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.
O

EtO2C

H2N

NH2

H
H+

EtOH,
heat

Ph
EtO2C
Me

NH
N
H

=> Biginelli-type
compounds

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
2X

+
NH2

H2N

HN

NH2

R
R

HN

NH2
O

O HO Me
HN

N
H
NH2

R
HN
O

Ph

CO2Et

EtO2C
H2O

Me

NH
N
H

The Mechanism: a Century of

Uncertainty
Second proposal in 1973
Sweet, F., Fissekis, J.D.. J. Am. Chem. Soc. 1973, 95, 8741.

O
H

EtO2C

H
O

H+
O

HO

O
OEt

OEt

OEt

O
H2N
Ph
CO2Et

HN
O

N
H

Me

H
HN
H2O

O
NH2 O

O
OEt

NH2

The Mechanism: a Century of

Uncertainty
Latest proposal in 1997
Kappe, C.O. J. Org. Chem. 1997, 62(21), 7203.

Ph

O
H +

H2N

OH

HN

NH2

Ph

H+

NH2

-H2O

H
N

NH2
O

O
R

HN

NH2

HN

NH2
O

Ph
Ph
EtO2C

EtO2C

NH
O
H2N

Hu, E.H., et.al.

J. Org. Chem. 1998. 63, 3454.

Me

Ph
EtO2C

NH
N
H

H2O

Me

NH
O
H2N

The Atwal* modification

Brought about by the need for better yields:
Ortho-substituted aryl aldehydes
Aliphatic aldehydes
R1
RO2C
Me

H
O

NH2

+
HN

X
R2

R1 H

R1 H
NaHCO3 RO2C
DMF

Me

N
N
H

Deprotect
R 2 Mostly 60-91%
yield
X

RO2C
Me

NH
N
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
EtO2C

5
6

Me

4
3NH
2

N1
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
RO2C
Antitumor
NH
Antiinflammatiry
Me
X
N
Analgesic
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
O
R

H
NH2

HN
R1

1. THF, HCl, 55C

2. TFA, CH2Cl2

O
O

Ar
NH

O
OH

P
O

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

O
R

O
+

HN
R1

H
1. HCl, THF/BTF, 50C

NH2
O
O

O
Tag = Si(CH2CH2C10F21)3

TAG

2. Extract w/FC-72
3. TBAF, THF/BTF

Ar

NH
R

O
O
O

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

H
EtO
Me

+
S

O
H2N

Yb(OTf)3
THF, reflux,
12 h

NH2

EtO2C
Me

NH
N
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
O

+
R

InCl3, THF

H2N

NH2

81-95 %

R2

R1

NH
R

X = O, S

N
H

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

R2

O
O
R

H
+

H2N

Yb(OTf)3 (5 mol %)
NH2

100C
81-99%

R2

R1

NH
R

N
H

Synthetic Examples
Natural Product Synthesis
The use of tethered Biginelli condensations for syntheses
of structurally diverse guanidine alkaloids
()-Ptilomycalin A:

H
N

N
OH

O
O

14

NH2
NH2

N
H O

Overman, L., et. al. J. Am. Chem. Soc. 1995, 117, 2657
R3O2C
R1
H

R3O2C
+ HO
R2

H2N

N
X

A: Morpholinium Acetate
CF3CH2OH, 60C, 48 hr
B: Polyphosphonate ester
CH2Cl2, 23C, 48 hr

H
N

R2

R3O2C

MacDonald, A. , Overman, L. J. Org. Chem. 1999, 64, 1520

H
N
H
+

R1
X

R2

syn

H
N
N
H

R1
X

anti

Synthetic Examples
Total synthesis of the HIGHLY POTENT
NEUROTOXIN: Saxitoxin
Tanini, H. et. al., J. Am. Chem. Soc. 1977, 99, 2818
O
H H
N
H2N

N
H
HO

NH2
NH

NH2

OH

Key Step:
H

O
ether

Me

MeO2C

+
NH

NH
C
O

RT

MeO2C

NH2
N

Me
MeO2C

NH

O
N

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,
O
1

+
OH

O
2

+ R

NC

O
1

H
N

O
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:
O
1

+
OH

O
2

O
H

H
O
1

O
O

+
R

NC

H R2

R
3

O
H R2

H
N

O
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
O
1

NC

H+

R R
3
C C N R
O

R R
3
C
C N R
OH OCMe
O

Acyl Group
Rearrangement

AcOH

R R
H 3
C
C N R
OCMe 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

HO

O
HClH2N

CO2Bn Et N, 0C ->RT
3

Diphosgene
N
H

CO2Bn

Dehydration

CN

CO2Bn
O

NHCbz
+
CN

CO2Bn
BocHN

+ FmocHN

0C ->RT,
3-5 days

O
CO2H

O
HN

FmocHN
O
BocHN

CbzHN

HN
O
NH

O
NH
O

CH2Cl2

Eurystatin A

s!
tep
s
9

N
H
O

CO2Bn

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
O

NC

H
OH

O
O

CH2Cl2

O
O

NH
O
O

O
O

O
N

Me

Hydrastine 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:
O
1

+
H

NH2

O
3

+
OH

NC

R
N
R2

R
NH
O

Mechanism involves linear and parallel sequences

first and second order reactions (no third or
above!)

Mechanism
R1CHO
1

R
H
N

R2NH2

HO

H
N

+ R4NC

R2

N
2

R2

HN 2
O
R

O
N
O
3

HN 2
R
O

Rearrangement

O
3

R
N
R2

R
NH
O

Generally Observed Properties of

the Ugi Reaction
Rxn is exothermic and usually complete in secondsminutes at room temperature
Aprotic, polar solvents are best, though the lowmolecular 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
+ CN
H-Leu-Gly-Ot Bu

+
R

Condensation
H

Z-Gly-Ala-NCHCO-Gly-OtBu
CH2CH(CH3)2

Cleavage
by hn

Z-Gly-Ala-Leu-Gly-OR

Synthetic Examples of the

Ugi Reaction
Synthesis of non-natural amino acids
Yamada, T. et. al. Synthesis. 1998, 991

BocHN

COOH

CN
COOCH3

CH2Cl2, RT
14 days

NH

H
N

BocHN
O

O
N
H

COOCH3

Synthetic Examples
Concise synthesis of benzodiazepines
Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021
1

O
4

R
OH

NBoc
R3

O
+

MeOH

R NH2

N
2
R

3N
R Boc

NC

O
AcCl/MeOH
Heat

R
N

N
R3

H
N
O

Synthetic Examples
Synthesis of the carbacephems containing a blactam moiety commonly found in antibiotics
Neyer, G., Achtaz, J., Danzer, B. Ugi, I. Heterocycles, 1990, 30, 863
O
O

DPO

H
+

NH3 O

Ph
DPO =

DPO
Ethylene Glycol/
Glycerol

NC

N
*

Ph

N
O

X
CO2H

Carbacephems
(X = OR, SR, Cl)

N
O

O
N
H

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
O

CN
+

COOCH3

O
+

OH

COOCH3
HN
O

O
N
H

N
N

NH

O
Nummularine-F

Synthetic Examples of the

Ugi Reaction
AcO

OAc
CO2H

EtO2CO

+ H N Pr +
2

OAc

AcO

+ CN Pr

O
H2O

Pr

N
H

Pr

CO2Et
HO
Pr

N
N

HO

O
Pr

HN
O

R
R=

HO

HO
HO

or

O
NH
O
H
H
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

R
TiCl4

O
Ti
Cl
L

(RNC, R1R2CO)

R
N

O
Ti
L Cl

O
R

OH

N
H R1 R2

Ti
L

N
R

R
2
R