Bromination and diazo-coupling of pyridinethiones; microwave assisted synthesis of isothiazolopyridine, pyridothiazine and pyridothiazepines

Article abstract of DOI:10.3390/molecules17066930

Isothiazolopyridines, pyridothiazines and pyridothiazepines are important compounds that possess valuable biological activities. This paper reports on the synthesis of these compounds using both conventional chemical methods and modern microwave techniques. 3-Bromo-6-hydroxy-4-methyl-2-thioxo-2,3- dihydropyridine-3-carboxamide, 5-arylazo-6-hydroxy-4-methyl-2-thioxo-1,2- dihydropyridine-3-carboxamides, 3,5-bis-arylazo-6-hydroxy-4-methyl-2-thioxo-2,3- dihydropyridine-3-caboxamide, 4-methyl-2,3,6,7-tetrahydroisothiazolo[5,4-b]- pyridine-3,6-dione, 2,2'-(methylene-bis-(sulfanediyl))bis(4-methyl-6-oxo-1,6- dihydropyridine-3-carboxamide), 2-hydroxy-5-methyl-4H-pyrido[3,2-e][1,3]- thiazine-4,7(8H)-dione and 2-arylmethylene-8-hydroxy-6-methyl-2,3,4,5- tetrahydropyrido-[3,2-f][1,4]thiazepine-3,5-diones have been prepared from 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide. Some of these compounds were prepared using microwave-assisted reaction conditions, that provided higher yields in shorter times than the conventional methods.

Full text of DOI:10.3390/molecules17066930

Molecules 2012, 17, 6930-6943; doi:10.3390/molecules17066930
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Bromination and Diazo-Coupling of Pyridinethiones;
Microwave Assisted Synthesis of Isothiazolopyridine,
Pyridothiazine and Pyridothiazepines
Ayman M. S. Youssef 1, Mohamed E. Azab 2,† and Mohamed M. Youssef 3,‡,
*
1
Department of Chemistry, Faculty of Science, Fayoum University, Fayoum 63514, Egypt
Department of Chemistry, Faculty of Science, El-Jabal El-Gharby University, Mezda,
Gheryan 65096, Libya
2
3
Department of Chemistry, Faculty of Science, Taif University, Taif 21974, Saudi Arabia
†
Current address: Department of Chemistry, Faculty of Science, Ain-Shams University,
Cairo 11566, Egypt.
‡
Current address: Department of Chemistry, Faculty of Science, Cairo University, Cairo 12613,
Egypt.
* Author to whom correspondence should be addressed; E-Mail: mmmyousef@yahoo.com;
Tel.: +966-59-607-2593 or +2-012-2245-1999.
Received: 25 April 2012; in revised form: 23 May 2012 / Accepted: 31 May 2012 /
Published: 6 June 2012
Abstract: Isothiazolopyridines, pyridothiazines and pyridothiazepines are important
compounds that possess valuable biological activities. This paper reports on the synthesis
of these compounds using both conventional chemical methods and modern microwave
techniques.
3-Bromo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide,
5-arylazo-6-hydroxy-4-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamides, 3,5-bis-arylazo-
6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-caboxamide, 4-methyl-2,3,6,7-tetra-
hydroisothiazolo[5,4-b]-pyridine-3,6-dione, 2,2'-(methylene-bis-(sulfanediyl))bis(4-methyl-
6-oxo-1,6-dihydropyridine-3-carboxamide),
2-hydroxy-5-methyl-4H-pyrido[3,2-e][1,3]-
thiazine-4,7(8H)-dione and 2-arylmethylene-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido-
[3,2-f][1,4]thiazepine-3,5-diones have been prepared from 6-hydroxy-4-methyl-2-thioxo-
2,3-dihydropyridine-3-carboxamide. Some of these compounds were prepared using
microwave-assisted reaction conditions, that provided higher yields in shorter times than
the conventional methods.

Molecules 2012, 17
6931
Keywords:
microwave;
bromination;
diazo-coupling;
pyridinecarboxamide;
isothiazolopyridine; pyridothiazine; pyridothiazepine
1. Introduction
In continuation of our research groups’ work in the field of synthetic organic chemistry [1–5]; we
would like to report here on the annulation of isothiazole, 1,3-thiazine and 1,4-thiazepine ring systems
to pyridine. Promising biological activities are reported in the literature concerning the targeted ring
systems: Isothiazolo[5,4-b]pyridines could be used as analgesics [6,7] and as CNS and antimicrobial
agents [8], pyrido[3,2-e][1,3]thiazines could be used as CNS and antioxidant agents [9] and as
analgesic agents [10] and pyrido[3,2-f]-[1,4]-thiazepines were used as calcium antagonists in
both cardiac and smooth muscles [11] and as channel blockers for treatment of cardiovascular
diseases [12]. Microwave-assisted technique offer several advantages over conventional methods of
synthesis. Reduced reaction times [13–15], less effects on the environment and better reaction yields
are some of the common advantages of using microwave irradiation. In the present research project,
we used both the microwave technique as well as conventional methods to prepare the targeted
compounds with expected biological activity.
2. Results and Discussion
The starting compound 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (2) was
prepared from 3-amino-3-thioxopropanamide [monothiomalonamide, (1)] [16] and ethyl acetoacetate
according to the literature procedure [17] (Scheme 1). Bromination of 2 with bromine in acetic acid
yielded 3-bromo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (3).
Our preference for structure 3 for the reaction product was based on the comparison of both the
1
1H-NMR and 13C-NMR spectra (DMSO-d6) of 2 and 3. In the H-NMR spectrum of 2, there are
two signals at δ 5.24 and δ 6.10 ppm corresponding to the pyridine-H3 and pyridine-H5, respectively.
1
The H-NMR spectrum of the reaction product revealed a signal at δ 6.12 ppm corresponding to
the pyridine-H5. The 13C-NMR spectrum of 2 showed two signals at δ 71.5 and δ 112.1 ppm
corresponding to C3 and C5, respectively. The reaction product showed two signals at δ 91.3
and 111.8 ppm corresponding to the same carbon atoms. The downfield shift of C3 indicates that
bromination took place on this carbon atom, favouring structure 3 for the reaction product. The
reaction product assigned structure 3 was most probably due to an initial protonation on the amide
carbonyl that leads to higher activity of position 3 in compound 2, and so the formation of the
kinetically controlled product 3 is favoured.
Attempts to couple compound 3 with benzenediazonium chloride to produce 4 have all failed, most
probably due to lack of aromaticity in compound 3. In contrast to the reaction of bromine with
compound 2, the latter compound coupled with some arenediazonium salts at position 5 to give the
monoarylazo derivatives. Thus, treatment of 2 with equimolar amounts of some arenediazonium salts
yielded 5-arylazo-6-hydroxy-4-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamides 5a–c (Scheme 1).

Molecules 2012, 17
Scheme 1. Bromination and diazo coupling of the pyridinethione derivative 2.
6932
CONH2
CH3COCH2COOEt
EtOH/KOH
+
CSNH2
1
CH3
N
CH3
Br
CONH2
CONH2
Br2/AcOH
HO
S
HO
N
S
3
Ar N2 Cl-
+
2
Ar N2 Cl-
+
CH3
N
CH3
N
Br
Ar
N
N
Ar
N
O
CONH2
S
CONH2
N
H
HO
S
4
CH3
Ar
N
O
CONH2
a) Ar = C6H4Cl-p
b) Ar = C6H4CH3-p
c) Ar = C6H4OCH3-p
N
H
N
H
S
5
Ar' N2 Cl-
+
CH3
CONH2
Ar
N
O
N
H
2 ArN2Cl
2
+
6c,d
N
S
N Ar`
Ar = C6H4-CH3-p,
C6H4-OCH3-p
N
a) Ar = C6H4-CH3-p; Ar` = C6H4Cl-p
b) Ar = C6H4-Cl-p; Ar` = C6H4CH3-p
c) Ar = Ar` = C6H4CH3-p
6
d) Ar = Ar` = C6H4OCH3-p
1
Structure 5 for the reaction product was based on a comparison between the H-NMR spectra of 2
and 5a that revealed the disappearance of the signals at δ 5.24 & 6.10 ppm in 5a. The disappearance of
the second one indicates that substitution takes place at position 5, while disappearance of the first one
is due to tautomerization and appearance of a D2O exchangeable signal at δ 12.86 ppm. Also, the
13C-NMR spectrum of compound 2 showed signals at 71.5 and 112.1, corresponding to C-3 and C-5,
respectively. The same two carbons in 5a showed signals at 72.3 and 123.8, respectively. The
downfield shift of C-5 signal indicates that substitution took place at this carbon atom. As further
evidence, the monoarylazo derivatives 5a,b could be coupled with some arenediazonium salts to give
bisarylazo derivatives (see below). An alternative ipso attack structure would have no aromaticity and
would not undergo further coupling.

Molecules 2012, 17
6933
The monoarylazo derivatives 5a,b coupled with some arenediazonium salts to give 3,5-bis-arylazo-
6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-caboxamides 6a,b (Scheme 1). Bisarylazo
derivatives 6c,d could be synthesized directly from 2 by treatment with double amount of the
diazonium salt (Scheme 1).
Next, we aimed to annulate five, six and seven-membered rings to the starting pyridine. A
five-membered ring is annulated by oxidation of 2 with potassium ferricyanide in ethanolic potassium
hydroxide solution, which led to the formation of 4-methyl-2,3,6,7-tetrahydroisothiazolo[5,4-b]-
pyridine-3,6-dione (7, Scheme 2).
Scheme 2. Formation of isothiazolopyridine, methylene-bis-sulfanediyl-bis-pyridinone
and pyridothiazine.
To annulate a six-membered ring to the starting pyridinethione derivative, compound 2 was allowed
to react with diiodomethane in ethanolic potassium hydroxide solution. The reaction product was
proved to be 2,2'-(methylene-bis(sulfanediyl))bis(4-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide)
(i.e., 8 instead of the expected pyrido[3,2-e][1,3]thiazine 9 (Scheme 2).
The IR spectrum of 8 displayed absorption bands at 3358 and 3171 cm−1 (NH) and 1681 and 1635 cm−1
1
(CO). Its H-NMR spectrum (DMSO-d6) showed signals at δ 2.22 ppm (s, 6H, 2CH3), 4.90 (s, 2H,
CH2), 6.27 (s, 2H, pyridine-H-5), 7.52–7.77 (brs, 4H, 2 NH2, D2O exchangeable) and 11.00 (s, 2H, 2 × NH,
D2O exchangeable). The mass spectrum of 8 showed the molecular ion peak at m/z 380 (1.5%),
corresponding to C15H16N4O4S2. The base peak appeared at m/z 53.
Treatment of 2 with ethyl chloroformate, in ethanol in the presence of sodium ethoxide, led directly
to the formation of 2-hydroxy-5-methyl-4H-pyrido[3,2-e][1,3]thiazine-4,7(8H)-dione (10, Scheme 2).

Molecules 2012, 17
6934
Heating under reflux compound 2 with chloroacetic acid and an appropriate aromatic aldehyde, in
acetic acid/acetic anhydride mixture in the presence of anhydrous sodium acetate, gave directly
2-arylmethylene-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine-3,5-diones 11a,b,
as shown in Scheme 3.
Scheme 3. Formation of pyridothiazepine derivatives.
The selection of structure 11 was based firstly on the 1H-NMR spectrum of the reaction product that
showed two types of exchangeable protons at δ 7.92 and 11.10 ppm. Secondly, structure 11 behaves
like a typical 2-hydroxypyridine and couples with arenediazonium salts to give the 7-arylazoderivatives 14,
(see below). Moreover, compounds 11a,b could also be synthesized in a stepwise fashion. Thus,
heating under reflux compound 2 with chloroacetic acid in acetic acid solution in the presence of
sodium acetate, yielded 2-[(3-carbamoyl-6-hydroxy-4-methylpyridin-2-yl)thio]acetic acid (12, Scheme 3).
Heating compound 12 in acetic acid/acetic anhydride solution, gave 8-hydroxy-6-methyl-2,3,4,5-
tetrahydropyrido[3,2-f][1,4]thiazepine-3,5-dione (13, Scheme 3). Compound 13 could also be directly
obtained from compound 2 by heating with chloroacetic acid in a mixture of acetic acid and acetic
anhydride at 100 °C in the presence of anhydrous sodium acetate. Compound 13 condensed with
p-chlorobenzaldehyde by heating under reflux in acetic acid in the presence of anhydrous sodium
acetate to give 11a, with identical m.p., m.m.p., and IR data (Scheme 3).
Compound 11b, as a typical 2-hydroxpyridine, coupled with arenediazonium salts to give
7-arylazo-2-(p-methoxyphenylmethylene)-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]-
thia-zepine-3,5-diones 14a–c, (Scheme 3).

Molecules 2012, 17
6935
Our research group has recently [17–19] been interested in performing synthesis of some
heterocyclic compounds under environmentally friendly, time saving microwave-assisted conditions.
Accordingly, we re-synthesized the previously described compounds 8, 10, 11a,b, 12 and 13 under
microwave conditions, aiming to increase reaction yields and reduce the reaction times. The results of
these preparations indicated that reaction yields were increased by 17–23% compared to the
conventional conditions. Reaction times were also significantly reduced. Table 1 summarizes the
benefits of using microwave conditions for the synthesis of the above-mentioned compounds.
Table 1. Comparison between traditional methods and microwave assisted methods of
synthesis of compounds 10, 12, 13a, 13b, 15 and 16.
Reaction Yield %
Reaction Time
Compound no.
Microwave Conventional Method Microwave Conventional Method
10
12
13a
13b
15
90
92
93
88
92
66
68
75
73
71
74
43
5 min
30 min
10 min
10 min
5 min
2 h
24 h
5 h
5 h
3 h
3 h
16
5 min
3. Experimental
3.1. General
Melting points were determined in open glass capillaries on a Gallenkamp melting point apparatus
and are uncorrected. IR spectra (KBr discs) were recorded on a Shimadzu FTIR-8201PC
spectrophotometer. 1H-NMR and 13C-NMR spectra were recorded on a Varian Mercury 300 MHz and
Varian Gemini 200 MHz spectrometers using TMS as an internal standard and DMSO-d6 as solvent.
Chemical shifts were expressed as δ (ppm) units. Mass spectra were recorded at 70 eV on a Shimadzu
GCMS-QP1000EX using an inlet type injector. All reactions were followed by TLC (silica gel,
aluminum sheets 60 F254, Merck). The Microanalytical Center of Cairo University performed the
microanalyses. Microwave reactions were performed with a Millstone Organic Synthesis Unit
(MicroSYNTH with touch control terminal) with a continuous focused microwave power delivery
system in a pressure glass vessel (10 mL) sealed with a septum under magnetic stirring. The
temperature of the reaction mixture was monitored using a calibrated infrared temperature control
under the reaction vessel, and control of the pressure was performed with a pressure sensor connected
to the septum of the vessel. 3-Amino-3-thioxopropanamide [monothiomalonamide (1)] and 6-hydroxy-
4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (2) were prepared according to literature
1
13
1
procedures [16,17]. Reported H-NMR and C-NMR of 2 [14] are given for comparison: H-NMR:
2.30 (s, 3H, CH3), 3.85 (br s, 1H, OH, D2O exchangeable), 5.24 (s, 1H, H-3), 6.10 (s, 1H, H-5), 7.40
(br s, 2H, NH2, D2O exchangeable); 13C-NMR: 20.3 (CH3), 71.5 (C-3), 112.1 (C-5), 137.3, 162.3
(sp2 C), 173.1 (CO), 188.0 (CS).

Molecules 2012, 17
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3.2. 3-Bromo-6-hydroxy-4-methyl-2-thioxo-1,2,3,6-tetrahydropyridine-3-carboxamide (3)
To a solution of 2 (2.84 g, 0.01 mole) in glacial acetic acid (50 mL), bromine (0.5 mL, 0.01 mole)
was added dropwise with stirring at room temperature in sunlight. The mixture was then stirred at
water bath for two hours and then diluted with cold water (30 mL). The resultant crude product
thus precipitated was collected by filtration, washed with water, dried and crystallized from dilute
dimethylformamide to afford 3 in 73% yield as pale brown crystals; m.p. 310 °C; IR ν: 3100–2250 cm−1
1
(OH, NH, hydrogen bond), and 1689 cm−1 (CO); H-NMR: 2.42 (s, 3H, CH3), 6.12 (s, 1H, pyridine-H),
11.91 (broad s, 3H, NH2, OH, D2O exchangeable); 13C-NMR: 13.5 (CH3), 91.3 (C-3), 111.8 (C-5),
131.5 (C-4), 158.9 (C-6), 171.1 (CO), 182.3 (CS); Mass spectrum m/z: 264 (49%), 262 (48.5%), 182
(100.0%), 154 (20.8%) and 99 (19%); Anal. Calcd for C7H7BrN2O2S: C, 31.95%; H, 2.68%; Br,
30.37%; N, 10.65%; S, 12.19%. Found: C, 32.20%; H, 2.50%; Br, 30.70%; N, 10.40%; S, 12.40%.
3.3. 5-Arylazo-6-hydroxy-44-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamides 5a–c
General procedure: To a cold solution of 2 (1.84 g, 0.01 mole) in pyridine (50 mL), containing
0.3 g potassium hydroxide, the arenediazonium chloride (0.01 mole) [prepared by adding concentrated
hydrochloric acid (3 mL) to aromatic amine (0.01 mol) at 0 °C and treating the resulting hydrochloride
with a cold solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 mL)] was added dropwise with
stirring at 0 °C. The coupling mixture was stirred at room temperature for two hours and then diluted
with water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed
with water, dried and crystallized from the proper solvent.
5-(p-Chlorophenylazo)-6-hydroxy-4-methyl-2-thioxo-1,2-dihydropyridine-3-carboxamide
(5a).
Crystallized from dioxane in 93% yield; m.p. 270 °C; IR ν: 3580–2122 (NH, OH) and 1651 (CO).
1H-NMR: 2.22 (s, 3H, CH3), 7.48–7.68 (m, 6H, 4 aromatic protons and NH2, D2O exchangeable),
12.86 (s, 1H, NH, D2O exchangeable), 13.87 (s, 1H, hydrogen bonded OH, D2O exchangeable);
13C-NMR: 13.4 (CH3), 72.3 (C-3), 123.8 (C-5), 129.8, 132.2, 134.5, 137.3, 146.0, 160.4 (Ar-H + pyridine
C-4, C-6), 172.7 (CO), 185.3 (CS); Mass spectrum m/z: 324 (15.1%), 322 (44.9%), 287 (24.5%), 276
(6.2%), 198 (3.8%), 111 (80%) and 60 (100.0%); Anal. Calcd for C13H11ClN4O2S: C, 48.37%; H,
3.44%; Cl, 10.98%; N, 17.36%; S, 9.93%. Found: C, 48.60%; H, 3.50%; Cl, 11.20%; N, 17.40%;
S, 10.20%.
6-Hydroxy-4-methyl-2-thioxo-5-(p-tolyldiazenyl)-1,2-dihydropyridine-3-carboxamide (5b). Crystallized
from dimethylformamide in 87% yield; m.p. 308 °C; IR ν: 3433–2160 (NH, OH) and 1678 (CO);
1H-NMR: 2.03 (s, 3H, CH3), 2.35 (s, 3H, CH3), 7.20–7.79 (m, 6H, 4 aromatic protons and NH2, D2O
exchangeable), 12.86 (s, 1H, NH, D2O exchangeable), 14.53 (s, 1H, hydrogen bonded OH, D2O
exchangeable); 13C-NMR: 13.4 (CH3), 72.0 (C-3), 122.8 (C-5), 129.8, 132.2, 134.5, 137.3, 146.0,
160.4 (Ar-H + pyridine C-4, C-6), 172.7 (CO), 185.3 (CS); Mass spectrum m/z: 302 (21.6%), 269
(7.5%), 257 (6.5%), 196 (5.8%), 168 (5.8%) and 91 (100.0%); Anal. Calcd for C14H14N4O2S: C,
55.61%; H, 4.67%; N, 18.53%; S, 10.61%. Found: C, 55.30%; H, 4.50%; N, 18.40%; S, 10.30%.

Molecules 2012, 17
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6-Hydroxy-5-(p-methoxyphenylazo)-4-methyl-2-thioxo-1,2-dihydropyridine-3-carbox-amide
(5c).
Crystallized from dimethylformamide in 91% yield; m.p. 254 °C; IR ν: 3580, 2122 (NH, OH) and
1
1666 (CO); H-NMR: 1.98 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.99–7.90 (m, 6H, 4 aromatic protons
and NH2, D2O exchangeable), 12.70 (s, 1H, NH, D2O exchangeable), 14.43 (s, 1H, hydrogen bonded
13
OH, D2O exchangeable); C-NMR: 13.6 (CH3), 55.8 (OCH3), 72.1 (C-3), 120.6 (C-5), 117.4, 132.5,
136.5, 140.3, 156.0, 160.6 (Ar-H + pyridine C-4, C-6), 173.5 (CO), 183.1 (CS); Mass spectrum m/z:
318 (16.1%), 274 (22.5%), 242 (9.5%), 183 (5.0%), and 107 (100.0%); Anal. Calcd for C14H14N4O3S:
C, 52.82%; H, 4.43%; N, 17.60%; S, 10.07%. Found: C, 53.00%; H, 4.70%; N, 17.60%; S, 10.30%.
3.4. 3,5-Bis-arylazo-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamides 6a–d
Route A: To a cold solution of 5 (0.01 mole) in pyridine (50 mL), containing potassium hydroxide
(0.3 g), the arenediazonium chloride (0.01 mole) [prepared by adding concentrated hydrochloric acid
(3 mL) to aromatic amine (0.01 mol) at 0 °C and treating the resulting hydrochloride with a cold
solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 mL)] was added dropwise with stirring at 0 °C.
The coupling mixture was stirred at room temperature for two hours and then diluted with water (30 mL).
The resultant crude product thus precipitated was collected by filtration, washed with water, dried and
crystallized from the proper solvent.
3-(p-Chlorophenylazo)-6-hydroxy-4-methyl-2-thioxo-5-(p-tolylazo)-2,3-dihydropyridine-3-carboxamide
(6a). According to the general method a cold solution of 5b (3.02 g, 0.01 mol) in pyridine (50 mL),
containing 0.3 g potassium hydroxide, the (p-chlorophenyl)diazonium chloride (0.01 mol) [prepared
by adding concentrated hydrochloric acid (3 mL) to p-chloroaniline (1.27 g, 0.01 mole) at 0 °C and
treating the resulting hydrochloride with a cold solution of sodium nitrite (0.69 g, 0.01 mole) in
water (5 mL)] was added dropwise with stirring at 0 °C. The coupling mixture was stirred at room
temperature for two hours and then diluted with water (30 mL). The resultant crude product thus
precipitated was collected by filtration, washed with water, dried and crystallized from ethanol to
afford 6a in 90% yield as a deep reed crystals. m.p. 249 °C; IR ν: 3406–2222 (NH, OH) and 1659
1
(CO); H-NMR: 2.09 (s, 3H, CH3), 2.63 (s, 3H, CH3), 7.26–8.90 (m, 10H, 8 aromatic protons and
13
NH2, D2O exchangeable), 14.23 (s, 1H, OH, D2O exchangeable); C-NMR: 10.3 (CH3), 25.1 (CH3),
94.8 (pyridine C-3), 110.6, 122.4, 128.7, 130.0, 131.9, 132.5, 136.5, 138.8, 144.3, 150.0, 160.4
(Ar-H + pyridine C-4, C-5, C-6), 172.3 (CO), 184.1 (CS); Mass spectrum m/z: 442 (17.1%), 440
(53.0%), 396 (12.6%), 268 (93.1%), 257 (2.7%), 228 (2.1%) and 91 (100.0%); Anal. Calcd for
C20H17ClN6O2S: C, 54.48%; H, 3.89; Cl, 8.04; N, 19.06; S, 7.27. Found: C, 54.80%; H, 3.90%; Cl,
7.90%; N, 19.30%; S, 7.30%.
5-(p-Chlorophenylazo)-6-hydroxy-4-methyl-2-thioxo-3-(p-tolylazo)-2,3-dihydropyridine-3-carboxamide
(6b). Crystallized from ethanol in 76% yield; m.p. 259 °C; IR ν: 3375–1909 (NH, OH) and 1659 (CO);
1H-NMR: 2.11 (s, 3H, CH3), 2.63 (s, 3H, CH3), 7.20–8.88 (m, 10H, 8 aromatic protons and NH2, D2O
exchangeable), 14.23 (s, 1H, OH, D2O exchangeable); 13C-NMR: 10.5 (CH3), 25.1 (CH3), 94.2
(pyridine C-3), 110.6, 122.5, 128.6, 130.0, 131.5, 132.3, 136.1, 139.0, 144.3, 150.0, 160.4 (Ar-H +
pyridine C-4, C-5, C-6), 172.0 (CO), 184.5 (CS); Mass spectrum m/z: 442 (23.9%), 440 (73.1%), 396

Molecules 2012, 17
6938
(18.7%), 268 (77.1%), 248 (2.1%) and 91 (100.0%); Anal. Calcd for C20H17ClN6O2S: C, 54.48; H,
3.89; Cl, 8.04; N, 19.06; S, 7.27. Found: C, 54.60%; H, 3.70%; Cl, 8.20%; N, 19.20%; S, 7.50%.
3,5-Bis-(p-tolylazo)-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (6c). Crystallized
1
from ethanol in 96% yield; m.p. 212 °C; IR ν: 3402–2226 (NH, OH) and 1659 (CO); H-NMR: 1.94
(s, 3H, CH3), 2.38 (s, 3H, CH3), 2.44 (s, 3H, CH3), 7.16–7.80 (m, 10H, 8 aromatic protons and NH2,
13
D2O exchangeable), 14.30 (s, 1H, OH, D2O exchangeable); C-NMR: 11.1 (CH3), 22.1 (CH3), 22.8
(CH3), 97.2 (pyridine C-3), 110.6, 122.5, 128.6, 129.6, 130.3, 135.3, 136.1, 139.0, 144.3, 148.1, 160.4
(Ar-H + pyridine C-4, C-5, C-6), 171.1 (CO), 184.0 (CS); Mass spectrum m/z: 420 (74.4%), 376
(5.4%), 329 (7%), 301 (6.6%), 210 (3.4%) and 91 (100.0%); Anal. Calcd for C21H20N6O2S: C,
59.98%; H, 4.79%; N, 19.99%; S, 7.63%. Found: C, 60.10%; H, 4.50%; N, 20.10%; S, 7.80%.
3,5-Bis-(p-methoxyphenylazo)-6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (6d).
Crystallized from ethanol in 87% yield; m.p. 248 °C; IR ν: 3418–2195 (NH, OH) and 1659 (CO);
1H-NMR: 2.17 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 7.04–8.13 (m, 10H, 8 aromatic
protons and 2H, NH2, D2O exchangeable), 14.17 (s, 1H, OH, D2O exchangeable); 13C-NMR: 11.5
(CH3), 53.1 (OCH3), 53.8 (OCH3), 92.5 (pyridine C-3), 110.3, 115.3, 123.2, 126.5, 130.1, 133.3,
135.2, 137.0, 155.0, 158.9, 160.2 (Ar-H + pyridine C-4, C-5, C-6), 173.0 (CO), 184.6 (CS); Mass spectrum
m/z: 452 (3.4%), 424 (66.5%), 408 (10.1%), 379 (13.3%), 273 (2.5%), 229 (22.1%) and 107 (100.0%);
Anal. Calcd for C21H20N6O4S: C, 55.74%; H, 4.46%; N, 18.57%; S, 7.09%. Found: C, 55.70%; H,
4.30%; N, 18.40%; S, 7.30%.
Route B: To a cold solution of 2 (0.92 g, 0.005 mole) in pyridine (50 mL), containing potassium
hydroxide (0.3 g), the arenediazonium chloride (0.01 mole) [prepared by adding concentrated
hydrochloric acid (3 mL) to aromatic amine (0.01 mol) at 0 °C and treating the resulting hydrochloride
with a cold solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 mL)] was added dropwise with
stirring at 0 °C. The coupling mixture was stirred at room temperature for two hours and then diluted
with water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed
with water, dried and crystallized. Compound 6c was thus obtained in 93% yield and matched the
same compound prepared by Route A in every aspect (m.p., mixed m.p. and IR spectrum). Compound
6d was thus obtained in 96% yield and matched the same compound prepared by Route A in every
aspect (m.p., mixed m.p. and IR spectrum).
3.5. 4-Methyl-2,3,6,7-tetrahydroisothiazolo[5,4-b]pyridine-3,6-dione (7)
To a solution of 2 (1.84 g, 0.01 mole) in ethanol (50 mL), in the presence of potassium hydroxide
(0.56 g, 0.01 mole), potassium ferricyanide (2.5 g, 0.01 mol) was added dropwise with stirring at room
temperature. The mixture was then stirred at room temperature for two hours and then diluted with
cold water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed
with water, dried and crystallized from dimethylformamide to afford 7 in 80% yield as a white powder;
1
m.p. 292 °C; IR ν: 3420 (NH) and 1681 and 1636 (2 CO); H-NMR: 2.42 (s, 3H, CH3), 6.11 (s, 1H,
13
pyridine-H5), 11.37 (br.s, 2H, 2 NH, D2O exchangeable); C-NMR: 23.1 (CH3), 112.3, 127.1, 131.4,
143.0 (pyridine C atoms), 165.3 (CO), 175.0 (CO); Mass spectrum m/z: 182 (27.3%), 154 (100.0%),

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107 (14.3%) and 99 (4.8%); Anal. Calcd for C7H6N2O2S: C, 46.14%; H, 3.32%; N, 15.38%; S,
17.60%. Found: C, 45.90%; H, 3.50%; N, 15.30%; S, 17.40%.
3.6. 2,2'-(Methylene-bis(sulfanediyl))bis(4-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide) (8)
Method A: To a solution of 2 (1.84 g, 0.01 mol) in ethanol (50 mL) in the presence of potassium
hydroxide (0.56 g, 0.01 mol), methylene iodide (0.53 mL, 0.005 mol) was added dropwise with stirring
at room temperature. The mixture was then stirred under reflux for two hours and then diluted with
cold water (30 mL). The resultant crude product thus precipitated was collected by filtration, washed
with water, dried and crystallized from dioxane to afford 8. Method B: The same reactants of method A
were heated under microwaves at 500 W and 140 °C for 5 min. The reaction mixture was treated in a
similar manner to method A to give compound 8. Compound 8 was obtained as a white powder in 68%
yield (Method A) or 90% yield (Method B); m.p. 304 °C; IR ν: 3358 and 3171 (NH) and 1681, 1635
(2 CO); 1H-NMR: 2.22 (s, 6H, 2 CH3), 4.90 (s, 2H, CH2), 6.27 (s, 2H, pyridine H-5), 7.52–7.77 (br.s,
4H, 2 NH2, D2O exchangeable), 11.00 (s, 2H, 2 NH, D2O exchangeable); 13C-NMR: 20.1 (CH3), 32.7
(CH2), 100.4, 125.1, 143.3, 148.0 (pyridine C atoms), 162.3 (CO), 171.2 (CO); Mass spectrum m/z:
380 (1.5%), 336 (2.0%), 321 (1.4%), 197 (29.4%), 183 (4.2) and 53 (100.0%); Anal. Calcd for
C15H16N4O4S2: C, 47.36; H, 4.24%; N, 14.73%; % S, 16.86%. Found: C, 47.20%; H, 4.30%; N,
14.70%; S, 16.80%.
3.7. 2-Hydroxy-5-methyl-4H-pyrido[3,2-e][1,3]thiazine-4,7(8H)-dione (10)
Method A: A mixture of 2 (1.84 g, 0.01 mole) and ethyl chloroformate (0.01 mole) was heated
under reflux in absolute ethanol (30 mL) in the presence of sodium ethoxide (0.46 g, 0.02 mole) for 24 h.
The reaction mixture was then poured onto water, the deposited precipitate was filtered off, dried and
crystallized from ethanol to give 10. Method B: The same reactants of method A were heated under
microwaves at 500 W and 140 °C for 30 min. The reaction mixture was treated in a similar manner to
method A to give compound 10. The product was obtained as a white powder in 75% yield (Method A)
and 92% yield (Method B); m.p. 205 °C; IR ν: 3410 and 3175 (NH, OH) and 1651 and 1645 (2 CO);
1H-NMR: 2.41 (s, 3H, CH3), 6.11 (s, 1H, pyridine-H), 8.13 (s, 1H, NH, D2O exchangeable), 9.16 (s,
1H, OH, D2O exchangeable); 13C-NMR: 21.0 (CH3), 123.8, 128.0, 134.9, 144.0, 160.1 (thiazine C-2 +
pyridine C atoms), 163.0 (CO), 171.6 (CO); Mass spectrum m/z: 210 (0.8%), 167 (100.0%), 150
(1.5%), 139 (21.0%) and 107 (21.9); Anal. Calcd for C8H6N2O3S: C, 45.71%; H, 2.88%; N, 13.33%; S,
15.25%. Found: C, 45.40%; H, 3.10%; N, 13.10%; S, 15.00%.
3.8. 2-Arylmethylene-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine-3,5-diones 11a,b
Method A: A mixture of 2 (1.84 g, 0.01 mole), chloroacetic acid (1.2 g, 0.012 mole), the appropriate
aromatic aldehyde (0.01 mole) and anhydrous sodium acetate (2 g) was refluxed in glacial acetic acid
(30 mL) and acetic anhydride (15 mL) for five hours. The reaction mixture was allowed to cool,
poured into water, the deposited precipitated thus formed was filtered off, washed with water, dried
and crystallized from the proper solvent. Method B: The same reactants of method A were heated
under microwaves at 500 w and 140 °C for 10 min. The reaction mixture was treated in a similar
manner to method A to give compounds 11a,b.

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2-(p-Chlorophenylmethylene)-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]-thiazepine-
3,5-dione (11a). Crystallized from dimethylformamide in 73% yield (Method A) and 93% yield
(Method B); m.p. 282 °C; IR ν: 3440–2927 (broad, OH and NH), 3024 (CH aromatic), 2927 (CH
aliphatic), 1764 and 1670 (2 CO); 1H-NMR: 2.35 (s, 3H, CH3), 6.25 (s, 1H, pyridine-H), 7.50–7.85 (m,
5H, 4 aromatic protons + methine proton), 7.92 (s, 1H, OH, D2O exchangeable), 11.10 (s, 1H, NH,
D2O exchangeable); 13C-NMR: 19.3 (CH3), 109.3, 122.0, 124.6, 130.9, 132.0, 134.4, 135.1, 136.9,
146.1, 156.3, 160.1 (pyridine C atoms + thiazepine C-2 + aromatic C atoms + methine C), 167.0 (CO),
171.2 (CO); Mass spectrum m/z: 348 (5.3%), 346 (16.7%), 235 (47.1%), 210 (11.5%), 179 (21.0%)
and 111 (100.0%); Anal. Calcd for C16H11ClN2O3S: C, 55.42%; H, 3.20%; Cl, 10.22%; N, 8.08%; S,
9.25%. Found: C, 55.30%; H, 3.40%; Cl, 10.10%; N, 8.20%; S, 9.40%.
8-Hydroxy-2-(p-methoxyphenylmethylene)-6-methyl-2,3,4,5-tetrahydro-pyrido[3,2-f]-[1,4]thiazepine-
3,5-dione (11b). Crystallized from dimethylformamide in 71% yield (Method A) and 88% yield
(Method B); m.p. 263 °C; IR ν: 3416–2924 (broad, OH and NH), 3068 (CH aromatic), 2924 (CH
1
aliphatic), 1747 and 1664 (2 CO); H-NMR: 2.40 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 6.13 (s, 1H,
pyridine-H), 6.85–7.75 (m, 5H, 4 aromatic protons + methine proton), 8.11 (s, 1H, OH, D2O
exchangeable), 11.40 (s, 1H, NH, D2O exchangeable); 13C-NMR: 18.8 (CH3), 108.5, 115.0, 120.1,
130.9, 132.0, 135.4, 136.1, 136.9, 146.1, 156.5, 160.0 (pyridine C atoms + thiazepine C-2 + aromatic
C atoms + methine C), 166.8 (CO), 170.4 (CO); Mass spectrum m/z: 342 (15.0%), 235 (42.5%), 207
(14.5%), 175 (11.8%) and 107 (100.0%); Anal. Calcd for C17H14N2O4S: C, 59.64%; H, 4.12%; N,
8.18%; S, 9.37%. Found: C, 59.80%; H, 4.30%; N, 8.50%; S, 9.40%.
3.9. 2-[(3-Carbamoyl-6-hydroxy-4-methylpyridin-2-yl)thio]acetic Acid (12)
Method A: A mixture of 2 (1.84 g, 0.01 mole), chloroacetic acid (1.2 g, 0.012 mole), and anhydrous
sodium acetate (2 g) was refluxed in glacial acetic acid (30 mL) for three hours. The reaction mixture
was then allowed to cool, poured into water, the deposited precipitated thus formed was filtered off,
washed with water, dried and crystallized from acetic acid to yield 12. Method B: The same reactants
of method A were heated under microwaves at 500 W and 140 °C for 5 min. The reaction mixture was
treated in a similar manner to method A to give compound 12. The product was obtained as purple
crystals in 74% yield (Method A) and 92% yield (Method B); m.p. 224 °C; IR ν: 3375–2473 (NH, OH)
1
and 1724 & 1651 (2 CO); H-NMR: 2.48 (s, 3H, CH3), 4.10 (s, 2H, CH2), 5.90 (s, 1H, pyridine-H),
10.23 (s, 1H, OH, D2O exchangeable), 11.10 (s, 2H, 2 NH, D2O exchangeable), 11.60 (s, 1H, COOH,
D2O exchangeable); 13C-NMR: 20.1 (CH3), 32.5 (CH2), 111.2, 115.4, 142.0, 153.6, 154.0 (pyridine C),
168.5 (CO), 173.9 (CO); Mass spectrum m/z: 242 (8.5%), 197 (51.5%), 151 (78.5%), 107 (11.0%) and
45 (100.0%); Anal. Calcd for C9H10N2O4S: C, 44.62%; H, 4.16%; N, 11.65%; S, 13.24%. Found: C,
44.70%; H, 4.40%; N, 11.80%; S, 13.10%.
3.10. 8-Hydroxy-6-methyl-2,3,4,5-tetrahydropyrido[3,2-f][1,4]thiazepine-3,5-dione (13)
Method A: A mixture of 2 (1.84 g, 0.01 mole), chloroacetic acid (1.2 g, 0.012 mole), and anhydrous
sodium acetate (2 g) in glacial acetic acid/acetic anhydride (30 mL/15 mL) was heated in a boiling
water bath for three hours. The reaction mixture was then allowed to cool, poured into water, the

Molecules 2012, 17
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deposited precipitate thus formed was filtered off, washed with water, dried and crystallized from
acetic acid to afford 13. Method B: The same reactants of method A were heated under microwaves at
500 W and 140 °C for 5 min. The reaction mixture was treated in a similar manner to method A to give
compound 13. Product 13 was obtained as a brown powder in 43% yield (Method A) and 66 % yield
(Method B); m.p. 258 °C; IR ν: 3400 and 3314 (NH, OH) and 1774 and 1678 (2 CO); 1H-NMR: 2.50
(s, 3H, CH3), 3.95 (s, 2H, CH2), 6.04 (s, 1H, pyridine-H), 9.31 (s, 1H, NH, D2O exchangeable), 11.55
(s, 1H, OH, D2O exchangeable); 13C-NMR: 19.4 (CH3), 38.9 (CH2), 110.0, 114.3, 140.1, 154.3, 155.0
(pyridine C), 167.4 (CO), 170.0 (CO); Mass spectrum m/z: 224 (17.0%), 196 (34.7%), 181 (10.3%),
153 (3.6%) and 107 (100.0%); Anal. Calcd for C9H8N2O3S: C, 48.21%; H, 3.60%; N, 12.49%; S,
14.30%. Found: C, 48.40%; H, 3.50%; N, 12.30%; S, 14.10%.
3.11. 7-Arylazo-2-(p-methoxyphenylmethylene)-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido[3,2-f]-
[1,4]thiazepine-3,5-diones 14a–c
To a cold solution of 11b (3.42 g, 0.01 mole) in pyridine (50 mL), containing potassium hydroxide
(0.3 g), the arenediazonium chloride (0.01 mole) [prepared by adding concentrated hydrochloric acid
(3 mL) to aromatic amine (0.01 mole) at 0 °C and treating the resulting hydrochloride with a cold
solution of sodium nitrite (0.69 g, 0.01 mole) in water (5 mL)] was added dropwise with stirring at 0 °C.
The coupling mixture was then stirred at room temperature for two hours and then diluted with water
(30 mL). The resultant crude product thus precipitated was collected by filtration, washed with water,
dried and crystallized from the proper solvent.
7-(p-Chlorophenylazo)-2-(p-methoxyphenylmethylene)-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido-
[3,2-f][1,4]thiazepine-3,5-dione (14a). Crystallized from dilute dimethyl-formamide in 63% yield;
m.p. 310 °C; IR ν: 3480–2100 (NH, OH) and 1740 and 1670 (2 CO); 1H-NMR: 2.45 (s, 3H, CH3), 3.88
(s, 3H, OCH3), 6.90–7.81 (m, 9H, 8 aromatic protons + methine proton), 9.23 (s, 1H, NH, D2O
exchangeable), 11.00 (s, 1H, OH, D2O exchangeable); 13C-NMR: 13.4 (CH3), 57.0 (OCH3), 109.0,
115.3, 124.3, 127.1, 127.9, 128.8, 129.7, 131.2, 135.1, 136.0, 142.9, 145.0, 156.4, 160.2, 161.3
(pyridine C atoms + thiazepine C-2 + aromatic C atoms + methine C), 169.0 (CO), 173.7 (CO); Mass
spectrum m/z: 482 (3.5%), 480 (11.3%), 373 (28.8%), 341 (5.7%) and 107 (100.0%); Anal. Calcd for
C23H17ClN4O4S: C, 57.44%; H, 3.56%; Cl, 7.37%; N, 11.65%; S, 6.67%. Found: C, 57.60%; H,
3.30%; Cl, 7.50%; N, 11.70%; S, 6.90%.
7-(p-Methoxyphenylazo)-2-(p-methoxyphenylmethylene)-8-hydroxy-6-methyl-2,3,4,5-tetrahydropyrido-
[3,2-f][1,4]thiazepine-3,5-dione (14b). Crystallized from ethanol in 72% yield; m.p. 332 °C; IR ν:
1
3454–2218 (NH, OH) and 1751 and 1666 (2 CO); H-NMR: 2.52 (s, 3H, CH3), 3.85 (s, 3H, OCH3),
3.95 (s, 3H, OCH3), 6.94–7.74 (m, 9H, 8 aromatic protons + methine proton), 9.15 (s, 1H, NH, D2O
exchangeable), 11.10 (s, 1H, OH, D2O exchangeable); 13C-NMR: 12.8 (CH3), 56.9 (OCH3), 57.9
(OCH3), 108.0, 114.3, 115.2 122.1, 125.6, 127.1, 129.8, 130.7, 135.1, 142.9, 145.0, 156.4, 159.1,
160.3, 163.8 (pyridine C atoms + thiazepine C-2 + aromatic C atoms + methine C), 168.3 (CO), 170.3
(CO); Mass spectrum m/z: 476 (15.1%), 369 (31.1%), 341 (5.2%), 273 (10.4%) and 107 (100.0%);
Anal. Calcd for C24H20N4O5S: C, 60.49%; H, 4.23%; N, 11.76%; S, 6.73%. Found: C, 60.60%; H,
4.10%; N, 11.70%; S, 6.90%.

Molecules 2012, 17
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7-(p-Tolylazo)-2-(p-methoxyphenylmethylene)-8-hydroxy-6-methyl-2,3,4,5-tetrahydro-pyrido[3,2-f]-
[1,4]thiazepine-3,5-dione (14c). Crystallized from ethanol in 66% yield; m.p. 325 °C. IR ν: 3414–2213
1
(NH, OH) and 1753 and 1661 (2 CO). H-NMR: 2.30 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.85 (s, 3H,
OCH3), 6.90–7.80 (m, 9H, 8 aromatic protons + methine proton), 9.41 (s, 1H, NH, D2O exchangeable),
11.22 (s, 1H, OH, D2O exchangeable); 13C-NMR: 11.0 (CH3), 21.9 (CH3), 55.9 (OCH3), 108.8, 113.7,
115.1 124.1, 125.3, 126.3, 128.8, 130.0, 135.1, 142.6, 144.1, 155.2, 157.0, 160.3, 162.9 (pyridine C
atoms + thiazepine C-2 + aromatic C atoms + methine C), 168.0 (CO), 171.7 (CO); Mass spectrum
m/z: 460 (17.5%), 353 (25.5%), 341 (6.6%), 253 (5.4%) and 107 (100.0%). Anal. Calcd for
C24H20N4O4S: C, 62.60%; H, 4.38%; N, 12.17%; S, 6.96%. Found: C, 62.40%; H, 4.50%; N, 12.10%;
S, 7.10%.
4. Conclusions
Several new isothiazolopyridines, pyridothiazines and pyridothiazepines have been synthesized
using both traditional methods and microwave assisted conditions. The latter methods proved much
more efficient in reducing reaction times as well as increasing the overall yield of the reactions.
Structures of the newly synthesized compounds were proven by both spectral and chemical methods.
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Sample Availability: Samples of the compounds are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).