stable singlet carbenes and their use as … singlet carbenes and their use as organocatalysis...
TRANSCRIPT
Stable Singlet Carbenes And Their Use As Organocatalysis
Brandon DutcherMichigan State University
May 8, 2008
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
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
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
Carbene reactivity
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
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
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
Effects on Spin Multiplicity
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
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
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
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
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
Solvent Effects
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
Substituent Effects
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
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
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
Stable Singlet Carbenes
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
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
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
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
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?
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
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
Benzoin Condensaton
Stetter Reaction
Enders, D.; Niemeier, O.;Henseler, A. Chem. Rev., 2007, 107, 5606
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
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
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
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
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
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
1,4-carbene Additions
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
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
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
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
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
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
Conjugate Addition
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
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
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
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
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
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
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
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
β-lactam Synthesis
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
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
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
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
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
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
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
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
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
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
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
Other Synthetic Utilities
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
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
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
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
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
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
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
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
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
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
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
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
Aknowlegements
Group membersAdam, Brandon M., Chris, Daljinder, Jason, Mike, Rahman, Sam, Thu, and Micah
Other friendsAman K., Tom, Gina
Dr. Tepe Dr. Jackson