An efficient catalytic method for the beckmann rearrangement of ketoximes to lactams by cyanuric chloride and phosphazene catalysts

Article abstract of DOI:10.1021/op800258s

The Beckmann rearrangement of ketoximes to lactams was successfully achieved by a very small amount of cyanuric chloride and phosphazene by carrying out the reaction in a mixed solvent of trifluoroacetic acid and toluene under mild conditions. For instance, the Beckmann rearrangement of cyclohexanone oxime was completely performed under the influence of 0.5 mol % of cyanuric chloride (CNC) or phosphazene (1,3,5-triazo-2,4,6-triphosphorine- 2,2,4,4,6,6-chloride: TAPC) in a 3:2 mixed solvent of trifluoroacetic acid and toluene at 70 °C for 4 h to give E-caprolactam, which is an important monomer of 6-Nylon, in almost quantitative yield. The same strategy could be applied to laurolactam synthesis from cyclododecanone oxime.

Full text of DOI:10.1021/op800258s

Organic Process Research & Development 2009, 13, 411–414
Full Papers
An Efficient Catalytic Method for the Beckmann Rearrangement of Ketoximes to
Lactams by Cyanuric Chloride and Phosphazene Catalysts
Masaharu Hashimoto, Yasushi Obora, and Yasutaka Ishii*
Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering and High
Technology Research Center, Kansai UniVersity, Suita, Osaka 564-8680, Japan
Abstract:
acetonitrile as a key solvent.4 However, they reported that the
yield of 2a from 1a was up to 30% even by the use of 10 mol
% of CNC under refluxing acetonitrile. Quite recently, we have
carried out the one-pot synthesis of lactam 2a via oximation of
cyclohexane using tert-butyl nitrite catalyzed by NHPI.5,6 In
addition, we showed that 1a can be rearranged by the use of
10 mol % of CNC in 1,1,1,3,3,3-hexafluoro-2-propanol (HFP)
to 2a (43%) and its condensate (3a) (22%) corresponding to
44% of 2a.6 Triphosphazene, like 1,3,5-triazo-2,4,6-triphos-
phorine-2,2,4,4,6,6-chloride (TAPC), available from commercial
sources, was found to promote efficiently the Beckmann
rearrangement of ketoximes to lactams.7 For example, the
reaction of 1a by TAPC (5 mol %) in HFP gave 2a (40%) and
its condensate (3a) (26%). However, one serious problem of
our method is that HFP, which is much more expensive than
acetonitrile, must be used as a solvent. Thus, a more efficient
method that does not use expensive HFP is necessary to effect
the Beckmann rearrangement of 1a to 2a in a large scale. In
this contribution, we report a very efficient method for the
Beckmann rearrangement of 1a to 2a by using CNC and TAPC
as catalysts. A key of this method is the use of a mixed solvent
of trifluoroacetic acid (TFA) and toluene (eq 1).
The Beckmann rearrangement of ketoximes to lactams was
successfully achieved by a very small amount of cyanuric chloride
and phosphazene by carrying out the reaction in a mixed solvent
of trifluoroacetic acid and toluene under mild conditions. For
instance, the Beckmann rearrangement of cyclohexanone oxime
was completely performed under the influence of 0.5 mol % of
cyanuric chloride (CNC) or phosphazene (1,3,5-triazo-2,4,6-triph-
osphorine-2,2,4,4,6,6-chloride: TAPC) in a 3:2 mixed solvent of
trifluoroacetic acid and toluene at 70 °C for 4 h to give E-capro-
lactam, which is an important monomer of 6-Nylon, in almost
quantitative yield. The same strategy could be applied to lauro-
lactam synthesis from cyclododecanone oxime.
Introduction
The Beckmann rearrangement of cyclohexanone oxime (1a)
with sulfuric acid to ꢀ-caprolactam sulfate is a very important
commercial process for producing the polymer material 6-ny-
lon.1 In 2005, about 4 million tons of ꢀ-caprolactam sulfate was
manufactured by this method. The drawback of this transforma-
tion is that the resulting lactam sulfate must be treated with a
base such as ammonia to isolate ꢀ-caprolactam (2a). As a result,
a vast amount of undesired ammonium sulfate is simultaneously
produced with lactam. In 2003, Sumitomo Chemical of Japan
industrialized a sulfate-free process for 2a which includes the
conversion of cyclohexanone to 1a upon treatment with H2O2
and NH3 on TS-1 followed by the vapor-phase Beckmann
rearrangement on high-silica zeolite catalyst.2 On the other hand,
Giacomelli et al. have recently reported that cyanuric chloride
(CNC) induces stoichiometrically the Beckmann rearrangement
of ketoximes to lactams.3 Thereafter, Ishihara et al. have applied
a catalytic reaction by using CNC with Lewis acid, ZnCl2, and
Results and Discussion
We previously reported that the rearrangement of 1a by CNC
and TAPC catalysts in HFP gives 2a in satisfactory yields
(Table 1, entries 1 and 2).6,7 These results indicate that a
fluorinated solvent such as HFP is suitable for the rearrangement
* To whom correspondence should be addressed. Tel: +81-6-6368-0793. Fax:
+81-6-6339-4026. E-mail: ishii@ipcku.kansai-u.ac.jp.
(1) Luedeke, V. D. In Encyclopedia of Chemical Processing and Design:
Chemical Processing Handbook; McKetta, J. J., Ed.; Marcel Dekker:
New York, 1978, p 72. (b) Rademacher, H. In Ullmann’s Encyclopedia
of Industrial Chemistry, 5th ed.; Gerhartz, W., Ed.; Wiley: New York,
1987; Vol. A8, p 201. (c) Wessermel, K.; Arpe, H.-J. Industrial Organic
Chemistry, 4th ed.; Wiley-VCH: Weinheim, 2003; p 239.
(2) Mantegazza, M. A.; Petrini, G.; Cesana, A. (Enichem Anic S.r.L.). EP
0564040, 1993.
(4) Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2005, 127,
11240.
(5) Hirabayashi, T.; Sakaguchi, S.; Ishii, Y. Angew. Chem., Int. Ed. 2004,
43, 1120.
(6) Hashimoto, M.; Sakaguchi, S.; Ishii, Y. Chem. Asian J. 2006, 1, 712.
(7) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2008,
73, 2894.
(3) De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67,
6272.
10.1021/op800258s CCC: $40.75  2009 American Chemical Society
Published on Web 01/06/2009
Vol. 13, No. 3, 2009 / Organic Process Research & Development
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Table 1. Beckmann rearrangement of cyclohexanone oxime to E-caprolactam by CNC and TAPC catalyst under various
conditionsa
yield (%)b
3a
catalyst
(mol %)
entry
solvent (mL)
time (h)
conv (%)
2a
4a
1c
2d
3
CNC (10)
TAPC (5)
CNC (0.5)
-
HFP (2)
2
2
4
4
4
4
4
4
4
4
4
4
1
4
4
>99
>99
93
43
22
trace
trace
n.d.
HFP (2)
40
26
TFA (2)
89
2
4
TFA (2)
20
18
n.d.
1
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
5
TAPC (0.5)
CNC (0.5)
CNC (0.5)
CNC (0.5)
CNC (0.5)
CNC (0.5)
TAPC (0.5)
CNC (0.5)
CNC (0.5)
CNC (0.25)
CNC (0.25)
TFA (2)
86
70
84
6
TFA (1)
68
1
7
TFA (1.2)/toluene (0.8)
TFA (30)/toluene (20)
TFA (1.0)/toluene (1.0)
TFA (0.8)/toluene (1.2)
TFA (1.2)toluene (0.8)
TFA (1.2)/toluene (0.8)
TFA (1.2)/toluene (0.8)
TFA (1.2)/toluene (0.8)
TFA (1.2)/toluene (0.8)
>99
>99
81
99(95)
93(89)
80
trace
trace
trace
trace
trace
trace
trace
trace
1
8e
9
10
11
12f
13g
14
15g
72
68
60
59
37
30
98
96
49
48
>99
97
a Cyclohexanone oxime (1a) (2 mmol) was allowed to react in the presence of CNC or TAPC at 70 °C for 1-4 h. b Based on GC. Numbers in parenthesis show isolated
yield. c Data from reference 6. d Data from reference 7. e 1a (50 mmol) was used as substrate. f Reaction was performed at 50 °C. g Reaction was performed at 100 °C.
CNC and TAPC. For the purpose of the reduction of TFA, when
the amount of TFA was reduced to one-half, the yield of 2a
was found to decrease to 68%. Thus, the reaction was examined
in a mixed solvent consisting of TFA and several other solvents.
From the scrutiny of various mixed solvents, the reaction in a
3:2 mixture of TFA and toluene was found to progress the
present rearrangement smoothly, giving 2a in almost quantita-
tive yield (entry 7). We performed the reaction on 50 mmol
scale of 1a and obtained 2a in 89% isolated yield (entry 8).
The most important feature of the reaction in a mixed solvent
Figure 1. Isolation of 2a from 2a-TFA salt by column chro-
matography on silica gel ((a) SiO2 20 g, 2a-TFA 1.1 g, eluent:
of TFA and toluene is that condensate 3a which is formed in
the reaction in HFP was negligibly small. Thus, several 3:2
mixed solvents consisting of TFA and one other solvent were
examined, and the yield of 2a was found to decrease in the
following order: a 3:2 mixture of TFA and toluene (>99%),
benzene (94%), MeCN (85%), acetone (82%), (n-Bu)2O (66%),
n-hexane (45%), AcOH (41%), and DMF (24%). However,
when TAPC was employed as a catalyst, no positive effect by
a mixed solvent was observed (entry 11). The reaction tem-
perature considerably affected the rearrangement of 1a. The
reaction at 50 °C resulted in the decrease of the yield of 2a
(30%), whereas 2a was obtained in high yield (96%) at 100
°C for 1 h (entries 12 and 13). When the amount of CNC was
decreased from 0.5 mol % to 0.25 mol %, the yield of 2a was
considerably decreased, but the reaction temperature was raised
to 100 °C to lead to 2a in high yield (97%) and 3a (1%) (entries
14 and 15).
AcOEt:MeOH (10:1). (b) SiO2 50 g, 2a-TFA salt 1.1 g, eluent:
H2O).
of 1a to 2a. However, it is difficult to carry out the rearrange-
ment in HFP in industrial scale, since the HFP is too expensive
to use as a solvent in large-scale synthesis. Thus, we need to
use other solvents which promote efficiently the rearrangement
of 1a. As a fluorous solvent such as HFP serves as a good
solvent for this purpose, we tried the reaction of 1a in several
fluorinated solvents. Among the fluorinated solvents examined,
we found that trifluoroacetic acid (TFA),8 which is far cheaper
than HFP, promotes the Beckmann rearrangement of 1a to 2a
by CNC. The rearrangement of 1a to 2a in TFA by CNC under
various conditions is summarized in Table 1.
Surprisingly, 2a was obtained in high yield (89%) from 1a
even with the use of 0.5 mol % of CNC in TFA (entry 3).
However, the reaction without CNC in TFA gave 2a in low
yield (18%) (entry 4). This indicates that the rearrangement is
not induced by the use only of TFA as a solvent. In the reaction
using TAPC catalyst in TFA, 1a rearranged to 2a in good yield
(84%) (entry 5). From these results, TFA was found to be a
good solvent to accelerate the rearrangement of 1a to 2a by
Cyclododecanone oxime (1b) was also rearranged to lau-
rolactam (2b), which is an important monomer of Nylon-12,
in good yield in the presence of CNC (0.5 mol %) in a 3:2
mixture of TFA and toluene at 70 °C for 4 h (eq 2).
(8) Price of TFA is approximately one-sixth that of HFP.
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of 2a-TFA salt using the same column by this method. As
shown in Figure 2b, 2a was obtained in pure form, although
the elution curve of TFA slightly broadened. Thus, the present
method can be applicable to the large-scale synthesis and
isolation of 2a.
On the other hand, laurolactam 2b was found to be easily
isolated from 2b-TFA. When the 2b-TFA salt was dissolved
in a 33% aqueous acetone at 80 °C, and the solution was
allowed to stand at room temperature, laurolactam 2b was
gradually crystallized and isolated by filtration in 95% yield
(>99% purity) (eq 3). However, laurolactam sulfate, prepared
independently from 1b and sulfuric acid, was dissolved in the
aqueous acetone to result in a complex mixture without
liberation of 2b, owing to occurrence of the reaction of 2b with
the aqueous acetone (eq 4).
Figure 2. Isolation of 2a from 2a-TFA salt by column chro-
matography on silica gel in preparative scale ((a) SiO2 200 g,
2a-TFA 20 g, eluent: AcOEt:MeOH (10:1)/MeOH), effluent rate
10 mL/min). (b) Isolation of 2a by using recycled silica column
under the conditions of Figure 2a.
Table 2. Isolation of 2a from 2a-TFA salt by using recycled
silica column (SiO2 20 g, 2a-TFA 1.1 g, eluent:
AcOEt:MeOH (10:1))
no. of uses
yield of 2a (%)a
purity (%)b
1
2
3
4
5
94
96
96
93
92
>99
>99
>99
>99
>99
a Isolated yields. b Determined by GC and HPLC.
It is well-known that 2a reacts with TFA to form a weak
salt (2a-TFA) which behaves as an ionic liquid.9 The 2a-TFA
salt was found to be easily separated into 2a and TFA on silica
gel, eluting with a mixed solvent or water. Figure 1 shows the
result of the elution of the 2a-TFA salt on silica gel with AcOEt:
MeOH (10:1) (Figure 1a) or water (Figure 1b).
The first 50 mL of a mixed solvent of AcOEt and MeOH
(10:1) contained only TFA, and then 2a was eluted in a pure
form in 94% yield (Figure 1a). It was found that water could
be used as an eluent instead of the mixed solvent, although a
slight excess of the eluent is needed to separate 2a (Figure 1b).
The silica gel column can be repeatedly used after separation
of 2a-TFA salt. After five uses, the result was almost the same
as that using the fresh column (Table 2).
Conclusion
We reported the efficient method of Beckmann rearrange-
ment of ketoximes to lactams. The reaction was achieved under
the influence of CNC and TAPC catalyst by using a mixed
solvent of trifluoroacetic acid and toluene.
Experimental Section
All starting materials were commercially available and used
without any purification. Cyclododecanone oxime (1b) was
prepared from cyclododecanone and hydroxylamine hydro-
chloride. GLC analysis was performed with a flame ionization
detector using a 0.22 mm × 25 m capillary column (BP-5). 1H
and 13C NMR spectra were measured at 270 and 67.5 MHz,
respectively, in CDCl3 with Me4Si as the internal standard. Mass
spectra (EI, GC/MS) were measured with an Agilent 5973
Network Mass Selective Detector. HPLC was conducted using
a Shimadzu Prominence with SPD-M20A diode array detector
(column, ODS-H80). The yields of products were estimated
from the peak areas based on the internal standard technique.
Compounds 2a and 2b are known compounds and have been
reported previously.7
Thus, 2a was obtained from the 2a-TFA salt without
treatment with a base.
In order to examine this method in preparative scale, we
tried the isolation of 2a from 2a-TFA salt in 20-g scale (Figure
2a,b). To reduce the eluent volume, methanol was used as an
eluent after elution of TFA with 300 mL of a 20:1 mixed solvent
of ethyl acetate and methanol. As shown in Figure 2a, pure 2a
could be obtained by this method. After completion of the
isolation of 2a, we repeated the isolation of an additional 20 g
(9) Du, Z.; Li, Z.; Guo, S.; Zhang, J.; Zhu, L.; Deng, Y. J. Phys. Chem. B
2005, 109, 19542.
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Typical Procedure for the Reaction of 1a (Table 1, entry
7). A mixture of CNC (0.01 mmol, 1.8 mg) in TFA (1.2 mL)
and toluene (0.8 mL) was placed in a 20 mL round-bottomed
flask, and 1a (2 mmol, 226 mg) was added to the flask. Then
the mixture was stirred at 70 °C for 4 h. After removal of the
solvent under reduced pressure, 2a (214 mg) was isolated by
column chromatography on silica gel (ethyl acetate:methanol
) 20:1) in 95% yield.
Isolation of 2a from 2a-TFA Salt by Column Chroma-
tography on Silica Gel (Figure 1 a). To a silica gel (20 g)
column filled with eluents (AcOEt:MeOH ) 10:1) was charged
2a-TFA salt (1.10 g, 4.85 mmol). Concentration of 2a and TFA
of the effluent was monitored by GC and HPLC in every 10-
mL effluent volume. The fraction containing 2a was collected.
After removal of the solvent under reduced pressure, 2a (515
mg) was isolated as a white solid in 94% yield as a pure form
(purity >99%).
was heated to 80 °C. The resulting clear solution was allowed
to stand at room temperature, and 2b was gradually crystallized.
The solid was collected by filtration and washed with H2O (10
mL). After removal of the solvent under reduced pressure, 2b
(936 mg) was isolated as a white solid in 95% yield (>99%
purity).
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transforma-
tions of Carbon Resources” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and “High-
Tech Research Center” Project for Private Universities: match-
ing fund subsidy from the Ministry of Education, Culture,
Sports, Science and Technology, 2005-2009.
Isolation of 2b from 2b-TFA Salt by Recrystallization
from Aqueous Acetone (eq 3). 2b-TFA (1.56 g, 5.0 mmol)
was dissolved in 33% aqueous acetone (30 mL), and the mixture
Received for review October 8, 2008.
OP800258S
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