Beckmann rearrangement: Thiamine hydrochloride as a remarkable catalyst for one-pot synthesis of amides from ketones

Article abstract of DOI:10.1016/j.tetlet.2020.151859

Thiamine hydrochloride catalyzed synthesis of amides from ketones including 3-acetyl coumarin via Beckmann rearrangement has been reported. The reaction is believed to involve oxime formation, cleavage of C[sbnd]C bond followed by C[sbnd]N bond formation in one-pot. Thiamine hydrochloride is stable, cheap, easy to handle and environmentally friendly.

Full text of DOI:10.1016/j.tetlet.2020.151859

Journal Pre-proofs
Beckmann Rearrangement : Thiamine hydrochloride as a remarkable catalyst
for one-pot synthesis of amides from ketones
Sheena Mahajan, Nancy Slathia, Kamal K. Kapoor
PII:
S0040-4039(20)30299-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151859
TETL 151859
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 February 2020
14 March 2020
18 March 2020
Please cite this article as: Mahajan, S., Slathia, N., Kapoor, K.K., Beckmann Rearrangement : Thiamine
hydrochloride as a remarkable catalyst for one-pot synthesis of amides from ketones, Tetrahedron Letters (2020),
doi: https://doi.org/10.1016/j.tetlet.2020.151859
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Beckmann Rearrangement : Thiamine hydrochloride as a remarkable
catalyst for one-pot synthesis of amides from ketones
a
a
a
Sheena Mahajan, Nancy Slathia and Kamal K. Kapoor *
a
Department of Chemistry, University of Jammu, Jammu, 180006, INDIA.
Department of Chemistry, University of Jammu, Jammu, 180006, INDIA.
email : kamalkka@gmail.com
a*
*
ABSTRACT
Thiamine hydrochloride catalyzed synthesis of amides from ketones including 3-acetyl coumarin
via Beckmann rearrangement has been reported. The reaction is believed to involve oxime
formation, cleavage of C-C bond followed by C-N bond formation in one-pot. Thiamine
hydrochloride is stable, cheap, easy to handle and environmentally friendly.
Keywords:
Beckmann rearrangement
thiamine hydrochloride
ketones
amides
acetamidocoumarin
Introduction
Beckmann rearrangement (BKR) is remarkable transformation for the synthesis of amides or
lactams from the corresponding ketones. It is often used in the synthesis of natural products and
1
pharmaceuticals. The preparation of amides from ketones occurs in two steps : oxime formation
followed by its Beckmann rearrangement. The conventional Beckmann rearrangement of
ketoximes makes use of strong Bronsted or Lewis acids such as conc. H SO , PCl in diethyl
2
4
5
ether, HCl in acetic anhydride which results in production of side products, environmental
2
hazards and serious corrosion problems. To overcome these problems, several methods have
been reported in the literature for Beckmann rearrangement of ketoximes.3-9 In view of the
1
0
importance of direct conversion of ketones to amides, several one-pot methods were developed
in the last few decades (Scheme 1). However, most of these methods suffered from one or more
drawbacks such as expensive reagents, harsh reaction conditions, long reaction time,
environmental hazards, tedious work up and separation issues. To overcome these drawbacks,
there exists a need to develop one-pot simple, cheap, fast and eco-benign methodologies to carry
out this transformation.

Thiamine hydrochloride also known as Vitamin-B is a colorless organosulfur compound
1
synthesized by bacteria, fungi, and plants. It contains aminopyrimidine and thiazole ring linked
by a methylene bridge. Due to its non-toxicity, stability, biodegradability and easy accessibility,
several chemists have employed it as a potent catalytic tool for various organic conversions.11
So, we wished to probe the direct conversion of ketones to amides in presence of catalytic
amount of thiamine hydrochloride (Scheme 1).
Previous Work :
o
NH OH.HCl, FeCl .6H O, 130 C, 40-85 min.
2
3
2
Tetrahedron Lett. 2015, 56, 1915.
o
NH OH.HCl, HCOOH, silica gel, 80 C, 2.5h
2
Russ. J. Org. Chem. 2016, 52, 196.
O
O
R2
R1
N
R1
R2
H
NH OH.HCl, CS-SalBr-Zn-L, CH CN, reflux, 3h
2
3
J. Mol. Struct. 2017, 1130 368.
o
NH OH.HCl, Fe O /SiO , dichloroethane, 85 C, 16-38h
2
2
3
2
ChemistrySelect 2018, 3, 1967.
This Work :
Thiamine Hydrochloride
O
1
O
2
(20 mol%)
+
NH OH. HCl
R2
2
R1
R2
R1
N
1,4-dioxane : H O (9:1),
2
H
o
90 C, 30-90 min
Scheme 1 One-pot synthesis of amides from ketones.
To begin with, a neat mixture of benzophenone oxime (2 mM) and thiamine hydrochloride (30
mol%) was heated at 120 ˚C and conversion to the desired amide was noticed after 30 min (65%
yield). However lowering the reaction temperature to room temperature (40˚C) and 90˚C resulted
in no product formation or incomplete conversion respectively. Further to explore the possibility
of in situ formation of oxime followed by its Beckmann rearrangement, a mixture benzophenone
(2 mM) 1a, hydroxylamine hydrochloride (1.2 eq.) and thiamine hydrochloride (30 mol%) was

heated at 120 ˚C. To our delight, the formation of desired amide was noticed after 30 min (72%
yield). The reaction was also conducted in different solvent systems and the results are
summarized in Table 1, which reveals that best reaction occurs in dioxane:H O (9:1) system
2
(
80% yield) (Table 1, entry 5). Thus it was noticed that the addition of about 10% H O makes
2
the reaction mixture homogeneous and improves the yield of the product.
Entry
Solvent systems used
Mode of the reaction
Yield
in %)
72
50
65
35
80
40
a
(
1
2
3
4
5
6
.
.
.
.
.
.
No solvent (Neat)
1,2-dichloroethane
1,4-dioxane
120 ˚C
Reflux
Reflux
Reflux
90 ˚C
Acetonitrile :H O*
2
1,4-dioxane : H O*
2
Ethanol : H O*
Reflux
2
a
Isolated Yields
9:1 mixture
*
Table 1 Solvent system scan.
Also, during optimization of the reaction conditions, it was observed that 20 mol% of thiamine
hydrochloride and 1.5 eq. of hydroxylamine hydrochloride gave the best results (Table 2, entry
5
).
O
O
Thiamine
hydrochloride
N
H
+
NH OH. HCl
2
o
1
,4-dioxane : H O, 90 C
2
1a
2a
Entry Amount of hydroxylamine
hydrochloride used
Amount of thiamine
hydrochloride used
Time
(in min.)
Yield
(in %)
a
(
in eq.)
1.2
1.5
1.5
1.2
1.5
2
1.5
1.5
1.5
(mol %)
1
2
3
4
5
6
7
8
9
.
.
.
.
.
.
.
.
.
-
-
60
60
60
60
60
60
60
60
60
No reaction
No reaction
10
20
20
20
30
50
100
50
90
95
95
90
80
Inseparable
spots on tlc
a
Isolated Yields
Table 2 Optimization of the amount of hydroxylamine hydrochloride and thiamine hydrochloride.

It is pertinent to mention here that Beckmann rearrangement of ketoxime to amide in 90 % yield
also occurred with 20 mol% of thiamine hydrochloride in dioxane : H O (9:1).
2
Various ketones having electron donating and electron withdrawing groups were reacted under
similar conditions and the results are shown in Figure 1. For alkylarylketones only one of the
two possible amides were obtained owing to better migratory aptitude of aryl group. 4-nitro-
benzophenone yielded 4-nitro-N-phenylbenzamide 2l while 4-methoxy-benzophenone gave
inseparable mixture of N-(4-methoxyphenyl) benzamide 2m(i) and 4-methoxy-N-
phenylbenzamide 2m(ii). In case of 2l the phenyl group migrated in preference to its 4-nitro
counterpart while in 2m very little preference of 4-methoxyphenyl was observed over the phenyl
group. Ketones containing heteroaromatic systems also gave products 2q-2u in excellent yields.
Isatin and ninhydrin also resulted in smooth conversion to the corresponding products 2t and 2u
respectively.
H
H
H
H
N
N
CH3
N
N
CH3
CH3
O
O
O
O
H C
3
2
a
2b
2c
2d
(95%, 60min)
(90%, 30 min)
(90%, 30 min)
(80%, 40 min)
H
N
CH3
H
H
H
N
N
CH3
N
CH3
CH3
O
O
O
O
OCH3
H CO
3
Cl
Br
2
e
2f
2g
2h
(85%, 40 min)
(85%, 70 min)
(90%, 30 min)
(93%, 30 min)
O
H
N
H
H
CH3
N
CH3
HO
N
CH3
N
H
O
O
O
O N
O N
2
HO
2
2
i
2j
2k
2l
(90%, 30 min)
(90%, 30 min)
(88%, 30 min)
(90%, 30 min)
OCH3
O
O
H
+
N
H
O
N
N
H
H CO
3
N
(i)
(ii)
H
O
2
m
2n
2o
(90%, 30 min)
(75%, 50 min)
(75%, 50 min)

H
N
O
N
H
N
O
H
N
CH3
N
CN
N
H
O
O
O
O
O
2
p
2q
2r
2s
(95%, 30 min)
(95%, 30 min)
(95%, 90 min)
(92%, 60 min)
O
O
O
N
NH
OH
O
O
(i)
(ii)
OH
H
N
O
N
OH
OH
N
O
N
H
O
N
O
(iii)
(
ii)
(i)
2
t
2u
(90%, 50 min)
(
75%, 50 min)
Figure 1 Formation of amides (2a-2u) from ketones in presence of Thiamine hydrochloride.
3
-acetamidocoumarin 2r represents a promising class building blocks for designing
pharmacologically useful agents for the treatment of various diseases.12 The present method
yields 3-acetamidocoumarin 2r from 3-acetyl coumarin in excellent yield. The spectral and
physical data of 2r resembles that with the known compound.
Plausible reaction mechanism
Initially thiamine hydrochloride activates the carbonyl carbon of benzophenone 1a to facilitate
the formation of its oxime A which undergo thiamine hydrochloride assisted Beckmann
rearrangement to give the corresponding amide 2a (Scheme 2).

HO
O
N
Thiamine
hydrochloride
O
NH OH.HCl
2
H
N
H
H
1a
A
Cl
Cl
N
N
S
H C
N
3
H C
3
OH
Thiamine
hydrochloride
HO
CH3
N
CH3
S
N
N
H
N
H
Cl
H
H
Cl
O
N
N
+
OH
HO
CH3
N
CH3
S
N
N
N
H
H
H
O
H
H
N
N
Tautomerism
OH
O
2a
Scheme 2 Plausible reaction mechanism for the synthesis of amides.

In summary, we have developed thiamine hydrochloride catalyzed direct conversion of ketones
to amides in presence of hydroxylamine hydrochloride. This protocol consists of in situ
formation of ketoxime followed by its conversion to amide in one-pot. In addition to this,
precursor for bioactive molecules i.e. 3-acetamidocoumarin can be easily accessed using this
protocol.
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Declaration of interests
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
H
H
H
H
N
N
CH3
N
N
CH3
CH3
O
O
O
O
H C
3
2
a
2b
2c
2d
(95%, 60min)
(90%, 30 min)
(90%, 30 min)
(80%, 40 min)
H
N
CH3
H
H
H
N
N
CH3
N
CH3
CH3
O
O
O
O
OCH3
H CO
3
Cl
Br
2
e
2f
2g
2h
(85%, 40 min)
(85%, 70 min)
(90%, 30 min)
(93%, 30 min)
O
H
N
H
N
H
CH3
CH3
HO
N
CH3
N
H
O
O
O
HO
O2N
O N
2
2
i
2j
2k
2l
(90%, 30 min)
(90%, 30 min)
(88%, 30 min)
(90%, 30 min)
OCH3
O
O
H
+
N
H
O
N
N
H
H CO
3
N
(i)
(ii)
H
O

2
m
2n
2o
(90%, 30 min)
(75%, 50 min)
(75%, 50 min)
H
N
O
N
H
N
O
H
N
CH3
N
CN
N
H
O
O
O
O
O
2
p
2q
2r
2 s
(95%, 30 min)
(95%, 30 min)
(95%, 90 min)
(92%, 60 min)
O
O
O
N
NH
OH
O
O
(i)
(ii)
OH
H
N
O
N
OH
OH
N
O
N
H
O
N
O
(iii)
(
ii)
(i)
2
t
2u
(90%, 50 min)
(
75%, 50 min)
Figure 1 Formation of amides (2a-2u) from ketones in presence of Thiamine hydrochloride.
GRAPHICAL ABSTRACT
H
H
N
H
N
Cl
Cl
NH OH.HCl
2
N
S
1
,4- dioxane:H O
O
2
H C
N
3
H C
3
R2
(
9:1)
R1
N
OH
O
H
o
R1
R2
90 C, 30-90 min
AMIDES
KETONES
Beckmann
Rearrangement

Highlights of the Revised Manuscript Ref No. : TETL-D-20-00285



One-pot conversion of ketones to amides.
Use of Vitamin-B as environmentally friendly, stable and biodegradable catalyst.
1
Easy access to 3-acetamidocoumarin, an important precursor for pharmaceuticals.
Entry
Solvent systems used
Mode of the reaction
Yield
in %)
72
50
65
35
80
40
a
(
1
2
3
4
5
6
.
.
.
.
.
.
No solvent (Neat)
1,2-dichloroethane
1,4-dioxane
120 ˚C
Reflux
Reflux
Reflux
90 ˚C
Acetonitrile :H O*
2
1,4-dioxane : H O*
2
Ethanol : H O*
Reflux
2
a
Isolated Yields
*
9:1 mixture
Table 1 Solvent system scan.
O
O
Thiamine
hydrochloride
o
N
+
NH OH. HCl
2
H
1
,4-dioxane : H O, 90 C
2
1a
2a
Entry Amount of hydroxylamine Amount of thiamine
Time
Yield
(in %)
a
hydrochloride used
hydrochloride used (in min.)
(mol %)
(
in eq.)
1.2
1.5
1.5
1.2
1.5
2
1
2
3
4
5
6
7
8
9
.
.
.
.
.
.
.
.
.
-
-
60
60
60
60
60
60
60
60
60
No reaction
No reaction
10
20
20
20
30
50
100
50
90
95
95
90
80
1.5
1.5
1.5
Inseparable spots on
tlc
a
Isolated Yields
Table 2 Optimization of the amount of hydroxylamine hydrochloride and thiamine hydrochloride.