A mild and highly efficient catalyst for Beckmann rearrangement, BF 3·OEt2

Article abstract of DOI:10.1002/cjoc.201190193

BF₃·OEt₂ (Boron trifluoride etherate), an inexpensive and commercially easily available Lewis acid stoichiometrically employed for Beckamann rearrangement in general, was now found to efficiently catalyze Beckmann rearrangement of ketoximes into their corresponding amides (up to 99% yield) in anhydrous acetonitrile under reflux temperature.

Full text of DOI:10.1002/cjoc.201190193

FULL PAPER
A Mild and Highly Efficient Catalyst for Beckmann
Rearrangement, BF •OEt
3
2
a
a
a
An, Na (安娜)
Pi, Hongjun (皮红军)
Liu, Lifeng (刘力锋)
,a,b
,a
Du, Wenting* (杜文婷)
Deng, Weiping* (邓卫平)
a
School of Pharmacy, East China University of Science and Technology,
1
30 Meilong Road, Shanghai 200237, China
b
Department of Pharmacy, Zhejiang Medical College, Hangzhou, Zhejiang 310053, China
BF •OEt (Boron trifluoride etherate), an inexpensive and commercially easily available Lewis acid
3 2
stoichiometrically employed for Beckamann rearrangement in general, was now found to efficiently catalyze
Beckmann rearrangement of ketoximes into their corresponding amides (up to 99% yield) in anhydrous acetonitrile
under reflux temperature.
Keywords Beckmann rearrangement, BF •OEt , catalyst, amide
3
2
Introduction
presumably due to its complexation with the immediate
product of the rearrangement. Recently, we found that
Beckmann rearrangement, as one of the fundamental
tools in organic chemistry, has carried out the transfor-
mation of aldoximes or ketoximes into amides/
24
the catalytic amount of catalysts, such as TsCl,
25
26
BOPCl and TAPC, were highly active for Beckmann
rearrangement. Herein we would like to report the first
1
lactams. The Rearrangement requires harsh conditions
3 2
example of the BF •OEt -catalyzed Beckmann rear-
rangement of ketoximes to produce corresponding am-
ides using only 10 mol% of the catalyst.
such as a large amount of oleum and high reaction tem-
perature. Besides, it also suffers from a considerable
large amount of ammonium sulfate byproduct. Hence,
2
extensive efforts have been devoted to the development
of an effective and mild catalytic system. Many catalytic
Results and discussion
3
systems, such as liquid phase system, vapor phase sys-
Initially, 20 mol% of BF
Beckmann rearrangement of acetophenone oxime in
anhydrous CH CN at refluxing temperature. To our de-
3 2
•OEt was tested for
4
5
tem, supercritical water system, and ionic liquids sys-
6
7
tem even microwave technique have thus been devel-
oped. And liquid phase catalytic Beckmann rearrange-
ment under mild conditions has become a topic of cur-
rent interest. As a consequence, many Lewis acids in-
stead of Brönsted acids have been reported to carry out
Beckmann rearrangement with good to excellent cata-
3
light, it did transform acetophenone oxime into N-acetyl
aniline smoothly in 84% yield. Further screening of the
catalyst loading turned out that 10 mol% of BF •OEt
3 2
was optimal considering the balance between the yield
of product and the catalyst loading (Table 1). And then
the solvent screening suggested that polar solvent anhy-
drous acetonitrile gave the best result (Entry 5, Table 2).
Next, the generality and scope of the boron trifluoride
etherate (10 mol%) catalyzed Beckmann rearrangement
in anhydrous acetonitrile were also investigated using the
optimal reaction condition. As summarized in Table 2,
Beckmann rearrangement of various representative ke-
toximes proceeded smoothly to give the corresponding
amides in good to excellent yields under the same condi-
tion. It is clear that excellent yields were obtained for the
rearrangement of diarylketone oximes into corresponding
amides. For the substituted acetophenone oximes, the
rearrangement was generally effective, however it was
found that only the oxime with electron-withdrawing
8
9
lytic activities, such as Me
3
OBF
4
/CF
3
SO
3
CH
,
3
, P
2 5
O ,
3
10
11
12
13
14
BPO
Ga(OTf)
4
,
AlCl
3
,
[RhCl(cod)]
2
,
Yb(OTf)
3
Y(OTf) ,
and SbCl /
5
1
5
16
17
18
3
,
Nd(OTf)
3
,
RuCl
3
,
HgCl
2
1
9
6
AgSbF . However, due to drawbacks such as toxicity,
high cost and relatively low catalytic activities (10— 50
mol% catalyst loading), these catalysts have not yet
been industrially utilized.
3 2
Interestingly, BF •OEt , as a cheap and commercially
available reagent, has been often employed as a highly
active promotor for Beckmann rearrangement in organic
2
0-23
synthesis,
but in stoichiometric amount. In the case
of Beckmann rearrangement of ketoxime ethyl carbon-
2
3
ates described by Chandrasekhar, an attempt to em-
ploy the catalytic amount of BF •OEt turned out failed
3
2
*
E-mail: duwt@ecust.edu.cn; weiping_deng@ecust.edu.cn; Tel./Fax: 0086-0571-87692839
Received September 5, 2010; revised December 28, 2010; accepted January 21, 2011.
Project supported by the National Natural Science Foundation of China (No. 20602011), New Century Excellent Talents in University, the Ministry
of Education, China (No. NCET-07-0283), and ‘111’ Project (No. B07023).
Chin. J. Chem. 2011, 29, 947— 950
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
947

An et al.
FULL PAPER
Table 1 Effect of amount of catalyst and solvents effect on
Beckmann rearrangement of acetophenone oxime
as new catalytic system for Beckmann rearrangement of
aromatic and alkyl ketoximes with good to excellent
yields under reflux condition. This highly active cata-
lytic system would provide an alternative way for
Beckmann rearrangement involved organic synthesis.
Further studies are in progress in our laboratory to focus
on clarifying the catalytic mechanism and further ex-
ploring the synthetic utility of this BF
Beckmann rearrangement system.
3 2
•OEt -catalyzed
Entry
Catalyst (mol%)
Solvent
Yield/%
56
1
2
3
4
5
6
7
8
BF
BF
3
•OEt
2
(5)
CH
CH
3
3
CN
CN
3
•OEt
2
(10)
76
Experimental
BF •OEt (20)
CH CN
84
3
2
3
All solvents were distilled under standard procedures
prior to use under nitrogen atmosphere (For example:
BF •OEt (10)
THF
Trace
23
3
2
BF •OEt (10)
Toluene
Dioxane
Dioxane
3
2
CH
3 2
CN distilled from CaH ; THF, dioxane, toluene dis-
1
BF •OEt (10)
Trace
Trace
76
tilled from sodium). H (400 MHz) chemical shifts are
reported in CDCl (δ 7.27) for H NMR, as standards
3
3
2
1
BF
3
•OEt
2
(10)
and coupling constants (J) are reported in hertz (Hz).
The following abbreviations are used to designate signal
multiplicity: s＝singlet, d＝doublet, t＝triplet, q＝
quartet, m＝multiplet, br＝broad.
BF •OEt (10)
CH CN
3
2
3
para-chloro group gave low reaction activity (60% yield,
Entry 12). Beckmann rearrangement of cyclodode-
canone oxime using the same condition gave the
laurolactam in good yield (71% yield, Entry 13). Un-
fortunately, the rearrangement of cyclohexanone oxime
gave only trace amount of ε-caprolactam (Entry 14).
3 2
General procedure of BF •OEt -promoted catalytic
Beckmann rearrangement of ketoximes
To a solution of ketoxime (2.0 mmol) in anhydrous
CH
3
CN (2 mL), 1 mL of BF
3 2 3
•OEt in CH CN (boron
trifluoride etherate in CH
3
CN solvent, 0.2 mol/L) was
3 2
Table 2 The generality and scope of BF •Et O-catalyzed
added. The mixture was refluxed for 3 h under a nitro-
gen atmosphere. After the reaction had been completed,
the organic layer was diluted with 10 mL of ethyl ace-
tate, washed with water and brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure.
The resulting crude product was purified by silica gel
column chromatography (using different ratios of ethyl
acetate and n-hexane as eluent according to different
products)
Beckmann rearrangement of ketoximes into corresponding am-
ides
1
2
Entry
R
R
Yield/%
76
1 (2a)
2 (2b)
3 (2c)
4 (2d)
5 (2e)
6 (2f)
7 (2g)
8 (2h)
9 (2i)
Ph
Ph
Me
Ph
All known compounds gave NMR spectra that
99
1
8,25
a
matched data reported in the cited references
p-(Me)C H
6
4
4
4
Ph
92
1
8
b
N-Phenylacetamide (2a) m.p. 114—115 ℃ (Lit
p-(Me)C
6
H
p-(Cl)C
6
H
4
98
1
c
114—116 ℃); H NMR (CDCl
3
, 400 MHz) δ: 8.59 (brs,
p-(Me)C H
6
p-(MeO)C H
6
4
4
98
1
7
H), 7.53 (d, J＝8.0 Hz, 2H), 7.28 (t, J＝7.7 Hz, 2H),
d
p-(Cl)C H
6
4
p-(MeO)C H
6
97
.09 (t, J＝7.4 Hz, 1H), 2.13 (s, 3H).
1
8
p-(Me)C
6
H
4
Me
95
91
N-Phenylbenzamide (2b) m.p. 164—165 ℃ (Lit
1
p-(MeO)C H
6
4
4
Me
Me
Me
Et
164—165 ℃); H NMR (CDCl , 400 MHz): δ: 8.03
3
(
2
7
brs, 1H), 7.87 (d, J＝7.3 Hz, 2H), 7.66 (d, J＝7.9 Hz,
o-(MeO)C H
6
99
H), 7.54 (t, J＝7.3 Hz, 1H), 7.46 (t, J＝7.5 Hz, 2H),
1
0 (2j)
1 (2k)
2 (2l)
3 (2m)
4 (2n)
m-(MeO)C
6
H
4
76
.37 (t, J＝7.9 Hz, 2H), 7.16 (t, J＝7.4 Hz, 1H).
1
pH
81
N-p-Tolylbenzamide and 4-methyl-N-phenylben-
1
p-(Cl)C H
Me
60
1
6
4
zamide (2c) H NMR (CDCl
3
, 400 MHz) δ: 7.92—
1
(CH
2
)
11
71
7.73 (m, 6H), 7.65 (d, J＝7.9 Hz, 2H), 7.55—7.49 (m,
3H), 7.38 (t, J＝7.8 Hz, 2H), 7.32—7.26 (m, 3H), 7.19—
7.14 (m, 2H), 2.44 (s, 3H), 2.35 (s, 3H).
1
(CH2)5
Trace
a
b
Overall yield of isomeric mixtures; Overall yield of isomeric
c
d
4-Chloro-N-p-tolylbenzamide and N-(4-chloro-
mixtures; Overall yield of isomeric mixtures; Overall yield of
isomeric mixtures.
1
phenyl)-4-methylbenzamide (2d) H NMR (DMSO-d
6
,
400 MHz) δ: 10.27 (brs, 1H), 10.21 (brs, 1H), 7.98 (d,
J＝8.4 Hz, 2H), 7.87 (d, J＝8.0 Hz, 2H), 7.82 (d, J＝8.7
Hz, 2H), 7.64 (d, J＝8.2 Hz, 2H), 7.59 (d, J＝8.4 Hz,
2H), 7.39 (d, J＝8.7 Hz, 2H), 7.33 (d, J＝7.9 Hz, 2H),
Chin. J. Chem. 2011, 29, 947— 950
Conclusions
3 2 3
In summary, we have developed BF •OEt /CH CN
9
48
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

A Mild and Highly Efficient Catalyst for Beckmann Rearrangement, BF
3
•OEt
2
7
.15 (d, J＝8.2 Hz, 2H), 2.38 (s, 3H), 2.27 (s, 3H).
2
(a) Heitmann, G. P.; Dahlhoff, G.; Niederer, J. P. M.;
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4
-Methoxy-N-p-tolylbenzamide and N-(4-meth-
1
3
oxyphenyl)-4-methylbenzamide (2e) H NMR (CDCl ,
4
8
2
7
00 MHz) δ: 8.17 (brs, 1H), 8.16 (brs, 1H), 7.80 (d, J＝
.4 Hz, 2H), 7.74 (d, J＝7.7 Hz, 2H), 7.53 (d, J＝6.3 Hz,
H), 7.51 (d, J＝5.1 Hz, 2H), 7.19 (d, J＝7.7 Hz, 2H),
.11 (d, J＝7.9 Hz, 2H), 6.86 (d, J＝9.6 Hz, 2H), 6.84
(
d, J＝9.2 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 2.38 (s,
3
H), 2.32 (s, 3H).
N-(4-Chlorophenyl)-4-methoxybenzamide and 4-
1
chloro-N-(4-methoxyphenyl)benzamide (2f) H NMR
(
6
DMSO-d , 400 MHz) δ: 10.22 (brs, 1H), 10.20 (brs,
1
7
H), 7.98 (d, J＝6.9 Hz, 2H), 7.96 (d, J＝6.7 Hz, 2H),
3
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.82 (d, J＝8.4 Hz, 2H), 7.68 (d, J＝8.5 Hz, 2H), 7.58
(
8
(
d, J＝8.1 Hz, 2H), 7.38 (d, J＝8.4 Hz, 2H), 7.05 (d, J＝
.4 Hz, 2H), 6.92 (d, J＝8.6 Hz, 2H), 3.83 (s, 3H), 3.74
s, 3H).
1
8
N-p-Tolylacetamide (2g) m.p. 149—150 ℃ (Lit
1
1
1
2
49—151 ℃); H NMR (CDCl
3
, 400 MHz) δ: 8.28 (brs,
H), 7.40 (d, J＝8.2 Hz, 2H), 7.09 (d, J＝8.1 Hz, 2H),
.30 (s, 3H), 2.12 (s, 3H).
N-(4-Methoxyphenyl)acetamide (2h) m.p. 128—
1
8
1
1
29 ℃ (Lit 129—130 ℃); H NMR (CDCl
3
, 400
MHz) δ: 8.09 (brs, 1H), 7.38 (d, J＝8.8 Hz, 2H), 6.81 (d,
J＝8.5 Hz, 2H), 3.76 (s, 3H), 2.10 (s, 3H).
N-(2-Methoxyphenyl)acetamide (2i) m.p. 85—86
4
5
6
1
8
1
℃
(Lit 85—86 ℃); H NMR (CDCl
3
, 400 MHz) δ:
8
.35 (d, J＝7.8 Hz, 1H), 7.79 (brs, 1H), 7.02 (t, J＝7.4
Hz, 1H), 6.94 (t, J＝7.4 Hz, 1H), 6.86 (d, J＝8.0 Hz,
1
H), 3.86 (s, 3H), 2.18 (s, 3H).
N-(3-Methoxyphenyl)acetamide (2j) m.p. 81—82
1
8
1
℃
(Lit 87—88 ℃); H NMR (CDCl
3
, 400 MHz) δ:
8
7
3
.58 (brs, 1H), 7.28 (s, 1H), 7.16 (t, J＝8.1 Hz, 1H),
.04 (d, J＝7.9 Hz, 1H), 6.64 (d, J＝8.0 Hz, 1H), 3.73 (s,
H), 2.13 (s, 3H).
N-Phenylpropionamide (2k) m.p. 106—107 ℃
1
8
1
(
8
Lit 103—104 ℃); H NMR (CDCl
3
, 400 MHz) δ:
.30 (brs, 1H), 7.55 (d, J＝7.9 Hz, 2H), 7.27 (t, J＝7.7
Hz, 2H), 7.08 (t, J＝7.3 Hz, 1H), 2.37 (q, J＝7.5 Hz,
2
1
H), 1.21 (t, J＝7.6 Hz, 3H).
N-(4-Chlorophenyl)acetamide (2l) m.p. 180 —
2
7
1
81 ℃ (Lit 180 ℃); H NMR (DMSO-d
6
, 400 MHz)
δ: 10.05 (brs, 1H), 7.60 (d, J＝8.5 Hz, 2H), 7.32 (d, J＝
8
.5 Hz, 2H), 2.04 (s, 3H).
Azacyclotridecan-2-one (2m) m.p. 150—151 ℃
2
8
1
(
Lit 143—145 ℃); H NMR (CDCl
3
, 400 MHz) δ:
6
2
1
.07 (brs, 1H), 3.26 (dd, J＝5.7, 10.5 Hz, 2H), 2.19—
.16 (m, 2H), 1.68—1.62 (m, 2H), 1.55—1.45 (m, 2H),
.34—1.27 (m, 14H).
7
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Chin. J. Chem. 2011, 29, 947— 950