The reaction of 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes and hydroxylamine hydrochloride: Facile synthesis of differently substituted isoxazoles

Article abstract of DOI:10.1002/jhet.5570450605

(Chemical Equation Presented) 2-Aroyl-3,3-bis(alkylsulfanyl)acrylaldehyde was utilized for the synthesis of three different isoxazoles by reacting with hydroxylaminehydrochloride. We synthesized differently substituted isoxazoles like (aryl)[5-(methylsulf

Full text of DOI:10.1002/jhet.5570450605

Nov-Dec 2008
1583
The Reaction of 2-Aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes And
Hydroxylamine Hydrochloride: Facile Synthesis of Differently
Substituted Isoxazoles
Annie Mathews, [a]* Karunalayam A. Sasikala, [b] Sholly C. George, [b] Kooramattom U.
Krishnaraj, [b] Naduthottiyil K. Sreedevi, [b] Marathu Prasanth, [b] Engoor R. Anabha, [b]
Karakkattu S. Devaky, [b] and Chittoorthekkathil V. Asokan.[b
[a] Post Graduate Department of Chemistry, Baselius College, Kottayam, Kerala, India, 686001
email: ocvengal@sify.com
[b] School of Chemical Sciences, Mahatma Gandhi University, Priyadarshini Hills, Kottayam, Kerala,
India, 686560
Received January 11, 2008
O
O
O
N
CHO
SMe
1 NH2OH.HCl
2 NH2OH.HCl
Ar
MeS
Ar
MeS
N
Ar
SMe
O
2 K2CO3/CH3CN
60 oC, 5 h
4 K2CO3 /CH3CN
85 oC, 10 h
N
2 NH2OH.HCl
4 K2CO3 /CH3CN
RT 10 h
O
N
Ar
SMe
N
OH
2-Aroyl-3,3-bis(alkylsulfanyl)acrylaldehyde was utilized for the synthesis of three different isoxazoles
by reacting with hydroxylaminehydrochloride. We synthesized differently substituted isoxazoles like
(aryl)[5-(methylsulfanyl)-4-isoxazolyl]methanones, 3-(methylsulfanyl)-5-phenyl-4-isoxazolecarbonitriles
and 5-aryl-3-(methylsulfanyl)-4-isoxazolecarbaldehyde oximes in good yields by varying the substrate-
reagent stoichiometry and temperature of the reaction medium.
J. Heterocyclic Chem., 45, 1583 (2008).
INTRODUCTION
Earlier we had reported the synthesis of 2-aroyl-3,3-
bis(alkylsulfanyl) acrylaldehydes from ꢀ-oxoketene
Isoxazoles are a class of heterocyclic compounds
having a remarkable number of applications and have
been demonstrated to be very versatile building blocks in
organic synthesis [1]. The biological activities of
substituted isoxazoles have made them a focus of
medicinal chemistry over the years. They are used as
potent drugs in a number of medicinal fields [2]. Some
isoxazole derivatives display agrochemical properties,
namely herbicidal and soil fungicidal activity and have
applications as pesticides and insecticides [3]. Isoxazoles
have also been used as dyes, electric insulating oils, high
temperature lubricants etc., while polyisoxazoles have
applications as semicondutors [4].
The construction of the isoxazole ring can be achieved
by either 1,3-dipolar cycloaddition of alkenes and alkynes
with nitrile oxide or by the reaction of hydroxylamine
with a three-carbon atom component [5]. Junjappa et al
have investigated in detail the reaction of hydroxylamine
with ꢀ-oxoketene dithioacetals using different reaction
conditions to afford alkylthio isoxazoles in high yields
[6].
dithioacetals [7]. During the course of our studies directed
towards exploring the synthetic potential of 2-aroyl-3,3-
bis(alkylsulfanyl)acrylaldehydes [8], we set out to study
the reaction of asymmetric bifunctional heteronucleo-
philes like hydroxylamine with 2-aroyl-3,3-bis(alkyl-
sulfanyl)acrylaldehydes in order to synthesize isoxazoles.
RESULTS AND DISCUSSION
Recently isoxazoles are used for chemical attachment
on semiconductor surfaces, which exhibit promising
applications in a wide spectrum of technological areas [9].
Moreover it was proved that 5-alkylthioisoxazoles have
anthelmintic activity [10]. Therefore synthesis of
isoxazoles with potential functional groups, which can act
as intermediates for further transformations or can attach
to semiconductors, will be of prime importance. We
expected that 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes
2, with different functional groups could afford a variety
of isoxazoles which could have promising applications.
Thus varying the substrate-reagent stoichiometry and

1584
A. Mathews, K. A. Sasikala, S. C. George, K. U. Krishnaraj, N. K. Sreedevi, M. Prasanth,
E. R. Anabha, K. S. Devaky, and C. V. Asokan
Vol 45
temperature of the reaction medium we synthesized three
different isoxazoles, (aryl)[5-(methylsulfanyl)-4-isoxa-
zolyl]methanones (3), 3-(methyl sulfanyl)-5-phenyl-4-
isoxazolecarbonitriles (4) and 5-aryl-3-(methylsulfanyl)-
4-isoxazolecarbaldehyde oximes (5) in good yields by the
reaction of 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes 2
and hydroxylamine (Scheme 1).
The above reaction could be explained as follows.
When 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes
2
were treated with one equivalent of hydroxylamine
hydrochloride at 60 °C, the amino group on the
hydroxylamine reacted with the more reactive aldehyde
group to form the corresponding aldoxime intermediate.
An intramolecular conjugate addition reaction of the
Scheme 1
SCH3
O
Ar
SCH3
1
1. DMF /POCl3
2. aq. K2CO3
O
O
O
N
CHO
1 NH2OH.HCl
2 NH2OH.HCl
Ar
Ar
MeS
N
Ar
SMe
O
2 K2CO3/CH3CN
60 oC, 5 h
4 K2CO3 /CH3CN
85 oC, 10 h
SMe
MeS
N
3
2
4
2 NH2OH.HCl
4 K2CO3 /CH3CN
RT 10 h
O
N
Ar
SMe
N
OH
5
Synthesis of (aryl)[5-(methylsulfanyl)-4-isoxazolyl]-
methanones (3). For the synthesis of (aryl)[5-(methyl-
sulfanyl)-4-isoxazolyl]methanones 3, we treated 2-
benzoyl-3,3-bis(alkylsulfanyl)acrylaldehyde 2 with one
equivalent of hydroxylamine hydrochloride in the
presence of 2 equivalents of K2CO3 in acetonitrile . The
reaction mixture was heated at 60 °C for 5 h. The reaction
was extended to other substituted acrylaldehydes to get
the corresponding isoxazoles in 60 - 90% yields (Scheme
2). The structure of the reaction products 3a-f were
established and confirmed by their elemental analyses and
spectral data (MS, IR, 1H NMR, 13C NMR).
hydroxyl group on the aldoxime to the ketene dithioacetal
moiety, followed by the elimination of an alkylsulfanyl
group resulted in the formation of the expected (aryl)[5-
(methyl/arylsulfanyl)-4-isoxazolyl]methanones 3 [11].
Synthesis of 5-aryl-3-(methylsulfanyl)-4-isoxazolec-
arbonitriles (4). The reaction of 2-aroyl-3,3-bis(alkyl-
sulfanyl)acrylaldehydes 2 with
2 equivalents of
hydroxylamine hydrochloride in acetonitrile at 85 °C for
10 h afforded 5-aryl-3-(methylsulfanyl)-4-isoxazole-
carbonitriles. We were curious to know whether both the
carbonyl groups would be involve in the reaction leading
to the formation of isoxazoloisoxazoles. Although both
the carbonyl groups in the acrylaldehydes were reactive
towards hydroxylamine the product formed suggested that
the after the aldoxime formation, N,S-acetal intermediate
was formed by a second molecule of hydroxylamine. This
intermediate underwent cyclisation reaction with the
second carbonyl group producing an isoxazolealdoxime 5.
This isoxazolealdoxime eliminated a water molecule at 85
°C to afford 5-aryl-3-(methylsulfanyl)-4-isoxazolecarbo-
nitriles 4 in 30 - 56% yields (Scheme 3). The structure of
the reaction products 4b-d were established and
confirmed by their elemental analyses and spectral data
Scheme 2
SR1
SR1
SR1
O
O
NH2OH.HCl / K2CO3.
CH3CN, 60 0C, 5 h
O
N
CHO
R
R
R1= Me, CH2Ph
3 (a-f)
2 a-f
R - a, 4-Cl; b, 4-OCH3; c, 3-OCH3; d, 3, 4-(OCH3)2; e, 4-H; f , 4-H.
1 - (a-e) , Me and f , PhCH2
R

Nov-Dec 2008
The Reaction of 2-Aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes And Hydroxylamine Hydrochloride
1585
(MS, IR, 1H NMR, 13C NMR). Compound 4a was
reported by Rudorf et al and its melting point was
compared with the reported value [11d].
by varying the substrate-reagent stoichiometry and
temperature of the reaction medium. Due to the potential
functional groups present in the new isoxazoles, they
could have been precursors for a variety of annulated
heterocycles having promising applications especially as
agrochemicals or as industrially useful compounds.
Scheme 3
N
O
2NH2OH.HCl /
4 K2CO3./ CH3CN
85 oC, 10 h
O
SMe
SMe
EXPERIMENTAL
SMe
R
General. Melting points were determined on Buchi 530
melting point apparatus and were uncorrected. The IR spectra
were recorded on KBr pellets using a Schimadzu IR-470
N
CHO
R
OH
5
1
spectrometer and the frequencies are reported in cm-1. The H
2 a-d
NMR and 13C NMR spectra were recorded on (300 MHz and 75
MHz spectrometer) using TMS as internal standard and CDCl3
or acetone-d6 as solvents. The CHN analyses were done on an
Elementar Vario EL III Serial Number 11042022 instrument.
The FAB mass spectra were recorded on a JOEL SX 102/DA-
6000 Mass Spectrometer/Data System using Argon as the FAB
gas. The EIMS spectra were recorded on a MICROMASS
QUATTRO 11 triple quadrupole mass spectrometer.
N
O
R- a, H; b, CH3; c, Br; d, OCH3
SMe
R
N
4 a-d
All commercially available reagents were purified before use.
The aroylketene dithioacetals and ꢀ-formylketene dithioacetals
were prepared by known procedure [1,13]. Anhydrous sodium
sulfate was used as drying agent. All purified compounds gave a
single spot upon TLC analyses on silica gel 7GF using an ethyl
acetate/hexane mixture as eluent. Iodine vapors or KMnO4
solution in water was used as developing agent for TLC.
Synthesis of 5-aryl-3-(methylsulfanyl)-4-isoxazole-
carbaldehyde oximes (5). In order to get the expected
isoxazoloisoxazoles in the above reaction we have to
prevent the dehydration reaction of the intermediate
oxime 5. So the 2-aroyl-3,3-bis(alkylsulfanyl)acryl-
aldehydes 2 were treated with 2 equivalents of hydroxyl-
amine hydrochloride in the presence of potassium
carbonate in acetonitrile at room temperature for 10 h.
The reaction afforded only 5-aryl-3-(methylsulfanyl)-4-
isoxazolecarbaldehydeoximes 5 in 40 - 54% yields and
still no isoxaloisoxazoles were obtained (Scheme 4).
Mechanism proposed in the synthesis of isoxazole-
carbonitrile 4 was further proved by the isolation of 5-
aryl-3-(methylsulfanyl)-4-isoxazolecarbaldehydeoximes 5
in this reaction which was carried out at room
temperature. The structure of the reaction products 5a-d
were established and confirmed by their elemental
Synthesis of (Aryl)[5-(methylsulfanyl)-4-isoxazolyl]metha-
nones from 2-aroyl-3,3-bis(alkylsulfanyl) acrylaldehydes (3).
General Procedure. 2-Aroyl-3,3-bis(alkylsulfanyl)acryl-
aldehyde 2 (0.5 g, 2 mmol) was dissolved in acetonitrile (20 mL)
at room temperature. To the above solution hydroxylamine
hydrochloride (0.14 g, 2 mmol) followed by K2CO3 (0.55 g, 4
mmol) were added and the reaction mixture was heated to 60 °C
for 5 h. It was cooled and poured into ice-cold water. The
semisolid obtained was extracted using ethyl acetate (3 X 25
mL), dried with anhydrous sodium sulfate and purified using
column chromatography on silica gel with hexane as the eluent.
Recrystallised from hexane/ethyl acetate (4:1) solution.
1
analyses and spectral data (MS, IR, H NMR, 13C NMR).
(4-Chlorophenyl)[5-methylsulfanyl)-4-isoxazolyl]meth-
anone 3a. Yield 70% (0.35 g); White solid; mp 98 °C; IR (KBr
Thermal cyclisation might enhance the conversion of 5 to
isoxazoloisoxazole by the alkanethiol elimination and
number of new heterocycles had been reported starting
from oximes [12]. Therefore compound 5 could be a
starting material for number of new compounds.
1
ꢁmax) 1674, 1550, 1362 cm–1; H NMR (300 MHz, CDCl3) ꢀ =
2.47 (s, 3H, SCH3), 7.45 - 7.5 (m, 2H, ArH), 8.02 - 8.06 (m, 2H,
ArH), 8.69 (s, 1H, 3CH isoxazole); 13C NMR (75 MHz, CDCl3)
ꢀ = 11.9 (SCH3), 115.7 (4C isoxazole), 124.4 (4C ArH), 129.3
(3, 3’C ArH), 130.2 (2, 2’ C ArH), 138.0 (1C ArH), 150.6 (3C
isoxazole), 168.0 (5C isoxazole), 184.1 (=CO); FABMS: m/z
(%) 254 (100), 206 (65), 165 (5), 107 (5); Anal: C11H8ClNO2S
To summarize, we have accomplished the synthesis of
three different isoxazoles starting from a single compound
Scheme 4
O
SMe
SMe
N
O
2NH2OH.HCl / 4K2CO3.
CH3CN, RT. 10 h
SMe
OH
CHO
R
N
R
5 a-d
2 a-d
R- a, H; b, Br; c, 4-OCH3; d, CH3

1586
A. Mathews, K. A. Sasikala, S. C. George, K. U. Krishnaraj, N. K. Sreedevi, M. Prasanth,
E. R. Anabha, K. S. Devaky, and C. V. Asokan
Vol 45
(253.71) Calcd: C, 52.08; H, 3.18; N, 5.52; S, 12.61; Found: C,
52.3; H, 3.12; N, 5.58, S; 12.69.
Synthesis of 5-aryl-3-(methylsulfanyl)-4-isoxazolecarbo-
nitriles from 2-aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes (4).
(4-Methoxyphenyl)[5-methylsulfanyl)-4-isoxazolyl]-
methanone 3b. Yield 70% (0.35 g); white solid; mp 100 °C; IR
General procedure. 2-Aroyl-3,3-bis(alkylsulfanyl)acrylalde-
hyde 2 (0.5 g, 2 mmol) was dissolved in acetonitrile (20 mL) at
room temperature. To this solution hydroxylamine hydro-
chloride (0.28 g, 4 mmol) followed by and K2CO3 (1.1 g, 8
mmol) were added and the reaction mixture was refluxed at 85
°C for 10 h. It was cooled and poured into ice-cold water. The
semisolid obtained was extracted with ethyl acetate (3 X 25
mL), dried with anhydrous sodium sulfate and purified by
column chromatography on silica gel using hexane as the eluent.
Recrystallised from hexane/ethyl acetate (4:1) solution.
1
(KBr ꢀmax) 1658, 1608, 1515, 1263 cm–1; H NMR (300 MHz,
CDCl3) ꢀ = 2.41 (s, 3H, SCH3), 3.78 (s, 3H, OMe), 6.93 (d, J = 9
Hz, 2H, ArH), 8.02 (d, J = 9Hz, 2H, ArH), 8.58 (s, 1H, 3CH
isoxazole proton); 13C NMR (75 MHz, CDCl3) ꢀ = 11.7 (SCH3),
55.3 (OMe), 114.4 (3, 3’C ArH), 114.5 (4C isoxazole), 118.4
(1C ArH), 126.7 ( 2, 2’C ArH), 150.4 ( 3C isoxazole), 163.4 (4C
ArH), 169.1 (5C isoxazole), 184.0 (=CO); FABMS: m/z (%) 250
(100), 202 (95), 155( 50), 120(45), 107 (50), 89 (45). 250 (2),
202 (40), 135 (100), 107 (45), 102 (54); Anal: C12H11NO3
(249.59); Calcd: C, 57.82; H, 4.45; N, 5.62; S, 12.86. Found: C,
57.84; H, 4.65; N, 5.52; S, 12.75.
(3-Methoxyphenyl)[5-methylsulfanyl)-4-isoxazolyl]meth-
anone 3c. Yield-65% (0.32 g); white solid; mp 80 °C; IR (KBr
ꢀmax): 2930, 1658, 1566, 1473, 1296 cm-1. 1H NMR (300 MHz,
CDCl3) ꢀ = 2.47 (s, 3H, SCH3), 3.88 (s, 3H, OMe)., 7.07 (s, 1H,
ArH), 7.38 (s, 1H, ArH), 7.64 - 7.67 (m, 2H, ArH), 8.69 (s,
1H,3CH isoxazole); 13C NMR (75 MHz, CDCl3): ꢀ = 11.9
(SCH3), 55.4 (OMe), 113.7 (4C isoxazole), 115.7 (2C ArH),
118.2 (4C ArH), 121.2 (6C ArH), 127.0 (5C ArH), 129.9 (1C,
ArH ), 150.4 (3C isoxazole), 159.5 (3C ArH), 169.0 (5C
isoxazole), 184.0 ( =CO); EIMS m/z (%) 250 (2), 202 (40),135
(100), 107 (45), 102(54); Anal: C12H11NO3S (249.59); Anal:
C12H11NO3S (249.59); Calcd: C, 57.82; H, 4.45; N, 5.62; S,
12.86. Found: C, 57.87; H, 4.48; N, 5.61; S, 12.36.
3-(Methylsulfanyl)-5-phenyl-4-isoxazolecarbonitrile 4a.
Yield 30% (0.12 g); white solid; mp 108-110 °C ( Reported value-
106-108 °C) [11d]; IR (KBr ꢀmax) 2229, 1604, 1568, 1496 cm–1;
1H NMR (300 MHz, CDCl3) ꢀ = 2.68 (s, 3H, SCH3), 7.72 - 7.62
(m, 3H, ArH ), 8.01 - 8.05 (m, 2H, ArH ); 13C NMR (75 MHz,
CDCl3) ꢀ = 13.6 (SCH3), 111.2 (-CN), 124.7 (4C isoxazole),
126.8 (3,3'C ArH), 129.4 (2,2'C ArH), 132.8 (4C ArH), 162.3
(3C isoxazole), 174.4 (5C isoxazole); FABMS (m/z, %): 217
(100); Anal: C11H8N2OS (216.26) Calcd: C, 61.09, H, 3.73, N,
12.95, S, 14.83. Found: C, 61.28; H, 3.68; N, 13.08; S, 14.70
5-(4-Methylphenyl-3-(methylsulfanyl)-4-isoxazolecarbo-
nitrile 4b. Yield; 43% (0.19 g); white solid; mp 96 °C;. IR (KBr
1
ꢀmax) 2993, 2223, 1604, 1562, 1427 cm–1. H NMR (300 MHz,
CDCl3) ꢀ = 2.44 (s, 3H, Me), 2.67 (s, 3H, SCH3), 7.36 (d, J = 8.9
Hz, 2H, ArH ), 7.94 (d, J = 9 Hz, 2H, ArH ); 13C NMR (75.47
MHz, CDCl3): ꢀ = 12.0 (SMe), 21.5 (CH3), 116.5 (CN), 126.8
(4C isoxazole), 127.6, 128.4 and 129.8, 144.7 (ArH), 162.2 (3C,
isoxazole), 174.6 (5C isoxaxole); EIMS: m/z (%) 231 (20), 216
(5), 208 (25), 202 (30), 149 (23), 119 (100), 102 (50); Anal.:
C12H10N2OS (230.29); Calcd.: C, 62.59; H, 4.38; N, 12.16; S,
13.92. Found: C, 62.38; H 4.33; N, 12.08; S, 14.06.
(3,4-Dimethoxyphenyl)[5-methylsulfanyl)-4-isoxazolyl]-
methanone 3d. Yield 90% (0.5 g); white solid; mp 80 °C. IR (KBr
1
ꢀmax) 2935, 1662, 1604, 573, 1485, 1276 cm–1; H NMR (300
MHz, CDCl3): ꢀ = 2.48 (s, 3H, SMe), 3.96 (s, 3H, OMe), 3.98
(s, 3H, OMe), 6.99 (d, J = 9 Hz, 1H, ArH), 7.77 (s, 1H, ArH ),
7.85 - 7.81(m, 1H, ArH), 8.69 (s,1H, isoxazole); 13C NMR (75
MHz, CDCl3): ꢀ = 11.9 (SCH3), 56.0 (OMe), 56.1 (OMe), 110.7
(4C isoxazole), 111.5 (2C ArH), 114.6 (5C ArH ), 118.6 (6C
ArH), 122.7 (1C ArH), 148.7 (3C isoxazole), 150.6 (3C ArH),
152.1 (4C ArH), 168.9 (5C isoxazole), 184.1 ( =CO); EIMS m/z
(%) 280 (15), 232 (50), 204 (20), 177(50) 165(80).; Anal:
C13H13NO4S (279.31): Calcd: C, 55.90; H, 4.69; N, 5.01; S,
11.48. Found: C, 55.67; H, 4.63; N, 5.13; S, 11.44.
[5-(Methylsulfanyl)-4-isoxazolyl](phenyl)methanone 3e.
Yield 65% (0.28 g); white solid;. mp 68 °C; IR (KBr ꢀmax): 1662,
1596, 1577 cm-1 ; 1H NMR (300 MHz, CDCl3 ): ꢀ = 2.68 (s, SCH3),
7.23 (s, 1H ArH), 7.51 (d, J = 8.49 Hz, 2H, ArH), 8.07 (d, J = 9 Hz,
2H, ArH), 8.70 (s, 3CH isoxazole proton), ); 13C NMR (75 MHz,
CDCl3): ꢀ = 11.7 (SCH3), 114.4 (3, 3’C ArH), 114.5 (4C
isoxazole), 118.4 (1C ArH), 126.70 ( 2, 2’C ArH), 150.4 (3C
isoxazole), 163.4 (4C ArH), 169.1 (5C isoxazole), 184.0 (=CO);
EIMS m/z (%): 220 (5), 172 (3), 167 (40), 150 (10), 105 (100);
Anal: C11H9NO2S (219.26): Calcd: C, 60.26; H, 4.14; N, 6.39; S,
14.62. Found: C, 59.97; H, 4.18; N, 6.34; S, 14.73.
[5-(Benzylsulfanyl)-4-isoxazolyl](phenyl)methanone 3f.
Yield 60 % (0.35 g); white solid; mp 110 °C; IR (KBr ꢀmax) 1643,
1596, 1562 cm–1; 1H NMR (300 MHz, CDCl3): ꢀ = 4.41 (s, 2H,
SCH2Ph), 7.44 - 7.52 (m, 6H, ArH), 7.56 - 7.76 (m, 2H, ArH ),
7.76 - 7.79 (m, 2H, ArH ), 8.74 (s, 1H, 3 CH isoxazole); 13C NMR
(75 MHz, CDCl3): ꢀ = 35.5 (SCH2Ph), 108.2 (4C isoxazole),
119.3, 127.5, 128.4, 128.83, 129.2, 133.1, 136.2, 140.6 (ArH),
160.7 (3C isoxazole), 162.5 (5C isoxazole), 186.7 (CO); FABMS:
m/z (%): 296(85); Anal: C17H13NO2S (295.36): Calcd: C, 69.13;
H, 4.44; N, 4.74; S, Found: C, 69.47; H, 4.47; N, 4.69.
5-(4-Bromophenyl-3-(methylsulfanyl)-4-isoxazolecarbo-
nitrile 4c. Yield: 56% (0.33 g); white solid; mp 148 °C; IR (KBr
1
ꢀmax) 2927, 2233, 1600,1558, 1488 cm–1; H NMR (300 MHz,
CDCl3) ꢀ = 2.69 (s, 3H, SCH3), 7.72 (d, J = 9Hz, 2H, ArH ),
7.92 (d, J = 9Hz, 2H, ArH); 13C NMR (75 MHz, CDCl3) ꢀ =
11.9 (SMe), 116.6 (CN). 127.8 (4C isoxazole), 128.7, 129.5 and
129.8, 145.7 (ArH), 163.5 (3C, isoxazole), 176.6 (5C isoxaxole);
FABMS (m/z, %): 297 (100), 295 (98), 226 (2), 185 (40), 183
(40), 120 (5), 107 (8); Anal: C11H7BrN2OS (295.16); Calcd.: C,
44.76; H, 2.39; N, 9.49. Found: C, 44.81; H, 2.34; N, 9.57
5-(4-Methoxyphenyl-3-(methylsulfanyl)-4-isoxazolecarbo-
nitrile 4d. Yield; 41% (0.2 g); white solid; mp 142 °C; IR (KBr
ꢀ
max) 2923, 2229, 1610,1585,1508 cm–1. 1H NMR (300 MHz,
CDCl3) ꢀ = 2.67 (s, 3H, SMe), 3.90 (s, 3H, OCH3), 7.05 (d, J= 9
Hz, 2H, ArH ), 8.01 (d, J = 9 Hz, 2H, ArH ); 13C NMR (75
MHz, CDCl3) ꢀ = 12.02 (SMe), 54.9 (OCH3), d 114.5 (CN).
126.8 (4C isoxazole), 127.9, 128.8 and 129.8, 146.7 (ArH
carbons), 162.2 (3C, isoxazole), 176.6 (5C isoxaxole); FABMS
(m/z, %): 247 (100), Anal: C12H10N2O2S (246.29): Calcd.: C,
58.52; H, 4.09; N, 11.37. Found: C, 58.82; H, 4.13; N, 11.43.
Synthesis of 5-aryl-3-(methylsulfanyl)-4-isoxazolecarbalde-
hydeoximes from 2-aroyl-3,3-bis(alkylsulfanyl) acryl-
aldehydes
General procedure. 2-Aroyl-3,3-bis(alkylsulfanyl)acrylalde-
hyde (0.5 g, 2 mmol) was dissolved in acetonitrile (20 mL) at
room temperature. To the above solution hydroxylamine
hydrochloride (0.28 g, 4 mmol) followed by K2CO3 (1.1 g, 8
mmol) were added and the reaction mixture was stirred for 10 h.

Nov-Dec 2008
The Reaction of 2-Aroyl-3,3-bis(alkylsulfanyl)acrylaldehydes And Hydroxylamine Hydrochloride
1587
It was poured into ice cold water and the semisolid obtained was
extracted with ethyl acetate (3 X 25 mL). The organic layer was
dried with anhydrous sodium sulfate and the solvent was
evaporated off. The crude product was purified by column
chromatography on silica gel using hexane/ethyl acetate (8:2) as
the eluent. The solid was recrystallised from hexane/ethyl
acetate (4:1) solution.
(m, 2H, ArH), 7.54 - 7.76 (m, 2H, ArH), 7.65 (s, 1H aldoxime),
8.23 (s, 1H, OH proton.), 13C NMR (75 MHz, CDCl3): ꢀ = 13.8
(SCH3), 21.4 (CH3) 108.5 (4C isoxazole), 126.3 (4C ArH), 127.9
(2, 2'C ArH), 128.9 (3, 3'C ArH), 131.6 (1C ArH), 138.7 (3C
isoxazole), 160.8 (aldoxime), 167.2 (5C isoxazole); FABMS:
(m/z, %): 249(100), 188(1), 167(2), 119(48), 107(5), 89(.5);
Anal: C12H12N2O2S (248.30): Calcd: C, 58.05; H, 4.87; N, 11.28.
Found: C, 57.97; H, 4.82; N, 11.34.
3-(Methylsulfanyl)-5-phenyl-4-isoxazolecarbaldehyde
oxime 5a. Yield 42% (0.19 g); white solid; mp 182 °C; IR (KBr
Acknowledgements. We thank CDRI, Lucknow, India for
providing the spectral data. Annie Mathews is grateful to UGC
and the management of Baselius College Kottayam for
sanctioning faculty improvement program to do the research.
1
ꢀmax) 3331, 1639, 1566, 1450 cm–1; H NMR (300 MHz, CDCl3)
ꢀ = 2.68 (s, 3H, SCH3), 7.51 - 7.55 (m, 3H, ArH), 7.60 - 7.69
(m, 3H, two ArH and one aldoxime proton), 8.23 (s, 1H, OH
proton); 13C NMR (75 MHz, CDCl3): ꢀ = 13.8 (SCH3), 108.6
(4C isoxazole), 126.8 (4C ArH), 127.5 (2, 2'C ArH), 128.9 (3,
3'C ArH), 130.6 (1C ArH), 139.6(3C isoxazole), 159.8
(aldoxime), 167.6 (5C isoxazole); FABMS: m/z (%): 235(100);
Anal: C11H10N2O2S (234.38): Calcd: C, 56.39; H, 4.30; N, 11.96.
Found: C, 56.02; H 4.24; N, 11.79.
REFERENCES
[1] Baraldi, P.G.; Barco, A.; Benetti, S.; Pollini,G.P.; Simoni.D.
Synthesis, 1987; 857.
[2] a) Lee, Y.-S; Hyean, K. B. Bioorg. Med. Chem. Lett., 2002,
12, 1395. b) Jiang, H.; Luo, X.; Bai, D. Current Med. Chem., 2003, 10,
2231.
[3] a) Hiroyuki, K.; Tsuneo, I.; Nobuo M.; Akira T.; Michio, M.,
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[6] a) Purkayastha, M. L.; Bhat, L.; Ila, H.; Junjappa, H.
Synthesis, 1995, 641; b) Purkayastha, M. L.; Ila, H.; Junjappa, H.
Synthesis, 1989, 20; c) Singh, O.M.; Ila, H.; Junjappa, H. J. Chem.
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5-(4-Bromophenyl)-3-(methylsulfanyl)-4-isoxazolecarbal-
dehyde oxime 5b. Yield; 43% (0.26 g); white solid; mp 186 °C;
1
IR (KBr ꢀmax): 3336, 1643, 1596, 1488 cm–1; H NMR (300
MHz, CDCl3 + DMSO, 1:1) ꢀ = 2.58 (s, 3H, SCH3), 7.58 - 7.61
(m, 2H, ArH), 7.67 - 7.70 (m, 2H, ArH), 8.13 (s, 1 H, aldoxime),
11.43 (s, 1H, OH proton); 13C NMR (75 MHz, CDCl3): ꢀ =
13.80 (SCH3), 107.7 (4C isoxazole), 125.6 (4C ArH), 127.5 (2,
2'C ArH), 128.9 (3, 3'C ArH), 130.7 (1C ArH), 140.6 (3C
isoxazole), 160.8 (aldoxime), 166.8 (5C isoxazole); FABMS:
m/z (%): 315 (50), 313 (50), 279 (20), 259 (20), 219 (60), 149
(80), 123 (40), 107 (60); Anal: C11H9BrN2O2S (313.17): Calcd:
C, 42.19; H 2.90; N, 8.95. Found: C, 42.45; H, 3.01; N, 8.98.
5-(4-Methoxyphenyl)-3-(methylsulfanyl)-4-isoxazolecar-
baldehyde oxime 5c. Yield; 40% (0.21 g); white solid; mp 180
[7] Anabha, E. R.; Asokan, C. V. Synthesis, 2006, 151.
[8] Mathews, A; Asokan, C. V. Tetrahedron, 2007, 63, 7845
.
1
°C; IR (KBr ꢀmax) 3321, 1643, 1608, 1512 cm–1. H NMR (300
[9] Tao, F.; Bernasek, S. L., J. Am. Chem. Soc. 2007, 129, 4815.
[10] a) Banerjee, A. K.; Bandyopadhyay, S.; Gayen, A. K.;
Sengupta, T.; Das, A. K.; Chatterjee, G. K.; Chaudhuri, S. K. Arzneim.
Forsch., 1994, 44, 863; b) Carr, J. B; Harry, G. D.; Hass, D. K. J. Med.
Chem., 1977, 20, 934 ; c) Carr, J. B.; Hass, D. K., U S Patent 3879533,
1975.
MHz, CDCl3): ꢀ = 2.63 (s, 3H, SCH3), 3.88 (s, OCH3), 7.04 -
7.01 (m, 2H, ArH), 7.63 - 7.60 (m, 2H, ArH), 7.79 (s, 1H
aldoxime), 8.21 (s,1H, OH ); 13C NMR (75 MHz, CDCl3) ꢀ =
13.5 (SCH3), 55.7 (OCH3) 110.6 (4C isoxazole), 125.8 (4C
ArH), 127.8 (2, 2'C ArH), 128.7 (3, 3'C ArH), 130.6 (1C ArH),
139.4 (3C isoxazole), 158.4 (aldoxime), 166.7 (5C isoxazole);
FABMS: (m/z, %): 265 (98), 242 (5), 180 (5), 121 (80, 107 (40),
88 (20); Anal: C12H12N2O3S (264.30): Calcd: C, 54.53; H, 4.58;
N, 10.60. Found: C, 54.23; H, 4.56; N, 10.66.
[11] a) Dieter, R. K.; Chang, H. J. J. Org. Chem., 1989, 54, 1088;
b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron, 1990, 46, 5423; c)
Kumar, S; Junjappa, H.; Ila, H. Tetrahedron, 2007, 40, 10067; d)
Rudorf, W. D.; Augustin, M. J. Prakt. Chem., 1978, 320, 585.
[12] a) Hassner, A.; Rakesh Maurya; Friedman, O.; Gottlieb, H,
E.; Padwa, A.; Austin, D. J. Org. Chem., 1993, 58, 4539.; b) Reshma, F.
K.; Rima, K.; Sulfala, S.; Vidya, G. D.; Santosh, G. T. Synth. Commun.,
2007, 37, 585.
5-(4-Methylphenyl)-3-(methylsulfanyl)-4-isoxazolecarbalde-
hyde oxime 5d. Yield; 54% (0.26g); white solid; mp 174 °C; IR
1
(KBr ꢀmax) 3331, 1656, 1608, 1512 cm–1. H NMR (300 MHz,
CDCl3): ꢀ = 2.43 (s, 3H, CH3), 2.63 (s, 3H, SCH3), 7.31 - 7.33
[13] Kolb, M. Synthesis, 1990, 171.