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
+
+
O
O
H2N
NH2
H
H+
EtOH,
heat
Ph
EtO2C
Me
NH
N
H
O
=> 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
O
NH2
O
R
R
HN
H
NH2
O
O HO Me
HN
N
H
NH2
R
HN
O
Ph
CO2Et
EtO2C
H2O
Me
NH
N
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
H
+
EtO2C
H
O
O
H+
O
O
HO
O
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.
O
Ph
O
H +
H2N
OH
HN
NH2
Ph
H+
NH2
H
-H2O
H
N
O
NH2
O
O
R
HN
NH2
HN
NH2
O
Ph
Ph
EtO2C
EtO2C
NH
O
H2N
O
Hu, E.H., et.al.
J. Org. Chem. 1998. 63, 3454.
Me
Ph
EtO2C
NH
N
H
O
H2O
Me
NH
O
H2N
O
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.
X
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
O
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
O
H
NH2
+
O
HN
R1
1. THF, HCl, 55°C
R
O
2. TFA, CH2Cl2
O
O
O
Ar
NH
R
N
1
O
OH
P
O
O
• Fluorous-Phase modifications
– Studer, A., et. al. J. Org. Chem., 1997, 62, 2917.
Ar
O
R
O
+
O
HN
R1
O
O
H
1. HCl, THF/BTF, 50°C
NH2
O
O
O
Tag = Si(CH2CH2C10F21)3
TAG
2. Extract w/FC-72
3. TBAF, THF/BTF
R
Ar
O
NH
R
1
N
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
O
H
EtO
Me
H
+
S
O
H2N
Yb(OTf)3
THF, reflux,
12 h
NH2
EtO2C
Me
NH
N
H
S
(+/-) 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
O
+
R
R
O
H
InCl3, THF
X
H2N
NH2
81-95 %
1
R2
R1
NH
R
X = O, S
N
H
X
• Heavy-Metal catalysis
» Ma, Y., et. al. J. Org. Chem. 2000, 65, 3864
R2
O
O
R
O
H
+
R
1
H2N
O
O
Yb(OTf)3 (5 mol %)
NH2
100°C
81-99%
R2
R1
NH
R
N
H
O
Synthetic Examples
• Natural Product Synthesis
– The use of tethered Biginelli condensations for syntheses
of structurally diverse guanidine alkaloids
• (–)-Ptilomycalin A:
H
H
N
N
OH
O
O
O
14
N
NH2
NH2
N
H O
Overman, L., et. al. J. Am. Chem. Soc. 1995, 117, 2657
R3O2C
R1
H
R3O2C
+ HO
R2
O
H2N
N
X
A: Morpholinium Acetate
CF3CH2OH, 60°C, 48 hr
B: Polyphosphonate ester
CH2Cl2, 23°C, 48 hr
H
N
R2
R3O2C
MacDonald, A. , Overman, L. J. Org. Chem. 1999, 64, 1520
H
N
H
+
R1
X
H
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
O
NH2
NH
N
NH2
OH
Key Step:
H
O
ether
Me
MeO2C
+
NH
NH
C
O
RT
MeO2C
NH2
N
Me
MeO2C
NH
O
N
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,
O
1
R
+
OH
O
2
R
3
H
+ R
NC
O
1
R
R
2
H
N
O
O
3
R
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
R
+
OH
H
O
2
R
O
H
O
1
O
R
R
2
1
R
H
O
1
R
O
O
3
+
R
R
NC
3
N
O
O
H
H R2
1
R
O
N
2
R
3
O
R
O
O
O
H R2
H
1
R
R
2
H
N
O
O
3
R
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
R
1
+
2
R
3
R
NC
H+
1
R R
3
C C N R
O
2
R R
3
C
C N R
OH OCMe
O
2
1
Acyl Group
Rearrangement
AcOH
2
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
H
HO
O
O
HCl·H2N
CO2Bn Et N, 0°C ->RT
3
H
Diphosgene
N
H
CO2Bn
Dehydration
CN
CO2Bn
O
NHCbz
+
CN
CO2Bn
BocHN
+ FmocHN
0°C ->RT,
3-5 days
O
CO2H
O
HN
FmocHN
O
BocHN
O
CbzHN
HN
O
NH
O
NH
O
CH2Cl2
H
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
O
NH
O
O
O
O
O
N
O
Me
Hydrastine O
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:
O
1
R
+
H
2
R
NH2
+
O
O
3
R
+
OH
4
R
NC
3
R
R
N
R2
1
4
R
NH
O
• Mechanism involves linear and parallel sequences
first and second order reactions (no third or
above!)
Mechanism
R1CHO
1
R
N
R
H
N
1
R
3
R
+
O
+
2
1
R
R2NH2
HO
H
N
1
R
3
R
N
O
R
+ R4NC
+
R2
N
2
R2
R
4
R
O
O
3
R
O
1
HN 2
O
R
O
N
O
3
R
R
4
R
1
HN 2
R
O
Rearrangement
O
3
R
R
N
R2
1
4
R
NH
O
3
R
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
O
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
H
1
O
R
OH
NBoc
R3
O
+
MeOH
2
R NH2
N
2
R
4
R
3N
R Boc
NC
O
AcCl/MeOH
Heat
R
2
R
N
4
1
R
R
N
R3
O
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 =
H
DPO
Ethylene Glycol/
Glycerol
NC
N
*
Ph
O
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
O
+
OH
N
COOCH3
HN
O
N
O
O
O
N
H
N
N
NH
O
Nummularine-F
Synthetic Examples of the
Ugi Reaction
AcO
OAc
CO2H
H
EtO2CO
+ H N Pr +
2
O
OAc
AcO
+ CN Pr
O
O
H2O
Pr
N
N
H
Pr
CO2Et
HO
Pr
N
N
O
HO
O
Pr
HN
O
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
1
R
2
R
O
Ti
L Cl
R
N
1
O
O
R
OH
N
H R1 R2
Ti
L
N
R
R
2
R
2
R