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The Biginelli and Related
(Passerini and Ugi) Reactions
Mike DeMartino
Group Meeting: August 27, 2003
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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
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Similarities
All are multicomponent Reactions (MCRs)
In MCRs, three or more reactants come together in a
single reaction vessel to form products that containportions 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.
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The Biginelli Reaction
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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
H
H2N NH2
O
O
EtO2C+ +
H+EtOH,heat
N
H
NH
OMe
EtO2C
Ph=> Biginelli-type
compounds
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The Mechanism: a Century of
Uncertainty Second proposal in 1973 Sweet, F., Fissekis, J.D..J.
Am. Chem. Soc. 1973, 95, 8741.
H2N NH2
O
+
O
EtO2C
NH
HN
O Me
CO2Et
Ph
H
OH
O
OEt
O
H
+
O
OEt
O HO
OEt
O
H
HN
O
NH2
OEt
O
OH2O
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The Mechanism: a Century of
Uncertainty Latest proposal in 1997 Kappe, C.O. J. Org. Chem.
1997, 62(21), 7203.
H2N NH2
O
+H
O OH
HN
Ph
NH2
O
H+
-H2O
H
N
Ph
NH2
O
H
Ph
NH
H2NO
EtO2C
Me ONH
NH
OMe
EtO2C
Ph
H2O
HN NH2
O
HN
O
NH2
R
Ph
NH
H2NO
EtO2C
O
Hu, E.H., et.al.J. Org. Chem.1998. 63, 3454.
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The Atwal* modification
Brought about by the need for better yields: Ortho-substituted
aryl aldehydes
Aliphatic aldehydes
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.
R1
RO2C
Me OHN
NH2
X
R2
NaHCO3
DMF
+
NH
NH
X
HR1
Me
RO2C
R2 NH
NH
X
HR1
Me
RO2CDeprotect
X = O, S (With an appropriate protecting group)
Mostly 60-91%yield
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Synthetic Manipulation
So, with the dihydropyrimidine in hand, whatcan 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
5
6
N
H
1
2
NH3
4
OMe
EtO2C
Ph
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Synthetic Examples
Solid phase synthesis for combinatorial scaffoldsof Biginelli
compounds
First example: Wipf, P., Cunningham, A. Tet. Lett.1995, 36,
7819.
Fluorous-Phase modifications Studer, A., et. al. J. Org. Chem.,
1997, 62, 2917.
Ar
O H
O
O
R1 O
RNH
2
OHN
O
O
P
+N
NHO
O
R
Ar
OR1
OH
O
1. THF, HCl, 55C2. TFA, CH2Cl2
Ar
O H
O
O
R1 O
R NH2
OHN
+
N
NHO
O
R
Ar
OR1
1. HCl, THF/BTF, 50C
2. Extract w/FC-72
O
O
TAG
Tag = Si(CH2CH2C10F21)3
O
O
3. TBAF, THF/BTF
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Synthetic Examples
Synthesis ofrac-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
HO
O
HEtO
O
Me O
H2N
S
NH2
+ Yb(OTf)3
THF, reflux,12 h N
H
NH
SMe
EtO2C
H
(+/-) Monastrol
OH
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Synthetic Examples Inorganic catalysis
Indium(III) Chloride mediated Biginelli reactions Brindaban, C.
R., et. al. J. Org. Chem. 2000, 65, 6270
Heavy-Metal catalysis Ma, Y., et. al. J. Org. Chem. 2000, 65,
3864
R 2
O H
+
R R 1
OO
H2N
X
NH2
X = O, S
InCl3, THF
NH
NHR1
O R2
XR81-95 %
R 2
O H
+
R R 1
OO
H2N
O
NH2NH
NHR1
O R2
OR
Yb(OTf)3 (5 mol %)
100C
81-99%
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Synthetic Examples
Natural Product Synthesis The use of tethered Biginelli
condensations for syntheses
of structurally diverse guanidine alkaloids
()-Ptilomycalin A:N
NH
NH OO
HHO
O14
N
O
NH2
NH2
R2
O
R3O2C
+ N HHO
R1
H2N X
A: Morpholinium AcetateCF3CH2OH, 60C, 48 hr
B: Polyphosphonate esterCH2Cl2, 23C, 48 hr
NH
N
R3O2C
R2
X
H H
R1
NH
NR3O2C
R 2 X
H H
R1
syn
anti
+
Overman, L., et. al. J. Am. Chem. Soc.1995, 117, 2657
MacDonald, A. , Overman, L. J. Org. Chem. 1999, 64, 1520
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Synthetic Examples Total synthesis of the HIGHLY POTENT
NEUROTOXIN: Saxitoxin Tanini, H. et. al., J. Am. Chem. Soc.1977,
99, 2818
HN
NH
N
NH
H
NH2
HO
OH
H2N
O NH2
O
MeO2C
NH
O
Me
H
C
NH
O
+
ether
RT
MeO2C
N O
NH2
N
NH
O
Me
MeO2C
Key Step:
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The Passerini Reaction
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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,
R1
O
OH R2
O
H
+R
3 NC+R
1
O
HN
R3
O R2
O
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More on Isocyanides
Only stable organic functionality with divalentcarbon
Found in many natural products
Preparation: Dehydration ofN-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
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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 thework of Baker et. al., Ugi postulated the following
mechanism:
R1
O
OH R2
O
H
+
R
3 NC+
R1
O
HN
R3
O R2
O
R1
O
O
H
O
R 2
R1
O
O
H
O
R 2
R1
OO
N
H
O
R2
HR
3
R1
OO
N
H
O
R2
HR
3
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Mechanism continued
Most of the many suggested mechanismssuggest 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
R3 NC+
R1
O
R2
H+
C C
O
R1
R2
N R3 AcOH
C C
OH
R1
R2
N R3
OCMe
O
Acyl Group
Rearrangement
C C
OCMe
R1
R2
HN R
3
O
O
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Details of the Reaction
Done at high reactant concentration
Done at low temperature
Little limitations on the aldehyde/ketone used
(extremely sterically bulky ketones)
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Synthetic Examples
Total synthesis of Eurystatin A (a prolylendopeptidase
inhibitor) -- Owens, T.D. et. al. Tet, Lett. 2001, 6271
HN
NH
HNO
OO
O
NH
OEurystatin A
HClH2N CO2Bn N
H
CO2BnH
O
HO
O
H
O
Et3N, 0C ->RT
Diphosgene
DehydrationCN CO
2Bn
CN CO2Bn
+
NHCbz
BocHN CO2H
+ FmocHNH
O
NH
CO2Bn
O
FmocHN
OO
BocHN
CbzHN
0C ->RT,
3-5 days
CH2Cl2
~9ste
ps!
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Synthetic Examples
Total synthesis of hydrastine, aphthalideisoquinoline alkaloid,
using a an
intramolecular Passerini reaction Zeigler, T., et. al. Tet.
Lett.1981, 22, 619
NCO
O
+ H
O
O
OHO
O
O
O NH
O
O
O O
O
O
O N Me
O
O O
O
Hydrastine
CH2Cl2
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The Ugi Reaction
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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:
Mechanism involves linear and parallel sequencesfirst and second
order reactions (no third orabove!)
R
3
O
OHR
1
O
H
+
R
4 NC+R
3
N
O R1
NH
O
R4
R2
R2 NH2+
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Mechanism
R1CHO + R2NH2NR
1
R2
NR1
R2
+
+
NR1
R2
H
NR1
R2
H
R4NC O
NR4
HN
R1
Rearrangement
HO
O
R3 O
O
R3+
O
O
R3
OR3
R2
O
N R
4
HN
R1
OR3
R2
R3
N
O R1
NH
O
R4
R2
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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.
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Synthetic Examples of the
Ugi Reaction The Ugi reaction can be utilized to make
peptidesand peptoids
Tripeptides in one pot
Couple two peptide fragments
Waki, M., Meienhofer, J.J. Am. Chem. Soc.1977., 99, 6075
Z-Gly-Ala-OH+
H-Leu-Gly-OtBu
CN +O
HR Z-Gly-Ala-NCHCO-Gly-O
t
Bu
CH2CH(CH3)2
R2CHCONH
Condensation
CleavageZ-Gly-Ala-Leu-Gly-OR
by hn
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Synthetic Examples of the
Ugi Reaction Synthesis of non-natural amino acids Yamada, T. et.
al. Synthesis. 1998, 991
BocHN COOH
NH
CN
COOCH3+
BocHN
HN
N
HO
O
COOCH3
CH2Cl2, RT
14 days
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Synthetic Examples
Concise synthesis of benzodiazepines Hulme, C., et. al. J. Org.
Chem. 1998, 63, 8021
OH
O
NBoc
R3
R4
+
R1
R2
NH2
NC
O
H
O
N
R2R
4
R
1
H
N
ON
R3
Boc
N
N
O
OR3
R1
R2
R4AcCl/MeOH
Heat
MeOH
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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
NO
CO2H
X
(X = OR, SR, Cl)
Carbacephems
DPO
NH3
O
O
O
H H
NC
+ NO
NH
DPO
O
DPO =N
O
Ph
*
Ph
Ethylene Glycol/
Glycerol
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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
O
N
COOCH3CN
+ +N
O
HN
O
COOCH3
O
CN
N
O
O
O
NH
NH
O
N
O
OH
Nummularine-F
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Synthetic Examples of the
Ugi Reaction
-T. Fukuyama, et. al. Tet. Lett. 1981, 22, 4155
AcOOAc
CO2HH2N
Pr EtO2COH
OCN
Pr+ + +
H2O
AcOOAc
O
NPr
O
NH
Pr
O
N
NPr
O
O
Pr
HO
R
R =HO
or
CO2Et
O
HN
NH
O
O
HO
CH2OH
HHO
HHO
Bicyclomycin
CO2Et
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Concluding Remarks
The Biginelli, Passerini, and Ugi reactions are
allmulticomponent 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
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Synthetic Examples
Titanium Tetrachloride assisted Passerinireaction
Carofiglio, T., et. al. Organomett., 1993, 12, 2726
TiCl4 + (RNC, R1R2CO) Ti
L
O
Cl
R
1
R2
NR
Ti
L
OR
1
R2
NR
Cl
Ti
L
O
R1
R2
N
R
NH
R
O
OH
R1 R2
