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
Thank You
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