A mild and efficient way to prepare ε-caprolactam by using a novel salt related with ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2010.05.145

The Beckmann rearrangement of several ketoximes has been performed by treatment with tosyl chloride, using ionic liquids as both solvent and catalyst, without the need of any other promoter. High levels of conversion and selectivity were observed in the majority of experiments. Work-up is very simple and the product can be isolated in high yields. When the method was applied to cyclohexanone oxime, the novel salt [TMG][TsO] instead of the ionic liquid was used. This procedure afforded a conversion of 100% to obtain pure ε-caprolactam in a 98% yield. [TMG][TsO] is easy to prepare, cheap, and not corrosive. It can be recovered and reused.

Full text of DOI:10.1016/j.tetlet.2010.05.145

Tetrahedron Letters 51 (2010) 4125–4128
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A mild and efficient way to prepare e-caprolactam by using a novel salt
related with ionic liquids
Miguel Vilas, Emilia Tojo *
Department of Organic Chemistry, Faculty of Chemistry, University of Vigo, Campus Universitario, Vigo 36310, Pontevedra, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The Beckmann rearrangement of several ketoximes has been performed by treatment with tosyl chloride,
using ionic liquids as both solvent and catalyst, without the need of any other promoter. High levels of
conversion and selectivity were observed in the majority of experiments. Work-up is very simple and
the product can be isolated in high yields. When the method was applied to cyclohexanone oxime, the
novel salt [TMG][TsO] instead of the ionic liquid was used. This procedure afforded a conversion of
Received 23 April 2010
Revised 28 May 2010
Accepted 28 May 2010
Available online 2 June 2010
1
00% to obtain pure
e-caprolactam in a 98% yield. [TMG][TsO] is easy to prepare, cheap, and not corrosive.
Keywords:
Ionic liquid
Beckmann rearrangement
Ketoximes
It can be recovered and reused.
Ó 2010 Elsevier Ltd. All rights reserved.
e-Caprolactam
1
. Introduction
The conversion of ketoximes to the corresponding amides,
reactions must be carried out in an anhydrous system which highly
reduces its application in an industrial scale.
Over the past decade, ionic liquids (ILs) have attracted great
interest because of their unusual properties, including negligible
vapor pressure, broad liquid temperature range, and high capacity
known as the Beckmann rearrangement, is one of the classical
and most popular reactions in organic chemistry.1 It represents a
powerful method in the chemical industry, particularly for manu-
facturing
the synthetic fibber Nylon 6. The reaction generally requires high
reaction temperatures and strongly acidic media, such as H SO
and SOCl2, which cause serious corrosion problems and large
amount of by-products. Thus, milder routes are required and alter-
native methods both in organic liquids and in vapor-phase have
been studied. Liquid-phase processes using catalysts such as
RuCl
phosphate, silica sulfate, and chlorosulfonic acid in organic sol-
vents have been carried out. Beckmann rearrangements in vapor-
phase using solid catalysts such as metal oxides and zeolites have
also been reported, however, such conditions cause rapid catalyst
deactivation. A few examples of solvent-free organo-catalyzed
Beckmann rearrangements have been reported, as well as in
supercritical water. Beckmann rearrangements of ketoximes by
treatment with p-toluenesulfonyl chloride (TsCl) and different ILs
as solvent and catalytic media such as NaOH and pyridine were
needed. Very recently,13 during the development of the present
work, TsCl-catalyzed Beckmann rearrangement of ketoximes with-
out the need of any other promoter has been described, but the
1
4
as specific solvents. Their use in place of hazardous volatile or-
ganic solvents makes organic synthesis environmentally benign.15
In recent years they have been used in the Beckmann rearrange-
ment with considerable success, but the use of some catalysts such
e-caprolactam, the basic monomer for the production of
2
2
4
3
16
17
18
19
2
as P O5, PCl5, other Lewis acid, and metaboric acid and high
temperatures (75–120 °C), were always needed. New ILs have been
designed for being used as both solvent and catalyst in the Beck-
20
mann rearrangement, such as caprolactam-based ILs, or sulfonyl
4
21
3
,
sulfamic acid, antimony salts, silica-supported dichloro-
chloride-functionalized ILs, however, the separation of the de-
5
6
7
sired product from the reaction mixture was difficult to achieve.
Though numerous procedures to obtain
e-caprolactam from
cyclohexanone oxime have been developed, further investigations
to obtain milder reaction conditions profitable for industrial pur-
poses, allowing a clean and simple extraction of e-caprolactam, are
still needed. The main purpose of this work was to find some IL that
could be used as solvent and/or catalyst of the Beckmann rearrange-
ment of cyclohexanone oxime by treatment with TsCl. Particularly
we were interested in obtaining a simple and mild procedure appli-
cable for industrial purpose, avoiding the use of expensive or corro-
sive catalysts, toxic solvents, and anhydrous conditions.
8
9
1
0
11
12
2
. Results and discussion
Initially, acetophenone oxime 1 was used as the substrate to
examine the feasibility of Beckmann rearrangement by treatment
*
Corresponding author. Tel.: +34 986 812290; fax: +34 986 812262.
E-mail address: etojo@uvigo.es (E. Tojo).
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.145

4
126
M. Vilas, E. Tojo / Tetrahedron Letters 51 (2010) 4125–4128
with TsCl using different ILs as the reaction medium (Scheme 1).
The results are summarized in Table 1. After 3.5–4.5 h N-phenyl-
acetamide 2 was obtained in excellent yields and mild conditions
lid salt that was identified by its spectral data as 1,1,3,3-tetrameth-
ylguanidine p-toluenesulfonate ([TMG][TsO], Scheme 4), which
made difficult the product extraction. In order to avoid the anionic
exchange that affords [TMG][TsO], this new salt was synthesized
and employed instead of the IL to promote the rearrangement.
Taking into account the TsCl and [TMG][TsO] solubility, acetone
as the reaction solvent was chosen (Scheme 5). Several experi-
ments were carried out using different reagent concentrations (Ta-
(
4
50 °C) when some ILs such as [MMIm][MSO ] were used. The for-
mation of the second possible amide (N-methylbenzamide) was
not observed. The highest reaction rate and yield were observed
for [MMIm][MSO
To explore the generality and scope of the method, it was ap-
plied to a series of alkyl and aryl oximes using [MMIm][MSO
Scheme 2). This IL was also chosen for its easy preparation as well
4
] (3.5 h, 95%).
4
]
(
Table 2
as its good balance of desirable physical and chemical properties.
These include thermal stability, low viscosity, and a good capacity
to dissolve organic substrates.
4
Beckmann rearrangement of different oximes in [MMIm][MSO ] using 1.1 equiv of
TsCl at 50 °C
Entry
R
1
R
2
Yield (%)
Time (h)
Ref.
As expected, the best results were obtained when aryl ketoxi-
mes were used as substrates showing 100% of conversion and more
than 75% of yield. Only one of the oximes (entry 1) was partially
hydrolyzed to afford the corresponding acetone. The reactions
are in general rapid and quantitative, one of the possible amides
being the only product recovered from the reaction mixtures. All
products were characterized by comparison of their melting
b
22
13
13
13
23
24
13
1
2
3
4
5
6
7
Me
Ph
Ph
p-(Me)-C
Me
Me
Ph
Me
Me
Me
15
98
92
94
75
95
50
0.3
4
5
4.5
7
6
a
a
a
6
H
4
a
p-(NO
2
)-C
6
H
4
a
C
10
H
7
c
(CH
2
)
5
30
1
13
points, IR, and H and C NMR spectra with those of the literature
see references Table 2). High levels of conversion and selectivity
a
b
c
Yields referred to pure isolated product.
The oxime was partially hydrolyzed back to acetone.
After 30 h of reaction only part of the starting material turns into
(
were observed in the Beckmann rearrangement of all ketoximes
except for acetone oxime (entry 1) and cyclohexanone oxime (en-
try 7).
e-
caprolactam.
In order to increase the conversion of cyclohexanone oxime 3 to
-caprolactam 4 (Scheme 3), the reaction using different ILs was
investigated.
OH
O
e
N
HN
TsCl
IL
Very high levels of conversion and selectivity to afford e-capro-
lactam were obtained with some ILs (Table 3) as shown by TLC.
However, separation of the desired product from the reaction mix-
ture through solvent extraction was very difficult to achieve. When
3
4
Scheme 3. Beckmann rearrangement of cyclohexanone oxime 3 to give
lactam 4 in different ILs.
e-capro-
[
HMIm][TFA] or [HMIm][TsO] was used, a partial solubility of the
product in the IL is observed, so -caprolactam is obtained impure
e
as a mixture with the IL. In the case of [TMG][Ac] and [TMG][TFA],
the reaction system became sluggish due to the formation of a so-
Table 3
Beckmann rearrangement of cyclohexanone oxime 3 in ILs using TsCl at 50 °C
Ionic liquid
HMIm][PF
[HMIm][TFA]
Time (h)
Conv.%
Sel. (%)
Yielda (%)
—b
[
6
]
>48
2.5
5.5
5
3.5
>48
—
—
O
H
N
c
Ph
Me
TsCl
IL
100
100
100
100
—
99
99
99
99
—
52
48
24
65
N
c
[
[
[
[
HMIm][TsO]
TMG][TFA]
TMG][Ac]
Me
OH
Ph
d
d
1
2
e
TMG][Lac]
—
Scheme 1. Beckmann Rearrangement of acetophenone oxime 1 in ILs.
a
b
c
Yields referred to pure isolated product.
The degradation of the IL is observed as the reaction progresses.
After extraction with EtOAc the reaction product is obtained impure as a
mixture with the IL.
Table 1
d
The reaction mixture becomes sluggish due to the formation of [TMG][TsO]
Beckmann rearrangement of acetophenone oxime 1 in different ILs using 1.1 equiv of
TsCl at 50 °C
which makes difficult the product extraction.
e
Only traces of e-caprolactam can be observed.
Entry
Ionic liquid
Yielda (%)
Time (h)
1
2
3
4
5
[MMIm][MSO
[HMIm][PF ]
6
4
]
95
90
92
—
3.5
3.5
4.0
—
Me N
+
2
-
O S
3
[HMIm][BF
4
]
NH
Me
2
b
[TMG][TFA]
Me N
2
[HMIm][TFA]c
—
—
a
b
c
Scheme 4. 1,1,3,3-Tetramethylguanidine p-toluenesulfonate ([TMG][TsO]) struc-
ture.
Yields referred to pure isolated product.
Only traces of amide appeared in TLC after 24 h.
No product was formed after 24 h.
OH
O
N
HN
TsCl, 60 ºC
TsCl (1.1 eq.), 50 ºC
O
H
N
R1
N
[TMG][TsO], acetone
R
2
[MMIm][MSO4]
R2
OH
R1
2
3
Scheme 2. Beckmann rearrangement of different oximes in [MMIm][MSO
.1 equiv of TsCl at 50 °C.
4
] using
Scheme 5. Beckmann rearrangement of cyclohexanone oxime 2 to give
lactam 3 by treatment with TsCl using [TMG][TsO] as the promoter.
e-capro-
1

M. Vilas, E. Tojo / Tetrahedron Letters 51 (2010) 4125–4128
4127
Table 4
sized according to the previous papers. The oximes were either ob-
tained from commercial sources or prepared by standard
procedures.
Beckmann rearrangement of cyclohexanone using TsCl in acetone/[TMG][TsO] at
6
0 °C
31
Entry
[TsCl] (equiv)
[[TMG][TsO]] (equiv)
Yielda (%)
Time (h)
1
2
3
4
5
1
1.5
2
1
2
1
1
1
2
2
95
98
97
95
98
18
12
9
13
6
4.1. General procedure for Beckmann rearrangement of
ketoximes in ILs (Tables 1–3)
The ketoxime (100 mg) and TsCl (1.1 equiv) were dissolved in IL
(
2 g). The mixture was stirred at 50 °C in a round-bottomed flask
a
Yields referred to pure isolated product.
until completion of the reaction as indicated by TLC with hexane/
AcOEt. The reaction mixture was then extracted with ethyl acetate
t
(
4 ꢀ 5 mL) or BuOMe (4 ꢀ 5 mL) depending on the IL, and the com-
bined organic layers were dried over anhydrous sodium sulfate.
The solvent was removed under vacuum affording a solid that
Table 5
Beckmann rearrangement of cyclohexanone using TsCl in acetone/[TMG][TsO] and
under anhydrous conditions at 60 °C
2
was recrystallized from MeOH/H O (10:1).
Entry
[TsCl] (equiv)
[[TMG][TsO]] (equiv)
Yielda (%)
Time (h)
4
.2. General procedure for Beckmann rearrangement of
b
1
2
0.6
0.6
0.6
—
98
28
11
18
c
cyclohexanone oxime promoted by TsCl/[TMG][TsO] (Table 4)
a
b
c
Yields referred to pure isolated product.
Product isolated by Section 4.2.
Product isolated by column chromatography.
[
TMG][TsO] (2 equiv) was dissolved in acetone (20 mL) heating
at 60 °C. Cyclohexanone (100 mg) and TsCl (2 equiv) were added
and the mixture was stirred at 60 °C for 6 h. Half of the acetone
was eliminated under vacuum and the reaction mixture was
cooled to 0 °C to precipitate [TMG][TsO], that was filtrated and
recovered as a pure solid. The solvent was then completely re-
moved under vacuum and water was added (10 mL) to precipitate
the excess of TsCl (only for entries 3 and 5), that was filtered and
recovered as a pure solid. Finally,
from the p-toluenesulfonic acid formed by extraction with CH
5 ꢀ 10 mL). The combined organic layers were dried over anhy-
drous sodium sulfate and the solvent was removed under vacuum
affording -caprolactam as pure white crystals.
ble 4). The best result was obtained heating at 60 °C and using
equiv of both TsCl and [TMG][TsO]. Excellent levels of conversion
100%) and selectivity (99%) were obtained. The reaction finished
in 6 h to obtain pure -caprolactam in a 98% yield. Pure [TMG][TsO]
2
(
e
was recovered from the reaction medium and reused.
e-caprolactam was separated
Knowing that the excess of TsCl needed was due to the presence
of water that produces its hydrolysis, this effect was investigated
by carrying out the reaction under anhydrous conditions. The sol-
2
Cl
2
(
2 3
vent was dried over K CO and distilled, TsCl was recrystallized
e
and dried under vacuum, and the reaction was carried out under
an inert atmosphere. As it is shown in Table 5, only catalytic
amounts of TsCl are needed if the reaction is carried out under
anhydrous conditions. If no [TMG][TsO] is added (entry 2), the
reaction proceeds very slowly to give a mixture that after purifica-
4
.3. Synthesis of 1,1,3,3-tetramethylguanidine p-toluenesulfo-
nate ([TMG][TsO])
Methanol (10 mL) and p-toluenesulfonic acid monohydrate
6.96 mmol) were loaded into a 50 mL round flask. A solution of
,1,3,3-tetramethylguanidine (6.96 mmol) in methanol (10 mL)
was added dropwise and the reaction mixture was stirred for 9 h
at room temperature. The solvent was removed under reduced
pressure affording a white solid that was recrystallized from ace-
tion by column chromatography affords a low yield of pure e-cap-
(
1
rolactam (28%). These results indicate that [TMG][TsO] acts as a
catalyst of both oxime tosylation and later rearrangement. In order
to clarify the catalytic mechanism and the effect of [TMG][TsO],
more experiments are now undergoing.
tone to afford [TMG][TsO] as colorless crystals in a yield of 99%
3
. Conclusions
1
(
7
1.98 g); mp 150.5–152 °C; H NMR (400 MHz, CDCl
3
, ppm, d):
0
.86 (br s, 2H, NH
2
0
), 7.69 (d, 2H, J = 8.0 Hz, ArH-2,2 ), 7.08 (d, 2H,
A new procedure to obtain
e
-caprolactam has been developed.
13
J = 8.0 Hz, ArH-3,3 ), 2.83 (s, 12H, NCH
NMR (100.6 MHz, CDCl
25.7, 39.5, 21.1. HRMS-ESI m/z (%): 690 [(TMG)
3
), 2.27 (s, 3H, Ar-CH
3
).
C
The Beckmann rearrangement of cyclohexanone oxime is carried
out by treatment with TsCl using a new salt, [TMG][TsO], as the
promoter. This procedure requires mild reaction conditions
3
, ppm, d): 161.7, 143.1, 139.2, 128.4,
+
1
3
(TsO)
2
] (5), 404
+
+
[
(TMG)
2
(TsO)+1] (12), 403.24741 [(TMG)
2
(TsO)] (C17H N O S
35 6 3
(
(
60 °C) and affords high levels of conversion of 100% and selectivity
99%) to obtain pure -caprolactam in a 98% yield. The catalyst is
requires 403.24859, 100).
e
cheap, easy to prepare, not corrosive and can be recovered and re-
used. The method does not require anhydrous conditions or toxic
solvents. All these characteristics make the procedure applicable
for an industrial purpose.
In addition, the Beckmann rearrangement of several ketoximes
has been performed by treatment with tosyl chloride, using ionic
liquids as both solvent and catalyst, without the need of any other
promoter. High levels of conversion and selectivity were observed
for aryl ketoximes, work-up is very simple and the product is iso-
lated in high yields.
Acknowledgments
We thank the Spanish Ministry of Education and Science and
the Xunta de Galicia for financial support under projects
CTQ2007-61788, CTQ2007-61272, and PGIDIT04BTF301031PR.
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