Norbornene-Mediated Palladium-Catalyzed Synthesis of Norbornene-Mediated Palladium-Catalyzed Synthesis of Fused Aromatic Carbocycles and HeterocyclesFused Aromatic Carbocycles and Heterocycles

Dino Alberico

Lautens GroupUniversity of TorontoDepartment of Chemistry

Charette Group PresentationUniversité de Montréal

January 27, 2006

OutlineOutline

• Part 1: Norbornene-Mediated Palladium-Catalyzed Alkylation/Alkenylation Sequence: Synthesis of Fused Aromatic Carbocycles

• Part 2: Norbornene-Mediated Palladium-Catalyzed Alkylation/Alkenylation Sequence: Synthesis of Tricyclic Heterocycles

• Part 3: Norbornene-Mediated Palladium-Catalyzed Alkylation/C-H Functionalization

Sequence: Synthesis of Annulated Indoles

R'

REWG

nR''

( )

O O

EWG

m n( ) ( )

N

R'

( )nR R''

The Catellani ReactionThe Catellani Reaction

Catellani, M. Top. Organomet. Chem. 2005, 14, 21. Catellani, M. Synlett 2003, 298.Catellani, M.; Cugini, F. Tetrahedron 1999, 55, 6595.Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119.

K2CO3, DMA, 20 °C+ +

PdCl

2

I

CO2Me

I

CO2Me

H H

+ +I

CO2MeI

CO2Me

H

Pd(OAc)2, KOAc, K2CO3,

DMF, 55°C

Original Work by Our GroupOriginal Work by Our Group

Lautens, M.; Alberico, D.; Bressy, C.; Fang, Y.-Q.; Mariampillai, B.; Wilhelm, T. Pure Appl. Chem. 2006, 78, 351. Lautens, M.; Piguel, S. Angew. Chem. Int. Ed. Engl. 2000, 39, 1045.Lautens, M.; Paquin, J.-F.; Piguel, S.; Dahlmann, M. J. Org. Chem. 2001, 66, 8127.

n = 1,2

R = Me, CF3, Cl, NR2, CH2OR, ORR' = naphthyl, Cl, F, NR2, ORY = esters, amides, cyano

R'

R

I

R'

REWG

+Pd(OAc)2, tri-2-furylphosphine,

Cs2CO3, norbornene, CH3CN, 85 °C

n n( )( )

H

Br

EWG

H

MechanismMechanism

Catellani, M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carreno, E.; Pregosin, P. S. J. Am. Chem. Soc. 2002, 124, 4336.Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed. Engl. 1997, 36, 119.

I

IL2Pd

PdL2I

Pd0L2

PdLL

PdBrL

L

CO2Et

PdL2X CO2Et

CO2Et

XL2Pd

XL2Pd CO2Et

Cs2CO3

CsI +CsHCO3

Cs2CO3

CsI +CsHCO3

Br CO2Et

CO2Et

Bromoenoate Substitution PatternsBromoenoate Substitution Patterns

Bromoenoates for Six-Membered Ring Carbocycles

Bromoenoates for Seven-Membered Ring Carbocycles

Alberico, D.; Paquin, J.-F.; Lautens, M. Tetrahedron 2005, 61, 6283.

Br CO2R'''

CO2R'''

R''1'

4'

6'

Br CO2R'''1'5'

6'

R''Br CO2R'''

1'6'

R'' XBr

CO2R'''4'1'

5'

CO2R'''Br BrR''

R"R''

1' 1'5'6'

7' 7'

6'

R'

R

I

R'

RCO2R'''

+

Pd(OAc)2 (10 mol%), tri-2-furylphosphine (20 mol%),

Cs2CO3 (2 equiv),norbornene (2 equiv)

CH3CN, 85°C

Br CO2R'''

R''n

nR''

( )( )

4’ Substituted Bromoenoates: 4’ Substituted Bromoenoates: Six Membered Ring CarbocyclesSix Membered Ring Carbocycles

R'

R

I

R'

RCO2EtPd(OAc)2 (10 mol%),

tri-2-furylphosphine (20 mol%),Cs2CO3 (2 equiv),

norbornene (2 equiv)

CH3CN, 85°C

Br CO2Et1'

4'

R''

CO2Et

CO2Et

OMOM

CO2Et

OMOM

F

N

O

Boc

CO2Et

NMeBoc

R''

81%

70% 40%

45%22%

CO2Et

OH

no reactiondecomposition

5’ Substituted Bromoenoates: 5’ Substituted Bromoenoates: Six Membered Ring CarbocyclesSix Membered Ring Carbocycles

R'

R

I

R'

R

+

Pd(OAc)2 (10 mol%), tri-2-furylphosphine (20 mol%),

Cs2CO3 (2 equiv),norbornene (2 equiv)

CH3CN, 85°C

Br CO2R'''1'5'

R''

CO2R'''

CO2Et CO2Et

CO2Et

CO2Me

Cl

OBn

Ph

R''

83% 70%

58%

44%

CO2Et

OH

not observed

6’ Substituted Bromoenoates: 6’ Substituted Bromoenoates: Six Membered Ring CarbocyclesSix Membered Ring Carbocycles

R'

R

I

R'

R

+

Pd(OAc)2 (10 mol%), tri-2-furylphosphine (20 mol%),

Cs2CO3 (2 equiv),norbornene (2 equiv)

CH3CN, 85°C

Br CO2Et1'

6'

CO2Et

CO2Et

18 h: <15%5 d: <15%

CO2Et

no reactiondecomposition

I

Br

EWG

EWG

Ortho Insertion of Secondary Alkyl HalidesOrtho Insertion of Secondary Alkyl Halides

Dr. Nils Rackelman and Alena Rudolph

Pd(OAc)2, PPh3,norbornene, Cs2CO3

DME, 180 °C, 5 min

I

X

I

( ) ( )m n X

O O

O

CO2t-Bu

CO2t-Bu

CO2t-Bu

CO2t-Bu

CO2t-Bu

O

CO2t-Bu

( )

( )m

n

83% 12% 90%

34%

TsN

CO2t-Bu

62%

4’-5’ Substituted Bromoenoates: 4’-5’ Substituted Bromoenoates: Six Membered Ring CarbocyclesSix Membered Ring Carbocycles

R'

R

I

R'

RCO2Et

+

Pd(OAc)2 (10 mol%), tri-2-furylphosphine (20 mol%),

Cs2CO3 (2 equiv),norbornene (2 equiv)

CH3CN, 85°CXBr

CO2Et4'1'

5'6' X

CO2Et CO2Et

O

26% not observed

CO2Et CO2Et

O

O Cl

22% 20%

Seven Membered Ring CarbocyclesSeven Membered Ring Carbocycles

Pd(OAc)2 (10 mol%), tri-2-furylphosphine (20 mol%),

Cs2CO3 (2 equiv),norbornene (2 equiv)

CH3CN, 85°C

+

R

IBr

G'G''CO2R''

G'''

R'

RCO2R''

G'

G''

G'''R'

54%

CO2Me

OTBS

61%

CO2Me

OMOM

59%

OMeCO2Me

OMOM

33%

CO2Me

OMOMCl

Further Functionalization of Carbocycles Further Functionalization of Carbocycles

CO2R'''R''

R'

R Cl

IBr CO2Et+

Cl

I

Br CO2Et

ClCO2Et

ClCO2EtCO2Et

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, 85 °C+

5% Pt/C (20 mol%), H2(g), 40 psi, EtOH, rt

83%

95%65%

Pd(OAc)2, S-PHOS, K3PO4, toluene, 100 °C,

phenylboronic acid

Alkylation/Heck Reaction/Diels-AlderAlkylation/Heck Reaction/Diels-Alder

OEtO2C

I CO2Et OBr

++

I CO2Et OBr

++

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, 85 °C

CO2Et

O

84%

OEtO2CCO2Et

O conditions

X

A:CH3CN, sealed tube, 90 °C, 18 hB: CH3CN, sealed tube, 90 °C, 5 hC: Me2AlCl, CH2Cl2, -78 °C, 4 hD: Me2AlCl, CH2Cl2, rt, 12 hE: ZnCl2, CH2Cl2, rt, 2 dF: ZnCl2, CH2Cl2, 40 °C, 3 dG: CH2Cl2, microwave irradiation

OBr BrO

Br

( )n

ORN

BrO

BrNR2

Alkylation/Heck Reaction/Diels-AlderAlkylation/Heck Reaction/Diels-Alder

Other Bromodienes to Examine

Part 2Part 2

Norbornene-Mediated Palladium-Catalyzed Alkylation/Alkenylation Sequence: Synthesis of Tricyclic Heterocycles

EWG

+

I

OBr

OBr

O O

EWG

Pd(OAc)2, PPh3, Cs2CO3, norbornene, DME

microwave irradiation 190 °C, 5 min

( ) ( ) ( )( )m n

m n

Synthesis of BenzoxepinesSynthesis of Benzoxepines

Lautens, M.; Paquin, J.-F.; Piguel, S. J. Org. Chem. 2002, 67, 3972.

RI

+

Pd(OAc)2 (10 mol%),TFP (20 mol%),

norbornene (2 equiv),Cs2CO3 (2 equiv),

R

CH3CN, 85 °C, 12 hR'R'

O

CO2Et

85%

O

CO2Et

23%

O

CO2Et

53%

O

CO2Et

75%

OMe

O

CO2EtMeO TBSO

84%

O

CO2Et

Cl

80%

O

CO2Et

AcHN

78%

O

CO2Et

BrO

EtO2C

72%

O

CO2Et

N

F

Three Component CouplingThree Component Coupling

Pd(OAc)2, PPh3, Cs2CO3norbornene, DME, 80°C

EWG

O

EWGR

O

I

In n( )( )

+ +

n = 1, 2, 3

EWG = CO2t-Bu, C(O)NMe2, C(O)NHt-Bu, CN

R I I Cl I OTBS= IO

I

R I

Pache, S.; Lautens, M. Org. Lett. 2003, 5, 4827.

EWG

+

I

OBr

OBr

O O

EWG

( ) ( )( )( ) m nm n

Bis Intramolecular Alkylations Followed Bis Intramolecular Alkylations Followed by an Intermolecular Heck Reactionby an Intermolecular Heck Reaction

CO2Me

Pd(OAc)2 (10 mol%),TFP (20 mol%),

Cs2CO3 (3 equiv),norbornene (2 equiv),+

I

OBr

OBr

(1 equiv)

O O

CO2Me

CH3CN (0.1 M), 85 °C, 12 h

CO2Me

Pd(OAc)2 (10 mol%),PPh3 (20 mol%),

Cs2CO3 (5 equiv),norbornene (5 equiv),+

45%

I

OBr

OBr

(1 equiv)

O O

CO2Me

degassed DME (0.1 M), 85 °C, 12 h

(2 equiv)

(5 equiv)

CO2Me

Pd(OAc)2 (10 mol%),PPh3 (20 mol%),

Cs2CO3 (5 equiv),norbornene (5 equiv),+

45%

I

OI

OI

(1 equiv)

O O

CO2Me

degassed DME (0.1 M), 85 °C, 12 h

(5 equiv)

33%

OptimizationOptimization

Concentration (0.05 M, 0.1 M, 0.2 M) Equivalents of acrylate (3, 5, 8) Equivalents of norbornene (2, 3, 5, 8) Equivalents of base (3.5, 5, 8) Ligands (PAr3, PR3, P(OR)3, AsAr3)

Optimization:

I

OBr

OBr

OO

CO2MePd(OAc)2 (10 mol%)

PPh3 (22 mol%)Cs2CO3 (5 equiv)

norbornene (3 equiv)DME, 80°C, 18 h

CO2Me+

73%

Microwave ReactionsMicrowave Reactions

I

OBr

OBr

OO

CO2MePd(OAc)2 (10 mol%)

PPh3 (22 mol%)Cs2CO3 (5 equiv)

norbornene (3 equiv)

CO2Me+

83% NMR yield79% isolated yield

DME, microwave 190°C, 5 min

P OMe

PPh3

P MeP F

333

83% (77%)

64% (60%) 68% (53%) 83% (74%)

OP

3

70% (55%)

Yields in parentheses correspond to non-microwave conditions.

79% (74%)

P(n-Bu)3

Heck Acceptor ScopeHeck Acceptor Scope

I

OBr

OBr

OO

EWGPd(OAc)2 (10 mol%)

PPh3 (22 mol%)Cs2CO3 (5 equiv)

norbornene ( 3 equiv)

EWG+

DME, microwave 190°C, 5 min

OO OO OOOO

80% 61%42%86%

CO2Me CO2tBu

OO OO

77%1:157%

CO2Bn CO2tBu

OO

CO2tBu

Me

CO2Me

NHAc

CONHtBu

OO

77%

OO

57%

N

OO

43%

N

OO

38%

SO2Ph

OO

37%

SOPh

OO

71%

CN

Ring Size ScopeRing Size Scope

I

OBr

OBr

OO

EWGPd(OAc)2 (10 mol%)

PPh3 (22 mol%)Cs2CO3 (5 equiv)

norbornene ( 3 equiv)

EWG+

DME, microwave 190°C( ) ( )

( ) ( )

m

m n

n

CO2Me

CO2Me

O O

70%MW 10 min

67%MW 10 min

O O

CO2tBu

80%MW 10 min

O O

CONMe2

80%MW 10 min

O O

CO2tBu

O O70%

MW 10 min

CO2tBu

68%MW 20 min

O O

5,6 Rings

6,6 Rings 7,7 Rings

MescalineMescaline

O

OMe

OO

OMeOMe

OMeMeO MeO

NH2 NH2 NH2

Mescaline

Mescaline - the active hallucinatory agent of peyote cactus - served as the prototype for SAR studies linking molecular structure to hallucinogenic activity - targets serotonin (5-HT2) and dopamine receptors

Mescaline Analogues - the dihydrobenzofuran rings serve as conformationally restricted bioisosteres of the aromatic methoxy group in the active conformation of mescaline during serotonin receptor activation

Peyote Cactus

Tricyclic Mescaline AnalogueTricyclic Mescaline Analogue

For previous synthesis, see:

1. Monte, A. P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott, D. B.; Nelson, D. L. Sanders-Bush, E.; Nichols, D. E. J. Med. Chem. 1997, 40, 2997.

2. Ahrendt, K. A.; Bergman, R. B.; Ellman, J. A. Org. Lett. 2003, 5, 1301.

I

OBr

OBr

OMe

OO

CO2tBu

OMe

I

II

OHOO

NH2

OMe

.HCl

Tricyclic Mescaline Analogue – SynthesisTricyclic Mescaline Analogue – Synthesis

I

OOBrBr

BrBr

K2CO3, acetone, reflux, 48 h

I

II

I

II

OH

I

OHHO

OMe

OMe

OMe

MeI, K2CO3, acetone, reflux

98%

1. nBuLi (1.6 M pentane), ether, -78°C2. B(OMe)3, rt3. 40% peracetic acid/acetic acid, 0°C

84% 77%

Tricyclic Mescaline Analogue – SynthesisTricyclic Mescaline Analogue – Synthesis

NHAc NO2N

O

O

I

OBr

OBr OO

NR2

NR2

+

OMe OMe

NR2=

Pd(OAc)2, PPh3, Cs2CO3, norbornene, DME

microwave 190°C, 5 min

no reaction

OO

NH2

OMe

.HCl

Tricyclic Mescaline Analogue – SynthesisTricyclic Mescaline Analogue – Synthesis

I

OBr

OBr

OO

CO2tBu

CO2tBu+

Pd(OAc)2, PPh3, Cs2CO3, norbornene, DME

microwave 190°C, 5 min

OMe OMe81%

OO

98%OMe

CO2tBu

OO

87%OMe

CO2H

10% Pd/C, H2(g), 40 psi,MeOH/EtOAc, rt, 12 h

TFA, CH2Cl2,rt, 12 h

I

OBr

OBr

OO

CO2Bn

CO2Bn+

Pd(OAc)2, PPh3, Cs2CO3, norbornene, DME

microwave 190°C, 5 min

OMe OMe75%

5% Pt/C, H2(g), 40 psi, EtOH, rt, 12 h

OO

79%OMe

CO2H

tert-Butyl Acrylate

Benzyl Acrylate

Tricyclic Mescaline Analogue – SynthesisTricyclic Mescaline Analogue – Synthesis

1.3% yield over 8 stepsMonte, A. P.; Waldman, S. R.; Marona-Lewicka, D.; Wainscott, D. B.; Nelson, D. L. Sanders-Bush, E.; Nichols, D. E. J. Med. Chem. 1997, 40, 2997.

32% yield over 7 stepsAhrendt, K. A.; Bergman, R. B.; Ellman, J. A. Org. Lett. 2003, 5, 1301.

65%

OO

OMe

CO2H DPPA, Et3N, benzyl alcohol,

toluene, reflux, 12 h

OO

OMe

NHCbz1. Pd(OH)2/C, H2(g), 40 psi, MeOH, rt, 12 h

2. HCl (1 M ether), rt, 1 h OO

NH2

OMe

.HCl

96%

27% overall yield over 8 stepsaverage yield/step: 85%

Other Tricyclic HeterocyclesOther Tricyclic Heterocycles

Alena Rudolph and Dino Alberico

EWG

I

EWG

( ) ( )

( )( )

m n

m n

Pd(OAc)2 (10 mol%)PPh3 (22 mol%)

Cs2CO3 (5 equiv)norbornene ( 3 equiv)

DME, microwave 190°C, 5 minX Y

Br BrX Y

OMe

SS

CO2tBu

43%

OO

CO2tBu

OO

CON(Me)2

65% 58%

O

SiSi

O

CO2tBu

60%

OO

CO2tBu

52%

OO

+

Intermolecular Alkylation Followed by an Intermolecular Alkylation Followed by an Intramolecular Heck Reaction Intramolecular Heck Reaction

Andrew Martins, Neema Kasravi, Udo Marquardt and Dino Alberico

+

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, 85 °C

45-96%

I

OY

H

R

R' Br

O

EWGR'

( )n

( )nR

n = 1, 2

R = p-NO2, m-OMe, m-Cl

EWG = CO2t-Bu, CO2Et, CO2Me, C(O)NMeOMe, C(O)N(CH2)4, SO2Ph, Ph

R' Br Br Ph

Br Cl

Br CO2Et

Br

HN

CO2EtBr NH

CO2Et

= Br

Alkylation/Cyanation SequenceAlkylation/Cyanation Sequence

Brian Mariampillai, Valerie Bidau and Dino Alberico

OO

CN

O

CN

O

CN

OO

82% 80%54%

(1 equiv)

O O

CN

Pd(OAc)2 (10 mol%), PPh3 (22 mol%), Cs2CO3 (2 equiv),

norbornene (3 equiv),Zn(CN)2 (1 equiv)

degassed DME (0.05 M), microwave irradiation

190 °C, 1 h

I

OBr

OBr

( ) ( )m n

( )( )m n

Alkylation/Cyanation SequenceAlkylation/Cyanation Sequence

Brian Mariampillai and Dino Alberico

CN CN CN

CN CN CN

NTs

NTs

NTs

O O O

78% 67%

90%

76%

61%74%

(1 equiv)X = O, NR

X

CN

Pd(OAc)2 (10 mol%), PPh3 (22 mol%), Cs2CO3 (2 equiv),

norbornene (3 equiv),Zn(CN)2 (1 equiv)

degassed DME (0.05 M), microwave irradiation

190 °C, 1 h

I

XBr

( )m

( )m

Part 3Part 3

Norbornene-Mediated Palladium-Catalyzed Alkylation/C-H Functionalization:

Synthesis of Annulated Indoles

NBr

H

R'

H

I

R ( )n R''

+ Pd(0), norborneneN( )

nR R''

R'

Aryl-Aryl Coupling via C-H Aryl-Aryl Coupling via C-H FunctionalizationFunctionalization

(a) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.(b) Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211.(d) Wolfe, J. P.; Thomas, J. S. Curr. Org. Chem. 2005, 9, 625. (e) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55.

Coupling using an organometallic compound

Coupling via C-H functionalization

X

+

X = I, Br, Cl, OTfM = Sn, B, ZnY = O, S, NR

Y

M

Ytransition metal catalyst

M

+

Y

X

Ytransition metal catalyst

X

+

Y Ytransition metal catalyst

H

H

Annulation via Annulation via Double C-H FunctionalizationDouble C-H Functionalization

N

I

R

N

R

H

Br H

Pd0

NH

Pd

X

ortho alkylation

alkyl-aryl bond formation

C-H functionalization

aryl-heteroaryl bond formation

C-H Functionalization of IndolesC-H Functionalization of Indoles

NMe

I

+NMe

Pd(OAc)2, PPh3, CsOAc, DMA, 125 °CH

H

NH

Br

O

N(i-Pr)2

N

O

N(i-Pr)2Pd(PPh3)4, KOAc,

DMA, 160 °C81%

Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050.

Kozikowski, A. P.; Ma, D. Tetrahedron Lett. 1991, 32, 3317.

Alkylation/Direct Arylation Sequence: Alkylation/Direct Arylation Sequence: Seven-Membered Annulated Indoles Seven-Membered Annulated Indoles

Bressy, C.; Alberico, D; Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148.

N

83%

MeO

CO2Me

N

80%

N

79%

MeO2C

CO2Me

N

54%

CO2Me

Cl

N

86%

MeO2C

NO2

N

85%

MeO2C NMeTs

N

Br

R

R' N

R

R'R''

I

+ R''

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °C

N

73%

MeO2C

N

50%

MeOMeO

CO2Me

Alkylation/Direct Arylation Sequence: Alkylation/Direct Arylation Sequence: Six-Membered Annulated IndolesSix-Membered Annulated Indoles

N

79%

CO2Me

N

93%

N

88%

NO2

NMeTsN

76%

TsMeN

N

38%NMeTs

N

Br

I

+

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °CR'' N R''

Alkylation/Direct Arylation SequenceAlkylation/Direct Arylation Sequence

I CO2Me

N+

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °C

Br

N

CO2Me

N

CO2Me

not observed

+

evident by 1H NMR and MS

I NO2

N

+

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °C

50%

Br

N

NO2

Attempts at Synthesizing Eight-Membered Annulated Indoles

C-3 Alkylbromo Indoles

Direct Arylation of PyrrolesDirect Arylation of Pyrroles

Dr. Christophe Blaszykowski

R'

H

I

( )n R''

+

R''

N

Br ( )n

N

R RR'

H

PdCl2, TFP,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °C

N

N

CO2Me

N

NO2

N NMeTs

O

N

NO2

CO2MeN

Cl

NMeTs

90% 76% 52%

75%91%77%

Alkylation/Direct Arylation Sequence: Alkylation/Direct Arylation Sequence: Annulated PyrazolesAnnulated Pyrazoles

Vangelis Aktoudianakis

Pd(OAc)2, tri(2-furyl)phosphine,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °CNN

Br

I

R

R'

NN

R

R'+

NN

NN

NN

NN

F

MeR

F3C

43% 51%

33% 32%

NN

Me

62%

Direct Arylation of FuransDirect Arylation of Furans

H

OBr

I NO2

H

O

NO2

O

NO2

Pd(OAc)2, TFP,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °Cnot observed evident by

1H NMR and MS

++

Alkylation/Direct Arylation Sequence: Alkylation/Direct Arylation Sequence: Annulated ThiophenesAnnulated Thiophenes

Andrew Martins and Dino Alberico

MeS

66 %

Me

Cl

S

53 %

Me

NO2

S

88 %

SMe

IMeS

Br

R R

Pd(OAc)2, tri(2-furyl)phosphine,norbornene, Cs2CO3

CH3CN, sealed tube, 90 °C+

NHAc

ConclusionsConclusions

n

S

( )

R

R'

X Y

EWG

m n( ) ( )

O O

m n( ) ( )

CN

R'

RY

nR''

( )

N

R'

( )nR R''

PdNR'

R''

R'''

R

O

EWGR'

( )nR

Acknowledgments Acknowledgments

Professor Mark Lautens

Vangelis AktoudianakisDr. Christophe Blaszykowski

Dr. Cyril BressyBrian Mariampillai

Andrew Martins Dr. Udo Marquardt

Prof. Jean-François PaquinAlena Rudolph

Neema Kasravi (2002)Olga Lifchits (2004)Valérie Bidau (2005)

Members of the Lautens Group

Merck FrosstNSERC - IRC

University of Toronto

University of Toronto – St. George Campus