Multicomponent Reactions - Ambhaikar (July 2004)
Multicomponent Reactions - Ambhaikar (July 2004)
Multicomponent Reactions - Ambhaikar (July 2004)
Definition
Multicomponent Reactions
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
+ CH2O + MeNH2
O
+ NH3
PhNH2
Strecker Synthesis (1838 first reported by Laurent & Gerhardt, 1850 by Strecker)
O R H NH2
+ NH3 + HCN
CN
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
+
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
N O O
+
CHO
MeNH2
MeO2C
CO2Me
+ CN
KOH/MeOH 20 oC, 2h
-chloroketone
3-acyloxy-2-azetidinone
tropinone
Sebti, S.; Foucand, A. Synthesis, 1983, 546. Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron Lett. 1997, 38, 2519.
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.
+
R3 NC
COOEt
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 +
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
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?
S N
C6H11NC
O
+ NH3 +
Br CHO
NHC6H11
( )n n>1
N H R2 O
R2 NHR3 O
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
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
R CHO +
R NH2 +
N
CN
+ HN3
R2 R
1
N N N N N
R1
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
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
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
S S N
U-4CR
H N N O O O
48%
+
N NR1R2
4 NR3 + R CHO
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.
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
H N N O COOMe
+
R2
CH3
R1 R2
Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
Narendra Ambhaikar
Organometallic Multicomponent Reactions Pd catalysed multi-component tetrahydrofuran synthesis
Multicomponent Reactions
R1 HO
R2
EtO2C
CO2Et
+
R3
Ar
Ar R2 R1
R3 O
D-serine
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
+ R3
H
munchnone
H
CH3
CH3
deprotection
N R
2
+
H
+
R3 Cl
CO
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
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.