Stable Singlet Carbenes And Their Use As … Singlet Carbenes And Their Use As Organocatalysis Brandon Dutcher Michigan State University May 8, 2008 Outline Introduction to carbenes

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


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


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


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-


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


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



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


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


H

O

R1

R3

O

R2

NMes

MesN

Cl(6 mol %)

DBU (12 mol %)THF, r.t., 8h

R3

R1 R2


734-chlorophenyl2-thienylMe7554-chlorophenylMe2-MeOPh6704-chlorophenyl2-furyl2-MeOPh586phenyl2-thienyl2-MeOPh478phenylphenylphenyl385tolyl2-thienyl2-MeOPh2884-chlorophenyl2-thienyl2-MeOPh1

Yield, %R3R2R1Entry


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



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


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



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


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


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


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


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


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


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




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


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


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



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%


N

NMes

MesCl

D


Ph OH

15 mol % E,DBU, MnO2

toluenePh OR

OROH


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


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




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


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




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

Documents

Stable Singlet Carbenes And Their Use As … Singlet Carbenes And Their Use As Organocatalysis Brandon Dutcher Michigan State University May 8, 2008 Outline Introduction to carbenes