ugi reactions

8/8/2019 Ugi Reactions

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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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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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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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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

ugi reactions

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