The Mannich Reaction

Rahul PatelM.S. IInd sem.

Department of medicinal chemistry

Contents

Background Reaction Mechanism Limitations Modifications Applications Conclusions

Carl Ulrich Franz Mannich (March 8, 1877 in Breslau-March 5, 1947 in Karlsruhe) was a German Chemist

From 1927 to 1943 he was Professor for pharmaceutical chemistry at the University of Berlin

His areas of expertise were Keto bases, Alcohol bases, Piperidine-Derivatives, Papaverine, Lactone and also Digitalis-Glycoside

Background

The Mannich reaction is the aminoalkylation reaction, involving the condensation of an enolizable carbonyl compound with a nonenolizable aldehyde (like formaldehyde) and ammonia, or a primary or a secondary amine to furnish a β-aminocarbonyl compound, also known as Mannich base

Background

Li, J.J. Name Reactions. 2. Springer 2003.

Mechanism

Li, J.J. Name Reactions. 2. Springer 2003.

O

R2R1

H

B:

Enolate

formation

O-

R1 R2

NR

R

N

R

RR2

R1

O

Li, J.J. Name Reactions. 2. Springer 2003.

MechanismBase Catalyzed Mannich reaction

Limitations

Thus the range of application is limited (e.g. confined toaminomethylation)

In many cases undesired side products are formed

The ability to control regio- and stereoselectivity is generallyunsatisfactory

ModificationsPreformed Mannich reagents

Higher concentration of the electrophile, leading to lower reaction temperatures and much shorter reaction times

Many undesired side reactions, which so often cause problems in the Mannich reaction, are avoided, even with sensitive substrates

Carbonyl component can be replaced with much more reactive synthetic equivalents such as enolates

Extended spectrum of application for the reaction

NR

R1

NR2R2N

R1

NR2R2O

R1

NN

N

R1NR2

NR2

R1 X

Imines Aminals N,O-acetals

benzotriazole aminals Iminium Salts

Modifications(cont.)

Preformed Mannich reagents

Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

Intermolecular amino -alkylation: Regioselective synthesis of Novel b-Amino Ketones and Aldehydes

Modifications(cont.)

Carbonyl Compounds (With Iminium salts)

H2C NMe2 ClO

PhO

Ph NMe2 HCl

Enolates (With N,O acetals)

OLi

+ N

OTiCl3Ph

O N

PhO N

Ph

+

anti syn: = 78:22

Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

Modifications(cont.)

OBBu2

PhPh

Me2N

NMe2+

O

Ph Ph

NMe2

+

O

Ph Ph

NMe2

anti syn

Boron enol ethers (With aminals)

Silyl enol ethers (With methelene iminium salts)

OSiMe3 NMe2CH2 I

OSiMe3

NMe2 HI

O

NMe2

1) HCl2) OH-

Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

Intramolecular Mannich ReactionsModifications(cont.)

Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

Modifications(cont.)

OH

R1NR

R

O

R1 NR2

NTMSO O

N

Vinylogous Mannich Reactions

Chem. Ber. 1979, 112, 1913.Tet.Lett. 1980, 21, 805.

Asymmetric mannich reaction

Angew. Chem. Int. Ed. 1998, 37. 1044-1070Angew. Chem. Int. Ed. 2004, 43. 5138-5175

Asymmetric mannich reaction

Org. Lett. 2010, 12, 708-711.

Applications

J. Pharm. Sci. 1996, 4, 715-733.

Applications

OHCHOMe2NH

HCl

O

N

F

F

F

O

HN

fluoxetin

HN

NH

O

O

HNR1

R2

HCHOHN

NH

O

O

NR1

R2

J. Med. Chem. 1976, 19, 345-350.J. Org. Chem. 1959, 24, 1069-1076.

Chem. Pharm. Bull. 1994, 8, 1676-1685.

O

(CH2O)n/AcOHN

H

O

N HCLHClHO

O

N

Tramadol

MedicinalCompoundsSynthesis

ApplicationsNatural Product Synthesis

NHOOC

COOMe

O

Bn

COCl2

BnN

MeOOC

COMe

HN

NHOOC

Bnn

O BnN

COCl2

O HNO

NHOOC

COOMeBn

OCOCl

2

BnN

COMe

COOMe

BnN

N

Cl

Epibatidine

Ferruginine

Anatoxin

Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

Natural Product SynthesisApplications

Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

SummaryNucleophilic addition of an enol to an iminium ion formed by the reaction of formaldehyde with a secondary amine

Multi-component condensation

Amino-methylation

Modifications like preformed mannich bases and use of different reagents like enolate s, silyl enol ethers etc. gives wide range of the synthesis and amino-alkylation

Wide synthetic applicationsorganic synthesis of natural compounds such as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone)

Agro chemicals such as plant growth regulators, paint- and polymer chemistry, catalysts and crosslinking

Medicinal compounds e.g. rolitetracycline (Antibiotic), fluoxetine (antidepressant), tramadol, and tolmetin (anti-inflammatory drug)

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