Narendra Ambhaikar

Definition

Multicomponent Reactions

Group Meeting 7/14/2004

Hantzsch Dihydropyridine synthesis (1882) 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 Several MCRs involve isonitriles- their unique structural features and chemical properties make them suited for such reactions Isocyanide multicomponent reaction methodologies have applications in most stages of the drug discovery process spanning lead discovery, lead optimization and final drug manufacture This presentation focuses on the construction of heterocycles 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. History of MCRs First 'officially' reported MCR was the Strecker synthesis of -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 Hantzsch Pyrrole Synthesis (1890) Other contributors to report heterocycles from Ugi reactioninclude Bienayme, Weber, Schreiber, Armstrong, Bossio
OHC CO2Et + O Ph N CO2Et O CHO CO2Et

NH3 +
F3C HN CO2Et

-ketoester

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

Radziszewski Imidazole Synthesis (1882)

O N N

+ CH2O + MeNH2
O

+ NH3

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

PhNH2

EtO2C Br EtO2C CO2Et

Strecker Synthesis (1838 first reported by Laurent & Gerhardt, 1850 by Strecker)
O R H NH2

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

+ NH3 + HCN

CN

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

R2 COOH

Biginelli Reaction (1891)

CHO CO2Et O O

R1CHO +

R2NH2

NaCN

HN R1

R2

H2O, HCl
N H2N COOH

HN R1

+
H2N NH2

CO2Et

+
HN O NH

CHO

O O

Ph NH2

+
S S

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

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

Narendra Ambhaikar

Multicomponent Reactions

Group Meeting 7/14/2004

Mannich reaction (1912)

N

Cyclic variations of the Passerini reaction

O O O O N H O

+
O

CH2O

MeNH2

NC

+
COOH

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.

bifunctional starting material Passerini, M. Gazz. Chim. Ital. 1923, 53, 331.

lactone

Robinson's synthesis of tropinone (1917)

CO2Me OHC O COOH O Cl N O CO2Me

N O O

+
CHO

MeNH2

MeO2C

CO2Me

+ CN

KOH/MeOH 20 oC, 2h

-chloroketone

3-acyloxy-2-azetidinone

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

tropinone

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

Bucherer-Bergs hydantoin Synthesis (1929)

O NH O N N NH O O O + NH3 + CO2 + HCN HN O N H T T Cl O

O CHO COOH NC 1. P-3CR 2. NH4COO heat N H

O O N HO Cl

+
OH

T = thymine -oxoaldehyde

hydantoin

2,4,5-trisubstituted oxazoles

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

Such oxazoles can be generated smoothly, with high diversity with all three positions variable Bossio, R.; Marcacinni, S.; Pepino, R.; Torroba, T. Liebigs Ann. Chem. 1991, 1107.

Passerini Reaction (1921)

N O O R1 OH R2 O O H N

+
R3 NC

COOEt

Lewis acid catalyst

N N HO COOEt

R2CHO +

R3NC

R1

-acyloxy carboxamide- commonly encountered motif in natural products and pharmacologically interesting peptides

pyrrolo[1,2-a]quinoxaline (CNS active substance) Kobayashi, K.; Matoba, T.; Susumu, I.; Takashi, M.; Morikawa, H.; Konishi, H. Chem. Lett. 1998, 551.

Narendra Ambhaikar
The Ugi Reaction (1959)
R1 CHO + R2 COOH + R3 N C + R4 NH2

Multicomponent Reactions
Post Ugi condensations
O R2 R1 O N R4 H N R3 R1 O
3 R1COOH + R2CHO + R NH2 +

Group Meeting 7/14/2004

NC

R3 N R2

O N H

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

R4 C O R2 N R
3

-acylaminocarboxamide
HN O R1 O R2 R4 NH2 N R3 O R4 N O HN O NH O O O MeO2C R
1

enamide

HCl
R41=R O R2 R3 CO2Me R1 O

R3 =
R3 N R2 O N H R
3

H N

R2 N O O

O N N R R5
1

2 NHR4 R

R4

R1

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

N-acyl iminium ion R2 =

O R1

munchnone R2 =
N H

MeO2C

R4

NHR4

+ MeNC +

L-Ala

MeOH, 20 oC

CO2Me R2

N R2

O N N O R4 R5

2,6-piperazine dione Ugi I.; Horl, W.; Hanusch, C.; Schmid, T.; Herdtweck, E. Heterocycles, 1998, 47, 985. Three component synthesis of lactams
R1 O O N H N R2 O

N R3

N R4

R3

Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6(10) , 3321.
R3

+ ( )n
COOH

R2NH2 + R3 NC

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

( )n

+
NPhth

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

NaSH

1. Asinger 2. HOMechanism?

PhthN S N CO2H NPhth

S N

C6H11NC
O

+ NH3 +
Br CHO

NHC6H11

penicillin derivative The Ugi lactam and aminodiacetic adduct syntheses

R1 R1 HOOC O NH2
3 + R2CHO + R NC

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

R
1

( )n n>1
N H R2 O

R2 NHR3 O

Application: synthesis of HIV protease inhibitor crixivan (Merck)

BocHN NH2

Boc

+ HCOOH
Cl Cl CHO

BocHN

Cl N

Cl H N

( )n

U-4CR
CHO O N

1. NEt3 2. KOtBu

N N CHO O H N

( )n

+
NC O N H R3

+
Boc

n=1, MeOH
O MeO R1 H N R2

N NH HN O N

OH N

1. H2, chiral catalyst 2. N2H4

H N O

OH

HN

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.

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

Narendra Ambhaikar

Multicomponent Reactions

Group Meeting 7/14/2004

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

O O O R3

Synthesis of Imidazoles via organocatalysis

R CHO +

R NH2 +
N

CN

+ HN3

HCl MeOH 29-100%

R2 R
1

N N N N N

R1

I Yields are low for aliphatic amines

R5 Tol O H SO2 O N H R2 N

OH R4 R5 H N O O R2

+
R4

R1NH2 AcOH

R4 R5

N R2 N R1

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

Bienayme, H.; Bouzid, K. Tetrahedron Lett. 1998, 39, 2735. Grieco three component synthesis of piperidines

(5-20 mol%) Et3N, solvent 35-60 oC

Based on the same strategy synthesis of oxazoles and thiazoles has also been reported. Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. E.; Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843.
O Ar H H

PhNH2 +

TFA, CH3CN

H Ar N H

Combination of MCRs A seven component reaction Br

CHO

Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768. Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855. Three component tandem aza [4+2]/allylboration reactions in the diversity oriented syntheisis of polysubstituted piperidines
O O B O O

CHO

+ NaSH + NH 3 Asinger reaction + MeOH

NC

S S N

U-4CR
H N N O O O

48%

+
N NR1R2

4 NR3 + R CHO

toluene 80 oC, 72h 42-77%

CO2 +
R1 OH NR N NR1R2 O
3

thiazoline

thiazolidine

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.

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

Ugi + Pictet-Spengler Reaction

H N

One-pot synthesis of pyrroles catalyzed by thiazolium salts

O COOH

20 mol%
SiX3 S O R4 R3 R N R

R1

Br

R1 R2

R O O R4 R
3

+
R4 R3 CHO CHO

+
NH2 NC

1. U-4CR 2. Pictet-Spengler 3. O2 Mechanism?

H N N O COOMe

+
R2

CH3

R5NH2 TsOH 4A sieves 54-82%

R1 R2

DBU, THF i-PrOH

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

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

Narendra Ambhaikar
Organometallic Multicomponent Reactions Pd catalysed multi-component tetrahydrofuran synthesis

Multicomponent Reactions

Group Meeting 7/14/2004

Ni catalyzed coupling of an enone, alkyne, and organozinc

O CO2Et CO2Et O O N O

R1 HO

R2

EtO2C

CO2Et

+
R3

Ar

Pd0 cat. base

Ar R2 R1

R3 O

D-serine

Me3Al Ni(COD)2 10 mol% O

N N O OTBS

HOOC HOOC

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

N O OTBS

N H

(+)--allokainic acid

Pd catalyzed multicomponent coupling of alkynes, imines and acid chlorides via munchnones (1,3-oxazolium-5-oxides) in the synthesis of pyrroles
R2 Cl N R2 R1 H 1 N R

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

5%
R4 + R5 O Cl

Pd O

/L
R
5

R1 R5 R4 N R R3
2

O R2

O R5 N R1

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

H3C H3 C N H3C N H H3C OH OH

+ R3
H

4 atm CO, EtNiPr2 56-95%

munchnone
H

Pd catalyzed of -amino acid derived imidazolines

R
1

Et3SiH Ni(COD)2 PBu3

CH3

CH3

N OSiEt3 H H3C OBn

deprotection

N R
2

+
H

+
R3 Cl

CO

[Pd2(dba)3] (5 mol%) ligand (10 mol%) CH3CN 62-92%

R3 R1 R2 H N
1 N R CO2-

O H H3C OBn

95% (single diastereomer) Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098.

(+)-allopumillotoxin

R2

Cu catalyzed multicomponent of imines, acid chlorides and alkynes in the synthesis of propargyl amides O CuI, 10 mol% R2 3 R2 EtNiPr2 O R N N 4 + CH3CN + R H RT Cl R3 R1 R1 H 77-99% 4
R

propargyl amides 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.

Narendra Ambhaikar

Multicomponent Reactions

Group Meeting 7/14/2004

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.