Efficient iodine-mediated beckmann rearrangement of ketoximes to amides under mild neutral conditions

Article abstract of DOI:10.1055/s-0030-1258217

Aryl ketoximes readily underwent Beckmann rearrangement to give N-substituted amides in excellent yields on electrophilic activation by elemental iodine in anhydrous acetonitrile under reflux. The main advantages of this environmentally friendly protocol include a high selectivity as a result of the absence of any accompanying deprotection to form the parent ketones as byproducts, mild neutral conditions, procedural simplicity, and particularly ease of isolation of the products.

Full text of DOI:10.1055/s-0030-1258217

PAPER
3705
Efficient Iodine-Mediated Beckmann Rearrangement of Ketoximes to Amides
under Mild Neutral Conditions
B
eckmannRearra
n
e
gement of
m
K
etoximes toAmid
a
es i C. Ganguly,* Pallab Mondal
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
Fax +91(33)25828282 ; E-mail: nemai_g@yahoo.co.in
Received 24 June 2010; revised 14 July 2010
acidic reagents and basic amides.4 This process also gen-
erates large amounts of waste, in the form of ammonium
or metal sulfates, particularly in large-scale industrial pro-
cesses such as the production of e-caprolactam, in which
Abstract: Aryl ketoximes readily underwent Beckmann rearrange-
ment to give N-substituted amides in excellent yields on electro-
philic activation by elemental iodine in anhydrous acetonitrile
under reflux. The main advantages of this environmentally friendly
protocol include a high selectivity as a result of the absence of any concentrated sulfuric acid is used. To circumvent these
accompanying deprotection to form the parent ketones as byprod-
limitations, and in response to the current concern for the
ucts, mild neutral conditions, procedural simplicity, and particularly
ease of isolation of the products.
development of environmentally benign chemical pro-
cesses, the rearrangement has been explored in the vapor
phase, in the liquid phase, and under solvent-free condi-
tions. Vapor-phase methods, with a particular focus on the
Key words: rearrangements, amides, ketoximes, catalysis, Beck-
mann rearrangements
sulfate-free industrial production of e-caprolactam, have
been performed by using heterogeneous solid catalysts,
such as high-silica zeolites,5 metal oxides,6 or clays7 at
temperatures as high as 300 °C. These methods frequently
suffer from low selectivities and rapid decay of the activ-
ity of the catalyst as a result of the high temperatures that
are used. Liquid-phase procedures have been attempted
using chlorosulfonic acid in N,N-dimethylformamide,8
ethyl chloroformate and boron trifluoride diethyl ether-
ate,9 anhydrous oxalic acid,10 2,2,2-trichloroethane-1,1-
diol (chloral hydrate),11 or organocatalysts such as sul-
famic acid,4 bis(2-oxo-3-oxazolidinyl)phosphinic chlo-
ride,12 cyanuric chloride in N,N-dimethylformamide,13
diethyl chlorophosphate,14 triphosphazene15 and poly(eth-
ylene glycol)-w-sulfonic acid,16 an O-alkyl-N,N-dimeth-
ylformamidium salt,17 iron(III) chloride impregnated
silica gel (silferc catalyst),18 iron(III) chloride and mont-
morillonite K-1019 catalyst, or mercury(II) chloride.20 Re-
cently, attempts have been made to use room-temperature
ionic liquids with Brønsted acidity21 or supercritical
water22 as alternative green media for the reaction, but
these have had mixed success. In addition to their limita-
tions in terms of low yields and the formation of byprod-
ucts, existing approaches often require reagents that are
expensive, noxious, or need to be prepared before use;
they also require toxic solvents and frequently involve
cumbersome procedures, such as high-vacuum opera-
tions.11 There was therefore a need to develop a simple
mild protocols for the synthesis of N-substituted amides
from ketoximes.
The Beckmann rearrangement of ketoximes to N-substi-
tuted amides is an organic transformation of immense
synthetic and mechanistic importance.1 This rearrange-
ment of ketoximes, which are readily prepared from the
corresponding ketones, provides an atom-economic con-
nection between the vast chemical space of ketones, with
their remarkable synthetic flexibility, and that of amides
and lactams. The products are widely used in drugs and
pharmaceuticals, and they also have host of industrial ap-
plications as detergents, lubricants, and raw materials for
polyamides such as nylon-6 and nylon-12.2 Alternative
routes to amides by the reaction of amines with activated
carboxylic acid derivatives, such as acid chlorides or acid
anhydrides, are less atom-economical and they involve
the use of noxious chemicals and the production of haz-
ardous waste materials. Mechanistically, the Beckmann
rearrangement of ketoximes involves the migration of an
aryl or alkyl moiety from carbon to nitrogen triggered by
the departure of the oximic hydroxy group with concomi-
tant cleavage of a C–C bond and formation of a C–N
bond. The success of the rearrangement hinges on the
electrophilic activation of the hydroxy function, which is
normally a poor nucleofuge. Conventional methods for
this activation are based on the use of strong Brønsted or
Lewis acids, such as concentrated sulfuric acid, hydrogen
chloride in acetic anhydride, or phosphorus pentachloride
in diethyl ether.1,3 These protocols are performed under
harsh conditions and they are incompatible with acid-sen-
sitive substrates. The neutralization of excess acids by a
base, such as ammonia or a metal hydroxide, during the
workup and isolation of the products is also somewhat
problematic because of the strong affinity between the
As part of our continuing program aimed at developing
synthetic protocols based on the use of elemental iodine as
a mild, water-compatible, Lewis acid in catalytic or sub-
stoichiometric amounts,23 we became interested in evalu-
ating it as a reagent for the Beckmann rearrangement. We
were encouraged in this search by recent reports in the lit-
erature on the use of iodine as a catalyst in the coupling of
homoallylic alcohols with aldehydes to give tetrahydro-
SYNTHESIS 2010, No. 21, pp 3705–3709
x
x.
x
x
.
2
0
1
0
Advanced online publication: 18.08.2010
DOI: 10.1055/s-0030-1258217; Art ID: Z16110SS
© Georg Thieme Verlag Stuttgart · New York

3706
N. C. Ganguly, P. Mondal
PAPER
pyrans (the Prins cyclization)24 and in hydroperoxidations stantial deoximation to acetophenone. Notably, there is
of carbonyl compounds with tert-butyl hydroperoxide.25
precedent in the literature for catalytic deoximation by io-
dine in water in the presence of an anionic surfactant (so-
dium dodecylsulfate),26 which provides micellar
solubilization as well as activation of the iodonium ion.27
Water presumably impedes the rearrangement process by
coordinating with iodine, thereby encouraging the com-
petitive deoximation process. A reaction using 50 mol%
of iodine in anhydrous refluxing acetonitrile gave excel-
lent results in terms of the yield and reaction time (98%, 1
h), and these conditions proved to be optimal.28 To estab-
lish the scope and generality of the method, a wide range
of ketoximes of various degrees of reactivity were treated
with iodine under the optimized reaction conditions
(Table 2).
We chose acetophenone oxime (1) as a representative sub-
strate, and subjected it to reactions with various amounts
of finely pulverized iodine in various solvents under re-
flux. The results of our initial exploratory experiments are
summarized in Table 1. It is pertinent to mention here that
attempts to conduct the reaction at lower temperatures,
even with prolonged exposure, were dismal failures. Our
experiments showed that the conversion to amide is mark-
edly dependent on the nature of the solvent used. Anhy-
drous acetonitrile proved to be the medium of choice,
whereas nonpolar dichloromethane or coordinating polar
or hydroxylic solvents such as tetrahydrofuran, N,N-di-
methylformamide, or methanol were unsuitable as reac-
tion media.
Acetophenone oxime or its derivatives bearing activating
(methoxy, O-allyl, or amino), moderately activating (ace-
toxy, acetoxamido), or electroneutral (methyl) groups
were smoothly converted into the corresponding N-sub-
stituted amides exclusively in yields of 88% to near-quan-
titive, without any accompanying cleavage of the ketones.
The structure of the amide formed was not perceptibly in-
fluenced by the sterochemical identity (E/Z) of the oxime,
and aryl moieties always migrated in preference to methyl
groups. Presumably, E or Z oximes interconvert under the
conditions of the reaction.13b,28 Hydroxy derivatives of
acetophenone oxime showed greater reluctance to under-
go rearrangment than did their less-activated methoxy or
acetoxy counterparts, which is contrary to what would be
expected on electronic grounds. This was particularly the
case for ortho-hydroxy derivatives. It is possible that the
presence of a free hydroxy group impedes the reaction by
providing an alternative coordination site for iodine and
this, coupled with a steric factor, decreases the reaction
rate for ortho-hydroxy derivatives. An unfavourable ef-
fect of a hydroxy group on the aromatic ring was also ev-
ident in the case of (4-hydroxyphenyl)(phenyl)methanone
oxime (entry 12).
Table 1 Optimization of the Iodine-Mediated Beckmann Rear-
rangement of Acetophenone Oxime (1)
O
NOH
H
N
I2, solvent
reflux
+
O
1
1a
1b
Entry I2
Solvent
Time Yield of Yield of
(mol%) (mL)
(h)a
1a (%)b 1b (%)
1
2
3
4
5
6
7
8
9
10 MeCN (4)
3
65
30
90
98
96
–
10
45
–
20
20
9:1 MeCN–H2O (4)
anhyd MeCN (4)
anhyd MeCN (4)
anhyd MeCN (4)
CH2Cl2 (4)
2
2
50
1
–
100
50
1
–
3
–
50
anhyd MeOH (4)
anhyd THF (4)
DMF (4)
4
25
–
10
–
50
4
The current procedure was successfully extended to
oximes of cyclic ketones or 1-(2-thienyl)ethanone and to
aliphatic and a,b-unsaturated ketones. The conversion of
cyclohexanone into e-caprolactam constitutes the most
important industrial application of the Beckmann rear-
rangement. Unfortunately, our procedure proved unsuc-
cessful with cyclohexanone oxime under the optimized
50
3c
20
–
a Reactions were performed on a 1-mmol scale, and the amounts of I2
and solvent used refer to 1 mmol of substrate.
b Isolated yields after column chromatography.
c The reaction was carried out at 100 °C.
The special facilitating role of acetonitrile is presumably conditions, yielding e-caprolactam in a disappointingly
linked to the absence of any significant interaction be- low yield of 6% along with intractable products. To our
tween it and iodine, thereby allowing the latter to assist in delight, however, the conversion was clean and smooth
the departure of hydroxy groups by electrophilic activa- with 20 mol% of iodine, giving e-caprolactam in 90%
tion, whereas hydroxylic solvent such as methanol, or yield within one hour. In all the cases investigated, the mi-
strongly coordinating solvents such as tetrahydrofuran
gration of the aryl moiety was unidirectional and a single
and N,N-dimethylformamide, deactivate iodine and inhib- product was always isolated. Aryl aldoximes, such as
it its activity as a catalyst. This explanation is confirmed oximes of 1,3-benzodioxole-5-carbaldehyde or 4-hy-
by an analogous effective partnership between iodine and droxy-3-methoxybenzaldehyde (vanillin) (entries 18 and
acetonitrile in the iodine-catalyzed elimination of a hy- 19), remained mostly unchanged and gave only about 15–
droxy group during the hydroperoxidation of carbonyl 22% of the parent aldehydes upon sluggish deoximation.
compounds.25 Selectivity was seriously compromised by Dehydration of aldoximes to aryl nitriles, which frequent-
the presence of water in the acetonitrile, resulting in sub- ly occurs under the influence of strong acids10 or bases,16
Synthesis 2010, No. 21, 3705–3709 © Thieme Stuttgart · New York

PAPER
Beckmann Rearrangement of Ketoximes to Amides
3707
was excluded here because of the mild neutral nature of iodine, as a nonmetallic Lewis acid, in anhydrous acetoni-
the reagent.
trile. Among the attractive features of this protocol are its
use of and inexpensive readily available reagent under
mild and neutral reaction conditions that are tolerated by
several common functional groups, its simple trouble-free
operational conditions, and its freedom from demanding
separation procedures for the isolation of products.
To explain the role of iodine in the Beckmann rearrange-
ment of aryl ketoximes, we propose the following tenta-
tive catalytic cycle (Scheme 1); this, however, is purely
hypothetical at the current stage of investigation.
In conclusion, we have developed a greener procedure for
the Beckmann rearrangement of ketoximes mediated by
Table 2 Iodine-Mediated Beckmann Rearrangements of Oximes in Anhydrous Acetonitrile
Entry
Substrate
Product
Time (h)a
Yield (%)b
NOH
H
N
O
R
R
R = H
R = 4-OMe
R = 4-Me
R = 4-OAc
R = 4-OAllyl
R = 4-OH
R = 4-NH2
R = 4-NHAc
R = 2-OH
1
2
3
4
5
6
7
8
9
1
0.5
1
98
97
>99
88
96
95
90
88
85
90
4
2.5
1.5
4
3
6
R = 2-OAc
10
3
NOH
H
N
11
12
2
5
98
85
O
NOH
H
N
O
HO
HO
H
NOH
N
13
14
4 h
1 h
86
88
S
O
S
O
NOH
NH
O
NOH
15
16
1 hc
90
95
NH
O
N
H
70%
NOH
2 h
H
N
Me
O
30%
Synthesis 2010, No. 21, 3705–3709 © Thieme Stuttgart · New York

3708
N. C. Ganguly, P. Mondal
PAPER
Table 2 Iodine-Mediated Beckmann Rearrangements of Oximes in Anhydrous Acetonitrile (continued)
Entry
17
Substrate
Product
Time (h)a
Yield (%)b
O
NOH
Ph
NH
Ph
4 h
97
15
22
O
O
O
O
O
O
CHO
NOH
18
19
5 h
5 h
O
O
NOH
CHO
OMe
OMe
OH
OH
a Reaction conditions: I2 (50 mol%), anhyd MeCN (4 mL), reflux.
b Refers to isolated yield after chromatographic purification; the amide or lactam products are known compounds with physical and spectral
properties that agreed closely with those reported in the literature.
c Reaction conditions: I2 (20 mol%), anhyd MeCN (4 mL), reflux.
(Na2SO4), and concentrated. The residue was filtered through a
short pad of silica gel (60–120 mesh, Spectrochem, India) using
EtOAc–PE (2:3) as an eluent to afford a white crystalline solid;
yield: 187 mg (85%); mp 210–212 °C (lit.29 214–216 °C).
Ar
I2
NOH
H2O
R
IR (KBr): 3335, 1651, 1611, 1597, 1580, 1537, 1514, 1439, 1376,
1323, 1251, 1175, 827 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 6.7 (d, J = 9.2 Hz, 2 H), 7.44–
7.52 (m, 5 H), 7.88 (d, J = 9.2 Hz, 2 H), 9.21 (s, 1 H), 9.97 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 115.0, 122.3, 127.5, 128.4,
130.8, 131.3, 135.3, 153.8, 161.9.
Ar
N
HOI
H
+ I
O
I
I
R
HO
Ar
R
R
O
H
N
NHAr
DEPT-135 NMR: d = 115.0, 122.3, 127.5, 128.4, 131.3.
MS (ESI): m/z = 236.1 [M + Na]+.
C
N
Me
C
N
R
Me
H2O
N
Ar
Acknowledgment
Scheme 1 Tentative catalytic cycle for the iodine-mediated Beck-
mann rearrangement
One of the authors (P.M.) is grateful to CSIR, India for financial as-
sistance by way a research fellowship. We gratefully acknowledge
the facilities provided by the DST-FIST and UGC, SAP programs
of the Government of India to the Department of Chemistry of the
University of Kalyani.
H2NOH·HCl and I2 were obtained from Merck, Germany and SRL,
India, respectively. IR spectra were recorded on a Perkin-Elmer
FTIR L120-000A, NMR spectra were recorded on Bruker AM-
300L (300 MHz), and mass spectra were recorded on an Applied
Biosystems MDS Sciex API 3200. Silica gel (60–120 mesh; Spec-
trochem, India) was used for column chromatographic separations
and purifications. PE refers to the fraction boiling at 60–80 °C. The
amide and lactam products are known compounds with physical and
spectral properties that agreed closely with those reported in the lit-
erature.
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