microwave synthesis symposiumphnh o nhph o 88% o 2004.10.21 ssf microwave synthesis symposium m. n....

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


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


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


Diverse Secondary Amines Needed:Selective PTP Inhibitors

PTPNH

N

OR'''

NH

RHN

OR'''

RR'

R'

OH

O

O



• 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


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%


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



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!)



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


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


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.


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!


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


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


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)


Lit. for Br-compounds: Larhed, M; et al. JOC, 2003, 68, 5750-5753


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%


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.



Novel Chemistry: Can add Diversity outside of published compounds.


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


*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*

microwave synthesis symposiumphnh o nhph o 88% o 2004.10.21 ssf microwave synthesis symposium m. n....

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