Direct synthesis of secondary amides from ketones through Beckmann rearrangement using O-(mesitylsulfonyl)hydroxylamine

Article abstract of DOI:10.1016/j.tetlet.2020.151822

The Beckmann rearrangement is a versatile method for the preparation of secondary amides from ketones via oxime intermediates and has been widely used in the synthesis of bioactive natural products and pharmaceuticals. Herein, we have developed a highly efficient direct method for the preparation of secondary amides and lactams from ketones using O-(mesitylsulfonyl)hydroxylamine (MSH). The reactions proceed rapidly at room temperature under mild condition without requiring any additive, and tolerate multiple functional groups. A simple aqueous work-up often furnished the products in excellent yield with high purity.

Full text of DOI:10.1016/j.tetlet.2020.151822

Journal Pre-proofs
Direct Synthesis of Secondary Amides from Ketones through Beckmann Re‐
arrangement using O-(Mesitylsulfonyl)hydroxylamine
Dinesh Chandra, Saumya Verma, Chandra Bhan Pandey, Ajay K. Yadav,
Puneet Kumar, Bhoopendra Tiwari, Jawahar L. Jat
PII:
S0040-4039(20)30257-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151822
TETL 151822
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
17 January 2020
5 March 2020
9 March 2020
Please cite this article as: Chandra, D., Verma, S., Bhan Pandey, C., Yadav, A.K., Kumar, P., Tiwari, B., Jat, J.L.,
Direct Synthesis of Secondary Amides from Ketones through Beckmann Rearrangement using O-
(Mesitylsulfonyl)hydroxylamine, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151822
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Graphical Abstract
Direct Synthesis of Secondary Amides from
Ketones through Beckmann Rearrangement using
O-(Mesitylsulfonyl) hydroxylamine
Leave this area blank for abstract info.
a
a
b
a
a
Dinesh Chandra , Saumya Verma , Chandra Bhan Pandey , Ajay K. Yadav , Puneet Kumar , Bhoopendra
,
b
,a
Tiwari* and Jawahar L. Jat*
Me
O
O
O
O
S
CH CN
O
3
R1
+
Me
R2
2
N
R1
R2
NH2
rt, 3-16 h
Me
H
1
Direct method from ketones
Metal- and additive-free
R , R = alkyl or aryl
Mild and operationally simple in an open flask
Water soluble by-products, therefore often chromatography-free
Excellent yields with broad substrate scope

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Direct Synthesis of Secondary Amides from Ketones through Beckmann
Rearrangement using O-(Mesitylsulfonyl)hydroxylamine
a
a
b
a
a
Dinesh Chandra , Saumya Verma , Chandra Bhan Pandey , Ajay K. Yadav , Puneet Kumar , Bhoopendra
,
b
,a
Tiwari* and Jawahar L. Jat*
a
Department of Chemistry, Babasaheb Bhimrao Ambedkar University (A Central University), Vidya Vihar, Raebareli Road, Lucknow-226025, India
Division of Molecular Synthesis & Drug Discovery, Centre of Biomedical Research, SGPGIMS-Campus, Raebareli Road, Lucknow, India
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The Beckmann rearrangement is a versatile method for the preparation of secondary amides
from ketones via oxime intermediates and has been widely used in the synthesis of bioactive
natural products and pharmaceuticals. Herein, we have developed a highly efficient direct
method for the preparation of secondary amides and lactams from ketones using O-
(mesitylsulfonyl)hydroxylamine (MSH). The reactions proceed rapidly at room temperature
under mild condition without requiring any additive, and tolerate multiple functional groups. A
simple aqueous work-up often furnished the products in excellent yield with high purity.
Available online
Keywords:
Beckmann rearrangement
O-(Mesitylsulfonyl)hydroxylamine
Ketone
Secondary amides
The ACS Green Chemistry Institute Pharmaceutical
Roundtable (GCIPR), comprising of top global pharmaceutical
manufacturers, in their 2006 and 2016 meetings, identified the
catalytic or sustainable direct preparation of amide functionality
(a) Recent Reports on the Traditional Beckmann Rearrangement
OH
O
N
O
conditions
R1
R1
R2
Cl
R1
R2
N
R2
1
H
as one of the key reactions to be developed. The Beckmann
(preformed)
rearrangement of oximes is a very effective method to access
amides and lactams, and is an industrial process to prepare the
B(OH)2
N
N
2
2
CO Ph
raw materials for polyamides, such as nylon-6 and nylon-12. It is
Cl
N
Cl
(
cat.)
Ca(NTf2)2 (cat.)
a versatile method used to incorporate an N-atom into cyclic or
acyclic ketones. Traditionally, the Beckmann rearrangement
(cat.)
perfluoropinacol (cat.)
CH3NO2:HFIP (1:4), rt
J. Am. Chem. Soc. 2018
(Ref. 4b)
Bu2NPF6 (cat.), 80 o
C
ZnCl2 (cat.), reflux
J. Am. Chem. Soc. 2005
Chem. Comm. 2018
(
Ref. 4j)
requires strongly acidic media (e.g. PCl
5
, H
2
SO
4
) and high
(Ref. 4a)
3
In general, this approach requires pre-formed oximes, metal catalysts, expensive
solvents, chromatographic purification or elavated reaction temparature
temperatures. These reaction conditions can produce large
amounts of undesired products and are untenable for sensitive
substrates. This limitation could be partly overcome with the
(b) The Beckmann Rearrangement using MSH Reagent
4
j
Tamura and co-workers
advent of milder reagents or catalysts such as cyanuric chloride,
OSO Mes
2
O
4
i
4d
O
N
BOP-Cl,
propyl
phosphonic
anhydride
(T3P),
MSH
2
Al O
R1
3
R2
triphosphagene, triphosgene, tosylchloride,4f cyclopropenium
salt, TFA, Ca(NTf
4
g
4k
R1
R2
R1
R2
N
H
4
e
4h
4a
4b
2
)
2
,
and boronic acid (Scheme 1a).
Two step process, isolation of oximes required; limited substrate scope;
alumina column chromatography required
Despite the development of these reagents, several major
limitations persist, such as: (a) the necessary preparation and
purification of ketoxime substrates, (b) column chromatographic
purification of the products, (c) and expensive solvents or
elevated reaction temperature.
(c) This Work
Me O
O
S
O NH2
O
O
Me
Me
R1
R1
R2
N
R2
CH3CN
H
One pot, metal and additive-free, broad substrate scope, functional group
tolerance, water soluble byproduct, column chromatography-free process

Corresponding author
E-mail: jawaharlj@bbau.ac.in ; btiwari@cbmr.res.in.
Scheme 1. The Beckman Rearrangement for the Preparation of Amides.

2
Tetrahedron
Therefore, a direct method devoid of the additional step of
product (which was obtained after basic aqueous workup) with n-
5
oxime substrate preparation is highly desired. To that end Hyodo
and co-workers very recently disclosed a direct method for the
preparation of amides from ketones via transoximation using
hexanes and no further purification was required.
With the optimized condition in hand, we investigated the
substrate scope for this MSH-mediated Beckmann
rearrangement. For these studies, para-substituted acetophenones
containing both electron-donating (Me, OH, OMe) as well as
electron-withdrawing substituents (Br, Cl, F) were valuable
substrates for the reaction and the products were obtained in
excellent yields after a n-hexane wash of the crude products (3a-
3g). The reactions with electron-rich derivatives were slightly
faster compared to the electron-deficient acetophenones. An
unprotected phenolic group was also tolerated (3d). The para-O-
allyl-substituted acetophenone also provided the corresponding
amide 3h in excellent yield. Methyl 4-acetylbenzoate 1j and p-
nitroacetophenone 1k were converted into the corresponding
amides 3j and 3k at 70 °C. In these cases the reaction stopped at
mesitylenesulfonyloxime intermediate A (Scheme 3) at room
temperature.
6
ethyl N-(phenylsulfonyl)oxyacetimidate. This reacts with
ketones to produce the corresponding sulfonyloxime, which in
2
the presence of TsOH·H O and water gives the corresponding
amides. Nonetheless, this elegant method requires: (a) Brønsted
acid and water as additives, (b) extended reaction times of 24 h,
(
c) column chromatographic purification. Prior to this, Tamura
and co-workers reported a two-step method for the conversion of
ketones to amides through the Beckmann rearrangement via
7
mesitylene sulfonyloxime using basic alumina in methanol. In
view of these limited studies, along with their intrinsic
difficulties, an improved method for the direct preparation of
secondary amides from ketones is needed.
Results and Discussion
As part of an ongoing program to develop efficient reagents and
transition metal catalyzed methods, we recently reported the
highly regio- and stereo-specific aziridination of unactivated
Scheme 2. Substrate Scope of the Ketones.a
O
Me
H
N
O
O
R2
CH3CN
S
alkenes using MSH8a and the Cu(OTf)
-catalyzed Beckmann
rearrangement of ketones using hydroxylamine-O-sulfonic acid.
R2
2
+
O
rt-70 o
R
R
C
O
NH2
Me
Me
8
c
3a-z
We were next interested in developing an efficient, one-pot,
1
2
mild, and possibly column chromatography-free method for
preparing secondary amides directly from ketones using MSH.
H
N
H
H
Me
N
Me
O
N
Me
O
Boc
O
Table 1. Optimization of the Reaction Conditions.a
R
O
N
H
3
a, R= H, 5 h, 98%
b, R= Me, 6 h, 90%
3
h, 6 h, 95%
3i, 6 h, 85%
3
Me
O
O
O
H
N
3c, R= OMe, 5 h, 95%
d, R= OH, 6 h, 92%
3e, R= Br, 8 h, 90%
S
H
N
H
Me
O
conditions
rt, 5 h
Me
O
N
Me
3
Me
+
NH2
O
Me
O
O
Me
3
f, R= Cl, 8 h, 90%
g, R= F, 10 h, 85%
Me
O2N
1a
2
3a
3k,b
3
O
3j,b 5 h, 92%
6 h, 90%
Yield 3a (%)b
H
Entry
Additive
TFA
Solvent
TFE
TFE
H
N
Cl
N
Me
H
N
c
H
1
2
3
4
5
6
82
85
87
81
80
98
70
78
85
77
80
MeO
MeO
Me
Me
N
Me
-
-
-
O
O
CH
2
Cl
2
O
O
THF
MeOH
Br
3l,
Cl
3n, 16 h, 40%c
3o, 16 h, 92%
b
3m, 5 h, 89%
-
3
h, 90%
HN
-
CH
3
CN
CN
CN
CN
O
d
7
-
-
-
-
-
CH
3
CH
3
CH
3
H
2
Me
O
e
f
8
Me
H
H
N
9
H
N
1
1
0
1
S
N
Me
Me
Me
N
R
EtOH
O
O
O
a
3t (66:33),d 6 h
61% yield of 3t
Reagents and conditions unless otherwise stated: 1a (0.5 mmol), 2 (1.0
mmol), solvent (2 mL), rt. Isolated yield. 10 mol% of TFA was used. 0.5
c
3
p, R = H, 16 h, 85% 3r, 16 h, 50%
3q, R = Ts, 8 h, 90%
3s, 6 h, 90%
b
c
d
c
e
f
mmol of MSH was used. 0.6 mmol of MSH was used, 0.75 mmol of MSH
was used, TFE = 2,2,2-trifluroethanol, TFA= trifluoroacetic acid. (MSH 2 is
highly energetic and explosive in nature; in our routine lab work we have
prepared moist MSH on up to a 2.0 g scale without any incident although care
must be taken while handling it in gram scale)
H
N
O
H
H
N
H
N
Me
N
Me
O
O
O
u (69:31),d 7 h
3v, 6 h, 80%
b
c
3x, 16 h, 80%
3
6
3
w,b 6 h, 90%
c
2% yield of 3u
Me
We began using acetophenone 1a as a model substrate and
MSH 2 as the aminating agent (Table 1). The Beckmann
rearrangement generally gives better yields in an acidic medium
and hence the reaction was performed in the presence of 10
mol% of TFA in 2,2,2-trifluoroethanol (TFE). The desired
product 3a was obtained in 82% yield at room temperature after 5
h (Entry 1). Gratifyingly, the reaction proceeded well with a
slightly improved yield in the absence of TFA (Entry 2). Further,
we examined the effect of different solvents. Acetonitrile turned
out to be the optimal solvent giving the desired product in 98%
yield (Entry 6). Lowering the MSH loading led to a diminished
yield (Entries 7, 8 and 9). It is worth noting that the product
could be isolated with high purity after washing the crude
OMe
HN
Me
H
N
H
N
O
Me
H
O
O
MeO
3y
H
H
3ya
HO
d
3z,b 6 h, 90%c
3
y and 3ya (63:37) , 6 h, 65%
a
3
Reagents and conditions: 1 (0.5 mmol), 2 (1.0 mmol), CH CN (2 mL), rt.
Reaction temperature of 70 °C. Column chromatography was required.
Ratio of non-separable regioisomers.
b
d
c
Products 3h, 3i and 3j bearing acid sensitive alkene, N-Boc,
and ester functionalities highlight the functional group tolerance
compared to literature methods that require strong acidic

3
conditions. meta-Substituted, as well as disubstituted
acetophenones, also reacted well to afford the desired products in
good to excellent yields (3l-3n). Other aromatic rings such as
naphthyl, indolyl, and thiophenyl were tolerated giving the
corresponding amides in good to excellent yields (3o-3r).
Propiophenone also furnished exclusively the phenyl migrated
product (3s). On the other hand, when α-branched or cycloalkyl-
phenylketones were used, a separable mixture of regioisomers
was formed due to the comparable migratory aptitude of the aryl
and branched alkyl groups (3t and 3u). Gratifyingly, aliphatic
cyclic and acyclic ketones were also smoothly converted into the
corresponding amides and lactams, albeit at elevated
temperatures (3v and 3w). Whereas benzophenone reacted well
to give amide in good yield, the unsymmetrical benzophenone
offered a mixture of products due to the comparable migrating
properties of the two aryl groups (3x and 3y). Even a complex
ketone such as pregnenolone gave the respective amide (3z) in
References
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2
1
9
0% yield.
[
3] (a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988-993; (b) Blatt,
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A plausible mechanism is described in Scheme 3. Ketone 1
reacts with MSH 2 to give mesitylenesulfonyloxime intermediate
A which undergoes Beckmann rearrangement via a concerted
[
4] (a) Kiely-Collins, H. J.; Sechi, I.; Brennan, P. E.; McLaughlin, M. G.
Chem. Commun. 2018, 54, 654-657; (b) Mo, X.; Morgan, T. D. R.; Ang,
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Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2008,
5
g
1
,2-intramolecular shift to form intermediate B, followed by
nucleophilic attack of H O to give C. Deprotonation of C
2
provides D, which further tautomerizes into the corresponding
amide 3.
O
O
H N
2
S
O
O
O
O
Ar
S
N
R1
R1
7
3, 2894-2897; (h) Ronchin, L.; Vavasori, A.; Bortoluzzi, M. Catal.
2
N
R2
Commun. 2008, 10, 251-256; (i) Zhu, M.; Cha C.; Deng, W.-P.; Shi, X.-
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J.; Helh, S.; Herzberger, S. Synthesis 1999, 1128-1133.
R1
R2
O
-H2O
Ar
R2
-ArSO3
1
A
B
Ar = mesityl
H O
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Gebru, H.; Guo K. J. Org. Chem. 2018, 83, 2040-2049; (b) Srivastava,
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Org. Chem. 2010, 75, 1197-1202; (d) Ganguly, N. C.; Mondal, P.
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Synthesis 2002, 1057-1059; (g) Luca, L. D.; Giacomelli, G.; Porcheddu,
A. J. Org. Chem. 2002, 67, 6272-6274.
2
H
O
H
H
O
O
ArSO3
R1
R1
N
R2
R2
-
ArSO H
R1
N
3
R2
H
N
D
C
3
Scheme 3. Proposed Mechanism.
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Chem. 2018, 83, 13080-13087.
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1
1
973, 215-216; (b) Tamura, Y.; Minamikawa, J.; Ikeda, M. Synthesis
977, 1-17.
In conclusion, we have developed a direct method for the
synthesis of secondary amides and lactams from a variety of
ketones using MSH. This method is operationally simple and
does not require acid or any other additive. Labile or reactive
functional groups such as ester, alcohol, phenolic-OH, Boc, halo,
and alkenes, were tolerated under our optimized reaction
conditions. The various secondary amides were obtained in good
to excellent yields. The products were isolated in high purity
after aqueous work-up.
[
8] (a) Sabir, S.; Pandey, C. B.; Yadav, A. K.; Tiwari, B.; Jat, J. L. J.
Org.Chem. 2018, 83, 12255-12260; (b) Sabir, S.; Kumar, G. Jat, J. L.
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709-3714.
Acknowledgements
Financial support by SERB (YSS/2015/000838 and
CRG/2018/004424), New Delhi, India is gratefully
acknowledged. S. V. thanks CSIR-New Delhi for the fellowship.
☐
The authors declare that they have no known
Declaration of interests
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.

4
Tetrahedron
☐
The authors declare the following financial
interests/personal relationships which may be
considered as potential competing 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.
Graphical Abstract

Direct method for synthesis of
Direct Synthesis of Secondary Amides from
Leave this area blank for abstract info.
Keto ns ee sc ot hn rdo au rgy h aBme ci dk em sa fn r no mR e ka re rt oa nn ge es mv ei na t using
O-(Mesitylsulfonyl) hydroxylamine
Beckmann rearrangement.

Open flask, operationally simple,
a a
b
a
a
Dinesh Chandra , Saumya Verma , Chandra Bhan Pandey , Ajay K. Yadav , Puneet Kumar , Bhoopendra
metal and additive free process.
,
b
,a
Tiwari* and Jawahar L. Jat*

Mild reaction condition and broad
functional group compatibility with
Me
O
O
O
O
S
CH CN
excellent yields.
O
3
R1
+
R2
N
1
2
NH
rt, 3-16 h
R
R
2
H
Me
Me

Water soluble by-products, therefore
Direct method from ketones
often chromatography free method.
Metal- and additive-free
1
2
R , R = alkyl or aryl
Mild and operationally simple in an open flask
Water soluble by-products, therefore often chromatography-free
Excellent yields with broad substrate scope