One Pot Copper Catalyzed Conversion of Oximes to

ThioamidesPaulami Bose, Dr. Niranjan Panda*

ObjectiveTo develop a facile and environmentally friendly synthetic method towards the preparation of thioamides.

Paulami BoseRoll. 412CY2006

A Presentation on:

Introduction Thioamides are important structural motifs found in many biologically

active molecules (figure 1).

Few thioamides show antitumor activity and even act as anti-thyroid drug.1

Also act as important precursors for various fine chemicals, heterocycles.

Figure 1. Examples of biologically active thioamide derivatives

Methamazole

Polythiouracil

Carbimazole

Structures of Chalcogenopyrylium Compounds

NH

NCH3

S

NH

NH

O

S

N

N

O S

N

SR2

R1

S

Cl R1= tBu, R2=R1=R2=R1=R2= tBu

NMe2

Reported Protocols From Different Precursors General procedure

Classical method

Willgerodt–Kindler Method

Jiang’s Method

R1 O

NH2

R1 S

NH2P2S5

R1 SH

NH

R Z

O

R1 N

O

R3

R2HNR1R2Lawesson's Reagent

or P4S10R1 N

S

R3

R2

O

S8

O

HN N

O

S

130 oC, 3h

TsOH

R1 X HNR3

R2Na2S.9H2O N

S

R3

R2R180-110 oC, 8h

DMF

Reported Protocols from Oximes Key Reaction: Beckmann Rearrangement

Other methods:

R NOH TiCl3OTf-[bmim]Br

(NH4)2S, 80 oCR NH2

S

NOH

R2

R1

PSCl3, H2O,Et3NR1 N

S

H

R2

R2R1

O (i) HO-NH2 .HCl/AcONa, 80-90 oC

EtOP

EtOS

SH(ii) N

HR1

R2

S

, dioxane

NOH

R2

R1

P2S5 (0.5 eq)R1 N

S

H

R2

BenzeneReflux

Beckmann Rearrangement Acid catalyzed direct conversion of Oximes to N- substituted amides.

For aldoximes, it is observed that 2

Limitations : 1. High reaction temperature required 2. use of large amount of strong Brønsted acids 3. huge amount of byproduct generated.

R NOHBeckmannRearrangent

Metal-catalyzed Rearrangement

R NH2

O

H N

O

H

R

N Conc. H2SO4R2 N

O

H

R1

HeatR2

R1 OH

Background of Project Importance of Copper catalyst

Reduction of catalyst cost Needs lower catalyst loading Requires milder reaction condition Tolerates various functional groups

Recently, Panda et al. reported that 3

Concept: Oxime is a useful precursor for synthesis of its amide, hence it can be presumed that in the presence of a thionating agent it can lead to its corresponding thioamide.

Ph I Ar NOHDMEDAK2CO3

o-xylene, 130 oC, 12 h

CuSO4.5H2OAr N

H

OPh

Results and Discussions The optimized scheme:

Entry Aldoxime Thioamide Yield [%]

1 80

2 40

3 79

4 20

5 75

NOH

ClNH2

S

Cl

NH2

S

NOH

MeO

NH2

S

MeO

NOH

O2NNH2

S

O2N

ON OH O

NH2

S

NOH

NOH

NH2

S

CuI (10 mol-%)

Et3N (2.5 equiv.)P2S5 (1equiv.)

DMF (3 mL),140 oC,12h

Conclusion One step protocol for direct conversion of aldoximes to

thioamides in the presence of copper catalyst.

Plausible mechanism:

NOH

NH2

S

CuI

Et3N, P2S5 DMF ,140 oC,12 h

R

NOH [Cu]

R

N OH

H

CuH2O

R

N Cu

R

N Cu

SHR

NH2

S

H2O

S

NMR Data of Benzothioamide

1H NMR (400 MHz, CDCl3) δ 7.90-7.87 (m, 2H, J=8 Hz), 7.55-7.51 (m, 1H, J=1.2 Hz), 7.45-7.41 (m, 2H, J=2 Hz);

13C NMR (100 MHz, CDCl3) δ 202.9, 139.2, 132.0, 130.1, 128.5, 126.9, 77.3, 77.0, 76.7.

References1. Bitton, A. Inflamm. Bowel Dis. 2005, 11, 513.2. J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, 1st ed., Oxford University Press, Oxford,

UK, UK, 2001, p. 997;3. N. Panda, R. Mothkuri, and D. K. Nayak, Eur. J. Org. Chem. 2014, 1602.

NH2

S