N-Methylimidazole-promoted efficient synthesis of 1,3-oxazine-4-thiones under solvent-free conditions

Article abstract of DOI:10.1007/s00706-008-0042-1

A novel method for oxazine ring formation is established using the reaction of ammonium thiocyanate and acid chlorides with napthols in the presence of N-methylimidazole to afford [1,3]oxazine-4-thione derivatives in excellent yields.

Full text of DOI:10.1007/s00706-008-0042-1

Monatsh Chem (2009) 140:467–471
DOI 10.1007/s00706-008-0042-1
SHORT COMMUNICATION
N-Methylimidazole-promoted efficient synthesis
of 1,3-oxazine-4-thiones under solvent-free conditions
Mohammad A. Khalilzadeh Æ Issa Yavari Æ
Zinatossadat Hossaini Æ Hasan Sadeghifar
Received: 17 May 2008 / Accepted: 10 July 2008 / Published online: 5 September 2008
Ó Springer-Verlag 2008
Abstract A novel method for oxazine ring formation is
established using the reaction of ammonium thiocyanate
and acid chlorides with napthols in the presence of
N-methylimidazole to afford [1,3]oxazine-4-thione deriv-
atives in excellent yields.
As part of our current studies on the development of new
routes in heterocyclic synthesis [17, 18], we report an
efficient synthesis of [1,3]oxazine-4-thiones.
Results and discussion
Keywords Oxazine Á 1-Naphthol Á 2-Naphthol Á
Benzoyl isothiocyanate Á Acid chloride
The reaction of ammonium thiocyanate (1) and acid
chlorides 2 with 1-naphtol (3) in the presence of N-meth-
ylimidazole led to 4 in 65–95% yields (Scheme 1).
Structures of compounds 4a–4g were confirmed by IR,
1H NMR, 13C NMR, and mass spectral data. For example,
Introduction
1
Oxazines constitute an important class of heterocycles,
which have attracted considerable synthetic interest due to
their wide range of biological activities [1–5]. Several
oxazines exhibit diverse pharmacological properties, such
as antagonism to progesterone receptor [6], antitumor [7],
antiviral [8, 9], antithrombotic [10], antimycobacterial
[11–13], anti-inflammatory [3], antidiabetic and hypolipi-
daemic [14] effects. Further to these applications, they
have also been reported as inhibitors of human leucocyte
elastase [15] and serotonin reuptake [16]. This prompted us
to establish a novel oxazine ring formation method to find
promising bioactive oxazine compounds.
the H NMR spectrum of 4a exhibited 11 proton reso-
nances and 18 carbon resonances, in agreement with the
proposed structure. The C=S group resonance in 13C NMR
spectra of 4a appears at 198.5 ppm. The mass spectrum of
4a displayed the molecular ion peak at m/z = 289.
A tentative mechanism for this transformation is pro-
posed in Scheme 2. It is conceivable that the reaction starts
with formation of alkanoyl or aroyl isothiocyanate 5,
R
N
OH
O
N
N
O
Me
S
+
NH4SCN
+
Cl
R
Solvent-Free, r.t.
1
2
3
4
Yield (%) of 4
2, 4
R
a
b
c
95
Ph
M. A. Khalilzadeh (&) Á Z. Hossaini Á H. Sadeghifar
Chemistry Department, Islamic Azad University,
PO Box 163, Qaemshahr, Iran
93
92
98
65
75
78
4-NO2-C6H4
4-Me-C6H4
4-Br-C6H4
4-Cl-C6H4
tBu
Et
d
e
f
g
e-mail: m.khalilzadeh@hotmail.com
I. Yavari
Chemistry Department, Tarbiat Modares University,
PO Box 14115-175, Tehran, Iran
Scheme 1
123

468
M. A. Khalilzadeh et al.
Scheme 2
N
O
S
O
NMe
+
N
3
1 + 2
N
N
C
S
R
R
_
NMe
5
6
_
O
R
O
NH
O
O
S
N
_
NMe
+
N
S
+
N
R
H
NMe
H
8
7
9
R
OH
NH
O
_
H2O
S
4
10
N
N
R
S
N
R
N
OH
O
N
OH
N
Me
O
O
Me
O
+
NH4SCN
+
Cl
R
S
Solvent-Free, r.t.
NH4SCN
+
+
Cl
R
12
1
11
2
Solvent-Free, r.t.
Yield (%) of 12
2, 12
R
13
2
1
14
a
b
c
Ph
90
93
4-NO2-C6H4
4-Me-C6H4 89
4-Br-C6H4 96
Yield (%) of 14
2, 14
R
a
b
Ph
85
90
d
e
4-Cl-C6H4
56
4-NO2-C6H4
Scheme 3
Scheme 4
followed by formation of the 1:1 adducts 6 and its sub-
sequent protonation by 1-naphthol to produce 7. Then, the
positively charged ion 7 is attacked by the anion of naph-
thol 8. Intermediate 9 undergoes cyclization reaction and
elimination of water to produce 4.
the starting material can be used without any activation or
modification.
Experimental
Also, the reaction of ammonium thiocyanate and acid
chlorides with 2-naphtol (11) in the presence of N-meth-
ylimidazole led to 12 in excellent yields (Scheme 3).
Structures of compounds 12a–e were assigned by IR, 1H
NMR, 13C NMR and mass spectral data. For example, the
1H NMR spectrum of 12a exhibited 11 proton resonances
and 18 carbon resonances in agreement with the proposed
structure. The C=S group resonance in 13C NMR spectra of
12a appear at 200.1 ppm. The mass spectrum of 12a dis-
played the molecular ion peak at m/z = 289. The reaction
of ammonium thiocyanate, acid chlorides with phenol 13 in
the presence of N-methylimidazole led to 14 in excellent
yields (Scheme 4).
N-methyl imidazole, 1-naphthol, 2-naphthol, phenol, acid
chlorides and ammonium thiocyanate were obtained from
Fluka and were used without further purification. Mp.:
Electrothermal-9100 apparatus; uncorrected. IR Spectra:
1
Shimadzu IR-460 spectrometer. H-, 13C-, and 31P-NMR
spectra: Bruker DRX-500 AVANCE instrument; in CDCl3
at 500.1, 125.7, and 202.4 MHz, respectively; d in ppm, J
in Hz. EI–MS (70 eV): Finnigan-MAT-8430 mass spec-
trometer, in m/z. Elemental analyses (C, H, N) were
performed with a Heraeus CHN–O–Rapid analyzer.
General procedure for the preparation of compounds 4,
12 and 14
In conclusion, the reaction of ammonium thiocyanate
and acid chlorides with naphthols in the presence of
N-methylimidazole led to 1,3-oxazine derivatives in
excellent yields. The present procedure has the advantage
that the reaction is performed under neutral conditions and
To ammonium isothiocyanate (0.15 g, 2 mmol) in a 50-ml
flask at r.t. was added acid chloride (2 mmol) via syringe.
The reaction mixture was stirred in a water bath at about
123

N-Methylimidazole-promoted efficient synthesis
469
2-(4-Bromophenyl)-4H-naphtho[2,1-e][1,3]oxazine-4-
thione (4d, C18H10BrNOS)
90 °C for 5 min. Then, naphthol (2 mmol) was added at
this temprature. The reaction mixture was allowed to cool
to room temperature. Finally, 0.032 g N-methylimidazole
(10 mol%) was added via syringe. The resulting mixture
was stirred at r.t. for 12 h. The progress of the reaction was
monitored by TLC analysis with 7:1 n-hexane-EtOAc as
eluent and visualisation with UV (254 nm). After com-
pletion of the reaction, 15 ml distilled water was added
over 5 min to the reaction mixture. The resulting precipi-
tate was collected by filtration on a Buchner funnel and
washed with 10 ml of cold (0 °C) diethyl ether to afford
the pure title compounds.
Yellow powders, mp 122–124°; yield 0.72 g (98%); IR
(KBr): ꢀm = 1,663, 1,573, 1,390, 1,240, 1,214 and
1,172 cm-1; EI-MS: 334 (M?, 5), 257 (68), 142 (48),
179 (45), 155 (100); 1H NMR: 7.39 (1 H, d, 3J = 7.5, CH),
3
7.49–7.55 (2 H, m, 2 CH), 7.71 (2 H, d, J = 8.1, 2 CH),
7.80 (1 H, d, 3J = 7.5, CH), 7.90–7.93 (2 H, m, 2 CH), 8.20
3
(2 H, d, J = 8.1, 2 CH) ppm; 13C NMR: 118.2 (CH),
121.2 (CH), 125.5 (CH), 126.3 (C), 126.6 (CH), 126.7
(CH), 126.9 (C), 128.2 (CH), 128.4 (C), 129.1 (C), 131.8 (2
CH), 132.2 (2 CH), 134.8 (C), 146.7 (C), 164.5 (C), 199.5
(C=S).
2-Phenyl-4H-naphtho[2,1-e][1,3]oxazine-4-thione
(4a, C18H11NOS)
2-(4-Chlorophenyl)-4H-naphtho[2,1-e][1,3]oxazine-4-
thione (4e, C18H10ClNOS)
Pale yellow powders, m.p. 107–109°; yield 0.55 g (95%); IR
ꢀ
Yellow powders, mp 120–122°; yield 0.42 g (65%); IR
(KBr): m = 1,654, 1,584, 1,443, 1,388, 1,263 and
1,215 cm-1; EI–MS: 289 (M?, 5); 212 (65); 147 (64); 142
(42); 77 (100); 1H NMR: 7.56–7.64 (5 H, m, 5 CH), 7.72 (1 H,
t, 3J = 7.3, CH), 7.89 (1 H, d, 3J = 7.3, CH), 8.00 (2 H, t,
3J = 8.2, 2 CH), 8.16 (1 H, t, 3J = 7.4, CH), 8.51 (1 H, d,
3J = 7.3, CH) ppm; 13C NMR: 118.6 (CH), 121.6 (CH),
125.8 (CH), 126.3 (CH), 126.7 (CH), 126.8 (CH), 127.3 (C),
128.4 (CH), 128.9 (2 CH), 129.7 (C), 130.5 (2 CH), 134.0
(C), 135.0 (C), 147.2 (C), 165.4 (C), 198.5 (C=S) ppm.
ꢀ
(KBr): m = 1,598, 1,575, 1,397, 1,256, 1,225 and
1,183 cm-1; EI–MS: 323 (M?, 10), 286 (74), 212 (66),
126 (56), 77 (64), 111(100); 1H NMR: 7.35 (1 H, d,
3J = 7.4), 7.40–7.48 (2 H, m, 2 CH), 7.70 (2 H, d,
3J = 7.6, 2 CH), 7.83 (1 H, d, 3J = 7.4, CH), 7.91–7.94 (2
H, m, 2 CH), 8.22 (2 H, d, 3J = 7.6, 2 CH) ppm; 13C NMR:
118.3 (CH), 121.5 (CH), 125.7 (CH), 126.4 (C), 126.7
(CH), 126.9 (CH), 127.1 (C), 128.4 (CH), 128.5 (C), 129.5
(C), 132.0 (2 CH), 132.4 (2 CH), 135.0 (C), 145.2 (C),
164.4 (C), 199.1 (C=S) ppm.
2-(4-Nitrophenyl)-4H-naphtho[2,1-e][1,3]oxazine-4-
thione (4b, C18H10N2O3S)
2-(Tert-butyl)-4H-naphtho[2,1-e][1,3]oxazine-4-thione
(4f, C16H15NOS)
Yellow powders, mp 167–169°; yield 0.62 g (93%); IR
ꢀ
(KBr): m = 1,657, 1,592, 1,512, 1,391, 1,345 and
1,250 cm-1; EI–MS: 334 (M?, 15), 257 (46), 212 (74),
Yellow powders, mp 120–122°; yield 0.40 g (75%); IR
1
77 (68), 122 (100); H NMR: 7.41 (1 H, d, J = 7.5, CH),
3
ꢀ
(KBr): m = 1,625, 1,570, 1,389, 1,265, 1,220 and
1,100 cm-1; EI–MS: 269 (M?, 10), 212 (82), 192 (62),
3
7.51–7.56 (2 H, m, 2 CH), 7.81 (1 H, d, J = 7.5, CH),
77 (47), 57 (100); 1H NMR: 1.18 (9 H, s, 3 Me), 7.30 (1 H,
3
7.88–7.93 (2 H, m, 2 CH), 8.32 (2 H, d, J = 8.0, 2 CH),
3
d, J = 7.4, CH), 7.40–7.46 (2 H, m, 2 CH), 7.80 (1 H, d,
8.43 (2 H, d, 3J = 8.0, 2 CH) ppm; 13C NMR: 118.1 (CH),
120.9 (CH), 123.8 (2 CH), 125.5 (C), 126.6 (CH), 126.7
(CH), 126.8 (C), 126.9 (CH), 128.3 (CH), 131.4 (2 CH),
134.7 (C), 134.8 (C), 146.5 (C), 151.0 (C), 163.4 (C), 197.5
(C=S) ppm.
3
3J = 7.6, CH), 7.91 (1 H, d, J = 7.5, CH), 8.75 (1 H, d,
3J = 7.6, CH) ppm; 13C NMR: 27.0 (3 Me), 41.5 (C),
122.5 (CH), 123.8 (CH), 124.1 (C), 124.9 (CH), 125.8
(CH), 126.4 (C), 128.2 (CH), 131.4 (CH), 138.4 (C), 150.8
(C), 180.6 (C), 201.4 (C=S) ppm.
2-(4-Methylphenyl)-4H-naphtho[2,1-e][1,3]oxazine-4-
thione (4c, C19H13NOS)
2-Ethyl-4H-naphtho[2,1-e][1,3]oxazine-4-thione
(4 g, C14H11NOS)
Pale brown powders, mp 114–116°; yield 0.56 g (92%); IR
ꢀ
Yellow powders, mp 118–120°; yield 0.38 g (78%); IR
(KBr): m = 1,672, 1,594, 1,393, 1,265, 1,216 and
1,179 cm-1; EI–MS: 303 (M?, 15), 226 (46), 213 (72),
ꢀ
(KBr): m = 1,632, 1,582, 1,391, 1,265, 1,321 and
1,254 cm-1; EI–MS: 241 (M?, 15), 212 (68), 164 (78),
77 (66), 90 (100); 1H NMR: 2.50 (3 H, s, Me), 7.38 (1 H, d,
1
3
3
3J = 7.3, CH), 7.41 (1 H, d, J = 7.3, CH), 7.50 (1 H, t,
77 (62), 29 (100); H NMR: 1.35 (3 H, t, J = 7.5, Me);
2.65 (2 H, q, 3J = 7.5, OCH2); 7.41 (1 H, d, 3J = 7.5, CH),
7.47–7.54 (2 H, m, 2 CH), 7.74 (1 H, d, 3J = 7.8, CH), 7.84
3J = 7.4, CH), 7.53 (2 H, d, 3J = 7.8, 2 CH), 7.80 (1 H, d,
3
3J = 7.4, CH), 7.90 (1 H, d, J = 7.3, CH), 7.98 (1 H, d,
3
3
3
3J = 7.3, CH), 8.26 (2 H, d, J = 7.8, 2 CH) ppm; 13C
(1 H, d, J = 7.5, CH), 8.72 (1 H, d, J = 7.8, CH) ppm;
13C NMR: 9.25 (Me); 21.4 (CH2), 123.2 (CH), 124.0 (CH),
124.4(C), 125.3 (CH), 126.7 (CH), 127.1 (C), 127.9 (CH),
132.2 (CH), 137.5 (C), 149.8 (C), 177.6 (C), 202.4 (C=S)
ppm.
NMR: 21.8 (Me), 118.3 (CH), 121.4 (CH), 125.5 (C), 126.0
(CH), 126.5 (CH), 126.6 (CH), 126.8 (C), 127.2 (C), 128.1
(CH), 129.5 (2 CH), 130.4 (2 CH), 134.8 (C), 144.7 (C),
147.0 (C), 165.3 (C), 198.1 (C=S) ppm.
123

470
M. A. Khalilzadeh et al.
3-Phenyl-1H-naphtho[1,2-e][1,3]oxazine-4-thione
(12a, C18H11NOS)
127.9 (CH), 128.6 (C), 128.9 (C), 129.6 (CH), 131.6 (C),
131.7 (2 CH), 132.0 (2 CH), 133.9 (C), 148.5 (C), 164.7
(C), 199.6 (C=S) ppm.
Pale yellow powders, mp 103–105°; yield 0.52 g (90%); IR
(KBr): ꢀm = 1,637, 1,616, 1,583, 1,497, 1,441 and
1,352 cm-1; EI–MS: 289 (M?, 10), 212 (46); 147 (86),
3-(4-Chlorophenyl)-1H-naphtho[1,2-e][1,3]oxazine-4-
thione (12e, C18H10ClNOS)
1
142 (64), 77 (100); H NMR: 7.50–7.54 (2 H, m, 2 CH),
Yellow powders, mp 121–123°; yield 0.36 g (56%), IR
3
3
7.56 (2 H, d, JHH = 7.9, 2 CH), 7.66 (1 H, t, JHH = 7.4,
-1
ꢀ
(KBr): m = 1,615, 1,572, 1,200, 1,169 and 1,154 cm
;
3
CH), 7.75 (1 H, d, JHH = 7.6, CH), 7.86 (1 H, d,
EI–MS: 323 (M?, 5), 286 (65), 212 (42), 126 (54), 77 (86),
111 (100); 1H NMR: 7.52–7.57 (2 H, m, 2 CH), 7.64 (2 H,
d, 3J = 7.5, 2 CH), 7.71 (1 H, d, 3J = 7.4, CH), 7.84 (1 H,
d, 3J = 7.3, CH), 7.91 (1 H, d, 3J = 7.4, CH), 7.96 (1 H, d,
3JHH = 7.5, CH), 7.90 (1 H, d, 3JHH = 7.4, CH), 7.93 (1 H,
d, 3JHH = 7.5, CH), 8.31 (2 H, d, 3JHH = 7.9, 2 CH) ppm;
13C NMR: 118.8 (CH), 121.3 (CH), 125.8 (CH), 126.7
(CH), 127.8(C), 127.9 (CH), 128.7 (2 CH), 129.5 (C),
129.8 (CH), 130.3 (2 CH), 131.6 (CH), 133.7 (C), 134.0
(C), 148.8 (C), 165.4 (C), 200.1 (C=S) ppm.
3J = 7.3, CH), 8.22 (2 H, d, J = 7.5, 2 CH) ppm; 13C
3
NMR: 118.6 (CH), 122.4 (CH), 126.1 (C), 126.8 (CH),
128.2 (CH), 128.4 (CH), 129.1 (C), 129.8 (C), 130.2 (CH),
131.4 (C), 131.9 (2 CH), 132.7 (2 CH), 134.1 (C), 149.5
(C), 165.7 (C), 198.9 (C=S) ppm.
3-(4-nitrophenyl)-1H-naphtho[1,1-e][1,3]oxazine-4-thione
(12b, C18H10N2O3S)
Yellow crystals, mp 169–171°; yield 0.62 g (93%); IR
2-Phenyl-4H-[1,3]-benzoxazine-4-thione
(14a, C14H9NOS)
ꢀ
(KBr): m = 1,630, 1,618, 1,593, 1,514, 1,344 and
1,273 cm-1; EI–MS: 334 (M?, 5), 257 (66), 212 (82), 77
Yellow powders, mp 114–116°; yield 0.41 g (85%); IR
1
(42), 122 (100); H NMR: 7.49–7.55 (2 H, m, 2 CH), 7.71
ꢀ
(KBr): m = 1,658, 1,579, 1,443, 1,387, 1,258 and
3
(1 H, d, J = 7.5, 2 CH), 7.82 (1 H, d, J = 7.6, 2 CH),
3
1,210 cm-1; EI–MS: 239 (M?, 5), 187 (60), 162 (85), 77
(100), 54 (42); 1H NMR: 7.31–7.42 (4 H, m, 4 CH), 7.74 (2
H, t, 3J = 7.5, CH), 8.12 (2 H, d, 3J = 8.5, 2 CH), 8.64 (1
3
3
8.88 (1 H, d, J = 7.6, CH), 7.92 (1 H, d, J = 7.5, CH),
8.35 (2 H, d, 3J = 8.1, 2 CH), 8.40 (2 H, d, 3J = 8.1, 2 CH)
ppm; 13C NMR: 118.6 (CH), 120.7 (CH), 123.8 (2 CH),
126.1 (C), 126.9 (CH), 127.8 (CH), 127.9 (C), 129.7 (CH),
131.3 (2 CH), 131.7 (CH), 133.8 (C), 135.0 (C), 148.2 (C),
151.0 (C), 163.5 (C), 199.8 (C=S) ppm.
3
H, d, J = 7.6, CH) ppm; 13C NMR: 118.2 (CH), 122.0
(CH), 124.2 (C), 127.1 (CH), 128.4 (2 CH), 129.6 (2 CH),
131.7 (CH), 131.9 (C), 135.1 (CH), 151.7 (C), 167.3 (C),
200.1 (C=S) ppm.
3-(4-Methylphenyl)-1H-naphtho[1,1-e][1,3]oxazine-4-
thione (12c, C19H13NOS)
2-(4-Nitrophenyl-4H-[1,3]-benzoxazine-4-thione
(14b, C14H8N2O3S)
Yellow powders, mp 132–134°; yield 0.54 g (89%); IR
Yellow powders, mp 120–122°; yield 0.51 g (90%); IR
ꢀ
(KBr): m = 1,647, 1,593, 1,495, 1,264, 1,232 and
1,166 cm-1; EI–MS: 303 (M?, 15), 226 (52), 213 (94),
77 (86), 90 (100); 1H NMR: 2.48 (3 H, s, Me), 7.35 (2 H, d,
3J = 7.2, 2 CH), 7.50–7.56 (2 H, m, 2 CH), 7.76 (1 H, t,
ꢀ
(KBr): m = 1,578, 1,592, 1,440, 1,375, 1,241 and
1,151 cm-1; EI–MS: 284 (M?, 10), 230 (60), 164 (72),
1
120 (100), 54 (36); H NMR: 7.32–7.45 (3 H, m, 3 CH),
3
8.35 (2 H, d, J = 8.2, 2 CH), 8.41 (2 H, d, J = 8.2, 2
3
3
3J = 7.8, CH), 7.87 (1 H, d, J = 7.5, CH), 7.91 (1 H, d,
3
CH), 8.74 (1 H, d, J = 7.6, CH) ppm; 13C NMR: 119.3
3
3J = 7.5, CH), 7.93 (1 H, d, J = 7.6, CH), 8.21 (2 H, d,
3J = 7.6, 2 CH) ppm; 13C NMR: 21.8 (Me), 118.8 (CH),
121.5 (CH), 125.8 (CH), 126.6 (CH), 127.0 (C), 127.8
(CH), 127.9 (CH), 129.4 (2 CH), 129.5 (C), 130.4 (2 CH),
131.6 (C), 134.0 (C), 144.5 (C), 148.9 (C), 165.5 (C), 198.9
(C=S) ppm.
(CH), 126.1 (2 CH), 127.4 (2 CH), 127.8 (CH), 128.5 (C),
129.2 (CH), 131.2 (CH), 136.3 (C), 150.0 (C), 152.7 (C),
168.4 (C), 199.2 (C=S) ppm.
Acknowledgments Financial support of this work from the Research
Council of Qaemshahr Azad University is gratefully acknowledged.
3-(4-Bromophenyl)-1H-naphtho[1,1-e][1,3]oxazine-4-
thione (12d, C18H10BrNOS)
References
Yellow powders, mp 123–125°; yield: 0.64 g (96%); IR
(KBr): m = 1,618, 1,574, 1,264, 1,152 and 1,064 cm-1; EI-
ꢀ
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1H NMR: 7.48–7.53 (2 H, m, 2 CH), 7.66 (2 H, d, 3J = 7.6,
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3
CH), 7.87 (1 H, d, J = 7.4, CH), 7.90 (1 H, d, J = 7.3,
3
CH), 8.01 (2 H, d, J = 7.6, 2 CH) ppm; 13C NMR: 118.7
(CH), 121.1 (CH), 125.9 (C), 126.7 (CH), 127.7 (CH),
123

N-Methylimidazole-promoted efficient synthesis
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