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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Microwave Synthesis Symposium:
San Francisco User Group Meeting
Embassy Suites HotelSouth San Francisco, CA 94080
October 21, 2004
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Matthew N. Mattson, Ph.D.Elan Pharmaceuticals, Inc.
800 Gateway Blvd. South San Francisco, CA 94080
Abstract: Using in situ generated carbon monoxide in a Microwave reactor, the amidation of aryl bromides was studied. An important acyl transfer step was improved in the Microwave-accelerated reaction. Formation of diverse amines for generating libraries of selective PTP inhibitors is presented.
Carbonylative Amidations Using Mo(CO)6 and Palladium Catalysis
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Protein Tyrosine Phosphatase Inhibitors
“Preparation of Oxoacetic Acids as Inhibitors of Protein Tyrosine Phosphatases (PTPs)”
Swinnen, D.; et al. PCT 2003, WO 2003064376, 346 pp.
“Protein Tyrosine Phosphatase Inhibition”
Ripka, W. C. Ann. Rep. Med. Chem. 2000, 35, 231-250.
• Oxalamides are potent reversible phosphate mimics. Multiple methodstoward diversification of these amidesare being pursued.
PTPNH
N
OR'''
NH
RHN
OR'''
RR'
R'
OH
O
O
• Phosphatases regulate many important biological pathways by specific de-phosphorylation of tyrosine-, as well as serine- and threonine-, phosphate groups on signaling proteins.
O P
O
O
O-O-NHH
NRAA
RAA'O
OH
O
NHHN
RAA
RAA'O
PTP
PTP-1B – insulin receptor/diabetes PTPalpha – cancer, osteoporosisPTP-SHP2 – proliferationPTP-CD45 – immune signaling
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Diverse Secondary Amines Needed:Selective PTP Inhibitors
PTPNH
N
OR'''
NH
RHN
OR'''
RR'
R'
OH
O
O
“Preparation of Oxoacetic Acids as Inhibitors of Protein Tyrosine Phosphatases (PTPs)”
Swinnen, D.; et al. PCT 2003, WO 2003064376, 346 pp.
• Need to form the amide second!
• May require novel chemistry with competing amine…
In this example, after first completing the amide formation, the reductive amination and catch+release yielded no amine.
NHN
O
NH
RHN
O
OHN
O
OHO
O
RR'
R'
OOH
O
1st 2nd
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Typical Literature: Carbonylative Amidation
Introducing Carbon Monoxide (CO) into regular apparatus… dangerous!
High Pressures Required!
Eur. Pat. Appl., 831095, 25 Mar 1998
Exotic catalyst required!
Introducing CO into vials in parallel – tricky, toxic
Journal of Molecular CatalysisA: Chemical, 212(1-2), 151-154; 2004
OOMe
BrPhNH2COg (1 atm)Bu3N
[PdCl2(As2L)]
Pd As
AsPh
Ph
Ph Ph
Si OEt
EtO OEt
ClCl
Catalyst:
OOMe
ONHPh
(Linked to silica resin)
77%
HN
NH
O
OBr
Br
PhNH2COg (10 atm)PdCl2(PPh3)2
120 oC, 24hAutoclave
HN
NH
O
OPhNH
NHPh
O
O88%
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Recent Literature: MicrowaveCarbonylative Amidation
5 mol% Pd(OAc)25 mol% DPPF4 eq. RR'NH1.5 eq. KOt-Bu1 eq. Imidazole
DMFMW 190oC - 15min
N
OR
BrG
GR'
70 - 94% yield
Carbonylation (CO) using Pd methods with DMF:
Hallberg, A.; et al. J. Org. Chem., 2002, 67, 6232-6235.
Requires excess of amine to compete against HNMe2
Successful only with DPPF ligand
Requires High Temp: 190 oC
Limited to electron-rich bromidesand iodides
Uses simple DMF!
H N
OMe
Me
1.5 eq. KO-tBu
1.0 eq. Imidazole MW - 190 oC
C O
HNMe
Me
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Recent Literature: MicrowaveCarbonylative Amidation
4 mol% Herrmann's Palladacycle10 mol% BINAP1.3 eq. RR'NH0.5 eq. Mo(CO)6
aq. K2CO3, diglyme MW 150oC - 15min
N
ORI
G GR'
(Br-)
Unhindered,nucleophilic amines
65 - 83% yield
Carbonylation (CO) using Pd methods with Mo(CO)6:
Larhed, M; et al. J. Comb. Chem., 2002, 4, 109-111.
Simply weigh in solid Mo(CO)6!
Works with electron-rich and electron-poor bromides and iodides
Aqueous base limits Molybdenum mirror averting potential vial hot spots/failure
Requires HOT Palladacycle catalyst (for bromides)
Limited to simple amines (No anilines!)
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Recent Literature: MicrowaveCarbonylative Amidation
10 mol% Pd(OAc)2 or 5 mol% Herrmann's Palladacycle3 eq. RR'NH3 eq. DBU1 eq. Mo(CO)6
THF/diglyme MW (I-) 100oC - 15min, (Br-) 150oC - 15min
N
ORI
G GR'
(Br-)53 - 92% yield
Carbonylation (CO) using Pd methods with Mo(CO)6:
Larhed, M; et al. JOC, 2003, 68, 5750-5753
Simply weigh in solid Mo(CO)6!
Works with alkyl and aryl amines!
Large excess of DBU and amine required
Requires HOT Palladacycle catalyst (for bromides)
Works best with electron-rich iodides and bromides
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Carbonylative Amidation: No Cylinder!
H N
OMe
Me
1.5 eq. KO-tBu
1.0 eq. Imidazole MW - 190 oC
C O
HNMe
Me
• CO from Dimethylformamide
Pd0
L
L
Carbonylation (CO) using Pd methods on Br-compounds:
Larhed, M; et al. JOC, 2003, 68, 5750-5753
Mo
C
CCC
C C O
OO
O
O
O
3.0 eq DBU
C O
(OC)6-nMo(DBU)n
ppt.
• CO from Mo(CO)6
PdIIX
LLAr
PdIIX
LL
Ar
O
PdIIX
LLH
Pd0
L
LBrAr
C O
K+ -O-tBuHO-tBuKX
Ar
ON
R1
R2
HNR1
R2
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Amine Model: Carbonylative Amidation10 mol% PdCl2(dppf)4 eq. BnNH23 eq. DBU1 eq. Mo(CO)6
diglyme, 170 oC
[Pd(OAc)2does not work!]
smallamount
NH
R R'HN
O
NH
R R'Br
“Palladacycles and a process for their preparation.”
Herrmann, W. A.; et al. 1998, US 5831107
Pd(OAc)2P
Pd
Ar Ar
OAc
"Herrmann's Palladacycle"
2
P
1.31 eq.
1.0 eq.Tol
+crystn
• Encouraging…5 mol% Herrmann's Palladacycle4 eq. BnNH23 eq. DBU1 eq. Mo(CO)6
diglyme, 170 oC 80%20% SMco-elute
NH
R R'HN
ONH
R R'Br
mixt.
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Breakthrough Conditions: Benzamide Synthesis
Lit: Larhed, M; et al. JOC, 2003, 68, 5750-5753
Br
NH
O
NH
O
5-10 mol% PdLn3 eq. RNH23 eq. DBU, [0.5 eq Imidazole]1 eq. Mo(CO)6
THF, MW 140-150oC
NH
O
difficult, electon-rich model bromide
Halide Amine PdLn Additive MW ToC-tmin % Amide4-MeOPh-Br BnNH2 Palladacycle 0 150-15 92
" PhNH2 " 0 150-15 684-CF3Ph-Br " " 0 150-15 53
4-AcNHPh-Br BnNH2 " 0 (Lit.) 150-12 40
Microwave carbonylationusing Mo(CO)6 - trials with added imidazole(by LC-MS) " " " 0.5 Imidazole 150-12 100
" " PdCl2(dppf) 0.5 eq 150-12 100" " Pd(OAc)2 0.5 eq 150-12 95" PhNH2 Palladacycle 0.5 eq 150-8 100" " PdCl2(dppf) 0.5 eq 150-8 100" " Pd(OAc)2 0.5 eq 150-8 100
• Direct comparison example produced 100% amide, while the Lit. conditions produced 40%.
• Works with aryl amines (aniline)!
• Only Pd(OAc)2 is needed!
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Improved Carbonylation, Amide Formation• CO from Mo(CO)6
Mo
C
CCC
C C O
OO
O
O
O
3.0 eq DBU
C O
(OC)6-nMo(DBU)n
ppt.
• Palladium Catalytic Cycle
PdIIX
LLAr
HNN
PdIIX
LL
Ar
O
PdIIX
LLH
Pd0
L
LBrAr
C O
Ar
ON N
Ar
ON
R1
R2
HNR1
R2
DBUHX-DBU
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Amidation of Various Bromides
Br
NH
O
NH
O
10 mol% Pd(OAc)23 eq. RNH23 eq. DBU, [0.5 eq Imidazole]1 eq. Mo(CO)6
THF, MW 150 oC - 15 min
NH
O
100%(LC-MS)
NH
ONH
O100%Br
NH
O same conditions
THF, MW 150 oC - 8 min
BrO
NH
O Osame conditions 90%(Lit. 68%) (para-OMe)THF, MW 150 oC - 12 min
Br
N NH
O
N
same conditions 100% (Lit. 0%) (failed for bromide and iodide)
THF, MW 150 oC - 6 min
Lit. for Br-compounds: Larhed, M; et al. JOC, 2003, 68, 5750-5753
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
Improved Conditions: Challenging Substrate
• Using 3-4 eq of amine competes completely over nucleophilic secondary amine.
• Works in the presence of secondary amine and amides – No effect on catalyst!
[Prepared amine using MW method (Biotage) during time with the Initiator MW reactor.]
NH
Br
OMe
O
Br
1) MeOBnNH2 MeOH, 1h
2) PS-BH4 - MW 140-4min3) catch+release
Diversification
10 mol% Pd(OAc)24 eq. BnNH23 eq. DBU, 0.5 eq Imidazole1 eq. Mo(CO)6
THF, MW 150oC-12min
NH
OMe
HN
O
100%
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
PTP Inhibitors Revisited: Access to Diverse Amide Groups
Benzyl amine example:
NHHN
O
NH
Br
10 mol% Pd(OAc)24 eq. BnNH23 eq. DBU, 0.5 eq Im1 eq. Mo(CO)6
THF, MW-150oCR'RR'R
NHN
OR'R
ClOEt
O
O1)
2) NaOH
OH
O
O
Works in the presence of additional functional groups.
“Preparation of Oxoacetic Acids as Inhibitors of Protein Tyrosine Phosphatases (PTPs)”
Swinnen, D.; et al. PCT 2003, WO 2003064376, 346 pp.
Novel Chemistry: Can add Diversity outside of published compounds.
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
It takes more than COto make a “CO-catalyst”.…
Mo
C
CCC
C C O
OO
O
O
O
3.0 eq DBU
C O
(OC)6-nMo(DBU)n
ppt.NH
OMe
HN
O
NH
O
N
PdIIX
LLAr
HNN
PdIIX
LL
Ar
O
PdIIX
LLH
Pd0
L
LBrAr
C O
Ar
ON N
Ar
ON
R1
R2
HNR1
R2
DBUHX-DBU
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2004.10.21 SSF Microwave Synthesis Symposium M. N. Mattson
*Thank You*
Biotage (Personal Chemistry)
To all of you for your attention
…any questions?
Microwave Synthesis Symposium: San Francisco User Group MeetingCarbonylative Amidations Using Mo(CO)6 and Palladium CatalysisProtein Tyrosine Phosphatase InhibitorsDiverse Secondary Amines Needed:Selective PTP InhibitorsTypical Literature: Carbonylative AmidationRecent Literature: Microwave Carbonylative AmidationRecent Literature: Microwave Carbonylative AmidationRecent Literature: Microwave Carbonylative AmidationCarbonylative Amidation: No Cylinder!Amine Model: Carbonylative AmidationBreakthrough Conditions: Benzamide SynthesisImproved Carbonylation, Amide FormationAmidation of Various BromidesImproved Conditions: Challenging SubstratePTP Inhibitors Revisited: Access to Diverse Amide GroupsIt takes more than CO to make a “CO-catalyst”.…*Thank You*