impact of microwave assisted organic synthesis on...
TRANSCRIPT
Impact of Microwave assisted Organic
Synthesis on High Throughput Chemistry
Ping Cao, High Throughput Chemistry,
Discovery Research,
GSK, Upper Providence, PA, US
Lead Discovery Process & High Throughput Chemistry
Biologicaltesting
SARAnalysis
ParallelchemicalSynthesis
ScreeningLibrary
Diversity andH2L Virtual
library
HTS
OtherCompound
Sources
Key Contributions from Microwave Assisted Chemistry toHigh Throughput Synthesis
• Rapid optimization of reaction conditions• Exploration of chemical diversity by new reaction• Preparation of monomers for library synthesis• Exploration of parallel library synthesis
CH3
SO2NH2
CHO
Br
+Pd(OAc)2, Xantphos
Cs2CO3, 1,4-dioxane
CH3
S
O
O NH
CHO
O
CH3 CH3
PPh2 PPh2
Ref: 1) Buchwald et al, Org. Lett. 2000, 2, 1101-1104. 2) Buchwald et al, J. Am. Chem. Soc. 2002, 124, 6043-6048.
CH3
SO2NHMe
R
B(OH)2
+
CH3
S
O
O N R
Me
Et3N/Py
Cu(OAc)2/CH2Cl2
Ref: Chan et al, Tetrahedron Lett. 1998, 39, 2933-2936.
Transition Metal Catalyzed N-Arylation of Sulfonamides
SO2NH2Br
+
R1 R2
CuI, K2CO3
microwave, 2h
SNH
O
O
R1
R2
Wu et al, Tetrahedron Lett. 2003, 3385-3386.
• Prolonged reaction time on microwave• Aryl Chlorides are inert to the transformation• Limited sulfonamides substrate scope
Transition Metal Catalyzed N-Arylation of Sulfonamides
5
NMe2
PCy2
N
Cl
+ SO2NH2
N
NHS
O
OPd/L
1 2
N
+
3 41eq 1.5eq
Optimized reaction conditions:• Hemilabile N,P ligand 5 was chosen as the ligand for catalyst• 2 mol% Pd, 180°C, 10 minute irradiation • 2 equiv Cs2CO3 or NaOt-Bu as base, 1,4 dioxane as solvent
Transition Metal Catalyzed N-Arylation of Sulfonamides
P. Cao, G. Li, G. Burton and R. Rivero, Org. Lett. 2003, 5, 4373.
N
Cl
+SO2NH2
N
NHS
O
O
1 2 3
1eq 1.5eq
• 78% conversion under thermal heating at 100°C, 17h• 0% conversion without Pd-catalyst under microwave irradiation
Transition Metal Catalyzed N-Arylation of Sulfonamides
entry Pd-catalysta Conv.%by-product 4%
1
2
3
4
5
6
Pd2(dba)3 + 5
Pd2(dba)3 + dppf
Pd2(dba)3 + Xantphos
Pd2(dba)3 + 6
Pd2(dba)3 + 717
Pd2(dba)3 + BINAP
100
100
86
100
60 10
0
0
0
0
0 N/A
b
8
9
10
Pd2(dba)3 + 817
Pd2(dba)3 + 917
Pd2(dba)3 + 1017
50
50
40
0
0
0
P(i-Pr)2Fe
P(i-Pr)2
7
PdClH
ClH
P
PPd
P
P
(i-Pr)2
(i-Pr)2
(i-Pr)2
(i-Pr)2
O
OH
O
OH
8
PdBrH
BrH
PdPH
PHt-Bu
t-But-Bu
t-Bu
t-But-Bu
9
PS-Pd-P(t-Bu)3
Fibre-Cat
10
Johnson Mattheyc Johnson Mattheyc
CombiPhosbStrema
O
PPh2 PPh2
5
NMe2
PCy2
Xantphos
6
dppf
PPh2Fe
PPh2
N NH..
Transition Metal Catalyzed N-Arylation of Sulfonamides
RSO
ONH
R'
+
1 mol% Pd2(dba)33 mol% ligand 51.4 equiv Cs2CO31,4-dioxane
Microwave 180oC, 10 min
N
Cy2PN
Cl
N
NS
O
O
RR'
SO2NH2
OMe
SO2NH2
Me
SO2NH2
SO2NH2
Cl
SO2NH2
OCF3
SO2NH2
F
SO2NH2
iPr
iPr
PriSO2NH2
SO2NH2
NO2
SO2NHMe
Me
41% 69% 70% 37% 74% 62%64% 61%
68% NR
NHS
OO
82%
Transition Metal Catalyzed N-Arylation of Sulfonamides
+
1 mol% Pd2(dba)33 mol% ligand 51.4 equiv Cs2CO31,4-dioxane
Microwave 180oC, 10 min
N
Cy2PSO2NH2
ArCl SO
ONHAr
Cl
NO2
Cl
COOMe
Cl
COOMe
NO2
N
ClN Cl
ClCl
45%62%54%61%53%52%60%
N ClN
Cl
OMe
Cl
Transition Metal Catalyzed N-Arylation of Sulfonamides
Microwave Induced Knoevenagel Condensation of AromaticKetones
Ar R
O+
microwave
NH4OAc/HOAc
R = Me, cyclopropyl, cyclohexyl, ....
SNH
O
X1 2
150oC
X = N, O
SNH
O
X
Ar
R+
SNH
O
X
R
Ar
Optimized reaction conditions:• Microwave heating is essential for clean condensation• NH4OAc/HOAc as reaction medium, 150 °C 7 mins• No condensation occurred under conventional conditions(piperidine/benzoic acid/toluene)
ketone
3
4
5
6
7
8
9
10
11
12
O
O
O
O
O
O
O
O
Br
OSMe
ONAc
100
100
100
100
100
0
71(100)
54(76)
62(95)
50(100)
42(100)
0
yield%a(conv.%)ketone
2
1
entry entry
a: purified yield after reverse phase HPLC.
yield%a(conv.%)
OO N
HO
OO
Cl
Microwave Induced Knoevenagel Condensation of AromaticKetones
14
15
16
17
OOMe
OCl
OS
ONAc
98(100)
90 (100)a
52 (70%)
- (100)
Ar R
O+ NH
S
O
NH
NHS
O
NH
Ar
Rmicrowave
150oC, 7 minNH
S
O
NH
R
Ar
yield%(conv.)ketone
13O
68 (86)
a: Performed on Smith Synthesiser
+
Entry
Microwave Induced Knoevenagel Condensation of AromaticKetones
Thiazolidinedione library by Knovenagel Condensation ofAromatic ketones
*
Cl
*
NHO
* * *
O
*
S
*
S
*
N+
O O
*
O
F
*
Br
*
N
O
*
NH2
R1
NHS
O
O
Ar
Me
Summary
• Rapid optimization of reaction conditions• Exploration of chemical diversity by new reaction• Application of microwave heating in parallel array synthesis
Acknowledgement
Gang Li
Ralph Rivero
George Burton
DR HTC
DR CASS