The Biginelli and Related

(Passerini and Ugi) Reactions

Mike DeMartino
Group Meeting: August 27, 2003
 Overview
• How these reactions are related
• The Biginelli Reaction
– Mechanism
– Modifications and chemical manipulation
– Biology
– Synthetic examples
• The Passerini Reaction
– Mechanism
– Synthetic examples
• The Ugi Reaction
– Mechanism
– Synthetic Reactions
• Concluding Remarks
 Similarities

• All are multicomponent Reactions (MCRs)

• In MCRs, “three or more reactants come together in a
single reaction vessel to form products that contain
portions of all the components.”
» Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.

• Has advantages over traditional linear syntheses.

• Manifestations in a variety of chemical sects.

The Biginelli Reaction
 The Biginelli Reaction
• Synthesis of 3,4-dihydropyrimidin-2(1H)-ones
was discovered in 1893 by Pietro Biginelli
» Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
EtO2C O
+ +
O H2N NH2
O
H

EtOH,
H+ heat

Ph
=> Biginelli-type
EtO2C compounds
NH

Me N O
H
 The Mechanism: a Century of
Uncertainty
• First proposal in 1933
» Folkers, K., Johnson, T.B. J. Am. Chem. Soc. 1933, 55, 3784.

EtO2C
O

O O HN NH2 O
2X + R
H2N NH2 R H HN NH2

O
O HO Me
Ph
CO2Et
HN N EtO2C
H NH
R
HN NH2 H2O
Me N O
H
O
 The Mechanism: a Century of
Uncertainty
• Second proposal in 1973
» Sweet, F., Fissekis, J.D.. J. Am. Chem. Soc. 1973, 95, 8741.

O EtO2C H
+ H+
H O O HO O
O O
O
OEt OEt OEt

H2N NH2

Ph
CO2Et O
HN H
HN
O N Me OEt
H H2O O
NH2 O
 The Mechanism: a Century of
Uncertainty
• Latest proposal in 1997
» Kappe, C.O. J. Org. Chem. 1997, 62(21), 7203.

O Ph OH Ph H
O H+
H + HN NH2 N NH2
H2N NH2 -H2O H
O O
O
HN NH2
R
HN NH2
O
Ph
Ph Ph
EtO2C
EtO2C
NH NH EtO2C
NH
O O
H2N Me N O H2O O O
Hu, E.H., et.al. H Me
H2N
J. Org. Chem. 1998. 63, 3454.
 The Atwal* modification
• Brought about by the need for better yields:
• Ortho-substituted aryl aldehydes
• Aliphatic aldehydes

R1 R1 H R1 H
RO2C NH2 RO2C
H + NaHCO3 RO2C N
Deprotect NH
HN X DMF R 2 Mostly 60-91%
Me O Me N X yield Me N X
R2 H H
X = O, S (With an appropriate protecting group)

• Since R1 can be significantly varied w/little affect on yield, the

“finicky” aldehyde problem can be circumvented.
*Atwal, K. S., et. al. J. Org. Chem. 1989, 54, 5898.
 Synthetic Manipulation
• So, with the dihydropyrimidine in hand, what
can be done?
• Partial of full oxidation (not trivial)
• Reduction of the ring to the hexahydropyrimidine
• Alkylation and acylation of the heteroatoms
• Manipulation of the ester at C(5)
• Manipulation of the methyl group at C(6) (halogenation,
nitration, etc.)
• Ring condensing reactions to make bi,tri-cycles
Ph
4
EtO2C 5
3NH
6 2
Me N1 O
H
 Biology
• The biological activity is what make these
pyrimdines such attractive targets
• (A 1930 patent for use of a Biginelli cmpd for protection of
wool from moths!?!)
• Antiviral activity
• Antibacterial activity Ar H
• Antitumor RO2C
NH
• Antiinflammatiry
• Analgesic Me N X
H
• Blood palette aggregation inhibitor
• Cardiovascular activity
• Potent calcium channel blockers
• Etc.
 Synthetic Examples
• Solid phase synthesis for combinatorial scaffolds
of Biginelli compounds
– First example: Wipf, P., Cunningham, A. Tet. Lett. 1995, 36, 7819.
Ar
O Ar
O H R
O O NH
NH2 1. THF, HCl, 55°C
R +
O 2. TFA, CH2Cl2 R N O
HN O 1
R1 O O P OH

O O
• Fluorous-Phase modifications
– Studer, A., et. al. J. Org. Chem., 1997, 62, 2917.
Ar

O H O Ar
O
NH2 1. HCl, THF/BTF, 50°C R
R + O NH
O TAG
HN O 2. Extract w/FC-72
R N O
R1 O 3. TBAF, THF/BTF 1
O O
O O
Tag = Si(CH2CH2C10F21)3
 Synthetic Examples
• Synthesis of rac-Monastrol
• Mitosis blocker by kinase Eg5 inhibition
• Utilization and extension (to thioureas) of the
Yb(OTf)3 catalysis work
» Dondoni, A., et. al. Tet. Lett. 2001, 43, 5913

OH
HO
O O
H
EtO H Yb(OTf)3 EtO2C
+ NH
Me O S THF, reflux,
12 h Me N S
H2N NH2 H
(+/-) Monastrol
 Synthetic Examples
• Inorganic catalysis
– Indium(III) Chloride mediated Biginelli reactions
» Brindaban, C. R., et. al. J. Org. Chem. 2000, 65, 6270
R2

O H O R2
X InCl3, THF
O O + R1 NH
H2N NH2 81-95 %
R R 1 R N X
X = O, S H

• Heavy-Metal catalysis
» Ma, Y., et. al. J. Org. Chem. 2000, 65, 3864
R2

O H O R2
O Yb(OTf)3 (5 mol %)
O O + R1 NH
H2N NH2 100°C
R R 1 81-99% R N O
H
 Synthetic Examples
• Natural Product Synthesis
– The use of tethered Biginelli condensations for syntheses
of structurally diverse guanidine alkaloids
O O
• (–)-Ptilomycalin A: H H
N O N NH2
14
NH2
N N
OH H O

Overman, L., et. al. J. Am. Chem. Soc. 1995, 117, 2657

H H
R3O2C
N
R1
R3O2C R1 A: Morpholinium Acetate
CF3CH2OH, 60°C, 48 hr R2 N X
H H syn
+ HO N
B: Polyphosphonate ester +
R2 O
H2N X CH2Cl2, 23°C, 48 hr
H H
R3O2C
N
R1

MacDonald, A. , Overman, L. J. Org. Chem. 1999, 64, 1520 R2 N X anti

H
 Synthetic Examples
• Total synthesis of the HIGHLY POTENT
NEUROTOXIN: Saxitoxin
– Tanini, H. et. al., J. Am. Chem. Soc. 1977, 99, 2818
O

O NH2
H H
N NH
H2N
N N NH2
H
HO
OH
Key Step:
H O
MeO2C Me
MeO2C Me ether NH2 MeO2C
NH NH
+ RT N O
NH C N O
O
The Passerini Reaction
Details of the Passerini Reaction
• Discovered in 1921 by Passerini
» Passerini, M. Gazz. Chim. Ital. 1921, 51, 126.

• A three component reaction involving:

– Aldehyde (or ketone)
– Carboxylic Acid
– Isocyanide
• Generally,
2
O O O R
3 NC H
1
+ 2 + R 1 N 3
R OH R H R O R
O
 More on Isocyanides
• Only stable organic functionality with divalent
carbon
• Found in many natural products

• Preparation: Dehydration of N-monosubstituted

formamides with phosgene or derivatives thereof
• Like carbenes, isocyanides can react with both
neucleophiles and electrophiles at the same carbon
center
• Used heavily in the synthesis of various heterocycles
 Mechanism
• Mechanism is still a subject of uncertainty
– Kinetic studies were conducted
– Termolecular reaction (3rd order rate law), first order in each of the reactants
» Baker, R.H., Stanonis, D. J. Am. Chem. Soc. 1951, 73, 699.
– Ugi discovered that the reaction is accelerated in aprotic solvents
(indicating a non-ionic mechanism)
– Based on this work (Ugi, I., Meyr, R., Chem. Ber. 1961, 94, 2229) and on the
work of Baker et. al., Ugi postulated the following mechanism:
H
O O O O
1
+ 2
1
R OH R H R O R 2
1
H R
O O 3 NC 3
+ R O O
1 R
R O R 2 N H
O
1 H R2
R
2
3 O O O R
R H
H 1 N 3
N R O R
O
H R2 O
 Mechanism continued
• Most of the many suggested mechanisms
suggest some sort of electrophilic activation
of the carbonyl, followed by neucleophilic
attack of the isocyanide.
• One exception:
» Saegusa, N., et. al. Tet. 1968, 24, 3795
2
O 1
+
H+ R R 3 AcOH
1 2
3 NC C C N R
R R R
O

2 2
1 1
R R R R H 3
3 Acyl Group C C N R
C C N R
OH OCMe Rearrangement OCMe O
O O
 Details of the Reaction

• Done at high reactant concentration

• Done at low temperature

• Little limitations on the aldehyde/ketone used

(extremely sterically bulky ketones)
 Synthetic Examples
• Total synthesis of Eurystatin A (a prolyl
endopeptidase inhibitor) -- Owens, T.D. et. al. Tet, Lett. 2001, 6271
O
H
HO
O O
Diphosgene
HCl·H2N CO2Bn Et N, 0°C ->RT H N CO2Bn Dehydration
3 H CN CO2Bn

O
NHCbz
CH2Cl2 FmocHN N CO2Bn
H H
+ + FmocHN 0°C ->RT, O
CN CO2Bn O 3-5 days O
BocHN CO2H BocHN

O O CbzHN

HN
HN
O
O NH
s!
s tep
NH ~ 9
O Eurystatin A
 Synthetic Examples
• Total synthesis of hydrastine, a
phthalideisoquinoline alkaloid, using a an
intramolecular Passerini reaction
» Zeigler, T., et. al. Tet. Lett. 1981, 22, 619
O
O NC + H O
CH2Cl2
OH NH
O O O
O
O O

O O

O O
O

O N
Me

Hydrastine O
O
O O
The Ugi Reaction
 Details of the Ugi Reaction
• Discovered in 1959
» Ugi, I., et. al. Angew. Chem. 1959, 71, 386
• Four component condensation involving:
– Amine (secondary or primary)
– Aldehyde (or ketone)
– Carboxylic Acid
– Isocyanide
• Generally: 1 4
O R R
O O
+ 2 NH2 + + 4 NC 3 NH
1
R 3 R R N
R H R OH
R2 O

• Mechanism involves linear and parallel sequences

first and second order reactions (no third or
above!)
 Mechanism
1
R1CHO + R2NH2 R N
R2

O H O
1 + 1
R N R N + 3
R 2
HO
3
R R2 O R

4
H R
1
N
R N 2 R
1
R + R4NC O
3
R O 3 HN 2
R O R
O
4
R 1 4
N O R R
1 Rearrangement
R 3 NH
O R N
3 HN 2 R2 O
R O R
 Generally Observed Properties of
the Ugi Reaction
• Rxn is exothermic and usually complete in seconds-
minutes at room temperature
• Aprotic, polar solvents are best, though the low-
molecular weight alcohols have been used
• Can be performed in biphasic media
• High (0.5-2M) reactant concentrations are best
• By virtue of the mechanism, Lewis acids can accelerate
the reaction
• Precondensation of the amine and the carbonyl
(preformation of the Schiff base) can increase yields.
 Synthetic Examples of the
Ugi Reaction
• The Ugi reaction can be utilized to make peptides
and peptoids
– Tripeptides in one pot
– Couple two peptide fragments
» Waki, M., Meienhofer, J. J. Am. Chem. Soc. 1977., 99, 6075

R2CHCONH
Z-Gly-Ala-OH
O Condensation
+ CN +
Z-Gly-Ala-NCHCO-Gly-OtBu
H-Leu-Gly-Ot Bu R H
CH2CH(CH3)2

Cleavage
Z-Gly-Ala-Leu-Gly-OR
by hn
 Synthetic Examples of the
Ugi Reaction
• Synthesis of non-natural amino acids
– Yamada, T. et. al. Synthesis. 1998, 991

BocHN COOH CN O
+ H
COOCH3 CH2Cl2, RT N
BocHN N COOCH3
14 days H
O

NH
 Synthetic Examples
• Concise synthesis of benzodiazepines
» Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021

H 1
O 1
R O R
H
O N
4 OH 2 MeOH 4 N
R + R NH2 R 2
R O
NBoc 3N
R3 R Boc
NC

O 2
R
AcCl/MeOH N
4 1
R R
Heat
N
O
R3
 Synthetic Examples
• Synthesis of the carbacephems containing a b-
lactam moiety commonly found in antibiotics
» Neyer, G., Achtaz, J., Danzer, B. Ugi, I. Heterocycles, 1990, 30, 863
O
DPO
H H
DPO O Ethylene Glycol/
+ O
Glycerol N
NH3 O O
NC N
H

Ph N
DPO = *
Ph O

N
O X
CO2H
Carbacephems
(X = OR, SR, Cl)
 Synthetic Examples of the
Ugi Reaction
• Total synthesis of the cyclopeptidic alkyloid
natural product: Nummularine - F
» Bowers, M.M., et. al. J. Chem. Soc. Perkin Trans. 1, 1989, 857
CN

O
CN COOCH3 O O
O
+ + COOCH3
OH N HN
N O

O
O O
NH
N N
H
N O
Nummularine-F
 Synthetic Examples of the
Ugi Reaction
OAc
OAc H AcO
AcO EtO2CO
+ H N Pr + + CN Pr O
2 O O
CO2H H2O Pr N
N Pr
H
CO2Et

HO
HO
Pr O
N
O
N HN
O Pr O NH
O O
R
HO H
HO H
R= or
HO CH2OH
CO2Et
Bicyclomycin

-T. Fukuyama, et. al. Tet. Lett. 1981, 22, 4155

 Concluding Remarks
• The Biginelli, Passerini, and Ugi reactions are all
multicomponent reactions that are manifested in many
facets of chemistry

• The Biginelli and Passerini reactions were discovered

very early on and were underappreciated and
underutilized until the late 1950s

• All three reactions have interesting mechanistic and

synthetic problems associated with them, some having
been solved, some yet to be
 Synthetic Examples
• Titanium Tetrachloride assisted Passerini
reaction
– Carofiglio, T., et. al. Organomett., 1993, 12, 2726

1 1
R 2 R
R 2
O O R
TiCl4 + (RNC, R1R2CO) Ti Ti
Cl
L N L Cl N
R R

1
R
2
O O R
R OH Ti
N L N
H R1 R2
R