the biginelli and related (passerini and ugi) reactions€¦ · •the biginelli reaction...
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The Biginelli and Related(Passerini and Ugi) Reactions
Mike DeMartinoGroup 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 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.
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
H
H2N NH2
O
O
EtO2C+ +
H+ EtOH, heat
NH
NH
OMe
EtO2CPh
=> Biginelli-type compounds
The Mechanism: a Century ofUncertainty
• First proposal in 1933» Folkers, K., Johnson, T.B. J. Am. Chem. Soc. 1933, 55, 3784.
H2N NH2
O
R H
O+2 X
HN NH2
O
HN
O
NH2R
O
EtO2C
NH
NH
OMe
EtO2CPh
HN NH
O
HN
O
NH2R
HO MeCO2Et
H2O
The Mechanism: a Century ofUncertainty
• 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
CO2EtPh
H
O H
O
OEt
OH+
O
OEt
O HO
OEt
O
HHN
ONH2
OEt
O
OH2O
The Mechanism: a Century ofUncertainty
• 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
OH
Ph
NH
H2NO
EtO2C
Me ONH
NH
OMe
EtO2CPh
H2O
HN NH2
O
HNO
NH2R
Ph
NH
H2NO
EtO2C
O
Hu, E.H., et.al. J. Org. Chem. 1998. 63, 3454.
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.
R1RO2C
Me OHN
NH2
XR2
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
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
5
6NH1
2NH3
4
OMe
EtO2CPh
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• Antitumor• Antiinflammatiry• Analgesic• Blood palette aggregation inhibitor• Cardiovascular activity• Potent calcium channel blockers• Etc.
NH
NH
X
H
Me
RO2CAr
Synthetic Examples• Solid phase synthesis for combinatorial scaffolds
of 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
RNH2
OHNO
O
P
+N
NHO
OR
Ar
OR1OH
O
1. THF, HCl, 55°C
2. TFA, CH2Cl2
Ar
O H
O
O
R1 O
R NH2
OHN+
N
NHO
OR
Ar
OR1
1. HCl, THF/BTF, 50°C
2. Extract w/FC-72O
O
TAG
Tag = Si(CH2CH2C10F21)3
O
O
3. TBAF, THF/BTF
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
HOO
HEtO
O
Me O
H2N
S
NH2
+ Yb(OTf)3THF, reflux,
12 h NH
NH
SMe
EtO2CH
(+/-) Monastrol
OH
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
OOH2N
X
NH2
X = O, S
InCl3, THF
NH
NHR1
O R2
XR81-95 %
R 2
O H+
R R 1
OOH2N
O
NH2NH
NHR1
O R2
OR
Yb(OTf)3 (5 mol %)
100°C81-99%
Synthetic Examples• Natural Product Synthesis
– The use of tethered Biginelli condensations for synthesesof structurally diverse guanidine alkaloids
• (–)-Ptilomycalin A:N
NH
NH OO
HH O
O 14 N
O
NH2NH2
R2 O
R3O2C+ N HHO
R1
H2N X
A: Morpholinium Acetate CF3CH2OH, 60°C, 48 hr
B: Polyphosphonate ester CH2Cl2, 23°C, 48 hr
NH
NR3O2C
R2 X
H HR1
NH
NR3O2C
R2 X
H HR1
syn
anti
+
Overman, L., et. al. J. Am. Chem. Soc. 1995, 117, 2657
MacDonald, A. , Overman, L. J. Org. Chem. 1999, 64, 1520
Synthetic Examples• Total synthesis of the HIGHLY POTENT
NEUROTOXIN: Saxitoxin– Tanini, H. et. al., J. Am. Chem. Soc. 1977, 99, 2818
HN
NH N
NHH
NH2
HOOH
H2N
O NH2
O
MeO2C
NH
O
Me
H
CNH
O
+etherRT
MeO2C
N O
NH2
N
NH
O
MeMeO2C
Key Step:
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,
R1
O
OH R2
O
H+ R
3 NC+R
1O
HN R
3O R 2
O
More on Isocyanides• Only stable organic functionality with divalent
carbon• Found in many natural products
• Preparation: Dehydration of N-monosubstitutedformamides with phosgene or derivatives thereof
• Like carbenes, isocyanides can react with bothneucleophiles and electrophiles at the same carboncenter
• 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:
R1
O
OH R2
O
H+
R3 NC+
R1
OHN R
3O R 2
O
R1
O
OH
O
R 2
R1 O
OH
O
R 2
R1
OON
HO
R2
HR
3
R1
OON
HO
R2
HR
3
Mechanism continued• Most of the many suggested mechanisms
suggest some sort of electrophilic activationof the carbonyl, followed by neucleophilicattack of the isocyanide.
• One exception:» Saegusa, N., et. al. Tet. 1968, 24, 3795
R3 NC+
R1
O
R2H+
C CO
R1 R
2
N R3 AcOH
C COH
R1 R
2
N R3
OCMeO
Acyl Group
RearrangementC COCMe
R1 R
2HN R3
OO
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
HN
NH
HN O
OO
ONH
O Eurystatin A
HCl·H2N CO2Bn NH
CO2BnH
OHO
OH
O
Et3N, 0°C ->RT
DiphosgeneDehydration CN CO2Bn
CN CO2Bn+
NHCbz
BocHN CO2H
+ FmocHN H
O
NH
CO2Bn
O
FmocHNO
OBocHN
CbzHN
0°C ->RT, 3-5 days
CH2Cl2
~9 steps!
Synthetic Examples• Total synthesis of hydrastine, a
phthalideisoquinoline alkaloid, using a anintramolecular Passerini reaction
» Zeigler, T., et. al. Tet. Lett. 1981, 22, 619
NCO
O
+ H
O
O
OHOO
O
O NHO
O
O O
O
O
O N Me
O
O OO
Hydrastine
CH2Cl2
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:
• Mechanism involves linear and parallel sequencesfirst and second order reactions (no third orabove!)
R3
O
OHR1
O
H+
R4 NC+ R
3N
O R1
NH
O
R4
R2R
2 NH2+
MechanismR1CHO + R2NH2
NR1R2
NR1R2
+
+
NR1R2
H
NR1R2
H
R4NC O
N R4
HN
R1
Rearrangement
HO
O
R3 O
O
R3+
O
O
R3OR3 R2
O
N R4
HN
R1
OR3 R2R
3N
O R1
NH
O
R4
R2
Generally Observed Properties ofthe 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 theUgi 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-Ot BuCN + O
HRZ-Gly-Ala-NCHCO-Gly-OtBu
CH2CH(CH3)2
R2CHCONHCondensation
Cleavage Z-Gly-Ala-Leu-Gly-ORby hn
Synthetic Examples of theUgi Reaction
• Synthesis of non-natural amino acids– Yamada, T. et. al. Synthesis. 1998, 991
BocHN COOH
NH
CNCOOCH3
+BocHN
HN N
HO
O
COOCH3CH2Cl2, RT
14 days
Synthetic Examples• Concise synthesis of benzodiazepines
» Hulme, C., et. al. J. Org. Chem. 1998, 63, 8021
OH
O
NBocR3
R4 +
R1
R2
NH2
NC
O
HO
NR2R4
R1
HN
ONR
3Boc
N
NO
OR3
R1
R2
R4AcCl/MeOH
Heat
MeOH
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
CO2HX
(X = OR, SR, Cl)Carbacephems
DPO
NH3
O
O
O
H H
NC
+ NO N
H
DPO
O
DPO =N
O
Ph*
Ph
Ethylene Glycol/
Glycerol
Synthetic Examples of theUgi Reaction
• Total synthesis of the cyclopeptidic alkyloidnatural product: Nummularine - F
» Bowers, M.M., et. al. J. Chem. Soc. Perkin Trans. 1, 1989, 857
O
N
COOCH3CN+ +
N
O
HN
OCOOCH3
O
CN
N
O
O
O
NH
NH
O
N
O
OH
Nummularine-F
Synthetic Examples of theUgi Reaction
-T. Fukuyama, et. al. Tet. Lett. 1981, 22, 4155
AcO OAc
CO2HH2N Pr EtO2CO H
O CN Pr+ + +H2O
AcO OAc
O
N Pr
O
NH
Pr
O
NN Pr
O
O
PrHO
R
R = HO or
CO2Et
O
HNNH
O
O
HO
CH2OH
HHOHHO
Bicyclomycin
CO2Et
Concluding Remarks• The Biginelli, Passerini, and Ugi reactions are all
multicomponent reactions that are manifested in manyfacets of chemistry
• The Biginelli and Passerini reactions were discoveredvery early on and were underappreciated andunderutilized until the late 1950s
• All three reactions have interesting mechanistic andsynthetic problems associated with them, some havingbeen solved, some yet to be
Synthetic Examples• Titanium Tetrachloride assisted Passerini
reaction– Carofiglio, T., et. al. Organomett., 1993, 12, 2726
TiCl4 + (RNC, R1R2CO) TiL
OCl
R1
R2
N R
TiL
OR
1
R2
N RCl
TiL
OR
1
R2
NR
NH
RO
OHR1 R2