O
H
H O
CO2CH3
CO2CH3
R
O
O N CO
2Et
R
O
O O R
N C CO2Et
R
O
NPh
H
O
O
Tandem Intramolecular Cyclization–Intermolecular Cycloaddition
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-donatingsubstituents) or lowering the LUMO (electron-withdrawing) will accelerate
the reaction.
Reactions of Diazoimides: [3+2] addition
74%
Et3SiH / BF3?Et2O
CH2Cl2 68%
Maier, M. E.; Evertz, K. Tetrahedron Lett. 1988, 29, 1677-1680.
ON
OBn
H CH3
N
MeH
MeOH
H
O
Bn O
N Me
O O O
N2Bn ON OBn COMe
H
Me
Me
PhCH3, 110 °C
O
N OBn
COMe
Padwa et. al. Tetrahedron Lett. 1992, 33, 4731-4734.
"high yield"
Rh2(OAc)4
PhH, refluxN Me
O O O
N2 N
O Me
H
H
O
O
N
ON
Me
O O
N2
N
N
OMe O
O
H
H
H
88%
Me
Me
O
RCHO
DMAD
Rh2(OAc)4 Rh
2(OAc)4
–N2
Chem 206D. A. Evans, K. Beaver
HH
Dipolar Cycloadditions: Carbonyl Ylides
O CO2Et
N2O
HH
H
OAc MeMe
H
H
O
O CO2Et
H
AcO Me Me
H
H
O
CO2EtO
MeMeAcO
H
Dauben, JOC 1993 7635 Tigilane Skeleton
(86%)
N
N
OMeO
Me O
N2
O
Bz
NBz
O N
MeO2C OM Me
NBz
NOMeO2C
O Me
H HRh2(pfb)4
N
N O EtMe CO
2Me
ON
N O EtMe CO
2Me
O
O
N
O O CO
2Me
N2Et
NMe
(95%)
Padwa, JOC 1995 6258
Padwa, JOC 1995 2704 Lysergic Acid Skeleton
Vindoline Skeleton
(93%)
N ZN
2
OO
R2 R2R1 Me
N
O
O
R1
R2 R2
Me
Z
ON O
Me
Z
R1
R2 R2
O Z
R1
R2 R2
N Me
O O O
N2 N
O
CO2Me
COCH3
MeO2C
O
MeO
Padwa, A.; Hertzog, D. L.; Chinn, R. L. Tetrahedron Lett. 1989, 30, 4077-4080.
85%
Rh2(OAc)4,
PhH, 80 °C
Maier, M. E.; Sch?ffling, B. Chem. Ber. 1989, 122, 1081-1087.
Yields = 44-63%R
1 = H, OBnR2 = H, Me
Z = COMe, CO2Me
Rh2(OAc)4
PhCH3, 110 °C
– Me–N=C=O
–+
Reactions of Diazoimides: [3+2] addition – [4+2] retroaddition
CO2MeMeO2C
N
O
O
Me
O
N
O
O
Me
OCO2Me
MeO2C O
CO2Me
MeO2C OHMe
N CO2Me
Carbonyl Ylids: Dipolar Cycloaddition–2
O
O
Rh2(OAc)4
Rh2(OAc)4
MeOH H
MeOH
Chem 206D. A. Evans, D. Barnes
N CHN
2OMe
O N O
O
HCO
2MeMeHC C CO2CH3
The Carbonyl Ylide - Azomethine "Dipole Cascade"
Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1989, 111, 6451-6452.Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1992, 114, 593-601.
The 1,3-proton shift is catalyzed by trace amounts of water. Azomethine ylide formation requires a proton at the tertiary center.
N
O
O
Me
N
O
O
Me
MeO2C
N
O
O
Me
N
Me CO2Me
O
O
H
H
N
Me CO2Me
OH
O
not observed
HC C CO2CH3
Intermolecular addition to α,β-unsaturated carbonyls
Spencer Tetrahedron Lett. 1967, 1865-1867.
2-methoxymethylenecholestanone-3
29%
CuSO4
160 °C
The Synthesis of Furans
OMe
O
OMe
O
OEtO2C
EtO2C
Et O CHN2O
Cu(acac)2
Hildebrandt, Tetrahedron Lett. 1988, 29, 2045-2046.
89%
CO2CH3
O OO
O
N2CH3O
CO2CH3
O OO
CH3O HO
Can you propose a rational mechanism for this transformation?
O
O OO
CO2CH3CH3O CO2CH3
O OO
CH3O O
Methyl vinhaticoate
hydrolysisdecarboxylation
~30%
CuSO4
160 °C
Spencer, T. A., et. al. JACS 1967, 89, 5497.
O CHOCH
3
Me CO2CH3
Me Me
Me CO2CH3
Me Me
EtO CHN2
O
O CO2Et
Me CO2CH3
Me Me
O
The Synthesis of Furans
rearrange
Carbonyl Ylids: Dipolar Cycloaddition (and More!)–3
Rh2(OAc)4
Chem 206D. A. Evans, D. Barnes Carbonyl Ylids: Dipolar Cycloaddition (and More!)–3
O R
O
MeO2C N2
TMSO
O R
O
MeO2C
TMSO
O R
O
MeO2C
Merck, TL 1994 9185
TMSO
(66%)
Zaragozic Acid Skeleton
H
O
OO
OH
HO2CHO
2C
OH CO2H
Ph
OAc
Me
Ph OMe
Application of Carbonyl Ylids to the Synthesis of Zaragozic acid:
H
RO
OO R
OH
HO2CHO
2C
OH CO2H
H
RO
OO R
OH
HO2CHO
2C
OH CO2H
C=O Ylid Transforms
H
RO
OO R
OH
HO2CHO
2C
OH CO2H
H
RO
OHOH
R
OH
HO2CHO
2C
OH CO2H
O OHO2C O
R OHH
ORH
OH
AHO2C
H A = CO2H
OHO2C
O
R OHH
ORH
OH
AHO2C
H
Hodgson et al. J. Chem. Soc. Perkin Trans I, 2000, 3432
ORO2C
O
R
OROR
N2RO2C
O OR
OR R
O
CHO–CO2R
N2EtO2C
O OTBSOTBS
MeO
Rh(II)
ORO2C
O
R
OTBSOTBS
Ot-BuO2CH
OEtO2C
O
R OTBSH
OTBSHOt-BuO2C
H
58% yield
Rh2(OAc)4
If you are anxious for over-exposure,to prepublication disclosure,
to good food and good drink,without leisure to think,
try IUPAC symposia."
Sir John Cornforth:
Chem 206
Ylid Formation versus Cyclopropanation
D. A. Evans, D. Barnes
313
3558
54
5350
31
15
RT80
RTRT
80
Pd2Cl2(C3H5)2Cu(PhCOCHCOMe)
2(MeO)
3PCuIRh
2(OAc)4None
%2%1Temp (°C)catalyst
2
1
catalyst
Bien, S.; Gillon, A.; Kohen, S. J. Chem. Soc. Perkin Trans. I. 1976, 489-492
EtO CHN2
O O
EtO
O O ML
n
OEtO
2C
O
OEtO O OEtO
O
OEtO
it is evident that these are reactions of metal carbenoids
Rh2(pfb)4
PhH, reflux
-
+ insertionproducts
H transfer
Doyle, M. P., et al. J. Org. Chem. 1991, 56, 820-829.Doyle, M. P.; Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397.
pfb = perfluorobutyrate
Me N t-Bu
O O
N2 CO2Et O
N
O
Me
O
EtO
O N
OMe O
EtO
CH2t-Bu
CH2t-BuL
4Rh2 O N
O
Me
OH
EtO
CH2t-Bu+
Carbene Heteroatom Transformations: Ylid Formation
Tandem O-H Insertion/Claisen Rearrangement
Me OMe
O
N2
O
Me
OH+
Me OCH3
HO
O
O
Me
Wood, JACS 1997 9641
98% ee 95% ee
OO
X
Me
CO2MeMe
[3,3] OO XMe
CO2MeMe
slow
fast
(66%)
Wood, JACS 1999, 121, 1748
Me OCH3
HO
O
O
Me
Me OMe
O
O
O
Me
PhH, ?, 20 min
OMeHO
CO2MeMe
PhH, ?, 18 hrs
Z-Enol Transition State
E-Enol Transition State 47% ee
(75%)
The opposite enantiomer is
observed!
Merck Thienamycin Process
NH
HMe OH H
N2 O O
O NO2
O
Rh2(oct)4
N
HMe OH H
O
OH
CO2p-NBPhH, 80 °C100%
N
HOH H
O
S
CO2
NH3
Salzmann, JACS 1980 6161
Thienamycin
X = H, Rh(II) ??
H
H+
Rh2(OAc)4
Chem 206M. Shair, K. Beaver
Ylide Formation
R
N2 OEt
O
catalyst R X OEt
O
R R
X is generally S, O or N and can be sp2 or sp3 hybridizedYlides often undergo sigmatropic rearrangements or cycloadditions
Reviews:
Barnes, Evening Seminar, March 16, 1993
Padwa, Chem. Rev. 1991 263Padwa, Chem. Rev. 1996 223
[2,3]-Sigmatropic rearrangement:
Stevens Rearrangement ([1,2] alkyl shift):
R2 N N2
R1 O
Rh2(OAc)4
N
O
R1 R2 N
O
R2 R1
West, JACS 1993 1177
OMe
SPh O
N2
O S
Ph
OE
SPhE OAcorenone B
Kido and Kato, JCS Perkins 1 1992 229
Vedejs, JACS 1989, 111, 8430
Methynolide has been synthesized by Vedejsusing 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 CO2Et
S CO
2Et S
CO2Et
S S
Et O
MeO
TfO CO2Et
S
EtO2CMe
Me
OHHO
Me
O
Carbene Heteroatom Transformations: Sulfonium & Oxonium Ylids
OMe
ClMeO
CO2MeO
N2O
MeMe
OMe
ClMeO
O Me
CO2MeO
OMe
ClMeO O
O
O
OH
Me
griseofulvin
Pirrung et al JACS, 1991, 113, 8561.
Me
Cu(I)
OH
AcO
H
Me
O
N2
OAcOMe
O
OAcOMe
O
Cu(I)or Rh(II)
Clark et al. Tetrahedron Lett. 1996, 37, 5605.
R2X
Rh2(OAc)4
DBU
KOt-Bu
Rh2(OAc)4