Synthesis of Substituted Imidazoles viaOrganocatalysis

Doug E. Frantz, Louis Morency, Arash Soheili, Jerry A. Murry,Edward J. J. Grabowski, and Richard D. Tillyer

Department of Process Research,Merck Research Laboratories,

Merck & Co.

Michael Rishel @ Wipf Group 1 3/27/04

Imidazoles as Targets in Medicinal Chemistry

N

N

N

N

HN

N

N

N

NNH

NN

OH

Cl

Losartan

N

NNH

O

SO3H

O

N

CO2H

O PO3H2

Orally available Angiotensin IIinhibitor -- Lilly

R1

R2

RR2

R1

X

N

N

N

X

Y

Imidazole CSAID Ligands -- SKB

N

N

HOOC

COOH

S

Eprosartan

p38 MAP kinase inhibitors

Michael Rishel @ Wipf Group 2 3/27/04

Debus Reaction

Debus imidazole synthesis

RR

O

O

O

R' H+

NH3

H2O NH

NR'

R

R

Debus, H. Liebigs Ann. Chem. 1858, 107, 199.

reaction provides 2- monosbstituted, and 2,(3,4 homo)trisubstitutedimidazoles

Michael Rishel @ Wipf Group 3 3/27/04

Proposed Mechanism of the Debus Reaction

RR

NH

NH

NH

R' H+

HNR

R

N

R'

H2N

H

NN

R

R

HR'

NH3

HN

NR'

R

R

Michael Rishel @ Wipf Group 4 3/27/04

Wallach Reaction

NH

HN R

O

O

RPCl5, POCl3

heat

Wallach chloroimidazole synthesis

Wallach, O. Ber. Dtsch. Chim. Ges. 1881, 14, 420.

N

N

Cl

R

R

II

Provides 1,2 disubstituted chloroimidazoles

Michael Rishel @ Wipf Group 5 3/27/04

Proposed Mechanism of the Wallach Reaction

N

N

Cl

R

R

NH

HN R

O

O

R

PCl5N

N RR

Cl

Cl

-Cl-

+Cl-

N

N

R

Cl

R

-H+

+H+

N

N

R

Cl

R

+H+

-H+

N

N

R

R

ClH

H

-H+

+H+Cl

N

N

H

RH

R

+H+

-H+Cl

N

N

R

R

+Cl- -Cl-

+Cl--Cl-

NN R

R

Cl

H

NN R

R

Cl

H H Cl

HCl

-Cl-

-Cl- II

II

I

I

Benincori, T.; Brenna, E.; Sannicolo, F. J. Chem Soc. Perk. Trans. I 1993, 675-679.

Michael Rishel @ Wipf Group 6 3/27/04

TosMIC Based Imidazole Synthesis

Synthesis from TosMIC

R'' NC

SO

O

TosMIC = tosylmethyl isocyanide

N

R

R'+

van Leusen, A. M.; Wildeman, J.; Oldenziel, O. H. J. Org. Chem. 1977, 42, 1153-9

1. NaH, DME2. H2O3. K2CO3, MeOH N

N

R'R

R'' Process regioselectively provides 1,5-di and a limited number of 1,4,5-trisubstituted imidazoles

Michael Rishel @ Wipf Group 7 3/27/04

Mechanism of TosMIC based Imidazole Synthesis

R''

NS

OO

C

N

R

R'+ [3+2]

NS

OO

R''R

NR N

N

R'R

R''

SO

O

+

Michael Rishel @ Wipf Group 8 3/27/04

Extension of the TosMIC Chemistry

Horne, D. A.; Yakushijin, K.; Buchi, G. Heterocycles, 1994, 139

NC

SO

O O

R+

H

O

N

R

SO

OR''NH2

N

N

R''

R

An Extension of the TosMIC chemistry

R'

R' = H or AlkR'' = H or AlkR and R' cannot both = Alk

R'

R'

Process regioselectively provides 4, 1,4, and 4,5mono- and disubstituted imidazoles

1,4,5 trisubstituted imidazoles are not easily madewith this methodology as a regioisomeric mixture of products results.

Michael Rishel @ Wipf Group 9 3/27/04

Modified TosMIC Imidazole Mechanism

O

N

R

SO

O R''NH2

R'

O

N

R

R'

NHR''R''NH2

O

NH

R

NHR''R''HNH

heat

HNNHR''OHR

NR''

+when R' = H

when R' = alk

O

NH

R

AlkNR''

N

N RHO

N HN

R''NH

R''

H2O

N

NHR''

N+

R

R''H

H

R''NH2

N

N+

R

R''H

H

HN

N

R

R''

HH

R''R

Alk

?

Michael Rishel @ Wipf Group 10 3/27/04

Synthesis of Imidazoles from Amidines

Selective synthesis of 1,2,5 substituted imidazoles

NH

R NHR' X

OR''

Br

X = CHO, CN

+K2CO3

CHCl3, H2ON

NR'

R

X

major

N

NR'

R

minor

+

modest yields, good selectivityammenable to the synthesis ofmultikilogram quantities of pharmaceutical intermediates

X

Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.; Pridgen, L. N. J. Org. Chem. 1997, 62, 8449.

Michael Rishel @ Wipf Group 11 3/27/04

Imidazoles from Amidines -- Mechanism

NH

R NHR' X

OR''

Br

+ N

R NHR'

XR''O

BrH

N N

R

R'

XHR''O

N N

R

R'

X

major

minor R'N

R NH

XR''O

BrH

N N

R

R'

X

Michael Rishel @ Wipf Group 12 3/27/04

Imidazole carboxylates from BICAs

1,5 imidazole carboxylates from amines and 3-bromo-2-isocyanoacrylates (BICAs)

R

Br

NC

COOMe

R'NH2

DMF, Et3NN

N

R'

COOMe

R

Nunami, K.-I.; Yamada, M.; Fukui, T.; Matsumoto, K. J. Org. Chem. 1994, 59, 7635.

Complementary to the amidine methodology

Michael Rishel @ Wipf Group 13 3/27/04

BICA Mechanism

R

Br

NC

COOMeR'NH2 +

NC

COOMe

A

B

R

NC

COOMeR'HN

R'HN

H

R

NC

COOMeR'N H

R

NC

COOMeR'HNR

NHR'

R

N

COOMeR'HN

N

HN

C

COOMe

R'R

N

N COOMe

R'R

Michael Rishel @ Wipf Group 14 3/27/04

Hetero Cope Rearrangement -- A Strategy to HighlySubstituted Imidazoles

Hetero-Cope Rearrangements to regioselectively provide highly Substituted imidazoles

Lantos, I.; Zhang, W.-Y.; Shui, X,; Eggleston, D. S. J. Org Chem. , 1993, 58, 7092.

R

NR'OH

NR''

Cl Ph+

R

NR'O

Ph NHR''

R''N Ph

N

NR1

R2

R3

Ph

highly regioselective synthsis of tetrasubstituted imidazoles. Limited by R-group requirements.

Michael Rishel @ Wipf Group 15 3/27/04

Mechanism of the Hetero Cope RearrangementApproach

R

NR'O

Ph NR''

N Ph R

NR'O

Ph NR''

R''N Ph

R''R

NR'O

Ph NHR''

R''N Ph

R

NR'O

Ph N+

R''N Ph

H

R''

H

R

NR'

R''N Ph

O

Ph NHR''N

NR1

R2

R3

Ph

PhCONHR''

Michael Rishel @ Wipf Group 16 3/27/04

Highly Substituted Imidazoles From b-Ketoamides

Regioselective synthesis of tetrasubstuted imidazoles from b-ketoamides under neutral reaction conditions

N

O

R2

O

R1

N

X

ammonium trifluoroacetateN

N

R2

R1

N

X

Methodology tolerates variance at positions 1,2 and 5 quite well.

Position 4 usually, but not always, aromatic.

Claiborne, C. F.; Liverton, N. J.; Nguyen, K. Tetrahedron Lett. 1998, 39, 8939.

Michael Rishel @ Wipf Group 17 3/27/04

Synthesis of b-Ketoamides… Nontrivial??

Michael Rishel @ Wipf Group 18 3/27/04

A Traceless Synthesis of b-Ketoamides

OO

H1. RNH22. LiBH4 O

HN R1

R3R2

O

X

ON R1

R2

R3

O

R4 Cl

O

OCl

R4 NR3

O

O

R1

R2

+

N

N

R1

R2

R3

R4

Lee, H. B.; Balasubramanian, S. Org. Lett. 2000, 2, 323.

A traceless entry into b-ketoamides -- and tetrasubstituted imidazoles

Michael Rishel @ Wipf Group 19 3/27/04

Thiazolium Catalyzed Synthesis of b-Ketoamides

O

HR1 R2 NH

R3

SO2Tol

+

SN OHR4

X

Et3N, CH2Cl2 35 oC

R2HN R3

OOR1

Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. Am.Chem. Soc. 2001, 9696.

Michael Rishel @ Wipf Group 20 3/27/04

Mechanism of b-Ketoamide Synthesis byOrganocatalysis

Murry, J. A.; Frantz, D. E.; Soheili, A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc. 2001, 123, 9696.

Michael Rishel @ Wipf Group 21 3/27/04

Regioselective, “One Pot” Synthesis of SubstitutedImidazole

Michael Rishel @ Wipf Group 22 3/27/04

One-Pot Synthesis of Di- andTrisubstituted Imidazoles

Michael Rishel @ Wipf Group 23 3/27/04

Synthesis of Tetrasubstituted Imidazoles

Michael Rishel @ Wipf Group 24 3/27/04

Application to the Synthesis of Substituted Oxazolesand Thiazoles

Michael Rishel @ Wipf Group 25 3/27/04

Conclusions

• A rapid, one-pot, regioselective, organocatalyzed synthesis of highlyfunctionalized imidazoles from b-ketoamides has been described

• The methodology has been extended to the synthesis of substitutedoxazoles and thiazoles

Michael Rishel @ Wipf Group 26 3/27/04