1

Amide Bond Formation

Presented By :

Gurudutt DubeyM.Tech. (Pharm.) I Semester

Department of Pharmaceutical Technology (Process Chemistry)National Institute of Pharmaceutical Education and Research, Mohali, Punjab (India)

2

O

OHR1 R2H2N

Coupling reagents

Base, solvent

O

NH

R1R2

O

OAR1 R2H2N+A -OA

Conventional method

Nature, 2011, 480, 471–479

3

NH2R2

Amine

R1

O

NH

R2O

NH

R2R1

OR1

NN

N MeMe

O

NH

R2Ar

O

NH

R2R1

R2

OR1

ArOH

O

R1 OClR3

AldehydeFormyl

cyclopropane

halo aldehyde hydroxyenone

NNN Ph

BF4

NNN Mes

Cl

Catalyst 1Catalyst 2

Oxidant(1 equiv.)base, HFIP

I

Catalyst 2 (5 mol%)HOAt, base

Catalyst 1 (5 mol%),base, imidazole

Catalyst 1 (1.5 mol%),base, 1,2,4-triazole

R1= Ar, EWGR2 = Ar, aliphaticR3 = H, Chloride, aliphatic

R1, R2 = Ar, aliphatic

R1= EWG,R2 = Ar, aliphatic

R1= Ar,R2 = Ar, aliphatic

New acylation reactions of aminesAmidation by catalytic acylation of amines

Nature, 2011, 480, 471–479

4Nucleophilic Carbene and HOAt Catalyzed Amide

Bond Coupling

PhClCl

H

O N

NN

F

F F

F

FBF4

(20 mol%)

HOAt (20 mol%), Et3N (1.2 equiv.)THF, t-BuOH, 25 oC, 6 hH2N Me

PhCl

NH

O

Me

89%

Mechanism:

J. Am. Chem. Soc. 2007, 129, 13797

5

PhMe

O

Me

OHNH2R

NNN Mes

Cl (5 mol%)

(iPr)2NEt (20 mol%)1,2,4-triazole (10 mol%)0.5 M CH2Cl2, 40 oC, 3 h

Ph NH

OR

Catalytic amide formation with -hydroxyenones as acylating reagents

Chem. Commun. 2009, 4566–4568

6Mechanism:

Breslow intermediate

7

R1 OH

Alcohol

H2N R2

Amine

Ruthenium catalyst (0.1-5 mol%),ligand

base, 110 oC(H2 extrusion)

R1 NH

OR2

R1, R2 = Ar, aliphatic

Ruthenium catalysts : NN PRu

CO

Ph

PhPh Ru

H

H

4

RuClCl

N Ru

P(t-Bu)2

NEt2

CO

H

N Ru

P(t-Bu)2

NEt2

CO

H

H

H2RHO

N Ru

P(t-Bu)2

NEt2

CO

H

H

RO

Milstein’s catalyst for conversion of alcohols into amides

Chem. Soc. Rev., 2011, 40, 3405–3415

8 Metal catalytized oxidative amidation of aminesO

R1

R2 NH2

NH

OR2R1

R1

R2 NH2

CuI(1 mol%)AgIO3(1 mol%)

TBHP, base

[Mn(2,6-Cl2TPP)Cl](0.3 mol%)

H2O2(2 equiv.),base, 25 oC

R1 = ArR1 = Ar, aliphatic

R1 = ArR1 = Peptide,Ar, aliphatic

ArBr

NO2

NHBocH2N

NH

OOMe

O

R2

R1

N-iodosuccinimide(1 equiv.)

base, H2O, 0 oC

HN

NH

OOMe

O

R2

R1BocHN

O

Ar

R1 = Me, R2 = Bn

Nature, 2011, 480, 471–479

Oxidative coupling of α-bromo nitroalkanes with amines

9 Amidation by catalytic generation of activated carboxylates

BOHHO

OH

BOHHO

N(Pr)2 BOHHO

IB

OHHO

FF

F

R1 OH

O

Carboxylicacid

H2N R2

Amine

Boronic acid catalyst (1-10 mol%)

25 oCR1 N

H

OR2

R1, R2 = Ar, aliphatic

Nature, 2011, 480, 471–479

10

Br

H2N Ph

Pd(OAc)2 (2 mol%)xantphos (2 mol%)CO (1 atm)

Na2CO3 (3 equiv)toluene, 80 oC, 15 h

94%

OHN Ph

Chem. Soc. Rev., 2011, 40, 3405–3415

Pd-catalysed aminocarbonylation of aryl bromides

11

R1 SH

O

Thioacid

R1

O

NH

R2

R1 = Amino acid, SaccharideR2 = Amino acid, Saccharide,Ar, aliphatic

C N R2C N R2O

25 oC-COS

Isocyanate Isonitrile

25 oCH2N R3

R1

O

NH

R3

R1

O

NH

R2

R1

O

NH

R2

ArS

NH

O

R2

O

SulfonamideBase, 25 oC

-SO2

Base, -N2

N NNR2

Azide

R1 = Amino acid, SaccharideR2 = Amino acid, Saccharide,Ar, aliphatic

R1 = Amino acid, peptideR2 = cyclohexyl, t-butylR3 = Saccharide, Amino acid

R1 = Ar, peptideR2 = Ar, SO2Ar, SO2-peptide,COOAr, Alkene

Nature, 2011, 480, 471–479

Amidation of thioacids

12

R SH

O -H

R S

O

R S

O

N3R' S

NN

N

R'RO +H

R NH

OR' N2 S

O N3

OBn

Me OH

S

O NH

OBn

Me

O2,6-Lutidine

MeOH, 25 oC, 2 h

96%Azide Thioacetic acid N

2,6-LutidinePh N3 Me OH

S

Ph NH

Me

O2,6-Lutidine

CHCl3, 60 oC, 15 h

86%Azide Thioacetic acid

The Reaction of Thio Acids with Azides

J. Am. Chem. Soc. 2003, 125, 7754-7755

Polar solvent :

Nonpolar solvent :

13 Reaction of Thioacids with Isocyanates and Isothiocyanates

R' S

O

NC

XR"

R' S

O

N XR"

+H

SCX-R' N

H

OR"

SO

OPh

NH2

(i) iPr2NEt, CH2Cl2, 25 oC, 1 h

(ii) PhNC=O 25 oC, 1 h

PhHN

ONH

OPh

90%

Org. Lett. 2009, 11, 3514-3517

14Microwave assisted amidation by acylation with amine derivatives

R1 OH

O

Carboxylicacid

R1

O

NH

R2

1. Microwave 150 oC2. NaOMe, MeOH

C N R2

Isonitrile

1. Microwave 150 oC2. Reduction

R1

O

NR2

CH3

R1 = Amino acidR2 = Saccharide

R1, R2 = Amino acid, Peptide, N-methylated peptide

Nature, 2011, 480, 471–479

15

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