Group Meeting
7/14/2004
Multicomponent Reactions
Narendra Ambhaikar
Definition
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
CO2Et
CHO
O
2
CO2Et
+
NH3 +
HN
F3C
β-ketoester
CO2Et
Hantzsch, A. Justus Liebegs Ann. Chem. 1882, 215, 1.
Isocyanide multicomponent reaction methodologies have applications in most stages of the drug
discovery process spanning lead discovery, lead optimization and final drug manufacture
Radziszewski Imidazole Synthesis (1882)
This presentation focuses on the construction of heterocycles
O
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 α-amino nitrile in 1850
+ CH2O + MeNH2
N
+ NH3
N
O
Radziszewski, B. Ber. Dtsch. Chem. Ges. 1882, 15, 1499.
A large portion of MCR chemistry has developed from isocyanides
Pioneering contribution by Ivar Ugi with his discovery of the Uge four component reaction
Ph
Hantzsch Pyrrole Synthesis (1890)
Other contributors to report heterocycles from Ugi reactioninclude Bienayme, Weber,
Schreiber, Armstrong, Bossio
O
OHC
PhNH2
CO2Et +
+
N
EtO2C
Br
Strecker Synthesis (1838 first reported by Laurent & Gerhardt, 1850 by Strecker)
CO2Et
Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
NH2
O
R
EtO2C
H
+ NH3 + HCN
R
CN
Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
Biginelli Reaction (1891)
CO2Et
CHO
R1CHO +
NaCN
R2NH2
HN
R1
CHO
O
Ph
R
2
H2O, HCl
R1
O
O
O
+
COOH
H2N
NH2
CO2Et
+
N
HN
NH
O
H2N
COOH
+
S
HN
R2
NH2
S
Arend, B. Westermann, N.; Risch, N. Angew. Chem. 1998, 110, 1096.
Arend, B. Westermann, N.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044.
Kappe, O. Acc. Chem. Res. 2000, 33, 879.
Baran Lab group meeting presentation by Mike DeMartino
Group Meeting
7/14/2004
Multicomponent Reactions
Narendra Ambhaikar
Cyclic variations of the Passerini reaction
Mannich reaction (1912)
N
+
CH2O
+
MeNH2
O
O
NC
O
O
O N
H
+
O
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.
COOH
O
bifunctional starting
material
lactone
Passerini, M. Gazz. Chim. Ital. 1923, 53, 331.
Robinson's synthesis of tropinone (1917)
O
CO2Me
OHC
COOH
O
+
MeNH2
+
MeO2C
N
CO2Me
+
O
CHO
tropinone
Cl
T
O
+
+
Cl
O
HN
O + NH3 + CO2 + HCN
NH
O
OH
R2CHO +
R3NC
R1
N
HO
2,4,5-trisubstituted oxazoles
Bossio, R.; Marcacinni, S.; Pepino, R.; Torroba, T. Liebigs Ann. Chem. 1991, 1107.
O
N
+
O
Such oxazoles can be generated smoothly, with high diversity with all three positions variable
Passerini Reaction (1921)
OH
2. NH4COO
heat
α-oxoaldehyde
Bucherer, T.; Barsch, H.; J. Prakt. Chem. 1934, 140, 151.
Kubik, S.; Meisner, R. S.; Rebek, J. Tetrahedron Lett. 1994, 36, 6635.
O
N
H
Cl
hydantoin
R2
O
NC 1. P-3CR
T = thymine
N
H
O
O O
R1
3-acyloxy-2-azetidinone
COOH
CHO
T
NH
N
O
O
O
N
O
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)
N
+ CN
α-chloroketone
CO2Me
Robinson, R. J. Chem. Soc. (London), 1917, 111, 876.
O
KOH/MeOH
20 oC, 2h
H
N
O
+
R3
O
α-acyloxy carboxamide- commonly
encountered motif in natural products
and pharmacologically interesting
peptides
NC
COOEt
Lewis acid
catalyst
N
COOEt
N
HO
pyrrolo[1,2-a]quinoxaline
(CNS active substance)
Kobayashi, K.; Matoba, T.; Susumu, I.; Takashi, M.; Morikawa, H.; Konishi, H. Chem. Lett. 1998, 551.
Group Meeting
7/14/2004
Multicomponent Reactions
Narendra Ambhaikar
Post Ugi condensations
The Ugi Reaction (1959)
R1 CHO + R2 COOH +
NC
3
R1COOH + R2CHO + R NH2 +
O
R2
R3 N C + R4 NH2
N
R4
R3
H
N
R1
R
R1
3
The Ugi reaction has been
the most extensively studied
and applied MCR in the drug
discovery process
N
R1
C
N
O
HN
R3
R
4
R1
O
HCl
NH2
N
R
R =R
O
H
N
O
2
R4
R2
R3
R1
R2
Variations of the Ugi Reaction
O
HN
O
+ MeNC +
L-Ala
R1
+
( )n
COOH
N
R
R
R2 =
NHR4
1
R4
N
H
R1
O
N
R2
O
N
R3
N
N
R3
R4
R4
R5
O
R3
N
H
N R2
( )n
N
Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6(10) , 3321.
O
R2NH2 + R3 NC
2
R2
N
Ugi I.; Horl, W.; Hanusch, C.; Schmid, T.; Herdtweck, E. Heterocycles, 1998, 47, 985.
O
munchnone
R2 =
CO2Me
CO2Me
R1
O
O
R1
O
MeO2C
2,6-piperazine dione
O
N
H
O
2
NHR4 R
R5
MeO2C
O
O
R1
R2
O
O
R2
3
N
NH
MeOH, 20 oC
Three component synthesis of lactams
R
N-acyl iminium ion
R3
O
O
N
O
N
Constrained Ugi adducts: Tethering two reaction partners
R3 =
41
R3
O
O
enamide
α-acylaminocarboxamide
R4
N
H
R2
O
O
H
O
N
Application: sequential Asinger Ugi Reactions in the synthesis of penicillin derivatives
OHC
O
COOMe
+
NPhth
Hanusch-Kompa, C. Ugi, I. Tetrahedron Lett. 1998, 39, 2725.
Harriman, G. C. B. Tetrahedron Lett. 1997, 38, 5591.
NaSH
+ NH3 +
Br
PhthN
1. Asinger
2. HO-
S
CO2H
Mechanism?
N
NPhth
S
C6H11NC
N
O
O
CHO
NHC6H11
penicillin derivative
Ugi, I.; Wishofer, E. Chem. Ber. 1962, 95, 136.
The Ugi lactam and aminodiacetic adduct syntheses
R
HOOC
NH2
N
3
+ R2CHO + R NC
H
R2
R3
Application: synthesis of HIV protease inhibitor crixivan (Merck)
R2
+ HCOOH
NHR3
O
O
NC
O
O
H
N
MeO
R1
R2
Cl
Boc
N
H
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.
R3
1. H2, chiral
catalyst
2. N2H4
BocHN
HN
H
N
CHO O
OH
H
N
N
N
N
N
N
O
1. NEt3
2. KOtBu
H
N
CHO O
CHO
NH
Boc
Cl
N
N
HN
Cl
U-4CR
Cl
+
+
n=1, MeOH
N
NH2
BocHN
N
n>1
( )n
O
R1
( )n
R1
( )n
1
OH
O
O
Crixivan
Rossen, K.; Pye, P. J.; Di Michele, L. M.; Volante, K.; Reider, P. J. Tetrahedron Lett. 1998, 39, 6823.
R4
Synthesis of Imidazoles via organocatalysis
A 'two-step one-pot' fused tetrazole synthesis (Ugi variation)
O
O
R2NH2 +
R1CHO +
CN
Group Meeting
7/14/2004
Multicomponent Reactions
Narendra Ambhaikar
O
R3
+ HN3
N
HCl
MeOH
29-100%
R2
R
N
O
R1
N
N N
alkyl-β-(N,N-dimethylamino)α-isocyanoacrylate
Tol
O
R5
OH
S
I
Yields are low for
aliphatic amines
N
1
N
SO2 O
R4
H
N
R5
O
+
R4
H
R2
N
H
(5-20 mol%)
Et3N, solvent
35-60 oC
Bienayme, H.; Bouzid, K. Tetrahedron Lett. 1998, 39, 2735.
R4
R1NH2
AcOH
R2
N
R2
R5
O
N
R1
Based on the same strategy synthesis of oxazoles and thiazoles has also been reported.
Grieco three component synthesis of piperidines
Frantz, D. E.; Morency, L.; Soheili, A.; Murry, J. E.; Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6, 843.
H
O
H
Ar
+
PhNH2 +
TFA, CH3CN
H
Ar
N
H
Combination of MCRs
A seven component reaction
Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768.
Grieco, P. A.; Bahsas, A. Tetrahedron Lett. 1988, 29, 5855.
Br
Three component tandem aza [4+2]/allylboration reactions in the diversity oriented
syntheisis of polysubstituted piperidines
CHO
+
+ NaSH + NH
3 Asinger
reaction
+ MeOH
O
O
B
+
4
NR3 + R CHO
R
U-4CR
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.
N
NR1R2 O
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
R1
1. U-4CR
2. Pictet-Spengler
3. O2
COOH
20 mol%
SiX3
+
S
O
R2
R
R4
R3
N
R
Br
CH3
DBU, THF
i-PrOH
Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. ASAP.
R1
R5
O
R2
O
R4
R
3
O
thiazolidine
NR1R2
O
O
O
thiazoline
NC
N
H
N
48%
NR3
1
OH
42-77%
O
N
CO2 +
toluene
80 oC, 72h
N
CHO
O
O
S
S
R5NH2
TsOH
4A sieves
54-82%
R1
R2
+
N
R4
R3
CHO
+
NH2
NC
Mechanism?
CHO
Domling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
H
N
N
O
COOMe
Group Meeting
7/14/2004
Multicomponent Reactions
Narendra Ambhaikar
Organometallic Multicomponent Reactions
Pd catalysed multi-component tetrahydrofuran synthesis
Ni catalyzed coupling of an enone, alkyne, and organozinc
O
R1
EtO2C
R2
CO2Et
+
HO
Ar
+
Pd0 cat.
base
I
R3
Ar
R
N
D-serine
R3
R2
O
1
Cavicchioli, M.; Sixdenier, E.; Derrey, A.; Bouyssi, D.; Balme, G. Tetrahedron. Lett. 1997, 38, 1763.
O
O
O
O
CO2Et
CO2Et
O
Me3Al
Ni(COD)2
10 mol% O
N
O
N
HOOC
N
OTBS
HOOC
N
H
O
(+)-α-allokainic acid
O
OTBS
Pd catalyzed multicomponent coupling of alkynes, imines and acid chlorides via
munchnones (1,3-oxazolium-5-oxides) in the synthesis of pyrroles
R2
Cl
5%
R1
N
+ R3
R2
O
R4 +
R5
H
Pd
H
1
N R
R
5
2
O
R1
/L
O
R
N
5
R
R4
Ni catalyzed coupling of an aldehyde, alkyne and organozinc or silane
O
R5
2
R2
Cl
4 atm CO, EtNiPr2
Chevliakov, M. V.; Montgomery, J. Angew. Chem. Int. Ed. Eng. 1998, 37, 3144.
R3
N
H3C
R1
munchnone
H3 C
56-95%
N
H
Pd catalyzed of α-amino acid derived imidazolines
N
R1
O
+
+
R
2
H
R
3
Cl
CO
[Pd2(dba)3] (5 mol%)
ligand (10 mol%)
CH3CN
62-92%
O
H
H3C OBn
R3
R1
N
R2
H
1
N R
CO2-
R2
Et3SiH
Ni(COD)2
PBu3
N
deprotection
OSiEt3
H
H3C OBn
95% (single diastereomer)
Tang, X. Q.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 6098.
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
+
CH3CN
+
R4
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.
H3C
CH3
CH3
N
H
H3C OH
OH
(+)-allopumillotoxin
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.
Group Meeting
7/14/2004