The separation of products out of the
reaction mixture depended on carbon chain of
aliphatic acid: in case of acetic acid and
propionic acid, the reaction mixture was
poured into ice-water and the obtained
solution was neutralized by ammonia solution
to pH 8; in remained cases, firsts, the reaction
mixture was distilled by steam to remove
unreacted organic acids, and residue was
neutralized by ammonia solution to pH 8.
Using our MW method for in these syntheses
we can reduce amount of aliphatic acids
added in reaction.
The mechanism of this reaction. The
reaction may proceed via
acylthiosemicarbazide 4 formed from
carboxylic acid and thiosemicarbazide in the
presence of concentrated acid at high
temperature, acylthiosemicarbazide 4 then
undergoes cyclozation at elevated
temperatures to provide the 1,3,4-thiadiazole
moiety 5. The dehydration of 5 is completed
by heating the reaction mixture at
temperatures between about 100C and
120C. Product 6, salt of 5-alkyl-2-amino-
1,3,4-thiadiazole, was formed. The preferred
cyclodehydration temperature is about 105
to 110C at which thiadiazole formation
occurs in about 3-4 hours. The heating time
varies inversely with the temperature. After
cyclodehydration is completed, preferably at
105C, the reaction mixture is diluted with
water and the acid is neutralized to provide
the aminothiadiazole free base (see scheme 2).
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518
Journal of Chemistry, Vol. 47 (4), P. 518 - 522, 2009
MICROWAVE-ASSISTED DIRECT SYNTHESIS OF SOME 5-ALKYL-
2-AMINO-1,3,4-THIADIAZOLES
Received 10 December 2008
Nguyen Dinh Thanh1*, Pham Hong Lan2 and Nguyen Thi Minh Hai1
1Faculty of Chemistry, Hanoi University of Science, VNU
2Institute E17,Head Department VI, Ministry of Public Security
Abstract
Some 5-alkyl-2-amino-1,3,4-thiadiazoles have been synthesized by the MW-mediated solvent-free
method. The reaction mixture is consisted of aliphatic acid, thiosemicarbazide and concentrated
sulfuric acid (98%). Molar ratio of thiosemicarbazide and carboxylic acid was 1:2, reaction time was
shortened (20 houres vs. 30 minutes). The structures of these aminothiadiazoles were confirmed by
spectrospcopic methods (IR and 1H-NMR).
I - Introduction
The different classes of thiadiazole
compounds have drawn attention of many
organic chemists during recent years, since
many of these compounds known to possess
interesting biological properties such as
antimicrobial [1], antituberculosis [2],
antiinflammatory [3], anticonvulsant [4],
antihypertensive [5], local anesthetic [6],
anticancer [7] and hypoglycemic activities
[8]. The 1,3,4-thiadiazole derivatives, hence,
were synthesized with the aim of new
antituberculosis drugs development. The most
common procedure for synthesis of 5-
substituted 2-amino- or 2-alkylamino-1,3,4-
thiadiazoles is the acylation of a
thiosemicarbazide or alkylthiosemicarbazides
followed by dehydration in the presence of
some inorganic acids, such as sulfuric acid,
polyphosphoric acid or phosphorus halides [9
- 11].
2-Amino-5-alkyl-1,3,4-thiadiazole
compounds are also conventionally prepared
by cyclization of a 4-alkylthiosemicarbazide
and cyclodehydrating the resulting product.
The cyclodehydration is customarily carried
out in the presence of concentrated sulfuric
acid or polyphosphoric acid. Other well
documented methods of cyclodehydration
involve the use of polyphosphoric acid,
phosphorous pentachloride, or acid chlorides
as catalytic agents. In this paper, the
syntheses of these amino compounds have
been performed using microwave-assistant
method.
II - Experimental
Melting points of the synthesized
compounds were measured on STUART
SMP3 (BIBBY STERILIN-UK). The FT/IR-
spectra were recorded on Magna 760 FT-IR
Spectrometer (NICOLET, USA) in KBr
pellets. The 1H-NMR spectra were recorded
on an AVANCE AMX500 FT-NMR
Spectrometer (BRUKER, Germany) at 500.13
MHz, using DMSO-d6 as solvent and TMS as
internal standard and coupling constants are
reported in Hz. Chemical shift are expressed
as δ unit. The reactions were carried out using
modified TIFANY 750W microwave oven.
Conventional method for synthesis of 5-
alkyl-2-amino-1,3,4-thiadiazoles (3af).
519
General Procedure. The synthetic reaction
was carried out as the procedure described in
the reference [9] with some modifications. A
mixture of aliphatic acid (0.2 mol),
thiosemicarbazide (0.075 mol) and 15 mL of
concentrated sulfuric acid was mixed up in a
round bottomed flask and heated for 20 hours
under reflux. After the reaction was complete
the reaction mixture was allowed to cool and
poured into ice water. The mixture was
basified using concentrated ammonium
hydroxide solution. The aminothiadiazole
product precipitated. It was filtered and the
crude product obtained, which was
recrystallized from aqueous ethanol (10-15%).
The pure product was dried over phosphorus
pentoxide under vacuum for 24 hours.
Microwave-assisted method for
synthesis of 5-alkyl-2-amino-1,3,4-
thiadiazoles (3af). General procedure. A
mixture of aliphatic acid 1 (0.2 mol),
thiosemicarbazide 2 (0.1 mol) was placed in a
50-mL one-necked, round-bottomed flask,
equipped with condenser, and mixed up.
Concentrated sulfuric acid (15 mL) was added
dropwise and the reaction mixture was stirred
carefully. The mixture as irradiated in the
domestic microwave oven for 30 min. The
reaction mixture was poured into ice-water
(for compounds 3a-d) or distilled with steam
for separation of unreacted organic acid (for
compounds 3e,f). The obtained solution was
basified using sconcentrated ammonium
hydroxide solution to pH 8 and filtered
precipitated solid by suction, washed carefully
with cold water and recrystallized from 96%
ethanol. The pure product was dried over
phosphorus pentoxide under vacuum for 24
hours.
2-Amino-5-methyl-1,3,4-thiadiazole
(3a). Pale yellow solid, 85%, mp 223 -
224C; νmax(KBr)/cm−1 3247 (NH), 3084
(NH), 2969 (CH), 1636 (NH), 1531, 1511; δH
(500 MHz; DMSO-d6; TMS) 6.932 (2H, s,
NH2), 2.434 (3H, s, CH3).
2-Amino-5-ethyl-1,3,4-thiadiazole (3b).
Pale yellow solid, 78%, mp 181 - 182C;
νmax(KBr)/cm−1 3301 (NH), 3101 (NH), 2976,
2771, 2721 (CH), 1640 (NH), 1524, 1494; δH
(500 MHz; DMSO-d6; TMS) 6.961 (2H, s,
NH2), 2.799 (2H, q, J 7.5 Hz, CH2CH3), 1.209
(3H, t, J 7.5 Hz, CH2CH3).
2-Amino-5-n-propyl-1,3,4-thiadiazole
(3c). Pale yellow solid, 78%, mp 194 -
195C; νmax(KBr)/cm−1 3271 (NH), 3111
(NH), 2958, 2928, 2870, 2799, 1643 (NH),
1531, 1494; δH (500 MHz; DMSO-d6; TMS)
6.973 (2H, s, NH2), 2.749 (2H, t, J 7.0 Hz,
CH2CH2CH3), 1.628 (2H, sextet, J 7.0 Hz,
CH2CH2CH3), 0.913 (3H, t, J 7.0 Hz, 3H,
CH2CH2CH3).
2-amino-5-isopropyl-1,3,4-thiadiazole
(3d). Pale yellow solid, 82%, mp 189 -
190C; νmax(KBr)/cm−1 3288 (NH), 3122
(NH), 2962, 2871, 2759 1630 (NH), 1524,
1511; δH (500 MHz; DMSO-d6; TMS) 6.967
(2H, s, NH2), 3.119 [1H, quintet, J 7.0 Hz,
CH(CH3)2], 1.233 [6H, t, J 7.0 Hz, CH(CH3)2].
2-amino-5-isobutyl-1,3,4-thiadiazole
(3e). Pale yellow solid, 74%, mp 214 -
215C; νmax(KBr)/cm−1 3288 (NH), 3122
(NH), 2982, 1632 (NH), 1531, 1511; δH (500
MHz; DMSO-d6; TMS) 6.966 (2H, s, NH2),
2.650 [2H, d, J 7.0 Hz, CH2CH(CH3)2], 1.877
[1H, q, J 6.5 and 7.0 Hz, CH2CH(CH3)2],
0.903 (6H, d, J 6.5 Hz, CH2CH(CH3)2]); δC
(125.76 MHz; DMSO-d6; TMS) 168.187,
157.253, 38.229, 28.683, 21.910.
2-amino-5-n-pentyl-1,3,4-thiadiazole
(3f). Pale yellow solid, 73%, mp 193 -
194C; νmax(KBr)/cm−1 3281 (NH), 3095
(NH), 2955, 2918, 2853, 1637 (NH), 1521,
1498; 1H-NMR (DMSO-d6): δ=6.949 (2H, s,
NH2), 2.766 (2H, t, J 7.5 Hz,
CH2CH2CH2CH2CH3), 1.602 (2H, t, J 7.5 Hz,
CH2CH2CH2CH2CH3), 1.289 (4H, quintet, J
7.5 Hz, CH2CH2CH2CH2CH3), 0.861 (3H, t, J
7.5 Hz, CH2CH2CH2CH2CH3).
III - Results and Discussion
Some 5-alkyl-2-amino-1,3,4-thiadiazoles
have been synthesized by the MW-mediated
solvent-free method (scheme 1). The reaction
520
mixture is consisted of aliphatic acid,
thiosemicarbazide and concentrated sulfuric
acid (98%). Molar ratio of thiosemicarbazide
and carboxylic acid was 1:2.
NN
SR NH2
R
OH
O
NH2
NH
S
NH2
+
concd. H2SO4
MW or under reflux
1a-f 2 3a-f
1 and 2: R=CH3(a), CH2CH3 (b), CH2CH2CH3 (c), CH(CH3)2 (d),
CH2CH(CH3)2 (e), CH2(CH2)3CH3 (f)
Scheme 1
The comparative results, regarding the
conventional preparation [9]
(Method A) and
MW-assisted syntheses of 3a-3f, using
domestic microwave unit (Method B), are
summarized in Table 1. In the last years a
growing interest in the use of microwave-
assisted reactions in organic synthesis and
medicinal chemistry could be observed.
Effects noticed with microwave dielectric
heating are different from heating: Microwave
irradiation produces efficient internal heating
(in-core volumeric heating) by direct coupling
of microwave energy with the molecules
(reagents, solvent,) that are present in the
reaction mixture. These are a shortening of
the reaction time, rate enhancement, better
selectivity, and reduction of thermally
degradative products when compared to
conventional syntheses [10].
We indicated that 2-amino-1,3,4-
thiadiazole could not be synthesized from
formic acid and thiosemicarbazide using MW
method, because almost amount of formic
acid was evaporated out of the reaction
mixture. This compound has been only
synthesized by refluxing the mixture of
formic acid and thiosemicarbazide in the
presence of concentrated sulfuric acid as
catalyst. Other aliphatic acids could be
obtained by two methods: conventional
method and microwave-assisted method.
Table 1: Some 5-alkyl-2-amino-1,3,4-thiadiazoles (3a-f)
Yield (%)a
Product R Conventional
methodb
MW
methodc
m.p.
(C)
3a CH3 72 85 223-224
3b CH3CH2 70 78 181-182
3c CH3CH2CH2 64 78 194-195
3d (CH3)2CH 65 82 189-190
3e (CH3)2CHCH2 64 74 214-215
3f CH3(CH2)3CH2 65 73 193-194
a Products purified by recrystallization; the spectroscopic data of compounds 3a-f were identical with those
of the authentic samples prepared previously by conventional method.b
Method A: Rxn. time: 20 h; molar
ratio 1/2=2.7/1; catalyst: concentrated H2SO4;
cMethod B: molar ratio 1/2=2/1; MW irradiation applying
50-75% of the maximum power (750 W), for 30 minutes; in some cases sequential irradiations (5-10 min.
each) were applied for the total time (30 min.).
521
The separation of products out of the
reaction mixture depended on carbon chain of
aliphatic acid: in case of acetic acid and
propionic acid, the reaction mixture was
poured into ice-water and the obtained
solution was neutralized by ammonia solution
to pH 8; in remained cases, firsts, the reaction
mixture was distilled by steam to remove
unreacted organic acids, and residue was
neutralized by ammonia solution to pH 8.
Using our MW method for in these syntheses
we can reduce amount of aliphatic acids
added in reaction.
The mechanism of this reaction. The
reaction may proceed via
acylthiosemicarbazide 4 formed from
carboxylic acid and thiosemicarbazide in the
presence of concentrated acid at high
temperature, acylthiosemicarbazide 4 then
undergoes cyclozation at elevated
temperatures to provide the 1,3,4-thiadiazole
moiety 5. The dehydration of 5 is completed
by heating the reaction mixture at
temperatures between about 100C and
120C. Product 6, salt of 5-alkyl-2-amino-
1,3,4-thiadiazole, was formed. The preferred
cyclodehydration temperature is about 105
to 110C at which thiadiazole formation
occurs in about 3-4 hours. The heating time
varies inversely with the temperature. After
cyclodehydration is completed, preferably at
105C, the reaction mixture is diluted with
water and the acid is neutralized to provide
the aminothiadiazole free base (see scheme 2).
Scheme 2
Conclusions
We have synthesized a series of 5-alkyl-2-
amino-1,3,4-thiadiazoles derivatives by one-
pot method under microwave irradiation, thus
providing a facile, rapid, efficient and
environmentally friendly method. Reaction
time was shortened (20 houres vs. 30
minutes). The sctructures of these
aminothiadiazoles were confirmed by IR- and
1H-NMR spectral data.
Acknowledgements: This publication is
completed with financial support from the Grant
QGTĐ.08.03, Vietnam National University,
Hanoi.
522
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Corresponding author: Nguyen Dinh Thanh
Faculty of Chemistry,
College of Sciences, Vietnam National University, Hanoi.
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