Group Meeting7/14/2004Narendra Ambhaikar Multicomponent Reactions

Definition

Multicomponents reactions (MCRs) are those reactions in which three or more reactants come together in a single reaction vessel to form a new product which contains portions of all the components"MCRs convert more than two educts directly in to their product by one-pot reactions"- Ivar Ugi

O

HR+ NH3 + HCN

NH2

CNR

History of MCRs

Several MCRs involve isonitriles- their unique structural features and chemical properties make them suited for such reactions

First 'officially' reported MCR was the Strecker synthesis of α-amino nitrile in 1850

A large portion of MCR chemistry has developed from isocyanides

Pioneering contribution by Ivar Ugi with his discovery of the Uge four component reaction

Other contributors to report heterocycles from Ugi reactioninclude Bienayme, Weber, Schreiber, Armstrong, Bossio

Strecker Synthesis (1838 first reported by Laurent & Gerhardt, 1850 by Strecker)

Hantzsch Dihydropyridine synthesis (1882)

OCO2Et2 NH3+ +

F3C

CHO

HN

CO2Et

CO2Et

Radziszewski Imidazole Synthesis (1882)

CH2O MeNH2 NH3++ +

O

O N

N

Hantzsch Pyrrole Synthesis (1890)

OHC CO2Et PhNH2 ++Br

EtO2CO N

Ph

CO2EtEtO2C

Biginelli Reaction (1891)

O

NH2H2N

OCO2Et

CHO

+ +HN NH

CO2Et

OKappe, O. Acc. Chem. Res. 2000, 33, 879.Baran Lab group meeting presentation by Mike DeMartino

Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.

Radziszewski, B. Ber. Dtsch. Chem. Ges. 1882, 15, 1499.

Hantzsch, A. Justus Liebegs Ann. Chem. 1882, 215, 1.

Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.

R1CHO NaCN+ HN

R1N

R2

H2O, HCl HN

R1 COOH

R2

S

CHO

O

O Ph

NH2S

COOH

H2N

+

R2NH2

Isocyanide multicomponent reaction methodologies have applications in most stages of the drug discovery process spanning lead discovery, lead optimization and final drug manufacture

Hulme, C.; Gore, V. Current. Med. Chem. 2003, 10(1), 51. Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, D. A.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. Ugi, I. Pure Appl. Chem. 2001, 73(1), 187.

Arend, B. Westermann, N.; Risch, N. Angew. Chem. 1998, 110, 1096.Arend, B. Westermann, N.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044.

β-ketoester

This presentation focuses on the construction of heterocycles

Group Meeting7/14/2004Narendra Ambhaikar Multicomponent Reactions

Bucherer-Bergs hydantoin Synthesis (1929)

N

NHO

O

ON

NHO

O NH3 CO2 HCN+ ++ HN

NHO

TT

O T = thymine

Bucherer, T.; Barsch, H.; J. Prakt. Chem. 1934, 140, 151.Kubik, S.; Meisner, R. S.; Rebek, J. Tetrahedron Lett. 1994, 36, 6635.

Mannich reaction (1912)

O

CH2O MeNH2 O

N

O+ +

Robinson's synthesis of tropinone (1917)

MeNH2+ +O

MeO2C CO2Me N

CO2Me

CO2Me

O

Robinson, R. J. Chem. Soc. (London), 1917, 111, 876.

Passerini Reaction (1921)

R1 OH

OR2CHO R3NC+ + R1 O

O R2HN

OR3

α-acyloxy carboxamide- commonly encountered motif in natural productsand pharmacologically interesting peptides

Cyclic variations of the Passerini reaction

O

COOH

NC

O

O

NH

O

bifunctional starting material

+

lactone

COOHCN

ClO

+ + O

O N

O

KOH/MeOH20 oC, 2h

3-acyloxy-2-azetidinone

Sebti, S.; Foucand, A. Synthesis, 1983, 546.Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron Lett. 1997, 38, 2519.

α-chloroketone

Passerini, M. Gazz. Chim. Ital. 1923, 53, 331.

CHO

O

Cl

COOH

OH

NC

N

ONH

O

Cl

HO

+ +

2,4,5-trisubstituted oxazoles

Such oxazoles can be generated smoothly, with high diversity with all three positions variable

1. P-3CR2. NH4COOheat

α-oxoaldehyde

Bossio, R.; Marcacinni, S.; Pepino, R.; Torroba, T. Liebigs Ann. Chem. 1991, 1107.

N

NC

+O

COOEtN

N

COOEt

HO

Lewis acidcatalyst

Kobayashi, K.; Matoba, T.; Susumu, I.; Takashi, M.; Morikawa, H.; Konishi, H. Chem. Lett. 1998, 551.

pyrrolo[1,2-a]quinoxaline (CNS active substance)

hydantoin

OHC

CHO

tropinone

Mannich, C.; Krosche, W. Arch. Pharm. 1912, 250, 647. Bur, S. K.; Martin, S. F. Tetrahedron, 2001, 57, 3221 (Review). Martin, S. F. Acc. Chem. Res.2002, 35, 895.

Group Meeting7/14/2004Narendra Ambhaikar Multicomponent Reactions

The Ugi Reaction (1959)

Application: synthesis of HIV protease inhibitor crixivan (Merck)

BocHNNH2

Cl CHO

Cl

NC

HCOOH

+ +

+U-4CR

BocHN

NCHO

ClCl

O

HN

1. NEt32. KOtBu

N

NBoc

CHO O

HN

NNH

Boc

HN O

1. H2, chiral catalyst2. N2H4

NN

HN O

OHHN

ON

OH

Crixivan

R1COOH + R2CHO + R3NH2

NC+

R1 N

O R2NH

OR3

HCl

R1 N

O R2NH

OR3

N

OO

R3

R1

R2

NH2

R41=R

N

HN

O

R2

R3O

R4

CO2MeMeO2C

N

MeO2C CO2Me

R1R2

R3

R2NHR4=

NO

R4

NR2

OR1

NN

R2O

R4

R3

OR5

R2NH

R5

R4=

NN

OR4

R1

O

R2NHR4

R3 =

Variations of the Ugi Reaction Constrained Ugi adducts: Tethering two reaction partners

R1

O

COOH( )nR2NH2 R3 NC++ N

O

R2

R1NH

OR3

( )n

Three component synthesis of lactams

Hanusch-Kompa, C. Ugi, I. Tetrahedron Lett. 1998, 39, 2725.Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591.

HOOC NH2

R1

( )n R2CHO R3NC++N

O

NR3

H

R2

R1 N

O

R2

ONHR3

R1

( )n

MeO

O

R1

HN

NH

O

R2

R3

n=1, MeOH

n>1

The Ugi lactam and aminodiacetic adduct syntheses

CHOR1 COOH N CR3 NH2R4R2+ + +R1

NHN

OR3

O

R2 R4

N

CR1

H R4

N

O

R2

OR3

HN

R1 N

O

R2

O

R4

R3

α-acylaminocarboxamide

O

O

O

MeNC L-Ala+ + O

O

NHHN

O

O

MeOH, 20 oC

2,6-piperazine dione

Ugi I.; Horl, W.; Hanusch, C.; Schmid, T.; Herdtweck, E. Heterocycles, 1998, 47, 985.

OHCCOOMe

NPhth NaSH

NH3Br CHO

+

+ +

1. Asinger2. HO-

N

S

NPhth

CO2HC6H11NC N

S

ONHC6H11O

PhthN

penicillin derivative

Application: sequential Asinger Ugi Reactions in the synthesis of penicillin derivatives

Ugi, I.; Wishofer, E. Chem. Ber. 1962, 95, 136.

Post Ugi condensations

Rossen, K.; Pye, P. J.; Di Michele, L. M.; Volante, K.; Reider, P. J. Tetrahedron Lett. 1998, 39, 6823.

The Ugi reaction has been the most extensively studied and applied MCR in the drug discovery process

Mechanism?

( )n

Park, S. J.;Keum, G.; Kang, S. B.; Koh, H. Y.; Lee, D. H. Tetrahdron Lett. 1998, 39, 7109.Ugi, I.; Horl, W.; Hanush-Kompa, C.; Schmid, T.; Herdtweck, E. Heterocycles, 1998, 47, 965.

enamide

N-acyl iminium ion munchnone

Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6(10) , 3321.

Group Meeting7/14/2004Narendra Ambhaikar Multicomponent Reactions

R1

O

SiX3

R2

R3

O

R4

NS

R CH3

R20 mol%

Br

DBU, THFi-PrOH

R2

R1 O

R3

O

R4

NR1R4

R3R2

R5

R5NH2TsOH

4A sieves

54-82%

+

Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. ASAP.

One-pot synthesis of pyrroles catalyzed by thiazolium salts

O

HR5

SO2

NH

R4

Tol

R2

O N

S OHI

(5-20 mol%)Et3N, solvent

35-60 oC

R5 O

R4 HN R2

O+

N

N

R4

R5R2

R1

R1NH2AcOH

Synthesis of Imidazoles via organocatalysis

Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. E.; Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843.

Based on the same strategy synthesis of oxazoles and thiazoles has also been reported.

R1CHO R2NH2 HN3

CNO

OR3

N

+ + +HCl

MeOHN

N

N NN

O

OR1

R1

R2

A 'two-step one-pot' fused tetrazole synthesis (Ugi variation)

Bienayme, H.; Bouzid, K. Tetrahedron Lett. 1998, 39, 2735.

Grieco three component synthesis of piperidines

Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768.Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855.

Ar H

O

NH

H

H

Ar

PhNH2+ +

Three component tandem aza [4+2]/allylboration reactions in the diversity oriented syntheisis of polysubstituted piperidines

N

B

NR1R2

OO

NR3

O

O

R4CHO+ + NNR3

O

ONR1R2OH

R1

Toure, B. B.; Hoveyda, H. R.; Tailor, J.; Agnieszka, U.-L.; Hall, D. Chem. Eur. J. 2003, 9, 466.

toluene80 oC, 72h

42-77%

Combination of MCRs

Br CHO NaSH + NH3+

CHOMeOH

CO2

+ +

+ NC

N

S N

S

O

HN

OO

U-4CR

thiazoline thiazolidine

48%

Domling, A.; Ugi, I. Angew. Chem. 1993, 105, 634.Domling, A.; Ugi, I. Angew. Chem. Intl. Ed. 1993, 32, 563.Review on the Asinger Reaction: Asinger, F.; Offermanns, H. Angew. Chem. Int. Ed. 1967, 6, 907.

A seven component reaction

Ugi + Pictet-Spengler Reaction

HN

COOH

NH2

CHO

CHO

NC++

1. U-4CR2. Pictet-Spengler3. O2

HN

N

OCOOMe

Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.

TFA, CH3CN

Asinger reaction

Yields are low for aliphatic amines

29-100%

alkyl-β-(N,N-dimethylamino)-α-isocyanoacrylate

Mechanism?

Group Meeting7/14/2004Narendra Ambhaikar Multicomponent Reactions

Organometallic Multicomponent Reactions

Dhawan, R.; Dghaym, R. D.; Arndtsen, B. A. J. Am. Chem. Soc. 2003, 125, 1474.Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107.Dhawan, R.; Arndtsen, B. A. J. Am. Chem. Soc. 2004, 126, 468.Dghaym, R. D.; Dhawan, R.; Arndtsen, B. A. Angew. Chem. Int.Ed. 2001, 40, 3228.

N

H3C OBnO

H

H3C

H

N

H3CCH3

OBnOSiEt3H

H3C

Et3SiHNi(COD)2

PBu3

95% (single diastereomer)

deprotection N

H3CCH3

OHOH

HH3C

(+)-allopumillotoxin

Pd catalysed multi-component tetrahydrofuran synthesis

Cavicchioli, M.; Sixdenier, E.; Derrey, A.; Bouyssi, D.; Balme, G. Tetrahedron. Lett. 1997, 38, 1763.

R2R1

HO

EtO2C CO2Et

R3

+ + Ar IPd0 cat.

baseO

Ar

CO2EtCO2Et

R1

R2 R3

Pd catalyzed multicomponent coupling of alkynes, imines and acid chlorides via munchnones (1,3-oxazolium-5-oxides) in the synthesis of pyrroles

N

HR2

R1

R3 R4

R5 Cl

O+ +

PdO

N

R2H

R5

Cl R1

/ L

2

4 atm CO, EtNiPr2

NR5R2

R3R4

R15%

N

OO

R5

R2

R1

munchnone 56-95%

N

HR1

R2

R3 Cl

OH R4+ +

CuI, 10 mol%EtNiPr2CH3CN

RT77-99%

N

R1

R2R3

O

R4

Cu catalyzed multicomponent of imines, acid chlorides and alkynes in the synthesis ofpropargyl amides

propargyl amides

N

HR2

R1

R3 Cl

O+ CO+

[Pd2(dba)3] (5 mol%)ligand (10 mol%)

CH3CN

62-92%

N N

R3

R1R1

HR2

R2CO2

-

Pd catalyzed of α-amino acid derived imidazolines

Ni catalyzed coupling of an aldehyde, alkyne and organozinc or silane

Ni catalyzed coupling of an enone, alkyne, and organozinc

D-serine

ON

ON

O

O

O

OTBS

Me3Al Ni(COD)2 10 mol%

ON

O

N

O

O

O

OTBSNH

HOOC

HOOC

(+)-α-allokainic acid

Chevliakov, M. V.; Montgomery, J. Angew. Chem. Int. Ed. Eng. 1998, 37, 3144.

Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098.

Group Meeting7/14/2004Narendra Ambhaikar Multicomponent Reactions

Some Useful Reviews on MCRs

Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.

Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321.

Tietze, L.. F.; Modi, A. Med. Res. Rev. 2000, 20, 304.

Posner, G. H. Chem. Rev. 1986, 86, 831.

Armstrong, R. M.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123.

Dax, S. L.; McNally, M. A.; Youngman, M. A.; Curr. Med. Chem. 1999, 6, 255.

Tietze, L. F.; Lieb, M. E. Curr. Opin. Chem. Biol. 1998, 2, 363.

Ugi, I. Pure and Appl. Chem. 2001, 73, 187.

Williams, T. J.; Zhang, L. Pure Appl. Chem. 2002, 74, 25.

Domling, A. Curr. Opin. Chem. Biol. 2000, 4, 318.