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![Page 1: Impact of Microwave assisted Organic Synthesis on …data.biotage.co.jp/pdf/presentations/1182_p_cao.pdf · Impact of Microwave assisted Organic Synthesis on High Throughput Chemistry](https://reader031.fdocuments.in/reader031/viewer/2022021901/5b83bfd97f8b9a23668db15f/html5/thumbnails/1.jpg)
Impact of Microwave assisted Organic
Synthesis on High Throughput Chemistry
Ping Cao, High Throughput Chemistry,
Discovery Research,
GSK, Upper Providence, PA, US
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Lead Discovery Process & High Throughput Chemistry
Biologicaltesting
SARAnalysis
ParallelchemicalSynthesis
ScreeningLibrary
Diversity andH2L Virtual
library
HTS
OtherCompound
Sources
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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
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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
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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
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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.
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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
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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
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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
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+
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
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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)
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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
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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
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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
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Summary
• Rapid optimization of reaction conditions• Exploration of chemical diversity by new reaction• Application of microwave heating in parallel array synthesis
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Acknowledgement
Gang Li
Ralph Rivero
George Burton
DR HTC
DR CASS