Potassium carbonate, a support for the green synthesis of azoles and diazines

Article abstract of DOI:10.1002/jhet.5570390530

A novel potassium carbonate mediated synthesis of 2-amino-1,3-thia/oxa zoles, 2-amino-1,3,4-thia/oxa diazines and 2-hydrazino-1,3,4-thiadiazines has been described here. The use of K₂CO₃ allows for an aqueous workup thereby eliminating the organic solvent from both the reaction step and post reaction stage, without compromising the yield and reaction time.

Full text of DOI:10.1002/jhet.5570390530

Sep-Oct 2002
Potassium Carbonate, a Support for the Green Synthesis
of Azoles and Diazines
1045
M. Kidwai*, R. Venkataramanan and B. Dave
Department of Chemistry, University of Delhi, Delhi-110007, INDIA
E-mail: mkidwai@mantraonline.com
Received March 21, 2002
A novel potassium carbonate mediated synthesis of 2-amino-1,3-thia/oxa zoles, 2-amino-1,3,4-thia/oxa
diazines and 2-hydrazino-1,3,4-thiadiazines has been described here. The use of K CO allows for an aque-
2
3
ous workup thereby eliminating the organic solvent from both the reaction step and post reaction stage, with-
out compromising the yield and reaction time.
J. Heterocyclic Chem., 39, 1045 (2002).
The environmentally benign synthesis of organic com-
of azoles by using K CO and extend this methodology for
2 3
pounds has come several step closer in recent years [1,2,3],
to the removal of organic solvents from the synthetic pro-
cedure. Strict environmental legislation has forced the
chemist to develop alternate synthesis of biologically and
synthetically important compounds. The solid supported
reaction is a step forward in this direction, with the elimi-
nation of solvent from the synthetic step itself. The use of
solid support in organic synthesis [2,3], especially when
coupled with microwave irradiation not only reduce the
reaction time and enhances the yield considerably, but also
eliminates the requirement of solvent from the reaction
step. An appreciable amount of solvent though is still
required for adsorption of the reagents and elution of the
other similar reactions leading to synthesis of diazines.
Microwave irradiation of thiourea/urea (1) and substi-
tuted ω-bromoacetophenone (2), deposited over K CO
[7a], (approximate temperature [8] 100-115 °C) for
about 2-3 minutes yielded the corresponding 2-amino
thiazoles/oxazoles (3) (Scheme 1). Formation of the
product was confirmed by literature [6,9] melting point
and spectroscopic data. The encouraging results of
2
3
Scheme 1
product. This was overcome partially by the K CO medi-
2
3
ated synthesis, developed [4] successfully by us for the
synthesis of thiohydantoins, wherein elution of the product
required only water. This methodology avoided the use of
external base to neutralize the HCl evolved, and required
aqueous work up. Further coupling of this solventless syn-
thesis with microwaves had associated benefits of shorter
reaction time, uniform heating and better yield in compari-
son to conventional heating.
K CO mediated reactions as compared to alumina sup-
2
3
ported on (Table 1), clearly indicates that without com-
promising much with yield and reaction time, an envi-
ronmentally more benign methodology has been devel-
oped. Unlike the earlier work involving basic alumina,
the post reaction step requires aqueous workup and iso-
lation of product on filtration only.
Azoles are useful structural elements in medicinal chem-
istry. They are well known for their antifungal activity and
also have found application in drug development [5] for
the treatment of allergies, hypertension, inflammation and
HIV infections. Substituted thiazoles and oxazoles have
been prepared by the condensation of substituted aceto-
phenone/benzylidene-acetone dibromide and thiourea/urea
in the presence or absence of Iodine. These procedures are
quite expensive, requiring longer reaction time, tedious
workup and often give low yield. We had modified the
procedure in our lab [6] to a relatively clean, efficient and
economical method, using alumina as solid support under
microwave irradiation. Though about 60 ml of
dichloromethane was utilized in the procedure for the elu-
tion of the product, which has to be avoided for the synthe-
sis to be environmentally benign. Therefore, in continua-
This technique was further extended for the synthesis of
thiadiazines, a therapeutically important class of com-
pounds. Reaction of thiocarbohydrazide (4) instead of
thiourea, gave the required 2-hydrazinothiadiazines (5)
(Scheme 2). On the other hand reaction with (thio)semi-
carbazide (6), which being unsymmetrically substituted at
the (thio)carbonyl with a hydrazine and an amino group-
ing, is expected to give two different products; 2-amino-
(thia/oxa)diazines (7) and 2-hydrazino(thia/oxa)zoles (8)
(Scheme 2). Under this methodology we exclusively
obtained the thia/oxa diazines (7) in good yield (Table 1).
When the same reaction was pursued conventionally in
solution phase, three spots including the one correspond-
ing to diazine (7) were observed in TLC after about 5-6
hours of refluxing in ethanol.
For comparative study both the reactions for the synthe-
sis of 2-hydrazinothiadiazines (5) and 2-amino(thia/oxa)-
diazines (7) were pursued in basic alumina/microwave and
tion of work [4] on synthesis over K CO , it was thought
2
3
worthwhile to further modify the solid supported synthesis

1046
M. Kidwai, R. Venkataramanan and B. Dave
Vol. 39
1
Table 1
Reaction Time and Yield for the Azoles and (Thia)Oxadiazines
KBr discs. H NMR spectra were recorded at 60 MHz on FT-
NMR-Hitachi R-600 spectrometer using TMS as internal stan-
dard and with chemical shifts in δ ppm. Elemental analysis was
performed on a Hareaus CHN Rapid Analyser. The microwave
irradiation was carried out in a Kenstar domestic microwave
oven, model no. OM-9925E at 2450 MHz (using energy output
800 W). The purity of the compounds was checked using silica
gel coated Al plates (Merck). The synthesis of 2-hydrazino-5-(p-
aminophenyl)-1,3,4-thiadiazine (5a) is representative of the gen-
eral procedure employed.
Compound
Reaction time/sec. (yield/%) M.P. in °C
No.
X
R
Basic Alumina K CO
(lit.m.p.[6,9])
2
3
in MWI [a]
in MWI
3a
3b
3c
3d
S
S
Cl
NH
Cl
120 (95)
120 (94)
120 (92)
160 (93)
160 (90)
162-164
(163-164)
173-175
(174-175)
166-167
(165-167)
151-153
(150-152)
209-211
203-204
205-206
200-203
191-192
201-203
120 (94)
150 (96)
165 (92)
2
O
O
2-Hydrazino-5-(p-aminophenyl)-1,3,4-thiadiazine (5a).
NH
2
2
2
To a Methanolic solution of 0.01 mole of substituted p-amino-
ω-bromoacetophonone (2) (0.5 g) and 0.01 mole of thiocarbo-
5a
5b
7a
7b
7c
7d
S
S
S
S
O
O
NH
Cl
NH
Cl
Cl
NH
150 (94)
180 (87)
160 (90)
180 (89)
150 (95)
160 (92)
160 (95)
180 (86)
180 (90)
180 (90)
160 (92)
160 (92)
hydrazide (4) (0.248 g), added 15 g of K CO [7a]. The reaction
2
3
mixture was air dried and irradiated in a domestic microwave
oven (800 W, 2450 MHz) for 160 seconds. On completion of
reaction, as monitored by TLC (after every 30 seconds) the reac-
tion mixture was treated with cold water. The product 5a
obtained from filtration was dried and recrystallized from
methanol.
2
[a] Yield as reported in the literature reference [6] for 3a-3d. Only
synthesis of azoles over basic alumina has been reported in the literature.
The reaction was also pursued over basic alumina [7b],
wherein the product was obtained on elution with ethanol. The
-1
1
compound 5a had IR (KBr) in cm : 3433, 3313, 1594, 1523; H
NMR (CDCl ): δ 3.3 (s, 2H, CH ), 6.8-7.1 (m, 4H, Ar-H).
Scheme 2
3
2
Anal. Calcd. for C H N S: C, 48.88; H, 4.97; N, 31.65.
9
11 5
Found: C, 48.81; H, 4.99; N, 31.59.
2-Hydrazino-5-(p-chloro phenyl)-1,3,4-thiadiazine (5b).
-1
This compound had IR (KBr) in cm : 3430, 3315, 1602, 1522;
1
H NMR (CDCl ): δ 3.4 (s, 2H, CH ), 7.2-7.4 (m, 4H, Ar-H).
3
2
Anal. Calcd. for C H N SCl: C, 44.93; H, 3.74; N, 23.28.
9
9 4
Found: C, 44.89; H, 3.78; N, 23.25.
2-Amino-5-(p-amino phenyl)-1,3,4-thiadiazine (7a).
-1
This compound had IR (KBr) in cm : 3452, 3345, 1598, 1530;
1
H NMR (CDCl ): δ 3.4 (s, 2H, CH ), 7.2-7.4 (m, 4H, Ar-H).
3
2
Anal. Calcd. for C H N S: C, 52.43; H, 4.85; N, 27.16.
9
10 4
Found: C, 52.38; H, 4.82; N, 27.21.
K CO /conventional heating. Over basic alumina under
2
3
2-Amino-5-(p-chloro phenyl)-1,3,4-thiadiazine (7b).
microwave irradiations, the reaction was marginally faster
with not much improvement in yield. Though, the product
obtained on elution was crystalline and need not be recrys-
tallized as compared to the K CO mediated synthesis.
-1
This compound had IR (KBr) in cm : 3458, 3348, 1607, 1531;
1
H NMR (CDCl ): δ 3.5 (s, 2H, CH ), 7.2-7.5 (m, 4H, Ar-H).
3
2
Anal. Calcd. for C H N SCl: C, 47.91; H, 3.55; N, 18.62.
9
8 3
2
3
Found: C, 47.97; H, 3.52; N, 18.76.
Under conventional heating the K CO mediated reaction
2
3
was not facile and gave much impure product after 6-7
hours of heating over oil bath.
2-Amino-5-(p-chlorophenyl)-1,3,4-oxadiazine (7c).
-1
This compound had IR (KBr) in cm : 3450, 3346, 1598, 1531;
In conclusion, a novel environment friendly methodol-
ogy for the synthesis of thia/oxa diazoles and thia/oxa
diazines has been developed. The K CO mediated syn-
1
H NMR (CDCl ): δ 3.9 (s, 2H, CH ), 6.8-7.1 (m, 4H, Ar-H).
3
2
Anal. Calcd. for C H N OCl: C, 51.58; H, 3.82; N, 20.04.
9
8 3
Found: C, 51.56; H, 3.75; N, 20.07.
2
3
thesis under microwave irradiation not only gave good
yield with less reaction time, but also requires only water
for the post-reaction workup.
2-Amino-5-(p-amino phenyl)-1,3,4-oxadiazine (7d).
-1
This compound had IR (KBr) in cm : 3452, 3349, 1602, 1535;
1
H NMR (CDCl ): δ 3.9 (s, 2H, CH ), 7.3-7.5 (m, 4H, Ar-H).
3
2
Anal. Calcd. for C H N O: C, 56.86; H, 5.26; N, 29.46.
9
10 4
EXPERIMENTAL
Found: C, 56.83; H, 5.23; N, 29.50.
Acknowledgement.
Melting points were determined using a Thomas Hoover melt-
ing point apparatus and are uncorrected. IR (KBr) spectra were
obtained on Perkin-Elmer FTIR-1710 spectrophotometers using
The author (R.V.) is thankful to Council of Scientific and
Industrial Research, India for the financial assistance.

Sep-Oct 2002
Potassium Carbonate, a Support for the Green Synthesis of Azoles and Diazines
1047
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