stable singlet carbenes and their use as … singlet carbenes and their use as organocatalysis...
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Stable Singlet Carbenes And Their Use As Organocatalysis
Brandon DutcherMichigan State University
May 8, 2008
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Outline
Introduction to carbenesCarbene stability
Singlet-triplet stateReactivity of singlet vs triplet state
Factors effecting carbene multiplictySterics and bond angles Solvent/ylide effectSubstituent effect
Occurrence in natureUtility in synthesis
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What is a Carbene?
Carbenes:Neutral, reactive intermediateContain a filled sp2 hybridized orbital (σ)Contain an empty unhybridized p-orbital (pπ)Ambiphilic
R
R
R
RC
R
R
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Spin Multiplicity:Singlet vs. Triplet State Carbene
Spin MultiplicityFundamental feature of carbenesDictates reactivity
Singlet Carbene contain filled and vacant orbitalZwitterionic character
Triplet carbene has 2 singly occupied orbitalsdiradical
11.4 Kcal/mol to pair electrons in orbitalSinglet carbene can be favored
CR
R
Singlet Triplet
Bertrand, G.; Bourissou, D.; Gabbai, F.P. Chem. Rev., 2000, 100, 39
CR
R
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Carbene reactivity
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Reactivity of Triplet Carbenes
Triplet stateRadical reactionCan abstract hydrogen
RCR
CRR C
R R
RCR
H
RC
RHC
R
R H
Bertrand, G.; Bourissou, D.; Gabbai, F.P. Chem. Rev., 2000, 100, 39
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Reactivity of Singlet Carbenes
Singlet stateAcid-Base reactivityCarbocation-like rearrangementsCan be nucleophilic and electrophilic
Bertrand, G.; Bourissou, D.; Gabbai, F.P., Chem. Rev., 2000, 100, 39Garcia-Caribay, M.A.; Theroff, C.; Shin, S.H.; Jerelius, J. Tet. Lett. 1993, 34(52), 8415-8418
RC
R
CR R
CR R
RC
R
OH
RC
R
OH
OOO
O
RR
RCH
RR
R
HR
RR
R
H
R
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Reactivity of Singlet vs. Triplet Carbenes
1:CHCO2Et
3:CHCO2Et
CO2Et CO2Et
CO2EtCO2Et
1 2
3 4
Ph2CO
1 2
0.373.2 ± 0.11.000.17 ± 0.1Ph2CO neat*0.930.13 ± 0.011.000.63 ± 0.03Pentane/C6F6 (1:1)0.920.15 ± 0.011.000.67 ± 0.01Pentane
3 + 421Conditions, solvent
Stereospecificcomponent
Product distribution
DeLuca, J.P., Swanson, J.; Dvorak, C.A.; Standard, J.M. J. Org. Chem. 1994, 59, 3026
* Triplet inducing reagent, alkene used as solvent
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Effects on Spin Multiplicity
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Spin Multiplicity: What Affects Spin State?
Small dihedral angle (~102°) allows singlet state, larger angle imposes triplet state (137°)
Solvents (Ylide Formation)
Substituents: Mesomeric(resonance) effect
π-donor (N, P, S, O);
R
R~102°
R
R
137°
ZZ ZZ
R
RN
R
RNC Me C Me
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Bond Angle/Steric Effects On Spin Multiplicity
Small substituentsSmaller dihedral angle; singlet state favored
Large, bulky substituents Dihedral angle large due to sterics; triplet state favored
Bertrand, G.; Bourissou, D.; Gabbai, F.P. Chem. Rev., 2000, 100, 39
C C
px
py
py
px
pπ
pπ
σσ
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Steric Effects On Spin Multiplicity
CH3C
H3C
dimethylcarbeneground state singlet
θ = 111°
diadamantylcarbeneground state triplet
Richards, C. A., Jr; et al. J. Am. Chem. Soc. 1995, 117, 10104.
Myers, D. R.; Senthilnathan, V. P.; Platz, M. S.; Jones, J., Jr. J. Am. Chem. Soc., 1986, 108, 4232
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Cyclopropylidene
Jones, W.M., J. Am. Chem. Soc., 1960, 82, 6200
Stereo-retention observed for reaction of both alkenes
PhPh
H3C
CH3
H3C CH3H3C CH3
Ph
Ph
H3C CH3
Ph
Ph
H3C CH3
Ph
Ph
H3C CH3
Ph
Ph
cyclopropylidene
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Diadamantylcarbene
H3C CH3 CHAd2
(Ad2C:)
Ad2CH2
CHAd2
Myers, D. R.; Senthilnathan, V. P.; Platz, M. S.; Jones, J., Jr. J. Am. Chem. Soc., 1986, 108, 4232
A B C
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Solvent Effects
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Solvent Effects on Singlet Carbene
∆GST of singlet-triplet energy gap measured in different solventsNon-bonding e- pairs of halogens can interact with empty p-orbital, minimal stabilizationLone pair of nitrogen gives a large amount of stabilization
Toscano, J.P.; Wang, Y.; Hadad, C.M.; J. Am. Chem. Soc., 2002, 124, 1761
-0.3 ± 0.08294Acetonitrile0.1 ± 0.1294CH2Cl2
0.2 ± 0.1294Freon-1130.3 ± 0.09294Hexane
∆G(Kcal/mol)T(K)Solvent
OMe
O SolventOMe
O
solvent
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Substituent Effects
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Substituent Mesomeric Effects
Resonance plays a large role in the stabilization of singlet carbenes
π-donors (N, O, P, S) donate lone pair electrons to stabilize empty orbital of carbene
σ-acceptors allow resonance of the σ orbital of the carbene
NR2
R2N
π-donation
R2B BR2
π-accepting
Bertrand, G.; Bourissou, D.; Gabbai, F.P. Chem. Rev., 2000, 100, 39
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π-Donor Substituent (D) Effects
Distributes positive charge over 3 atoms.
Increases pπ energy, while σenergy remains essentially unchanged.
Net ionic charge on carbene center; nucleophilic
NR2
R2N
σ
pπ
σ
a2
pπ (b1)
b1
CD--D
DC
D DC
D1/2 δ+ 1/2 δ+
δ-
Bertrand, G.; Bourissou, D.; Gabbai, F.P. Chem. Rev., 2000, 100, 39
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Measure Of Stability By Nitrogen Substituents
H2N CNH2
CH4+86.6 Kcal/mol
H2N
H2C
NH2CH2
Calculated Energy Changes for Isodesmic Reactions
Schwarz, H; Heinemann, C.; Müller, T.; Apeloig, T.Y. J. Am. Chem. Soc., 1996, 118, 2023
NHC
HN CH4 NH
H2C
HN CH2+92.7 Kcal/mol
NHC
HN CH4 NH
H2C
HN CH2+112.2 Kcal/mol
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Stable Singlet Carbenes
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First Isolable Stable Singlet Carbene
First crystallized carbeneSolution (in THF-d6) under CO atmosphere showed no decay after 7 yearsReadily crystallizes, crystals of several millimeters per sideDoes not decompose at its melting point (240°C)
Arduengo, A.J., III; Harlow, R.L.; Kline, M; J. Am. Chem. Soc.,1991, 113, 361
Space filling model of X-ray crystal structure
N
NH
H
NaH
THFcat. DMSO
N
NH
HCl
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More Stable Singlet Carbene
1,3-dimethylimidazol-2-ylidineModerately stable oil
Arduengo, A.J., III Acc. Chem. Res., 1999, 32, 913
N
N
CH3
CH3H
H
N
N
CH3
CH3H3C
H3C
1,3,4,5-tetramethylimidazol-2-ylidineStable crystalline material at room temperature under N2 atmosphere
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Electron Density of a Stable Carbene
Valence electron density of 1,3,4,5-tetramethylimidazol-2-ylidine-d12
Density in ring-plane
Electron density detected in sp2
orbital of carbene center
Measured by combination of electron and neutron diffraction, and NMR spectroscopy
NN
C
C
D3CD3C
DD
D D
DD
Arduengo, A. J., III, et.al, J. Am. Chem. Soc. 1994, 116, 6812-6822.Arduengo, A.J., III Acc. Chem. Res., 1999, 32, 913
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Electron Density of a Stable Carbene
π-Electron Density measure 70 pm above plane of ring
Nitrogen lone pairs and C-C double apparent
Electron density not apparent on carbon 2, denotes empty p-orbital
NN
C
C
D3CD3C
DD
D D
DD
Arduengo, A. J., III, et.al, J. Am. Chem. Soc. 1994, 116, 6812-6822.Arduengo, A.J., III Acc. Chem. Res., 1999, 32, 913
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Quick Summary of Singlet Stability Factors
Large substituents favor triplet carbene, while small substituents favor singlet
Solvent can play a role in singlet stability
π-donating substituents greatly stabilize singlet carbene
π-donating substituents allow for nucleophilic carbene
Why does this matter?
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Stable Singlet Carbene in Nature
Thiamine (Vitamin B1)
Found in yeast (Saccharomycescerevisiae)
Coenzyme for many biological pathways, including transketolaseenzyme in Saccharomycescerevisiae
Active form obtained by pyrophosphorylation of alcohol, and deprotonation
S
N
HO
N
N
NH2
CH3
H3C
Thiamine (vitamin B1)
Cl
Jansen, B. Vita. and Horm., 1949, 7, 83Schneider, G.; Nilsson, U.; Meshalkina, L.; Lindqvist, Y. J. Biol. Chem., 1997, 272, 1864
S
N
O
N
N
NH2
CH3
H3C
PO
O OH
POH
OOH
Active Form
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Mechanism of Thiamine In Transketolase
Breslow, R. J. Am. Chem. Soc., 1958, 80, 3719
S
N
R
CH3
Ar
Cl
S
N
R
CH3
ArO
OHHO
R2
S
N
R
CH3
Ar
O
HO
OHR2 S
N
R
CH3
Ar
O
HO
R2 H
O
S
N
R
CH3
Ar
HO
HO
OR2
proteinO
HO
protein
Cl
ClCl
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Benzoin Condensaton
Stetter Reaction
Enders, D.; Niemeier, O.;Henseler, A. Chem. Rev., 2007, 107, 5606
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Benzoin Condensation
O
CN
O
CN
HO
CN
protontransfer
O
OO
CN
OHO
H
ONaCN
ether
HO O
Lapworth, A. J Chem. Soc., Trans, 1904, 85, 1206
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Benzoin Condensation Using Carbene Catalysts
S
N
R
CH3Ar Cl
S
N
R
CH3
ArH
O
S
N
R
CH3
ArO
S
N
R
CH3
ArHO
H
O
S N
RCH3
Ar
O OH
O OH
Cl
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719
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Asymmetric Intramolecular BenzoinCondensation
OR O Azolium A, B or C (10-20 mol %)
KOtBU or DBU, r.t.43-93%
61-98% ee
OR
OH
R = Me, Et, nBu, iBu, Bn
NN N
RO Ph
BF4
A: R = TBSB: R = TIPS
NN N Ph
C
BF4
Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem. Int. Ed, 2006, 45, 1463
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Stetter Reaction
RCN
OH R1 X
O NC
HO RX
O NC
O RX
OH
NC
O RX
O
R
OX
O
R H
OCN
R CN
O H
R CN
OH
R H
O
R1 X
O
R
OX
O
CN
X= OAlkyl, OAryl, Aryl, Alkyl
Stetter, H., Schreckenberg, M. Angew. Chem. Int. Ed., 1973, 12, 81
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Carbene Catalyzed Stetter Reaction
S
N
R H
O
R1 X
O
R
OX
O
Bn
HOCl
Base
Stetter, H. Angew. Chem. Int. Ed., 1976, 15, 81
Total Synthesis of (±)-Hirsutic Acid CTrost B.M., Shuey C.D., Dininno F., Mcelvain S.S. J. Am. Chem. Soc., 1979, 101 1284
MeO2C HO
MeO2C
O
O
O
HO2CH
H
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Asymmetric Stetter Reaction
O
X
EWG20 mol % cat. A or B
20 mol % KHMDS
toluene, 23°C55-99%
30-99% eeX = O, CH2, NBocEWG = CO2Et, CN, COSEt, Weinreb amide
O
X
EWG
*
X
OCO2Et
20 mol % catalyst C20 mol % KHMDS
toluene, 23°C60-97%
42-99% eeX = CH2 or NBocn = 1,2
X CO2Et
O
n n
*
NN N
O FF
F
FFBF4
A
NN N
BF4CF3
B
NN N
BF4C
Rovis, T., Alaniz, J.R., Kerr, M.S., Moore, J.L. J. Org. Chem., 2008, 73, 2033
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1,4-carbene Additions
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Umpolung Michael Addition
CO2Et
OTs
CO2Et10% IMes•HCl10% KOt-Bu
2.0 equiv K3PO4THF, 60°C
with Pd2(dba)3 1.2% yield (GC)
without Pd2(dba)3 24% yield (GC)
Fu, G.C.; Fischer, C.; Smith, S.W.; Powell, D.A. J. Am. Chem. Soc., 2006, 128, 1472
N N
Cl
IMes•HCl
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Umpolung Michael Addition
N
N
NAr
ArPh X
O
OEt
X
O
OEt
NN N ArAr
Ph
X
OOEt
NNN
Ar
ArPh
EtO2C N
NN
CO2Et
base
base H
Ar
Ar
Ph
Fu, G.C.; Fischer, C.; Smith, S.W.; Powell, D.A. J. Am. Chem. Soc., 2006, 128, 1472
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Umpolung Michael Addition
94162 (X = OTs)8983 (X = Cl)
48336
81165
7764
9481 (X = Br)Yield, %Time (h)SubstrateEntry
NN N
CO2Et
Br ArAr
PhClO4Cat. 10 mol %
2.5 equiv K3PO4glyme, 80°C
CO2Et
nnAr = p-anisyl
Cat.
X
CO2Et
Br
CO2Et
CO2Et
Br
O
Br
O
OEt
Fu, G.C.; Fischer, C.; Smith, S.W.; Powell, D.A. J. Am. Chem. Soc., 2006, 128, 1472
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R
Catalyst
R
O
R R
O
Cat R
O
R
Cat
Mechanism Comparison
Basavaiah, D., Rao, K.V., Reddy, R.J., Chem. Soc. Rev., 2007, 36, 1581
R
BaseR
O
R
R
O
Base
NN
Base =
DABCOR
O
H
R
R
OO
R
Base
R
R
OOH
R
BaseR
R
OOH
R
Baylis-Hilman
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Aza-Morita-Baylis-Hilman
ONTs
Ar
Cat. (10 mol %)t-BuOK
toluene, r.t.n
O
nAr
HN TsN N
Pri
Pri
iPr
iPrCat.
74364-F-C6H42772364-Cl-C6H428
98364-Cl-C6H42680242-Furyl1575244-F-C6H41477244-NO2C6H41382364-MeO-C6H4129615C6H511
Yield, %Time (h)ArnEntry
Ye, S., He, L.,Jian, T. J. Org. Chem., 2007, 72, 7466
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Aza-Morita-Baylis-Hilman
N
NAr
ArN
NAr
Ar
Ar'
TsN
O
NNAr
Ar
O
NNAr
Ar
NTs
Ar'
O
NNAr
Ar
NHTs
Ar'
NTs
Ar'
O NHTs
Ar'
Ye, S., He, L.,Jian, T. J. Org. Chem., 2007, 72, 7466
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Conjugate Addition
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Cyclopentenes via Carbene Catalysis
Nair, V.; Vellalath,S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc, 2006, 128, 8736
H
O
O
NMes
MesN
Cl(6 mol %)
DBU (12 mol %)THF, r.t., 8h
90%MeO
Cl
MeO
Cl
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Cyclopentenes via Carbene Catalysis
H
O
R1
R3
O
R2
NMes
MesN
Cl(6 mol %)
DBU (12 mol %)THF, r.t., 8h
R3
R1 R2
Nair, V.; Vellalath,S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc, 2006, 128, 8736
734-chlorophenyl2-thienylMe7554-chlorophenylMe2-MeOPh6704-chlorophenyl2-furyl2-MeOPh586phenyl2-thienyl2-MeOPh478phenylphenylphenyl385tolyl2-thienyl2-MeOPh2884-chlorophenyl2-thienyl2-MeOPh1
Yield, %R3R2R1Entry
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Cyclopentenes via Carbene Catalysis
N
N
H
O
R1
R1
OH
N
N
R3
OR2
O
R3R2
R1
O N
N
R
R
R
RR
R
OR3
O N
NR
R
R2
R1
O
O
R3R2
R1R3
R2
R1
Nair, V.; Vellalath,S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc, 2006, 128, 8736
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Cyclopentenes via Carbene Catalysis
Ar2H
Ar1H
NNAr4 Ar4
HO
O
Ar3
Ar3
Ar1Ar2
O
Cat.O
Ar2
N
N
Ar4
Ar4OHOAr1
Ar3
Ar1Ar2
Ar3
Steric Repulsion
X
Ar2 H
Ar1H
N N Ar4Ar4
OH
O
Ar3
Ar3
Ar1Ar2
O
Cat. O Ar3
Ar1Ar2
O
Cat. O
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O
Ar2
HH Ar1
Ar3
OH N
NAr4
Ar4
Ar3
Ar1Ar2
OCat
O
Cyclopentenes via Carbene Catalysis
Hydrogen Bonding
X
H
Ar2H Ar1
Ar3
OO
H
N
NAr4
Ar4Ar3
Ar1Ar2
Ar3
Ar1Ar2
OCat
O
Ar2
N
N
Ar4
Ar4OHOAr1
Ar3
Ar1Ar2
Ar3
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Cyclopentenes via Carbene Catalyzed Oxy-Cope
O
NNN
Me
MeMeCl
R1 H
O
MeO2C
O
R2
MeO2C
R1
R2
10 mol %
15 mol % DBUDCE, 0-23°C, 40 h
99 (82)5:153Ph2-furyl699 (67)6:158Ph4-BrPh5
99>20:1932-furylPh499 (79)11:1504-BrPhPh399 (68)5:1584-MeOPhPh299 (68)11:178PhPh1
%eecis:transYield, %R2R1Entry
Bode, J.W.; Chiang, P.;Kaeobamrung, J. J. Am. Chem. Soc., 2007, 129, 3520
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Cyclopentenes via Carbene Catalyzed Oxy-Cope
Bode, J.W.; Chiang, P.;Kaeobamrung, J. J. Am. Chem. Soc., 2007, 129, 3520
HOO
MeO2CR1
R2N N
N
Ar
HOO
MeO2CR1
R2N N
N
Ar
OO
MeO2CR1
R2N N
N
Ar O
O
MeO2C
R1
R2
N N
N
Ar
O
O
MeO2C
R1
R2MeO2C
R1
R2
oxy-cope
Tautomerization aldol
acylation
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Cyclopentenes via Carbene Catalyzed Oxy-Cope
Bode, J.W.; Chiang, P.; Kaeobamrung, J. J. Am. Chem. Soc., 2007, 129, 3520
O
N
N
N
O
Me
Me
Me
Ph
OHPh
OOMe
OCO2MePh
OH
*Cat
CO2Me
Ph
Ph
Boat Oxy-Cope TS
Ph
O
H
N
N
N
O
Me Me
Me
PhPh
O
PhOO
H
PhPhPh
*CatPh
Ph
Ph
Chair Oxy-Cope TS
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β-lactam Synthesis
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β-lactam Synthesis
O
O
R2
R1
R3R2
R1
R3R1 H
O
R2
O
R3
Cat. 10 mol %
15 mol % DBUDCE, 0-23°C, 40 h
-CO2
N
O
R3
R1
R4R3
R1
R4R1 H
N
R3
O
R4
-CO2
R2
R2X
Bode, J.W.; Chiang, P.;Kaeobamrung, J. J. Am. Chem. Soc., 2007, 129, 3520
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β-lactam Synthesis via Carbene Catalyzed Oxy-Cope
O
NNN Mes
Cl
R1 H
O
Ar1
N
Ar2Ar1
R1
Ar2
10 mol %
15 mol % DBU0.1 M EtOAc,r.t
15 h
N
H
SO2Ar
O
SO2Ar
9963Ph4-MeO-C6H4n-Pr575
77
768194
Yield, %
99Ph4-Br-C6H4Me6
994-Br-C6H44-Br-C6H4n-Pr4
99 (5:1)bPhPh399PhPhn-Pr2
>99PhPhMe1ee (%)Ar2Ar1R1Entrya
Me
a Ar = 4-MeOC6H4. b Diastereomeric ratio
Bode, J.W.; He, M. J. Am. Chem. Soc., 2008, 130, 418
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β-lactam Synthesis via Carbene Catalyzed Oxy-Cope
Bode, J.W.; He, M. J. Am. Chem. Soc., 2008, 130, 418
NH O
Ar1R1
Ar2 N N
N
Mes
NHO
Ar1R1
Ar2 N N
N
Mes
NO
Ar1R1
Ar2 N N
N
Mes N
O
Ar1
R1
Ar2
N N
N
MesN
O
Ar1
R1
Ar2
Ar1
R1
Ar2
oxy-cope
aldol
acylation
ArO2S ArO2S
ArO2HS
SO2ArSO2Ar
X
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Staudinger Reaction
Ph Ph
CO
N
Ph
Ph
NPh
O
Ph
PhPh
pet. ether
~73%
Staudinger, H. Lieb. Annel. Der. Chem., 1907, 356, 51
R2 R1
CO
N
R3
R4
R1
R2N
OR4
R3
R1
R2N
OR4
R3
NR3
O
R4
R1R2
Singh, G. S. Tetrahedron, 2003, 59, 7631
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Staudinger Catalyzed via Carbene
1936:64974Ts4-ClC6H44
765
321
Entry
9675:25724Boc4-ClC6H4
9575:25684Cbz4-ClC6H4
8960:40534Ts2-furyl
-955:45593Ts2-furyl6378:22992Ts2-furyl-3855:45931Ts2-furyl
%eecis/transYield %Cat.RAr
CO
EtPh
N
Ar H
R Cat., base
THFN
O R
ArPhEt
N NN
PhBn
BF4
N NN
Ph
BF4
O
N NN
BnPh
Cl
N NN
PhPhOTBSPh BF4
1 2 3 4
Ye, S.; Zhang, Y.; He, L.; Wu, X.; Shao, P. Org. Lett., 2008, 10, 277
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Mechanistic Insight
CO
R2Ar1
XN N R3R3
X
NN R2
R2
N
Ar2 H
R
X
NN R3
R3
NO R
Ar2Ar1R2
NAr2 R
Ar2N
R
O
R2Ar1
Ye, S.; Zhang, Y.; He, L.; Wu, X.; Shao, P. Org. Lett., 2008, 10, 277
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Mechanistic Insight
CO
R2Ar1
XN N R3R3
X
NN R2
R2 OAr1
R2
N
Ar2 H
R
X
NN R3
R3 O
Ar1
R2Ar2
NR
NO R
Ar2Ar1
R2
Ye, S.; Zhang, Y.; He, L.; Wu, X.; Shao, P. Org. Lett., 2008, 10, 277
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Mechanistic Insight
N
NAr
Ar
NTs
Ph
CO
EtPh
THF, rt
88%
NO Ts
PhPhEt
trans/cis = 76:24Ar = 2,6-iPr2C6H3
N
NAr
Ar
NTs
Ph N
NAr
Ar
NTs
Ph
Ye, S.; Zhang, Y.; He, L.; Wu, X.; Shao, P. Org. Lett., 2008, 10, 277
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Carbene Catalyzed Ring Expansion of β-lactams
997DCM118a
2124DCM117
864DCM516
922DCM2015
405THF2044
765THF2033
<548THF2022
802THF2011
Yield %Time (h)solventXCat.Entry
N
HCHO
O PMP N OO
PMP
cat. (X mol %)
DBU (X mol %)
PhPhN
N
Ar
Ar1 Ar = 2,4,6-(Me)-C6H22 Ar = 2,6-(iPr)C6H3
Cl
NN
N
PhPh
Ph
ClO4
3
NN N
O
Ph
BF4
4
You, S.; Li, G.; Li, Y.; Dai, L. Org. Lett., 2007, 9, 3519
a. Carried out under reflux
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Carbene Catalyzed Ring Expansion of β-lactams
1 (1 mol %)DBU (1 mol %)
DCM, refluxN
HR2R1 CHO
O R3N OO
R2R1
R3
7816Ph, H, Mes79724Ph, Et, PMP69724Me, Me, PMP59924n-C5H11, H, PMP485242-thienyl, H, PMP39812PMP, H, PMP2998Ph, H, PMP1
Yield, %Time (h)Substrate, R1, R2, R3Entry
N
N
Mes
Mes
Cl
1
You, S.; Li, G.; Li, Y.; Dai, L. Org. Lett., 2007, 9, 3519
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Carbene Catalyzed Ring Expansion of β-lactams
You, S.; Li, G.; Li, Y.; Dai, L. Org. Lett., 2007, 9, 3519
N
NR
RN
O
Ph CHO
PMP
N
NR
RHO
NPMP
Ph
O
N
NR
RHO
Ph
ON
PMP
N
NR
RO
Ph
ON
PMP
N
Ph
PMP
OO
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Other Synthetic Utilities
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Tandem Oxidation of Alcohols to Esters
R H
ONHC
R NHC
HO H [O]R NHC
O
R OH[O]
NHCCatalyst
R OR1
O
NHC
HO HR
1) [O]
2) R1OH
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Tandem Oxidation of Alcohols to Esters
Ph OHCat. A-E, DBU
MnO2, MeOHPh OMe
O
83482E7931210E6402420D502420C402420B302420A202420 mol % DBU only1
Yield, %Time (h)Mol %AzoliumEntry
N
S
N
N
N N
N
N
NMe
MeMe Me
Me R
R
Me
MeI I ICl
A B C, R = MeD, R = 2,4,6-Me-Ph E
Scheidt, K.A.; Maki, B.E.; Chan, E.M.; Org. Lett., 2007, 9, 371
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Tandem Oxidation of Alcohols to Esters
NNNMe Me
R
OH
HN
NN
Me
Me
R H
O
MnO2
R OH
R
O
NN
N
Me
Me
R1OH
MnO2oxidation
R OR1
O
I
IIIII
R
OH
NN
N
Me
Me
slow
Scheidt, K.A.; Maki, B.E.; Chan, E.M.; Org. Lett., 2007, 9, 371
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Tandem Oxidation of Alcohols to Esters
R OH10 mol % D, DBU
MnO2, n-BuOHR On-Bu
O
PhH
On-Bu
O
93 %
PhOn-Bu
O
85%
H3COn-Bu
O87 %
OOn-Bu
O
73%
On-Bu
O
91%
Scheidt, K.A.; Maki, B.E.; Chan, E.M.; Org. Lett., 2007, 9, 371
N
NMes
MesCl
D
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Tandem Oxidation of Alcohols to Esters
Ph OH
15 mol % E,DBU, MnO2
toluenePh OR
OROH
Scheidt, K.A.; Maki, B.E.; Chan, E.M.; Org. Lett., 2007, 9, 371
742-(trimethylsilyl)ethanol6822-methoxyethanol5822,2,2-trichloroethanol40tert-butanol3892-propanol295Methanol1
Yield, %alcoholEntry
N N
NMe
MeI
E
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Enantioselective Addition of Homoenolatesto Nitrones
Scheidt, K.A.; Phillips, E.M.; Reynolds, T.E. J. Am. Chem. Soc., 2008, 130, 2416
R1
O
HR2 H
NO Ar
Cat.NO
O
R1R R2
MeOHNOH
MeO2C
R1R R2
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Enantioselective Addition of Homoenolatesto Nitrones
NN NAr R3
R
O
H
R
OH
NN
NR3
Ar
R
OH
NN
NR3
Ar
R1 NR2
O
R1H
NOR2
RO
NN
NR3
Ar
R1
NR2O
NO
O
R1R R2
NR1
R2
O
R3O
Ar
OH
R3OH DBU
Scheidt, K.A.; Phillips, E.M.; Reynolds, T.E. J. Am. Chem. Soc., 2008, 130, 2416
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Enantioselective Addition of Homoenolatesto Nitrones
Scheidt, K.A.; Phillips, E.M.; Reynolds, T.E. J. Am. Chem. Soc., 2008, 130, 2416
Ph
O
H
Ph H
NO Ph
A-D (10 mol %)TEA (20 mol %)
DCM
then DBU, MeOHN
PhPh
O
MeO
Ph
OH
9320:170-25D5878:1510D4-338:1520C3-658:1460B2-4:1750A1
ee (%)drYield (%)Temp (°C)Azolium saltEntry
NN
N MesO
Ph Ph BF4D
NNN
Mes
O
BF4
C
O
N NNPh
Ph
Ph
Mes
BF4
B
NN
N Mes
ClA
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Enantioselective Addition of Homoenolatesto Nitrones
R1
O
H
R2 H
NO Ar
Cat (10 mol %)TEA (20 mol %)
DCM
then DBU, MeOHN
R1
R2
O
MeO
Ar
OH
8972PhPh4-MeO-C6H469473PhPh2-napthyl79264PhPhC3H78
9078PhPh4-Cl-C6H4593804-Cl-C6H6PhPh4-0PhcyclohexylPh3
9071Ph4-Me-C6H4Ph29370PhPhPh1
ee, %Yield, %ArR2R1Entry
Scheidt, K.A.; Phillips, E.M.; Reynolds, T.E. J. Am. Chem. Soc., 2008, 130, 2416
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Enantioselective Addition of Homoenolatesto Nitrones
Scheidt, K.A.; Phillips, E.M.; Reynolds, T.E. J. Am. Chem. Soc., 2008, 130, 2416
MeOHN
PhPh
PhO
NPh
Ph
O
MeO
Ph
OHPd(OH)2/CH2, MeOH
82%
1 M HClMeOH
88%N
O
Ph Ph
Ph
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Triazolium Salt Synthesis
NH
O(MeO)2SO2
MeCN, 80°C90%
NH
OMeN
NH2HN Ph
PhNHNH2
23°C, 4 h84%
40% KOH(aq)87%
NNHHN Ph
HCl
H2O95%
NNH2HN Ph
ClCH(OMe)3
o-dichlorobenzene71%
NN N Ph
Cl
MeOSO3 MeOSO3
Rovis, T., Alaniz, J.R., Kerr, M.S., J. Org. Chem., 2005, 70, 5725
NH
YZ O
RN
YZ
RN
N
Ar
X
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Conclusions
Substituents play a large role in reactivity and stability of carbenes
Large range of synthetic utility
Varying substitution can produce asymmetric catalysts
Precatalyst salt can readily be synthesized from chiral starting materials
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Aknowlegements
Group membersAdam, Brandon M., Chris, Daljinder, Jason, Mike, Rahman, Sam, Thu, and Micah
Other friendsAman K., Tom, Gina
Dr. Tepe Dr. Jackson