Efficient microwave-assisted synthesis of oximes from acetohydroxamic acid and carbonyl compounds using BF3·OEt2 as the catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.07.015

An efficient synthesis of oximes by reaction of carbonyls with acetohydroxamic acid using BF₃·OEt₂ as a catalyst is described.

Full text of DOI:10.1016/j.tetlet.2011.07.015

Tetrahedron Letters 52 (2011) 4701–4704
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Efficient microwave-assisted synthesis of oximes from acetohydroxamic
acid and carbonyl compounds using BF3ÁOEt2 as the catalyst
⇑
Madabhushi Sridhar , Chinthala Narsaiah, Jillella Raveendra, Godala Kondal Reddy,
Mallu Kishore Kumar Reddy, Beeram China Ramanaiah
Fluoroorganics Division, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of oximes by reaction of carbonyls with acetohydroxamic acid using BF3ÁOEt2 as a
catalyst is described.
Received 23 May 2011
Revised 4 July 2011
Accepted 5 July 2011
Available online 14 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbonyls
Oximes
Acetohydroxamic acid
Acid catalysis
Oximes are of great interest as intermediates in organic synthe-
sis for the preparation of nitriles,1 nitro compounds,2 amines,3
amides,4 isooxazolines,5 isoquinolines,6 and oximes are also very
important ligands in the formation of mono- and polynuclear
metal complexes.7 Oxime functionality is an important structural
feature in several biologically active compounds such as perillar-
tine, an oxime of perillaldehyde, which is about 2000 times as
sweet as sucrose8 and, pralidoxime and obidoxime, which are
important antidotes for organophosphate poisoning9 (Fig. 1). In
addition, oximes are also found as antimicrobial agents,10 insecti-
cides,11 antioxidants,12 vasodilators,13 and inhibitors of P450.14
The classical methods for the preparation of oximes include reac-
tion of a carbonyl compound with hydroxylamine hydrochloride
in the presence of a stoichiometric amount of a base,15 reaction
of nitrite such as ethyl nitrite with an active methylene com-
pound16 and reduction of a nitro compound.17
Acetohydroxamic acid (CH3CONHOH), also known as LithostatÒ,
is a stable organic compound, which is derived from the reaction of
hydroxyl amine and ethyl acetate. Acetohydroxamic acid is a drug
used for the treatment of urinary tract infections18 and it is also
widely employed as a chelating agent in UREX process, for separa-
tion of uranium from spent nuclear fuel.19 However, in organic
chemistry, synthetic applications of acetohydroxamic acid have
scarcely been explored and herein, we report the first application
OH
N
I
HO
OH
N
OH
N
N
N
Cl
Cl
N
O
N
Pralidoxime
Obidoxime
Perillartine
Figure 1. Some biologically active oximes.
⇑
Corresponding author. Tel.: +91 040 27191772; fax: +91 040 27160387.
E-mail address: smiict@gmail.com (M. Sridhar).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.015

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M. Sridhar et al. / Tetrahedron Letters 52 (2011) 4701–4704
BF3.Et2O/ MeOH
reflux, 3.5-8h
O
NOH
CH3CONHOH
or
R
R'
R
R'
MW, 6-10 min
1a-t
2a-t
82-95% (microwave heating)
76-87% (conventional heating)
Scheme 1. In our preliminary study, a variety of Lewis and Bronsted acids such as BF3ÁOEt2, Bi(OTf)3, Yb(OTf)3, Sc(OTf)3, Zn(OTf)2, InBr3, InCl3, ZnCl2, p-toluene sulfonic acid
(PTSA), H2SO4, and HCl were studied as catalysts for promoting the reaction of acetohydroxamic acid with benzaldehyde1a under reflux in methanol to obtain benzaldoxime
2a and the results are shown in Table 1.
Table 1
of acetohydroxamic acid for the efficient preparation of oximes
Acid catalyzed conversion of benzaldehyde to benzaldoxime with acetohydroxamic
acid
from carbonyls using BF3ÁOEt2 as a catalyst under reflux in metha-
nol as shown in Scheme 1.
CH=NOH
CHO
Among all the catalysts studied (Table 1), BF3ÁOEt2 gave ben-
zaldoxime 2a in maximum yields (87%, 3.5 h,) under reflux in
methanol. We studied a variety of aldehydes 1a–j and ketones
1k–t under similar conditions and obtained corresponding oximes
2a–t in 76–87% yields. We have also studied these reactions under
microwave heating and obtained oximes 2a–t in 83–95% yields in
relatively short reaction times (6–10 min) when compared to those
observed under conventional heating (3.5–8 h) as shown in Table
2.20
In this study, both aldehydes and ketones formed only oximes
when methanol was used as a solvent. However, in aprotic solvents
such as dichloromethane, acetonitrile, and tetrahydrofuran, they
reacted differently with acetohydroxamic acid, for example, under
Catalyst (10 mol%)
MeOH, reflux
CH3CONHOH
1a
2a
Entry
Catalyst
Reaction time (h)
2a Yielda (%)
1
2
3
4
5
6
7
8
9
10
BF3ÁOEt2
Bi(OTf)3
Yb(OTf)3
Sc(OTf)3
InBr3
InCl3
ZnCl2
PTSA
H2SO4
HCl
3.5
6
87
83
78
75
68
65
55
62
73
58
7
7
8
8
12
12
6
reflux in dichloromethane using BF3ÁEt2O as
a catalyst; we
obtained only oxime with an aldehyde and a mixture of oxime ace-
tate and oxime with a ketone as shown in Table 3.
6
a
Isolated yields.
Table 2
Reaction of acetohydroxamic acid with carbonyls in MeOH using BF3ÁEt2O as a catalyst
O
NOH
BF3.Et2O/ MeOH
reflux or MW
CH3CONHOH
R
R'
R
R'
1a-t
2a-t
Entry
Carbonyl 1
Oxime 2
Conventional heating
Microwave heating
%Yielda (reaction time, h)
%Yielda (reaction time, min)
a
87(3.5)
95(6)
89(8)
CHO
CH=NOH
CH=NOH
b
85(4.0)
87(5.0)
Cl
F
CHO
Cl
F
F
F
F
F
F
CHO
F
CH=NOH
c
90(8)
F
F
MeO
O2N
N
CHO
CHO
d
e
f
85(3.5)
78(8.0)
83(4.5)
92(7)
83(10)
87(8)
MeO
CH=NOH
CH=NOH
O2N
N
CHO
CHO
CH=NOH
CH=NOH
g
78(4.0)
83(6)
N
H
N
H

M. Sridhar et al. / Tetrahedron Letters 52 (2011) 4701–4704
4703
Table 2 (continued)
Entry
Carbonyl 1
Oxime 2
Conventional heating
Microwave heating
%Yielda (reaction time, h)
%Yielda (reaction time, min)
CHO
CH=NOH
OH
h
i
86(3.5)
92(6)
OH
CHO
CH=NOH
78(5.0)
84(7)
CHO
4
CH=NOH
4
NOH
j
76(3.5)
80(4.0)
84(4.0)
80(4.5)
82(6)
87(7)
89(6)
87(7)
O
k
l
O
O
NOH
m
NOH
NOH
O
n
o
p
85(3.5)
83(4.0)
80(4.0)
93(7)
90(8)
86(8)
Ph
F
Ph
F
O
O
NOH
NOH
MeO
MeO
O
NOH
OH
q
r
80(3.5)
88(5.0)
90(6)
92(9)
OH
Ph
O
NOH
Ph
Ph
Ph
Ph
O
NOH
s
83(3.5)
78(6.0)
95(7)
83(8)
O
O
N
H
N
H
O
O
NOH O
t
Ph
CF3
CF3
a
Isolated yields. All products were characterised by 1H NMR, 13C NMR, mass and IR spectral data.
Table 3
Reaction of acetohydroxamic acid with aldehydes/ketones in dichloromethane under BF3ÁEt2O catalysis
O
NOH
NOAc
BF3.Et2O (10 mol%)
CH2Cl2, reflux
CH3CONHOH
R
R'
R
R'
R
R'
1
2
3
R = alkyl, aryl
R' = alkyl, aryl or H
Entry
Aldehyde
Ketone
Reaction time (h)
Yielda (%)
Oxime 2
Oxime acetate 3
1
2
3
4
5
6
7
8
9
1a
1b
1c
1j
4/0
5.0
6.0
5.5
5.0
5.0
5.5
4.5
5.0
90
87
72
82
55
46
52
50
46
0
0
0
0
1k
1l
1m
1n
1o
35
48
32
27
40
a
Isolated yields.
In our study, oxime was formed as the only product in methanol
and formation of oxime acetate was not detected (tlc) at any stage
during the course of the reaction in this solvent. Possibly, oxime
acetate undergoes rapid hydrolysis or methanolysis21 in methanol

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M. Sridhar et al. / Tetrahedron Letters 52 (2011) 4701–4704
LA
O
O
LA
O
O
O
O
H2O
R
R
R
O
LA
-H2O
N
N
NH
R' OH
NHOH
N
R'
R'
LA
O
R
R
R'
O
LA
O
R'
LA= Lewis Acid
-LA
OH
R'
R
N
H2O
LA
N
CH3COOH
R'
OCOCH3
R
Scheme 2. In summary, we have shown an unprecedented microwave-assisted rapid synthesis of oximes in high yields by reaction of carbonyls with acetohydroxamic acid
using BF3ÁOEt2 as a catalyst and methanol as a solvent.
11. Nakayama, A.; Iwamura, H.; Niwa, A.; Nakagawa, Y.; Fujita, T. J. Agric. Food
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and converts into oxime. The formation of oxime acetate involves
the unusual migration of the acyl group from N to O and the plausi-
ble reaction pathway for conversion of a carbonyl into an oxime via
oxime acetate under Lewis acid (LA) catalysis is shown in Scheme 2.
A similar mechanism is also possible with a Bronsted acid.
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Practical Organic Chemistry; Longman, 1986. p 1113.
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Acknowledgments
C.N. is thankful to UGC, New Delhi; J.R., G.K.R., and M.K.K.R. are
thankful to the CSIR, New Delhi for the award of Junior Research
Fellowships. B.C.R. is thankful to the CSIR, New Delhi for the award
of Senior Research Fellowship.
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277, 31–36.
20. Typical procedure for preparation of oxime under conventional heating:
Benzaldehyde 1a (1.0 g, 9.4 mmol), acetohydroxamic acid (1.1, 14.1 mmol),
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