A simple method for the synthesis of 5-isoxazolyl-4-thioxo-1,3,5- benzoxadiazocines

Article abstract of DOI:10.1002/jhet.38

Synthesis of novel isoxazolyl 1,3,5-benzoxadiazocines 5 has been accomplished by condensation of 3-amino-5-methylisoxazole 1 with salicylaldehydes, followed by reduction, treatment with arylisothio-cyanates, and subsequent ring closure in the presence of

Full text of DOI:10.1002/jhet.38

134
A Simple Method for the Synthesis of 5-Isoxazolyl-4-thioxo-
1,3,5-benzoxadiazocines
Vol 46
E. Rajanarendar,* E. Kalyan Rao, and A. Siva Rami Reddy
Department of Chemistry, Kakatiya University, Warangal 506 009, Andhra Pradesh, India
*E-mail: eligeti_rajan@yahoo.co.in
Received March 28, 2008
DOI 10.1002/jhet.38
Published online 11 February 2009 in Wiley InterScience (www.interscience.wiley.com).
Synthesis of novel isoxazolyl 1,3,5-benzoxadiazocines 5 has been accomplished by condensation of
3-amino-5-methylisoxazole 1 with salicylaldehydes, followed by reduction, treatment with arylisothio-
cyanates, and subsequent ring closure in the presence of formaldehyde. The methodology used in this
synthesis is the first approach of its kind.
J. Heterocyclic Chem., 46, 134 (2009).
INTRODUCTION
heterocycles linked to the isoxazole moiety [9], we
undertook the synthesis of isoxazolyl benzoxadiazocines
to explore the pharmacological activity of these com-
pounds. Herein, we present our results on the synthesis
of isoxazolyl 1,3,5-benzoxadiazocines by adopting sim-
ple methodology.
Benzoxadiazocines have been claimed to exhibit sed-
ative, muscle relaxant and anticonvulsant effects [1].
Oxadiazocines are shown to act as bacteriocides, hyp-
notic agents [2], central nervous system stimulants [3],
and are also known to possess pharmacological activity
[4]. The biological importance and considerable thera-
peutic potential of these compounds generated interest
in designing the synthesis of a number of derivatives
[5], which might become potential drug candidates
as inhibitors of HIV-1 reverse transcriptase [6]. Very
recently, oxadiazocines are reported to have been used
as immuno therapeutics, antimicrobial drugs, and vac-
cines [7]. Similarly isoxazole nucleus can be found fre-
quently in the structure of numerous naturally occur-
ring and synthetic compounds with interesting biologi-
cal and pharmacological properties [8]. In spite of such
a high potential significance for benzoxadiazocines and
oxadiazocines, a survey of literature showed that little
attention has been given toward the synthesis of this
class of heterocyclic compounds. In view of this, and
as a sequel to our work on the synthesis of a variety of
RESULTS AND DISCUSSION
The reaction of 3-amino-5-methylisoxazole 1 with
substituted salicylaldehydes in hot alcohol led to the for-
mation of Schiff bases 2 in quantitative yields. The
Schiff bases 2 on reduction with sodium borohydride
produced
2-[(5-methyl-isoxazol-3-yl-amino)-methyl]
phenols 3 in moderate to good yields. The nucleophilic
addition of amino methyl phenols 3 with aryl isothio-
cyanates has been carried out in hot chloroform with
stirring for 6 h. The resulting product has been identified
as N-(5-methyl-isoxazol-3-yl)-N-(2-hydroxybenzyl)-N0-
aryl thioureas 4. The thioureas 4 on heating with formal-
dehyde in methanol solution underwent ring closure,
involving an internal Mannich reaction, to give novel
C
V
2009 HeteroCorporation

January 2009 A Simple Method for the Synthesis of 5-Isoxazolyl-4-thioxo-1,3,5-benzoxadiazocines
135
Scheme 1
General procedure for the preparation of 2-[(5-methyl-3-
isoxazolyl)imino]methylphenols (2a–2e). 3-Amino-5-methyl-
isoxazole 1 (0.01 mol) and salicylaldehyde (0.01 mol) were
refluxed in ethanol (10 mL) for 2 h. The solution was cooled
and the separated solid was collected by filtration and re-crys-
tallized from pet ether.
5-(5-methyl-isoxazol-3-yl)-3-aryl-3,4,5,6-tetrahydro-2H-
1,3,5-benzoxadiazocine-4-thiones
good yields (Scheme 1).
5 in moderate to
It can be concluded that a simple and efficient method
to synthesize isoxazolyl benzoxadiazocines in good
yields under mild conditions has been achieved. It is
possible that these compounds may have applications as
drugs; the activity data will be published elsewhere.
This happens to be the first report on the synthesis of
benzoxadiazocines linked to an isoxazole unit.
2-[(5-Methyl-3-isoxazolyl)imino]methylphenol
(2a). This
compound was obtained as yellow crystals, yield 95%; mp 57–
59ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.38 (s, 3H, CH3),
5.95 (s, 1H, isoxazole-H), 6.82–7.55 (m, 4H, ArH), 8.82 (s,
1H, AN¼¼CHA), 12.02 (bs, 1H, OH, D2O exchangeable). EI-
MS: m/z 203 (M þ Hþ); IR (KBr): 3400 (OAH), 1607
(C¼¼N), 1577, 1400 (C¼¼C), 1282 cmꢁ1 (CAO). Anal. Calcd.
for C11H10N2O2 (202): C, 65.34; H, 4.95; N, 13.86. Found: C,
65.38; H, 5.10; N, 13.79.
EXPERIMENTAL
4-Methyl-2-[(5-methyl-3-isoxazolyl)imino]methylphenol (2b).
This compound was obtained as yellow crystals, yield 90%;
mp 68–70ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.41 (s, 3H,
CH3), 2.50 (s, 3H, CH3), 6.02 (s, 1H, isoxazole-H), 6.80–7.50
(m, 3H, ArH), 8.75 (s, 1H, AN¼¼CHA), 12.85 (bs, 1H, OH,
D2O exchangeable). EI-MS: m/z 217 (M þ Hþ); IR (KBr):
3390 (OAH), 1615 (C¼¼N), 1580, 1450 (C¼¼C), 1275 cmꢁ1
(CAO). Anal. Calcd. for C12H12N2O2 (216): C, 66.66; H, 5.55;
N, 12.96. Found: C, 66.60; H, 5.62; N, 12.90.
All the melting points were determined on a Cintex melting
point apparatus and are uncorrected. Analytical TLC was per-
formed on Merck precoated 60 F254 silica gel plates. Visual-
ization was done by exposing to Iodine vapor IR spectra (KBr
pellet) were recorded on Perkin-Elmer BX series FTIR spec-
trophotometer. 1H NMR spectra were recorded on a Varian
Gemini 300 MHz spectrometer. Chemical shift values are
given in ppm (d) with tetramethylsilane as internal standard.
Mass spectral measurements were carried out by EI method on
a Jeol JMC-300 spectrometer at 70 eV. Elemental analyses
were performed on a Carlo Erba 106 Perkin-Elmer model 240
analyzer.
4-Methoxy-2-[(5-methyl-3-isoxazolyl) imino] methyl phenol
(2c). This compound was obtained as yellow crystals, yield
1
90%; mp 80–82ꢀC, H NMR (300 MHz, CDCl3): d ¼ 2.35 (s,
3H, CH3), 3.8 (s, 3H, OCH3), 6.12 (s, 1H, isoxazole-H), 6.80–
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E. Rajanarendar, E. K. Rao, and A. S. R. Reddy
Vol 46
1
7.10 (m, 3H, ArH), 8.80 (s, 1H, AN¼¼CHA), 12.05 (bs, 1H,
OH, D2O exchangeable). EI-MS: m/z 233 (M þ Hþ); IR
(KBr): 3385 (OAH), 1620 (C¼¼N), 1575, 1425 (C¼¼C), 1280
cmꢁ1 (CAO). Anal. Calcd. for C12H12N2O3 (232): C, 62.06;
H, 5.17; N, 12.06. Found: C, 62.15; H, 5.13; N, 12.14.IR.
4-Chloro-2-[(5-methyl-3-isoxazolyl)imino]methylphenol (2d).
This compound was obtained as yellow crystals, yield 88%;
mp 93–95ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.41 (s, 3H,
CH3), 5.90 (s, 1H, isoxazole-H), 7.50–8.02 (m, 3H, ArH), 8.85
(s, 1H, AN¼¼CHA), 12.50 (bs, 1H, OH, D2O exchangeable).
EI-MS: m/z 237 (M þ Hþ); IR (KBr): 3405 (OAH), 1615
(C¼¼N), 1580, 1400 (C¼¼C), 1275 cmꢁ1 (CAO). Anal. Calcd.
for C11H9N2O2Cl (236): C, 55.93; H, 3.81; N, 11.86. Found:
C, 56.05; H, 3.85; N, 11.88.
mp 105–107ꢀC, H NMR (300 MHz, CDCl3): d ¼ 2.35 (s, 3H,
CH3), 3.70 (s, 2H, ACH2A), 4.50 (bs, 1H, NH, D2O exchange-
able), 6.02 (s, 1H, isoxazole-H), 7.00–7.50 (m, 3H, ArH),
10.02 (bs, 1H, OH, D2O exchangeable). EI-MS: m/z 239 (M þ
Hþ); IR (KBr): 3550 (NAH), 3415 (OAH), 1630 (C¼¼N),
1510 (C¼¼C), 1205 cmꢁ1 (CAO). Anal. Calcd. for
C11H11N2O2Cl (238): C, 55.46; H, 4.62; N, 11.76. Found: C,
55.50; H, 4.58; N, 11.80.
4-Bromo-2-[(5-methyl-3-isoxazolyl)amino]methylphenol (3e).
This compound was obtained as brown crystals, yield 80%; mp
121–123ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.40 (s, 3H,
CH3), 3.95 (s, 2H, ACH2A), 5.00 (bs, 1H, NH, D2O exchange-
able), 5.95 (s, 1H, isoxazole-H), 7.20–7.80 (m, 3H, ArH), 9.80
(bs, 1H, OH, D2O exchangeable). EI-MS: m/z 283 (M þ Hþ); IR
(KBr): 3500 (NAH), 3395 (OAH), 1615 (C¼¼N), 1560 (C¼¼C),
1180 cmꢁ1 (CAO). Anal. Calcd. for C11H11N2O2Br (282): C,
46.80; H, 3.90; N, 9.92. Found: C, 46.95; H, 4.01; N, 9.85.
General procedure for the preparation of N-(2-hydroxy-
benzyl)-N-(5-methyl-3-isoxazolyl)-N0-phenylthioureas (4a–4f).
To chloroform solution (15 mL) of amino methylphenols 3
(0.01 mol) arylisothio cyanate (0.01 mol) was slowly added
with stirring. The reaction mixture was stirred at 90ꢀC for 6 h.
The solvent was removed by distillation under reduced pres-
sure and the crude product was re-crystallized from ethanol.
N-(2-Hydroxybenzyl)-N-(5-methyl-3-isoxazolyl)-N0-phenyl-
thiourea (4a). This compound was obtained as brown crystals,
4-Bromo-2-[(5-methyl-3-isoxazolyl)imino]methylphenol (2e).
This compound was obtained as yellow crystals, yield 95%;
1
mp 110–112ꢀC, H NMR (300 MHz, CDCl3): d ¼ 2.35 (s, 3H,
CH3), 6.02 (s, 1H, isoxazole-H), 7.70–8.02 (m, 3H, ArH), 8.90
(s, 1H, AN¼¼CHA), 12.40 (bs, 1H, OH, D2O exchangeable).
EI-MS: m/z 281 (M þ Hþ); IR (KBr): 3368 (OAH), 1612
(C¼¼N), 1489 (C¼¼C), 1275 cmꢁ1 (CAO). Anal. Calcd. for
C11H9N2O2Br (280): C, 47.14; H, 3.21; N, 10.00. Found: C,
47.20; H, 3.29; N, 9.95.
General procedure for the preparation of 2-[(5-methyl-3-
isoxazolyl)amino]methyl phenols (3a–3e). To an ethanolic so-
lution (10 mL) of Schiff base 2 (0.01 mol) sodium borohydride
(0.02 mol) was slowly added with stirring. The reaction was con-
ducted at room temperature with stirring for 30 min. The solid
that separated on pouring the reaction mixture into ice-cold water
was collected filtration and re-crystallized from ethanol.
1
yield 85%; mp 100–102ꢀC, H NMR (300 MHz, CDCl3): d ¼
2.30 (s, 3H, CH3), 4.60 (s, 2H, CH2), 6.01 (s, 1H, isoxazole-
H), 6.8–7.8 (m, 9H, ArH), 8.52 (bs, 1H, NH, D2O exchange-
able), 9.42 (bs, 1H, OH, D2O exchangeable). EI-MS: m/z 340
(M þ Hþ); IR (KBr): 3239 (NAH), 3180 (OAH), 1641
(C¼¼N), 1582, 1515 (C¼¼C), 1225 cmꢁ1 (C¼¼S). Anal. Calcd.
for C18H17N3O2S (339): C, 63.71; H, 5.01; N, 12.38.Found: C,
63.59; H, 4.95; N, 12.35.
2-[(5-Methyl-3-isoxazolyl)amino]methylphenol
(3a). This
compound was obtained as brown crystals, yield 82%; mp 85–
87ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.25 (s, 3H, CH3),
4.31 (s, 2H, ACH2A), 5.20 (bs, 1H, NH, D2O exchangeable),
5.66 (s, 1H, isoxazole-H), 6.80–7.25 (m, 4H, ArH), 9.45 (bs,
1H, OH, D2O exchangeable). EI-MS: m/z 205 (M þ Hþ); IR
(KBr): 3640 (NAH), 3376 (OAH), 1631 (C¼¼N), 1458 (C¼¼C),
1210 cmꢁ1 (CAO). Anal. Calcd. for C11H12N2O2 (204): C,
64.70; H, 5.88; N, 13.72. Found: C, 64.65; H, 5.82; N, 13.66.
4-Methyl-2-[(5-methyl-3-isoxazolyl)amino]methylphenol (3b).
This compound was obtained as brown crystals, yield 85%;
mp 79–81ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.30 (s, 3H,
CH3), 2.50 (s, 3H, CH3), 4.35 (s, 2H, ACH2A), 5.50 (bs, 1H,
NH, D2O exchangeable), 5.70 (s, 1H, isoxazole-H), 7.00–7.50
(m, 3H, ArH), 10.05 (bs, 1H, OH, D2O exchangeable). EI-MS:
m/z 219 (M þ Hþ); IR (KBr): 3500 (NAH), 3368 (OAH),
1605 (C¼¼N), 1455 (C¼¼C), 1065 cmꢁ1 (CAO). Anal. Calcd.
for C12H14N2O2 (218): C, 66.05; H, 6.42; N, 12.84. Found: C,
66.01; H, 5.98; N, 12.81.
4-Methoxy-2-[(5-methyl-3-isoxazolyl)amino]methylphenol (3c).
This compound was obtained as brown crystals, yield 85%;
mp 92–93ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.35 (s, 3H,
CH3), 3.7 (s, 3H, CH3), 4.00 (s, 2H, ACH2A), 5.50 (bs, 1H,
NH, D2O exchangeable), 5.80 (s, 1H, isoxazole-H), 6.85–7.40
(m, 3H, ArH), 9.85 (bs, 1H, OH, D2O exchangeable). EI-MS:
m/z 235 (M þ Hþ); IR (KBr): 3490 (NAH), 3350 (OAH),
1620 (C¼¼N), 1460 (C¼¼C), 1150 cmꢁ1 (CAO). Anal. Calcd.
for C12H14N2O3 (234): C, 61.53; H, 5.98; N, 11.96. Found: C,
61.88; H, 5.88; N, 11.85.
N0-(4-Chlorophenyl)-N-(2-hydroxybenzyl)-N-(5-methyl-3-
isoxazolyl) thiourea (4b). This compound was obtained as
brown crystals, yield 88%; mp 124–126ꢀC, 1H NMR (300
MHz, CDCl3): d ¼ 2.35 (s, 3H, CH3), 4.94 (s, 2H, CH2), 5.96
(s, 1H, isoxazole-H), 7.01–7.82 (m, 8H, ArH), 8.80 (bs, 1H,
NH, D2O exchangeable), 9.50 (bs, 1H, OH, D2O exchange-
able). EI-MS: m/z 374 (M þ Hþ); IR (KBr): 3300 (NAH),
3225 (OAH), 1640 (C¼¼N), 1575 (C¼¼C), 1230 cmꢁ1 (C¼¼S).
Anal. Calcd. for C18H16N3O2SCl (373): C, 57.90; H, 4.28; N,
11.26. Found: C, 57.86; H, 4.25; N, 11.29.
N0-(4-Bromophenyl)-N-(2-hydroxybenzyl)-N-(5-methyl-3-
isoxazolyl) thiourea (4c). This compound was obtained as
brown crystals, yield 80% mp 133–135ꢀC, 1H NMR (300
MHz, CDCl3): d ¼ 2.38 (s, 3H, CH3), 4.85 (s, 2H, CH2), 6.00
(s, 1H, isoxazole-H), 7.23–7.85 (m, 8H, ArH), 9.00 (bs, 1H,
NH, D2O exchangeable), 10.25 (bs, 1H, OH, D2O exchange-
able). EI-MS: m/z 418 (M
þ
Hþ); Anal. Calcd. for
C18H16N3O2SBr (417): C, 51.79; H, 3.83; N, 10.07. Found: C,
51.82; H, 3.85; N, 9.98. IR (KBr): 3350 (NAH), 3200 (OAH),
1515 (C¼¼C), 1225 cmꢁ1 (C¼¼S).
N-(2-Hydroxybenzyl)-N-(5-methyl-3-isoxazolyl)-N0-(4-meth-
ylphenyl) thiourea (4d). This was obtained as compound
brown crystals, yield 85%; mp 120–122ꢀC, 1H NMR (300
MHz, CDCl3): d ¼ 2.40 (s, 3H, CH3), 2.52 (s, 3H, CH3), 4.75
(s, 2H, CH2), 6.12 (s, 1H, isoxazole-H), 7.50–8.20 (m, 8H,
ArH), 8.90 (bs, 1H, NH, D2O exchangeable), 10.08 (bs, 1H,
OH, D2O exchangeable). EI-MS: m/z 354 (M þ Hþ); IR
4-Chloro-2-[(5-methyl-3-isoxazolyl)amino]methylphenol (3d).
This compound was obtained as brown crystals, yield 80%;
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January 2009 A Simple Method for the Synthesis of 5-Isoxazolyl-4-thioxo-1,3,5-benzoxadiazocines
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(KBr): 3329 (NAH), 3215 (OAH), 1510 (C¼¼C), 1220 cmꢁ1
(C¼¼S). Anal. Calcd. for C19H19N3O2S (353): C, 64.58; H,
5.38; N, 11.89. Found: C, 64.49; H, 5.32; N, 11.92.
CH3), 2.48 (s, 3H, CH3), 4.75 (s, 2H, CH2), 5.85 (s, 2H, CH2),
6.05 (s, 1H, isoxazole-H), 7.25–7.98 (m, 8H, ArH). EI-MS: m/
z 366 (M þ Hþ); IR (KBr): 1618 (C¼¼N), 1215 cmꢁ1 (C¼¼S).
Anal. Calcd. for C20H19N3O2S (365): C, 65.75; H, 5.20; N,
11.50. Found: C, 65.81; H, 5.15; N, 11.48.
8-Methyl-5-(5-methyl-3-isoxazolyl)-3-phenyl-3,4,5,6-tetrahy-
dro-2H-1,3,5-benzoxadiazocine-4-thione (5e). This compound
was obtained as pale brown crystals, yield 80%; mp 155–
157ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.42 (s, 3H, CH3),
2.52 (s, 3H, CH3), 4.60 (s, 2H, CH2), 5.80 (s, 2H, CH2), 6.02
(s, 1H, isoxazole-H), 7.00–7.65 (m, 8H, ArH). EI-MS: m/z 366
(M þ Hþ); IR (KBr): 1610 (C¼¼N), 1225 cmꢁ1 (C¼¼S). Anal.
Calcd. for C20H19N3O2S (365): C, 65.75; H, 5.20; N, 11.50.
Found: C, 65.70; H, 5.22; N, 11.47.
8-Methoxy-5-(5-methyl-3-isoxazolyl)-3-phenyl-3,4,5,6-tetra-
hydro-2H-1,3,5-benzoxadiazocine-4-thione (5f). This com-
pound was obtained as pale brown crystals, yield 80%; mp
165–167ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.38 (s, 3H,
CH3), 3.80 (s, 3H, OCH3), 4.80 (s, 2H, CH2), 6.00 (s, 2H,
CH2), 6.15 (s, 1H, isoxazole-H), 7.00–7.50 (m, 8H, ArH). EI-
MS: m/z 382 (M þ Hþ); IR (KBr): 1625 (C¼¼N), 1235 cmꢁ1
(C¼¼S). Anal. Calcd. for C20H19N3O3S (381): C, 62.99; H,
4.98; N, 11.02. Found: C, 63.05; H, 5.01; N, 11.00.
N-(2-Hydroxy-5-methylbenzyl)-N-(5-methyl-3-isoxazolyl)-
N0-phenylthiourea (4e). This compound was obtained as
brown crystals, yield 88%; mp 136–138ꢀC, 1H NMR (300
MHz, CDCl3): d ¼ 2.41 (s, 3H, CH3), 2.50 (s, 3H, CH3), 4.66
(s, 2H, CH2), 5.98 (s, 1H, isoxazole-H), 7.20–8.00 (m, 8H,
ArH), 9.00 (bs, 1H, NH, D2O exchangeable), 10.05 (bs, 1H,
OH, D2O exchangeable). EI-MS: m/z 354 (M þ Hþ); IR
(KBr): 3380 (NAH), 3290 (OAH), 1565 (C¼¼C), 1235 cmꢁ1
(C¼¼S). Anal. Calcd. for C19H19N3O2S (353): C, 64.58; H,
5.38; N, 11.89. Found: C, 64.55; H, 5.35; N, 11.95.
N-(2-Hydroxy-5-methoxybenzyl)-N-(5-methyl-3-isoxazolyl)-
N0-phenylthiourea (4f). This compound was obtained as
brown crystals, yield 80%; mp 127–129ꢀC, 1H NMR (300
MHz, CDCl3): d ¼ 2.38 (s, 3H, CH3), 3.80 (s, 3H, OCH3),
4.70 (s, 2H, CH2), 6.20 (s, 1H, isoxazole-H), 7.00–7.85 (m,
8H, ArH), 8.98 (bs, 1H, NH, D2O exchangeable), 9.80 (bs,
1H, OH, D2O exchangeable). EI-MS: m/z 370 (M þ Hþ); IR
(KBr): 3375 (NAH), 3185 (OAH), 1560 (C¼¼C), 1215 cmꢁ1
(C¼¼S). Anal. Calcd. for C19H19N3O2S (369): C, 61.78; H,
5.14; N, 11.38. Found: C, 61.82; H, 5.08; N, 11.35.
General procedure for the preparation of 5-(5-methyl-
isoxazol-3-yl)-3-aryl-3,4,5,6-tetrahydro-2H-1,3,5-benzoxadia-
zocine-4-thiones (5a–5f). To an ethanolic solution (15 mL) of
thioureas 4 (0.01 mol), Formaldehyde (0.01 mol) was slowly
added with stirring. The mixture was refluxed for 6–8 h
(Monitored with TLC). The gummy product obtained, after the
removal of solvent, was processed with pet ether. The product
was purified by re-crystallization from ethanol.
Acknowledgments. The authors thank Prof. S. Sri Hari, Head,
Department of Chemistry, Kakatiya University, Warangal for the
facilities and Dr. J.S. Yadav, Director, Indian Institute of Chemi-
cal Technology, Hyderabad for recording 1H NMR and Mass
Spectra.
REFERENCES AND NOTES
5-(5-Methyl-3-isoxazolyl)-3-phenyl-3,4,5,6-tetrahydro-2H-
1,3,5-benzoxadiazocine-4-thione (5a). This compound was
obtained as pale brown crystals, yield 90%; mp 128–129ꢀC,
1H NMR (300 MHz, CDCl3): d ¼ 2.30 (s, 3H, CH3), 4.55 (s,
2H, CH2), 5.88 (s, 2H, CH2), 6.02 (s, 1H, isoxazole-H), 7.02–
7.65 (m, 9H, ArH). EI-MS: m/z 352 (M þ Hþ); IR (KBr):
1610 (C¼¼N), 1220 cmꢁ1 (C¼¼S). Anal. Calcd. for
C19H17N3O2S (351): C, 64.95; H, 4.84; N, 11.96. Found: C,
65.01; H, 4.82; N, 11.92.
3-(4-Chlorophenyl)-5-(5-methyl-3-isoxazolyl)-3,4,5,6-tetra-
hydro-2H-1,3,5-benzoxadiazocine-4-thione (5b). This com-
pound was obtained as pale brown crystals, yield 85%; mp
145–147ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.36 (s, 3H,
CH3), 4.62 (s, 2H, CH2), 6.00 (s, 2H, CH2), 6.20 (s, 1H, isoxa-
zole-H), 7.23–7.85 (m, 8H, ArH). EI-MS: m/z 386 (M þ Hþ);
IR (KBr): 1625 (C¼¼N), 1210 cmꢁ1 (C¼¼S). Anal. Calcd. for
C19H16N3O2SCl (385): C, 59.22; H, 4.15; N, 10.90. Found: C,
59.17; H, 4.10; N, 11.00.
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3-(4-Bromophenyl)-5-(5-methyl-3-isoxazolyl)-3,4,5,6-tetra-
hydro-2H-1,3,5-benzoxadiazocine-4-thione (5c). This com-
pound was obtained as pale brown crystals, yield 85%; mp 160–
1
162ꢀC, H NMR (300 MHz, CDCl3): d ¼ 2.40 (s, 3H, CH3), 4.80
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(s, 2H, CH2), 6.05 (s, 2H, CH2), 6.25 (s, 1H, isoxazole-H), 7.50–
7.88 (m, 8H, ArH). EI-MS: m/z 430 (M þ Hþ); IR (KBr): 1600
(C¼¼N), 1202 cmꢁ1 (C¼¼S). Anal. Calcd. for C19H16N3O2SBr (429):
C, 53.14; H, 3.72; N, 9.79. Found: C, 53.09; H, 3.70; N, 9.75.
5-(5-Methyl-3-isoxazolyl)-3-(4-methylphenyl)-3,4,5,6-tetra-
hydro-2H-1,3,5-benzoxadiazocine-4-thione (5d). This com-
pound was obtained as pale brown crystals, yield 88%; mp
140–142ꢀC, 1H NMR (300 MHz, CDCl3): d ¼ 2.38 (s, 3H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet