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''
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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