Norbornene-Mediated Palladium-Catalyzed Synthesis of Norbornene-Mediated Palladium-Catalyzed Synthesis of Fused Aromatic Carbocycles and Heterocycles Fused Aromatic Carbocycles and Heterocycles Dino Alberico Lautens Group University of Toronto Department of Chemistry Charette Group Presentation Université de Montréal January 27, 2006
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Norbornene-Mediated Palladium-Catalyzed Synthesis of Fused Aromatic Carbocycles and Heterocycles
Charette Group Presentation Université de Montréal January 27, 2006. Norbornene-Mediated Palladium-Catalyzed Synthesis of Fused Aromatic Carbocycles and Heterocycles Dino Alberico. Lautens Group University of Toronto Department of Chemistry. Outline. - PowerPoint PPT Presentation
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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.
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
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