Microwave-assisted synthesis of new isoxazolyl triazinethiones and isoxazolyl oxadiazinethiones in dry media

Article abstract of DOI:10.1002/jhet.5570420437

Trimolecular condensation of N-(3-methyl-5-styryl-isoxazol-4-yl)-N'-aryl thioureas (2), paraformaldehyde and primary amines using montmorillonite K-10 in dry media under microwave irradiation leads to isoxazolyl triazinethiones (3) in high yield. Condensa

Full text of DOI:10.1002/jhet.5570420437

May-Jun 2005
711
Microwave-assisted Synthesis of New Isoxazolyl triazinethiones
and Isoxazolyl oxadiazinethiones in Dry Media
E. Rajanarendar*, K. Ramu, D. Karunakar and P. Ramesh
Department of Chemistry, Kakatiya University, Warangal – 506 009, India
Received October 5, 2004
Trimolecular condensation of N-(3-methyl-5-styryl-isoxazol-4-yl)-N'-aryl thioureas (2), paraformalde-
hyde and primary amines using montmorillonite K-10 in dry media under microwave irradiation leads to
isoxazolyl triazinethiones (3) in high yield. Condensation of 2 with paraformaldehyde alone under similar
conditions provide isoxazolyl oxadiazinethiones (4) in excellent yield.
J. Heterocyclic Chem., 42, 711 (2005).
Introduction.
normal conventional heating mode [14]. The trimolecular
condensation of primary amines, N,N'-unsymmetrical
substituted thioureas (2) and paraformaldehyde supported
on montmorillonite K-10 under microwave irradiation in
dry media led to the formation of new 1-(3-methyl-5-
styryl-isoxazol-4-yl)-3-aryl/alkyl-5-alkyl-hexahydro-
1,3,5-triazine-2-thiones (3) in high yields within 5 min-
utes (Scheme 1). When the reaction was conducted under
conventional heating mode, it required 4-5 hours and the
product yield was poor (Table 1). Similarly, condensation
of N,N'-disubstituted thioureas (2) and paraformaldehyde
supported on montmorillonite K-10 clay under solvent-
free conditions using microwave irradiation resulted new
3-(3-methyl-5-styryl-isoxazol-4-yl)-2,3,5,6-tetrahydro-
4H-5-aryl/alkyl-1,3,5-oxadiazine-4-thiones (4) in good
yields in 5 minutes (Scheme 2). Conventional heating
using ethanol and excess conc. HCl and formalin solution
in the same reaction required 4-5 hours and resulted in
very low yield of the product (Table 1) and it also
involves environmental problem, as disposal of excess
catalyst leads to environmental pollution.
Microwave dielectric heating has been widely exploited
for the acceleration of organic reactions during the last
decade [1-3]. Microwave irradiation in solvent-free condi-
tions has attracted much significance in organic synthesis
[4-6]. K-10 clays as catalysts have received considerable
attention and have been employed in several organic reac-
tions [7-9]. As a sequel to our work on isoxazole deriva-
tives synthesis [10-12], we now wish to report an efficient
and simple procedure for the synthesis of isoxazolyl tri-
azinethiones through trimolecular condensation of primary
amines, isoxazolyl thioureas and paraformaldehyde using
montmorrillonite K-10 clay under microwave irradiation
in dry media and also isoxazolyl oxadiazinethiones by two
component condensation of isoxazolyl thioureas with
paraformaldehyde. Very few reports [13] are available in
the literature concerning the synthesis of unsymmetrical
substituted triazinethiones and oxadiazinethiones under
conventional heating conditions.
Results and Discussion.
Montmorrillonite K-10 has Lewis acid character and it
appears that paraformaldehyde is slowly decomposed to
formaldehyde, which then reacts with the primary amine to
give an amine-formaldehyde adduct which leads to an
iminium species, which then reacts with the nitrogen atom
of N,N'-disubstituted thiourea (2) to form the first N-C-N
The reaction of 4-amino-3-methyl-5-styryl isoxazole
(1) with alkyl/arylisothiocyanates in toluene under
microwave irradiation afforded N-(3-methyl-5-styryl-
isoxazol-4-yl)-N'-arylthioureas (2) in excellent yields. It
is significant to note that the microwave reaction is com-
pleted within 1.0 minute compared to 4-6 hours under
Scheme 1
3a = R = CH , R’ = CH
3e = R = CH , R' = CH CH CH
3 2 2 3
3
3
3b = R = Ph, R' = CH
3f = R = Ph, R' = CH CH CH
3
2 2 3
3c = R = CH , R' = CH CH
3g = R = CH , R' = CH CH CH CH
3 2 2 2 3
3
2
3
3d = R = Ph, R' = CH CH
3h = R = Ph, R' = CH CH CH CH
2
3
2 2 2 3

712
E. Rajanarendar, K. Ramu, D. Karunakar and P. Ramesh
Vol. 42
Scheme 2
4a = R = CH , 4b = R = Ph, 4c = R = C H -Br(p), 4d = R = C H -CH (p)
3
6
4
6
4
3
Scheme 3

May-Jun 2005
Microwave-assisted Synthesis of New Isoxazolyl triazinethiones
713
Table 1
Synthesis of Isoxazolyl Triazinethiones 3 and Isoxazolyl Oxadiazinethiones 4: Comparison Between Conventional Heating
and Microwave-assisted Methods
Entry
R
R'
Conventional heating method
Time
(hrs)
Microwave-assisted method
Yield [a]
%
Yield [a] %
Time
(min)
3a
3b
3c
3d
3e
3f
CH3
Ph
CH3
CH3
5
5
5
4
4
5
4
5
4
4
5
4
40
40
40
40
40
35
35
30
35
30
25
30
5
6
5
5
4
5
5
4
4
4
4
4
80
90
85
80
90
85
80
85
85
80
80
85
CH3
Ph
CH2CH3
CH2CH3
CH2CH2CH3
CH2CH2CH3
CH2CH2CH2CH3
CH2CH2CH2CH3
CH3
Ph
3g
3h
4a
4b
4c
4d
CH3
Ph
CH3
Ph
--
--
--
--
p-BrC6H4
p-CH3C6H4
[a] Isolated yields after column chromatography.
Method A (Conventional).
bond. Thermal generation of second iminium electrophile,
triggers ring closure to give the triazinethione (3)
(Scheme 3). Formation of oxadiazinethione (4) could
occur by the nucleophilic attack of urea nitrogen on
formaldehyde followed by dehydration on the surface of
the catalyst (Scheme 3). Montmorillonite K-10 besides
giving solid support also acts as a catalyst in these
processes.
A mixture of N,N'-disubstituted thiourea 2 (1 mmol) 30%
formaldehyde (1 mmol) and primary amine (1 mmol) in toluene
(10 ml) was heated under reflux for 4-5 hours. The solvent was
distilled off, the residue was triturated with petroleum ether and
the crude product obtained was chromatographed over a silica gel
column. Elution with ethyl acetate afforded triazinethione.
Method B(MORE-Microwave-induced Organic Reaction
Enhancement).
Conclusion.
A mixture of N,N'-disubstituted urea 2 (1 mmol),
paraformaldehyde (0.5 g) and primary amine (1 mmol) and 1 g
montmorillonite K-10 were irradiated by microwave at 540 watts
in a Teflon vessel for 5 minutes. The reaction mixture was
extracted with dichloromethane, filtered and washed with water.
The organic phase was separated and concentrated by rotary
evaporator. The crude product was chromatographed over a sil-
ica gel column. Elution with ethyl acetate afforded the products
In summary, we have developed an efficient and high
yield procedure for the synthesis of new isoxazolyl tri-
azinethiones (3) and isoxazolyl oxadiazinethiones (4) in dry
media using K-10 clay. To the best of our knowledge this
represents the first report on the synthesis of triazinethiones
and oxadiazinethiones substituted with isoxazole moiety by
using microwave irradiation by trimolecular condensation
and two-component condensation respectively.
1
3. All the products were characterized by IR, H NMR, Mass
spectral and elemental analysis data.
1-(3-Methyl-5-styryl-isoxazol-4-yl)-3,5-dimethyl-hexahydro-
1,3,5-triazin-2-thione (3a).
EXPERIMENTAL
This compound was obtained as colourless crystals; mp 154
Microwave irradiation was carried out in LG microwave oven,
model No. LGMS 257PL (2450 MHz, 900 watts). Analytical
-1
1
°C; IR: 1232 (C=S) cm ; H NMR: δ 2.32 (s, 3H, isoxazole
CH ), 2.83 (s, 3H, NCH -5), 3.54 (s, 3H, NCH -3), 4.42 (s, 2H,
3
3
3
TLC was performed on Merck precoated 60 F silica gel plates.
254
CH -4), 4.62 (s, 2H, CH -6), 6.62 (d, J = 15 Hz, 1H, CH =CH),
2
2
α
Melting points were determined on a Cintex melting point appa-
ratus and are uncorrected. IR spectra (KBr pellet) were obtained
6.75 (d, J = 15 Hz, 1H, CH=CH ), 7.12-7.53 (m, 5H, H
(m/z 328, M , 20%), (m/z 243, 100%).
); MS:
β
arom
+
1
on a Perkin Elmer BX series FT-IR spectrophotometer. H NMR
Anal. Calcd. for C
H N OS: C, 62.19; H, 6.09; N, 17.07.
17 20 4
spectra were obtained on a Varian Gemini instrument at 300 MHz
Found: C, 62.18; H, 6.09; N, 17.08.
in CDCl using TMS as internal standard. Mass spectra were
3
recorded using JEOL JMC D-300 spectrometer at 70 eV. The sil-
ica gel (0.040 x 0.063 mm) used for column chromatography was
purchased from Merck. C, H and N analyses were carried out on
a Carlo Erba 106 and Perkin-Elmer model 240 analysers.
1-(3-Methyl-5-styryl-isoxazol-4-yl)-3-phenyl-5-methyl-hexahy-
dro-1,3,5-triazin-2-thione (3b).
This compound was obtained as colourless cryatals; mp 188 °C;
-1
1
IR: 1225 (C=S) cm ; H NMR: δ 2.30 (s, 3H, isoxazole CH ),
3
General Procedure for the Synthesis of 1-(3-Methyl-5-styryl-
isoxazol-4-yl)-3-aryl/alkyl-5-alkyl-hexahydro-1,3,5-triazin-2-
thiones (3a-h).
2.82 (s, 3H, NCH -5), 4.61 (s, 2H, CH -4), 4.84 (s, 2H, CH -6),
3 2 2
6.82 (d, J = 15 Hz, 1H, CH =CH), 6.95 (d, J = 15Hz, 1H,
α
+
CH=CH ), 7.00-7.62 (m, 10H, H
); MS: (m/z 390, M , 100%).
β
arom

714
E. Rajanarendar, K. Ramu, D. Karunakar and P. Ramesh
Vol. 42
Anal. Calcd. for C
Found: C, 67.70; H, 5.66; N, 14.39.
H
N OS: C, 67.69; H, 5.64; N, 14.35.
dro-1,3,5-triazin-2-thione (3h).
This compound was obtained as colourless crystal; mp 165 °C;
22 22
4
-1
1
IR: 1225 (C=S) cm ; H NMR: δ 1.02 (t, J = 6.2Hz, 3H, CH ),
1-(3-Methyl-5-styryl-isoxazol-4-yl)-3-methyl-5-ethyl-hexahy-
3
1.35 (m, J = 6.2Hz, 2H, CH ), 1.62 (m, J = 6.2Hz, 2H, CH ), 2.32
dro-1,3,5-triazin-2-thione (3c).
2
2
(s, 3H, isoxazole CH ), 3.12 (t, J = 6.2Hz, 2H, CH ), 4.52 (s, 2H,
3
2
This compound was obtained as colourless crystals; mp 110
CH -4), 4.75 (s, 2H, CH -6), 6.97 (d, J = 15 Hz, 1H, CH =CH),
2
2
α
-1
1
°C; IR: 1220 (C=S) cm ; H NMR: δ 1.22 (t, J = 7.5Hz, 3H,
CH ), 2.42 (s, 3H, isoxazole CH ), 3.23 (q, J=7.5Hz, 2H, CH ),
7.12 (d, J = 15Hz, 1H, CH=CH ,), 7.23 – 7.65 (m, 10H, H
MS: (m/z 432, M , 10%), (m/z 131, 100%).
);
β
arom
3
3
2
+
3.52 (s, 3H, NCH -3), 4.54 (s, 2H, CH -4), 4.60 (s, 2H, CH -6),
3
2
2
Anal. Calcd. for C
H N OS: C, 69.44; H, 6.48; N, 12.96.
25 28 4
6.61 (d, J = 15Hz, 1H, CH =CH), 6.80 (d, J = 15 Hz, 1H,
α
Found: C, 69.45; H, 6.48; N, 12.95.
+
CH=CH ), 7.00-7.42 (m, 5H, H
); MS: (m/z, 342, M , 20%),
β
arom
General Procedure for the Synthesis of 3-(3-Methyl-5-styryl-
isoxazol-4-yl)-2,3,5,6-tetrahydro-4H-5-aryl/alkyl-1,3,5-oxadi-
azine-4-thiones(4a-d).
(m/z 131, 100%).
Anal. Calcd. for C
H N OS : C, 63.15; H, 6.43; N, 16.37.
18 22 4
Found: C, 63.14; H, 6.44; N, 16.36.
Method A (Conventional).
1-(3-Methyl-5-styryl-isoxazol-4-yl-3-phenyl-5-ethyl-hexahydro-
N,N'-Disubstituted thiourea 2 (1 mmol) was added with stir-
ring to 30% formaldehyde solution (1 mmol) and the mixture
treated with conc. HCl (1 ml). After heating at 90-95 °C for 4-5
hours, the reaction mixture (monitored by TLC) was cooled and
neutralized with NaOH. The solid thus obtained was collected by
filtration and chromatographed using silica gel column. Elution
with benzene:ethyl acetate (1:1) afforded the oxadiazine thiones.
1,3,5-triazin-2-thione (3d).
This compound was obtained as colourless crystals; mp 175
-1
1
°C; IR: 1230 (C=S) cm ; H NMR: δ 1.20 (t, J = 7.5Hz, 3H,
CH ), 2.40 (s, 3H, isoxazole CH ), 3.22 (q, J= 7.5Hz, 2H, CH ),
3
3
2
4.52 (s, 2H, CH -4), 4.71 (s, 2H, CH -6), 6.80 (d, J = 15 Hz, 1H,
2
2
CH = CH), 7.02 (d, J = 15 Hz, 1H, CH=CH ); 7.11-7.52 (m,
α
β
+
10H, H
); MS: (m/z 404, M , 10%), (m/z 131, 100%).
arom
Anal. Calcd. for C
H N OS: C, 68.31; H, 5.94; N, 13.86.
Method B (MORE).
23 24 4
Found: C, 68.31; H, 5.95; N, 13.86.
A mixture of N,N'-disubstituted thiourea 2 (1 mmol) and
paraformaldehyde (0.5 g) and montmorillonite K-10 (1 g) was
irradiated by microwave at 540 watt in a Teflon vessel for 5 min-
utes. The reaction was extracted with dichloromethane, filtered
and washed with water. The organic layer was separated and
vacuum distilled then the crude residue, on passing through silica
gel column, afforded the products 4 by elution with benzene:eth-
1-(3-Methyl-5-styryl-isoxazol-4-yl)-3-methyl-5-n-propyl-hexa-
hydro-1,3,5-triazin-2-thione (3e).
This compound was obtained as colourless crystals; mp 105
-1
1
°C; IR: 1225 (C=S) cm ; H NMR: δ 1.02 (t, J = 7.0Hz, 3H,
CH ), 1.32 (m, J = 7.0Hz, 2H, CH ), 2.35 (s, 3H, isoxazole CH ),
3
2
3
3.01 (t, J = 7.0Hz, 2H, CH ), 3.52 (s, 3H, NCH -3), 6.67 (d, J =
2
3
1
ylacetate (1:1). All the products were characterized by IR, H
NMR, Mass spectral and elemental analysis data.
15 Hz, 1H, CH =CH), 6.85 (d, J = 15Hz, 1H, CH=CH ), 7.00 –
α
β
+
7.35 (m, 5H, H
); MS: (m/z 356, M , 25%), (m/z 131, 100%).
arom
Anal. Calcd. for C
Found: C, 64.03; H, 6.75; N, 15.70.
H N OS: C, 64.04; H, 6.74; N, 15.73.
3-(3-Methyl-5-styryl-isoxazol-4-yl)-2,3,5,6-tetrahydro-4H-5-
methyl-1,3,5-oxadiazin-4-thione (4a).
19 24 4
This compound was obtained as colourless crystals; mp 130
°C; IR : 1120 (C-O-C), 1230 (C=S) cm , H NMR: δ 2.30 (s, 3H,
1-(3-Methyl-5-styryl-isoxazol-4-yl)-3-phenyl-5-n-propyl-hexa-
hydro-1,3,5-triazin-2-thione (3f).
-1 1
isoxazole CH ), 3.32 (s, 3H, NCH ), 4.80 (s, 2H, CH -6), 5.05 (s,
3
3
2
This compound was obtained as colourless crystals; mp 170
2H, CH -2), 6.72 (d, J = 15 Hz, 1H, CH =CH), 6.92 (d, J = 15
2
α
-1
1
°C; IR: 1222 (C=S) cm ; H NMR: δ 1.12 (t, J = 7.0Hz, 3H,
CH ), 1.40 (m, J = 7.0Hz, 2H, CH ), 2.35 (s, 3H, isoxazole CH ),
+
Hz, 1H, CH=CH ), 7.00-7.45 (m, 5H, H
); MS: (m/z 315, M ,
β
arom
3
2
3
20%), (m/z 131, 100%).
3.12 (t, J = 7.0Hz, 2H, CH ), 4.42 (s, 2H, CH -4), 4.66 (s, 2H,
2
2
Anal. Calcd. for C
H N O S: C, 60.95; H, 5.39; N, 13.33.
16 17 3 2
CH -6), 6.80 (d, J = 15Hz, 1H, CH =CH), 6.94 (d, J = 15 Hz, 1H,
2
α
Found: C, 60.96; H, 5.38; N, 13.30.
+
CH=CH ), 7.05 – 7.44 (m, 10H, H
); MS (m/z 418, M ,
β
arom
10%), (m/z 131, 100%).
3-(3-Methyl-5-styryl-isoxazol-4-yl)-2,3,5,6-tetrahydro-4H-5-
phenyl-1,3,5-oxadiazin-4-thione (4b).
Anal. Calcd. for C
H N OS: C, 68.89; H, 6.22; N, 13.39.
24 26 4
Found: C, 68.90; H, 6.21; N, 13.40.
This compound was obtained as colourless crystals; mp 140
°C; IR: 1125 (C-O-C), 1228 (C=S) cm ; H NMR: δ 2.25 (s, 3H,
-1
1
1-(3-Methyl-5-styryl-isoxazol-4-yl)-3-methyl-5-n-butyl-hexahy-
dro-1,3,5-triazin-2-thione (3g).
CH ), 4.80 (s, 2H, CH -6), 5.12 (s, 2H, CH -2), 6.85 (d, J = 15
3
2
2
Hz, 1H, CH =CH), 7.02 (d, J = 15 Hz, 1H, CH=CH ), 7.14-7.55
α
β
This compound was obtained as colourless crystals; mp 98 °C;
+
(m, 10H, H
); MS: (m/z 377, M , 10%), (m/z 131, 100%).
-1
1
arom
IR: 1220 (C=S) cm ; H NMR: δ 0.92 (t, J = 6.2Hz, 3H, CH ),
3
Anal. Calcd. for C
H N O S: C, 66.84; H, 5.03; N, 11.14.
21 19 3 2
1.30 (m, J = 6.2Hz, 2H, CH ), 1.55 (m, J = 6.2Hz, 2H, CH ), 2.32
2
2
Found: C, 66.85; H, 5.05; N, 11.18.
(s, 3H, isoxazole CH ), 3.05 (t, J = 6.2Hz, 2H, CH ), 3.52 (s, 3H,
3
2
NCH -5), 4.60 (s, 2H, CH -4), 4.82 (s, 2H, CH -6), 6.80 (d, J =
3-(3-Methyl-5-styryl-isoxazol-4-yl)-2,3,5,6-tetrahydro-4H-5-p-
bromophenyl-1,3,5-oxadiazin-4-thione (4c).
3
2
2
15 Hz, 1H, CH =CH), 7.02 (d, J = 15 Hz, 1H, CH=CH ), 7.22-
α
β
+
7.65 (m, 5H, H
); MS: (m/z 370, M , 100%).
arom
This compound was obtained as colourless crystals; mp 100
Anal. Calcd. for C
H N OS: C, 64.86; H, 7.02; N, 15.13.
20 26 4
-1
1
°C; IR: 1120 (C-O-C), 1225 (C=S) cm ; H NMR: δ 2.33 (s, 3H,
CH ), 4.90 (s, 2H, CH -6), 5.14 (s, 2H, CH -2), 6.82 (d, J = 15
Found: C, 64.89; H, 7.01; N, 15.15.
3
2
2
1-(3-Methyl-5-styryl-isoxazol-4-yl)-3-phenyl-5-n-butyl-hexahy-
Hz, 1H, CH =CH), 7.04 (d, J = 15 Hz, 1H, CH=CH ), 7.34-7.45
α
β

May-Jun 2005
Microwave-assisted Synthesis of New Isoxazolyl triazinethiones
715
[2] S. Caddick, Tetrahedron, 51, 10403 (1995).
[3] A. Loupus, A. Petit, A. Hamelin, F. Texier-Boullet, P. Jacqualt
and D. Mathe, Synthesis, 1213 (1998).
[4] L. Deloude and P. Laszlo, J. Org. Chem., 61, 6360 (1996).
[5] R. S. Varma and R. Dahiya, Syn. Lett., 857 (1997).
[6] R. S. Varma and H. M. Meshram, Tetrahedron Lett, 38, 7973
(1997).
(d, J = 8.0 Hz, 2H, p-bromophenyl), 7.60 – 7.72 (d, J = 8.0 Hz,
2H, p-bromophenyl); MS (m/z 456, M , 20%), (m/z 131, 100%).
+
Anal. Calcd. for C
H N O SBr: C, 55.26; H, 3.94; N, 9.21.
21 18 3 2
Found: C, 55.29, H, 3.95, N, 9.19.
3-(3-Methyl-5-styryl-isoxazol-4-yl)-2,3,5,6-tetrahydro-4H-5-p-
methylphenyl-1,3,5-oxadiazin-4-thione (4d).
[7] K. Smith, Solid Supports and Catalysts in Organic Synthesis,
Ellis Harwood, Chichester (1992).
[8] R.L. Augustine, Heterogenous Catalysis for the Synthetic
Chemists, Marcel Dekker, Inc., New York, 519-584 (1996).
[9] K. Toshima, Y. Ushilei, G. Matsuo and S. Matsumura,
Tetrahedron Lett., 38, 7375 (1997).
This compound was obtained as colourless crystals; mp 126
-1
1
°C; IR: 1120 (C-O-C), 1232 (C=S) cm ; H NMR: δ 2.40 (s, 3H,
CH ), 4.82 (s, 2H, CH -6), 5.04 (s, 2H, CH -2), 6.62 (d, J = 15
3
2
2
Hz, 1H, CH =CH), 6.80 (d, J = 15 Hz, 1H, CH=CH ), 7.02-7.12
α
β
(d, J = 7.5 Hz, 2H, p-methylphenyl), 7.20-7.55 (d, J = 7.5 Hz, 2H,
+
p-methylphenyl); MS: (m/z 432, M , 100%).
[10] E. Rajanarendar, M. Srinivas and K. Ramu, Synth. Commun.,
33(17), 3077 (2003).
Anal. Calcd. for C
H N O S: C, 67.51; H, 5.37; N, 10.74.
22 21 3 2
[11] E. Rajanarendar, D. Karunakar and M. Srinivas, Indian J.
Chem., 42B, 643 (2003).
Found: C, 67.48; H,5.38; N, 10.73.
[12] E. Rajanarendar, K. Ramu and M. Srinivas, Indian J.
Heterocyclic Chem., 13, 53 (2003).
[13] D. H. Clemens and W. D. Emmons, J. Org. Chem., 26, 767
(1961).
REFERENCES AND NOTES
E-mail: eligeti_rajan@yahoo.co.in; to whom correspon-
*
dence should be addressed.
[14] E. Rajanarendar, Md. Afzal and D. Karunakar, Indian J.
Chem., 42B, 353 (2003).
[1] R. A. Abramovitch, Org. Prep. Proc. Intl., 23, 68 (1991).