Efficient Beckmann rearrangement and dehydration of oximes via phosphonate intermediates

Article abstract of DOI:10.1016/j.tetlet.2007.01.120

Under mild conditions, conversion of a variety of ketoximes and aldoximes to their corresponding amides and nitriles proceeded in the presence of diethyl chlorophosphate with excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.01.120

Tetrahedron Letters 48 (2007) 2639–2643
Efficient Beckmann rearrangement and dehydration of oximes
via phosphonate intermediates
*
A. R. Sardarian, Z. Shahsavari-Fard, H. R. Shahsavari and Z. Ebrahimi
Chemistry Department, College of Science, Shiraz University, Shiraz 71454, Iran
Received 9 December 2006; revised 14 January 2007; accepted 23 January 2007
Available online 27 January 2007
Abstract—Under mild conditions, conversion of a variety of ketoximes and aldoximes to their corresponding amides and nitriles
proceeded in the presence of diethyl chlorophosphate with excellent yields.
Ó 2007 Published by Elsevier Ltd.
Amides and nitriles are of particular interest in prepara-
tive organic chemistry. Great efforts have been made to
prepare amides and nitriles from their corresponding
ketoximes and aldoximes by Beckmann rearrangement
and dehydration, respectively.
disadvantages, for example: (a) the use of anhydrous
reaction conditions, (b) toxic and hazardous chemicals,
(c) tedious and cumbersome work-up procedures, (d)
the need to prepare the reagent prior to the reaction,
1
1
5–19
and (e) long reaction times.
Therefore, the search
for a more convenient method is ongoing.
The Beckmann rearrangement of ketoximes is a well-
known transformation of ketoximes to N-substituted
amides and is a topic of current interest of organic
Herein we report a simple and efficient process for the
Beckmann rearrangement of ketoximes to amides and
the dehydration of aldoximes to nitriles using diethyl
chlorophosphate in toluene where the molar ratio of
diethyl chlorophosphate and oxime is 1:1. The method
is simple, isolation of the product from reaction mixture
is easy and the yields are high.
2
,3
chemists. In general, it requires a strong acid, a rela-
tively high reaction temperature and harsh reaction con-
3
,4
ditions, and generates a large amount of waste. Thus,
milder conditions have been sought and until now mild
conditions were essentially related to forming activated
oxime derivatives which were found to rearrange under
the mild conditions, for example using chlorosulfonic
The Beckmann rearrangement of a series of aryl and
alkyl ketoximes to the corresponding amides has been
studied (Scheme 1).
5
6
7
8
acid, sulfamic acid, cyanuric chloride/DMF, chloral,
9
anhydrous oxalic acid, O-alkyl-N,N-dimethylformami-
dium salt, and ethyl chloroformate/boron trifluoride
etherate. Recently, the Beckmann rearrangement was
reported in ionic liquids at room temperature and
supercritical water. The drawbacks in such methods
are (a) the use of toxic solvents, (b) expensive reagents,
1
0
1
1
As shown in Table 1, good to excellent yields were
obtained for the Beckmann rearrangement of cyclo-
pentanone oxime, 1-phenyl-propan-2-one oxime and
1,3-diphenyl-propan-2-one oxime (entries 4–6) without
any by-product or parent ketone formation. For entry
4, the Beckmann rearrangement occurred at room tem-
perature after one hour with 100% conversion. The best
results were obtained when the aryl ketoximes (entries 1,
1
2
1
3
(
(
c) production of considerable amounts of by-products,
d) long reaction times, and (e) low yields. Therefore, the
development of a simple, clean, highly efficient and
selective Beckmann rearrangement is still in demand.
2, 3, and 8) were applied in the Beckmann rearrange-
Dehydration of aldoximes to nitriles is also an impor-
tant transformation in organic synthesis. A number of
methods have been introduced, which have their own
ment. In the case of 4-chlorobenzophenone oxime (entry
7), q-chloro-benzanilide was obtained in 58% yield in 2 h.
1
4
All the product amides were separated from the reaction
mixture by neutralization with an aqueous solution of
sodium hydroxide (5%) and then extraction with ether.
*
Corresponding author. Tel.: +98 711 2284822; fax: +98 711
286008; e-mail: sardarian@susc.ac.ir
2
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.01.120

2640
A. R. Sardarian et al. / Tetrahedron Letters 48 (2007) 2639–2643
O
OH
O
P(OEt)2
O
N
N
(
EtO) POCl
H O
2
2
R2
R1
C
N
Toluene
Reflux
R2
NHR1
R1
R2
R1
R2
Scheme 1.
Table 1. Rearrangement of ketoximes to amides in the presence of diethyl chlorophosphate
a
b
Entry
Ketoxime
Amide
Mp (Lit.)
Yield (%)
Reaction time (min)
30
NOH
H
N
2
0
1
113 (114–15)
91
O
NOH
H
N
2
0
2
3
151 (152)
92
91
25
20
O
NOH
H
N
20
162 (162–5)
O
O
NOH
2
0
4
5
6
40 (39.5)
87
82
90
60
5
NH
O
2
0
59 (61)
N
NOH
H
O
2
0
68 (68)
5
N
NOH
H
NOH
O
7
166–7
58
94
120
30
N
H
Cl
Cl
NOH
Cl
O
8
NHCH3
134
Cl
a
21
All the products are known.
Isolated yield.
b
Evaporation of ether and column chromatography pro-
vided the pure amides. The amides could also be purified
by short column chromatography without neutraliza-
tion of the produced acid. According to Table 1, in most
cases, the selectivity was high.
of aldoximes to nitriles in excellent yields, Table 2
(Scheme 2).
All the nitriles were purified using the same procedure as
used for the purification of the amides. According to
Table 2, excellent yields were obtained from benzaldox-
imes with different substituents (hydroxyl, methyl,
chloro, nitro, and dimethylamino groups in ortho-,
Diethyl chlorophosphate in toluene also proved to be an
efficient, versatile and rapid system for the dehydration

A. R. Sardarian et al. / Tetrahedron Letters 48 (2007) 2639–2643
Table 2. Dehydration of aldoximes to nitriles in the presence of diethyl chlorophosphate
2641
a
b
Entry
Aldoxime
Nitrile
Mp (Lit.)
Yield (%)
Reaction time (min)
2
0
1
CH NOH
CN
70 (70–1)
90
94
90
60
30
30
CH NOH
CN
CN
2
0
2
3
210 (210–12)
H3C
HO
H3C
HO
CH
NOH
2
0
79 (79–80)
CH NOH
CN
2
0
4
5
6
7
94 (93–6)
93
92
93
89
60
35
20
40
OH
OH
2
0
O2N
CH NOH
O2N
CN
149 (147)
CH NOH
CN
2
0
115 (114–17)
O2N
Cl
O N
2
2
0
0
CH NOH
Cl
CN
92 (90–3)
42 (43–5)
CH
NOH
CN
2
8
9
27
88
180
30
Cl
Cl
CH
NOH
CN
2
0
65 (66)
HC NOH
CN
N
2
0
10
77–8 (76–9)
94
240
N
c
1
1
1
2
CH
NOH
CN
186
98
94
5
N
N
H
H
HC NOH
CN
2
0
170–1 (170–2)
15
HC NOH
CN
2
0
13
109 (110–112)
97
5
2
2
1
1
4
5
Me2N
CH
NOH
Me N
CN
74–5 (69–71)
98
95
5
2
2
2
181 (183)
120
CH
NOH
CN
a
b
c
23
All the products are known.
Isolated yield.
Boiling point.

2642
A. R. Sardarian et al. / Tetrahedron Letters 48 (2007) 2639–2643
O
References and notes
O
O
P(OEt)2
1
. (a) Tennant, G. In Comprehensive Organic Chemistry;
Barton, D., Ollis, D. W., Sutherland, I. O., Eds.;
Pergamon Press: Oxford, 1979; Vol. 2, p 528; (b)
The Chemistry of Triple Bonded Functional Groups;
Patai, S., Rappoport, S., Eds.; Wiley: New York, 1983,
Part 1; (c) Moruoka, K.; Yamamoto, H. In Comprehen-
sive Organic Chemistry; Trost, B. M., Fleming, I.,
Winterfeld, E., Eds.; Pergamon Press: Oxford, 1991; Vol.
NOH
N
(
EtO) PCl
2
R
C N
toluene
reflux
R
H
R
H
Scheme 2.
6
, p 381.
para-, and meta-positions, entries 1–7 and 14) in less
than one hour, except for 2-chlorobenzaldoxime (entry
2
. Moruoka, K.; Yamamoto, H. In Comprehensive Organic
Chemistry; Trost, B. M., Fleming, I., Winterfeld, E., Eds.;
Pergamon Press: Oxford, 1991; Vol. 6, p 763.
8
2
) which even after 3 h refluxing in toluene gave only a
7% yield of the desired product.
3. Smith, M. B.; March, J. Advanced Organic Chemistry,
5
1
th ed.; John Wiley & Sons: New York, 2001; p
415.
Pyridine-4-carbaldoxime did not undergo dehydration
under the same conditions. When triethylamine was
added to the reaction mixture to neutralize the pro-
duced hydrochloric acid from the reaction of the
oxime with diethyl chlorophosphate, dehydration
occurred but the yield of the reaction was only 37%
after 4 h. Further addition of triethylamine did not
increase the yield but when the initial reaction mixture,
including the same equivalent of the oxime, diethyl
chlorophosphate, and triethylamine, was heated at
4
5
. Gawly, R. E. Org. React. 1988, 35, 1.
. (a) Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett.
2
005, 46, 671; (b) Kira, M. A.; Shaker, Y. M. Egypt.
J. Chem. 1973, 6, 551.
. Wang, B.; Gu, Y.; Luo, C.; Yang, T.; Yang, L.; Suo, J.
Tetrahedron Lett. 2004, 45, 3369.
7. De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem.
2002, 67, 6272.
8. Chandrasekhar, S.; Gopalaiah, K. Tetrahedron Lett. 2003,
6
4
4, 755.
. Chandrasekhar, S.; Gopalaiah, K. Tetrahedron Lett. 2002,
3, 2455.
9
1
60–165 °C, all of the oxime was consumed and the
4
corresponding nitrile was obtained in 94% yield. Pyr-
role-2-carbaldoxime (entry 11), which is a weaker base
than pyridine-4-carbaldoxime, was dehydrated quanti-
tatively to the corresponding nitrile after five minutes
in boiling toluene without using triethylamine. Poly-
nuclear aromatic aldoximes (entries 9, 12, and 13) were
converted easily and rapidly to the desired nitriles in
excellent yields.
1
1
0. Izumi, Y. Chem. Lett. 1990, 2171.
1. Antikumar, S.; Chandrasekhar, S. Tetrahedron Lett. 2000,
4
1, 5427.
1
2. (a) Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 403; (b)
Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron Lett. 2001,
42, 8441; (c) Gui, J.; Deng, Y.; Hu, Z.; Sun, Z. Tetra-
hedron Lett. 2004, 45, 2681.
13. (a) Ikushima, Y.; Hatakeda, K.; Sato, O.; Yokoyama, T.;
Arai, M. J. Am. Chem. Soc. 2000, 122, 1908; (b) Sato, O.;
Ikushima, Y.; Yokoyama, T. J. Org. Chem. 1998, 63,
In conclusion, a simple and efficient technique for direct
conversion of ketoximes and aldoximes via Beckmann
rearrangement and dehydration to the corresponding
amides and nitriles, respectively, has been presented
which has advantages over the previously reported
methods.
9
100; (c) Boero, M.; Ikeshoji, T.; Liew, C. C.; Terakura,
K.; Parrinello, M. J. Am. Chem. Soc. 2004, 126, 6280; (d)
Ikushima, Y.; Sato, O.; Sato, M.; Hatakeda, K.; Arai, M.
Chem. Eng. Sci. 2003, 58, 935.
1
4. (a) Konwar, D.; Boruah, R. C.; Sandhu, J. S. Tetra-
hedron Lett. 1990, 31, 1063; (b) Kato, Y.; Ooi, R.; Asano,
Y. J. Mol. Cat. B: Enzym. 1999, 6, 249; (c) Lee, K.;
Han, S.-B.; Yoo, E.-M.; Chung, S.-R.; Oh, H.;
Hong, S. Synth. Commun. 2004, 34, 1775; (d) Venkat
Narsaiah, A.; Nagaiah, K. Adv. Synth. Cat. 2004,
General procedure: For each reaction, the oxime
(
5 mmol) and toluene (1 ml) were charged into a 50 ml
two necked round-bottom flask equipped with a mag-
netic stirrer and condenser. The reaction was heated to
reflux and diethyl chlorophosphate (5 mmol) was added
to the mixture. The reaction was heated for 20–120
minutes and then cooled to room temperature. The
crude mixture was neutralized with 10 ml of an aqueous
solution of sodium hydroxide (5%) and then extracted
with diethyl ether (10 ml). Drying the ethereal layer
over anhydrous sodium sulfate and then filtration and
evaporation of the solvent gave the crude product,
which was purified by short column chromatography
over silica gel using n-hexane and ethyl acetate (9:1–
3
46, 1271; (e) Heravi, M. M.; Khadijeh, B.;
Hekmat Shoar, R.; Oskooie, H. A. J. Chem. Res. 2005,
90.
5
1
5. (a) Sosnovsky, G.; Krogh, J. A. Synthesis 1978, 703; (b)
Sacdnya, A. Synthesis 1983, 748; (c) Molina, P.; Alajarian,
M.; Vilaploma, M. J. Synthesis 1982, 1016.
6. Ho, T. L.; Wong, C. M. Synth. Commun. 1975, 5,
423.
17. Dulcere, J. P. Tetrahedron Lett. 1981, 22, 1599.
18. (a) Mai, K.; Patia, G. Synthesis 1986, 1037; (b) Narayana
Rao, M.; Kumar, P.; Garyah, K. Org. Prep. Proced. Int.
1
1
989, 21, 230.
1
9. (a) Katritzky, A. R.; Zhang, G. F.; Fan, W. G. Org. Prep.
Proced. Int. 1993, 25, 315; (b) Olah, G. A.; Narang, S. C.;
Garcia-Luna, A. Synthesis 1980, 659.
5
:5) as eluent.
2
0. CRC Handbook of Chemistry and Physics, 87th ed.; Lide,
D. R., Ed.; CRC Press, 2006.
Acknowledgment
2
1. Registry numbers of the amide products: N-phenyl-
acetamide: 103-84-4, N-p-tolylacetamide: 103-89-9,
N-phenylbenzamide: 93-98-1, piperidin-2-one: 675-20-7,
We gratefully acknowledge the support of this work by
Shiraz University research council.

A. R. Sardarian et al. / Tetrahedron Letters 48 (2007) 2639–2643
2643
N-benzylacetamide: 588-46-5, N-benzyl-2-phenyl-acetam-
ide: 7500-45-0, 4-chloro-N-phenylbenzamide: 6833-15-4,
rile: 893-62-1, 2-hydroxybenzonitrile: 611-20-1, 4-nitro-
benzonitrile: 619-72-7, 3-nitrobenzonitrile: 619-24-9, 4-
chlorobenzonitrile: 623-03-0, 2-chlorobenzonitrile: 873-32-
5, 2-naphthonitrile: 613-46-7, anthracene-9-carbonitrile:
1210-12-4, phenanthrene-9-carbonitrile: 2510-55-6, 1H-
pyrrole-2-carbonitrile: 4513-94-4, 4-dimethylamino benzo-
nitrile: 1197-19-9, isonicotinonitrile:100-48-1, heptanenit-
rile: 629-08-3.
2
-chloro-N-methylbenzamide: 3400-31-5.
2
2. CRC Handbook of Tables for Organic Compound Identi-
fication, 3rd ed.; Rappaport, Z., Ed.; The Chemical
Rubber, 1967.
2
3. Registry numbers of the nitrile products: benzonitrile: 100-
4
7-0, 3-methylbenzonitrile: 620-22-4, 3-hydroxybenzonit-