Synthesis of some new fused and polyfused [1,2,4]triazolo-[3,4-b][1,3,4] thiadiazepines

Article abstract of DOI:10.1007/s10593-005-0283-4

7-[1,3-Dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3, 4-b][1,3,4]thiadiazepine-6,8-dione and 7-[5-oxo-1,3-dithiolan-2-ylidene]-3- phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]-thiadiazepine-6,8-diones were obtained by treating

Full text of DOI:10.1007/s10593-005-0283-4

Chemistry of Heterocyclic Compounds, Vol. 41, No. 8, 2005
SYNTHESIS OF SOME NEW FUSED
AND POLYFUSED [1,2,4]TRIAZOLO-
[3,4-b][1,3,4]THIADIAZEPINES
O. A. Abd Allah
7-[1,3-Dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-6,8-
dione and 7-[5-oxo-1,3-dithiolan-2-ylidene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazepine-6,8-diones were obtained by treating 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazepine-6,8-diones with CS2 and chloroacetyl chloride, respectively. Treatment of
the above compounds with mercaptoacetic acid gave 1,2-dibromoethane or the corresponding spiro
polyfused heterocycles. Some other triazolothiadiazepine derivatives including spiro polyfused
compounds were also synthesized.
Keywords: 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazepines, spiro compounds.
The synthesis of [1,2,4]triazolo[3,4-b][1,3,4]thiadiazepines had been thoroughly studied and developed
because of their important characteristics as antimicrobial and antibacterial agents [1-3]. From this point and
starting with 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-6,8-dione first prepared by the
author in [3], the synthesis of new polyfused compounds was the objective of this research.
One-pot reaction of 3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]-thiadiazepine-6,8-dione (1)
[3] with equimolar ratios of CS2, dihalo compounds (1,2-dibromoethane or chloroacetyl chloride), and a double
molar amount of NaOH gave compounds 2 or 3, respectively (Scheme 1). The reaction pathway was postulated
to proceed through a nucleophilic addition of the active methylene group in compound 1 at the carbon disulfide
molecule to get the intermediate disodium dithiocarbamate A, which in turn was cyclized with
1,2-dibromoethane or chloroacetyl chloride, yielding 7-[1,3-dithiolan-2-ylidene]-3-phenyl-5,6,7,8-
tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-6,8-dione (2) and 7-[1,3-dithiolane-5-oxo-2-ylidene]-3-
phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-6,8-dione (3). With the same reaction
mechanism and also in one-pot reaction under solid-liquid phase-transfer catalysis (PTC) [DMF–K2CO3–
tetrabutylammonium bromide (TBAB)], compound
1
was treated with an equimolar ratio of
phenylisothiocyanate or phenylisocyanate and 1,2-dibromoethane, affording compounds 4a,b, respectively
(Scheme 1, Table 1).
Spiro-polyfused derivatives 5 or 6 were prepared through nucleophilic addition of mercaptoacetic acid at
the activated ethylenic double bond in compounds 2 or 4, respectively. The reaction proceeds via a nucleophilic
attack of the SH group of mercaptoacetic acid at the ethylenic double bond in compounds 2 or 3 followed by
intramolecular cyclization through H2O elimination to yield the condensed products 5 or 6. The IR and 1H NMR
spectral
data
were consistent
with
the
proposed
structures
(cf.
Scheme
1).
The
__________________________________________________________________________________________
Chemistry Department, Faculty of Science, Sohag, Egypt; e-mail: omymatif@yahoo.com. Published in
Khimiya Geterotsiklicheskikh Soedinenii, No. 8, 1256-1264, August, 2005. Original article submitted June 18,
2002; revision submitted June 8. 2005.
1076
0009-3122/05/4108-1076©2005 Springer Science+Business Media, Inc.

dithiomethylmethylene derivative 7 was prepared by the reaction of compound 1 with an equimolar ratio of CS2
and with a double molar amount of both NaOH and methyl iodide. Compound 7 was used as a key intermediate
in the preparation of heterocyclic system by the reaction with ethylenediamine to afford the corresponding
7-[1,3-imidazolo-2-ylidene-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-6,8-dione] (8)
(cf. Scheme 1, Table 1).
Scheme 1
N
N
N
N
HSCH2COOH
S
S
N
N
N
N
Ph
Ph
H
O
O
H
S
O
S
N
N
O
N
N
1
BrCH2CH2Br
S
S
N
N
S
N
N
Ph
Ph
CS2 / NaOH
H
3
O
OH
H
O
S
O
O
SNa
S
SNa
Z
2
N
N
N
N
S
N
N
Ph
HSCH2COOH
O
S
N
N
ClCOCH2Cl
Ph
H
O
O
H
S
S
S
O
O
S
S
O
4
O
5
N
N
S
ArNCS / BrCH2CH2Br
PTS
N
N
Ph
H
O
X
O
PhN
6a,b
N
N
N
N
S
N
N
S
Ph
N
N
Ph
NH2CH2CH2NH2
CS2 / MeI
H
O
H
O
NH
SMe
O
O
HN
SMe
7
8
N
N
S
Ph
N
N
S
H
NH2
S + NCCH2X
O
Y
9–10a,b
6 a X = S, b X = O; 9 X,Y = COOEt; 10 a X,Y = CN,
b X,Y = CONH2
1077

1078

1079

1080

According to the Gewald reaction in the synthesis of numerous 2-aminothiophenes [4-6] by using one-
pot procedure, compound 1 reacted with sulfur and activated nitriles, namely, ethyl cyanoacetate, malononitrile,
or cyanoacetamide in DMF and in the presence of Et3N as a catalyst at room temperature yielding
thiophenotriazolothiadiazepine derivatives 9, 10a,b, respectively. (cf. Scheme 1).
6,8-Dioxo-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-7-acetohydrazide (11)
was prepared by the reaction of compound 1 with chloroacetohydrazide and catalytic amount of Et3N in boiling
dioxane. Compound 11 was allowed to react with CS2 and KOH to yield 3-phenyl-7-(5-thioxo-1,3,4-oxadiazol-
2-ylmethylene)-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine-6,8-dione (12) (cf. Scheme 2).
Scheme 2
N
N
N
N
CS2 / KOH
S
S
N
N
N
ClCH2CONHNH2
Ph
Ph
N
H
O
H
H
O
N
N
O
O
CH2CONHNH2
11
12
CH2
O
S
S
N
N
N
N
N
N
N
N
HC(OEt)3
NH2NH2
O
CS2
S
N
N
Ph
S
S
N
N
N
N
Ph
Ph
H
O
O
Ph
H
N
N
H
O
H
NH
NH
O
O
1
O
O
S
CHNHNH2
CHOEt
14
13
N
N
N
15
S
Br2C(CN)2
S
Ph
N
H
O
CN
O
16
CN
RNHNH2
N
HSCH2COOH
N
N
N
O
S
N
O
Ph
S
CN
NH2
COOH
N
CN
NH
N
H
Ph
N
H
O
O
S
H
N
RN
17a,b a R = H, b R = Ph
18
H
7-[Ethoxymethylene]-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b]-[1,3,4]-thiadiazepine-6,8-dione
(13) was prepared in excellent yield through the condensation of compound 1 with ethyl orthoformate via the
elimination of two EtOH molecules. The corresponding hydrazino derivative 14 was prepared by treating
compound 13 with hydrazine hydrate. The product was cyclized with CS2 through nucleophilic attack of the NH2
group at CS2 to form the SH group which in turn underwent a nucleophilic addition at the ethylenic double bond,
yielding the spiro polyfused thiadiazolotriazolothiadiazepine derivative 15 in excellent yield.
6,8-Dioxo-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepin-7-ylidenemalononitrile
(16) was obtained by treating compound 1 with dibromomalononitrile and double moles of Et3N. The IR
spectrum of this compound showed the presence of the adsorption bands corresponding to 2CN groups at 2197
and 2189 cm-1 (Scheme 2).
1081

The spiro polyfused pyrazolotriazolothiadiazepine derivatives 17a,b and thiophenotriazolothiadiazepine
18, respectively, were prepared via the addition reaction of hydrazine hydrate, phenylhydrazine, or
mercaptoacetic acid at the activated ethylenic double bond in compound 16 (cf. Scheme 2).
The active methylene group in compound 1 underwent a nucleophilic addition reaction at different
activated ethylenic double bonds, namely, 2-oxo-2,3-dihydroindolylidenemalononitrile, benzothiazolidene-
nitrile, or p-chlorobenzylidenecyanoacetamide in boiling dioxane and catalytic amount of Et3N to yield a new
series of pyranotriazolothiadiazepine derivatives 19-21, respectively (cf. Scheme 3). The reaction pathway was
suggested to proceed via the addition of the active CH2 group of compound 1 to the activated double bond of
ylidenenitrile to yield the intermediate Michael adduct which was cyclized through the addition of the OH group
at the cyano group. IR spectra of products 19-21 showed characteristic bands corresponding to NH2
(3320-3450), NH (3500-3425) and CN (2199-2187). 1H NMR spectra of the products are in agreement with the
proposed structure.
Scheme 3
CN
N
N
S
N
CN
O
N
Ph
NH2
CN
HN
O
O
N
H
O
Dioxane / TEA
H
19
H
N
CN
CN
N
N
S
N
O
Ph
S
NH
CN
HN
1
O
S
Dioxane / TEA
NH
N
N
20
N
CN
S
Ar–CH=
Ph
O
CONH2
NH
HN
O
Dioxane / TEA
CONH2
Ar = p-chlorophenyl
Ar
21
EXPERIMENTAL
Synthesis of Compounds 2, 3 (General Procedure). A mixture of compound 1 (0.01 mol), CS2
(0.01 mol), and NaOH (0.02 mol in 10 ml of water) in DMF (30 ml) was stirred for 4 h, 1,2-bromoethane or
chloroacetyl chloride (0.01 mol) was added dropwise, and the mixture was stirred again for 4 h and poured into
ice-cold water (300 ml). The resulting solid mass was filtered off, washed with water successively, dried, and
recrystallized from the proper solvent.
1082

Synthesis of Compounds 5, 6 (General Procedure). A mixture of compound 2 or 3 (0.01 mol) and
mercaptoacetic acid (0.01 mol) in DMF (20 ml) was refluxed for 3 h. The reaction mixture was poured into cold
water (200 ml). The separated product was filtered off, dried, and crystallized from the suitable solvent.
Synthesis of Compound 4a,b (General procedure). A mixture of anhydrous potassium carbonate (4 g),
compound 1 (0.01 mol), and a catalytic amount of TBAB in DMF (20 ml) was treated with phenyl
isothiocyanate or phenyl isocyanate (0.01 mol) and stirred for 1 h at room temperature. 1,2-Dibromoethane (0.01
mol) was added, and the mixture was stirred for an additional 4 h at room temperature. The reaction mixture was
filtered, and the filtrate was added to ice-cold water (100 ml). The separated solid was filtered off and
crystallized from the proper solvent.
Synthesis of Compound 7. A mixture of compound 1 (0.01 mol) in DMF (20 ml), CS2 (0.01 mol), and
NaOH (0.023 mol in 10 ml water) was stirred for 4 h. CH3I (0.02 mol) was added, and the reaction mixture was
stirred for an additional 4 h and poured into ice-cold water (200 ml). The precipitate was filtered off, dried, and
crystallized from DMF–H2O.
Synthesis of Compound 8. Ethylenediamine (0.002 mol) was added to a solution of compound 7
(0.002 mol) in DMF (20 ml). The reaction mixture was stirred at room temperature until the evolution of MeSH
ceased. The reaction mixture was poured into ice-cold water (200 ml), and the separated solid was collected by
filtration and crystallized from DMF–H2O.
Synthesis of Compounds 9, 10a,b (General Procedure). A mixture of compound 1 (0.01 mol), sulfur
(0.01 mol), and activated nitriles, namely, ethyl cyanoacetate, malononitrile, or cyanoacetamide (0.01 mol) in
dioxane (30 ml) and a few drops of triethylamine was stirred for 6 h. The precipitate was collected by filtration
and crystallized from the proper solvent to give compounds 9, 10a,b.
Synthesis of Hydrazide Derivative 11. Chloroacetohydrazide (0.01 mol) was added to a mixture of
compound 1 (0.01 mol) and triethylamine (0.01 mol) in dioxane (20 ml). The reaction mixture was refluxed for 6
h, concentrated, and cooled. The precipitate was filtered off and crystallized from ethanol.
Synthesis of Compound 12. KOH (0.02 mol in 5 ml H2O) was added to a solution of compound 11
(0.02 mol) in DMF (20 ml), the mixture was cooled, and CS2 (0.022 mol) was added dropwise. The reaction
mixture was refluxed until the evolution of H2S ceased (~18 h). The mixture was cooled and poured into ice-cold
water (200 ml) with several drops of dil. HCl. The resulting solid mass was filtered off, washed with water, dried
and crystallized from DMF–H2O.
Synthesis of Compound 13. A mixture of compound 1 (0.003 mol) and triethyl orthoformate (3 ml) was
refluxed for 5 h in acetic anhydride (20 ml). The reaction mixture was concentrated and cooled. The precipitate
was filtered off, washed with water, dried, and crystallized from acetic acid–H2O.
Synthesis of Hydrazino Derivative 14. Hydrazine hydrate (0.02 mol) was added to a solution of
compound 13 (0.02 mol) in DMF (20 ml). The reaction mixture was refluxed for 5 h, cooled, and added to ice-
cold water (200 ml). The precipitate was filtered off and crystallized from DMF–H2O.
Synthesis of Compound 15. A mixture of compound 14 (0.03 mol) and CS2 (0.035 mol) in DMF
(30 ml) was refluxed for 6 h. The separated solid was collected by filtration and crystallized from DMF.
Synthesis of Compound 16. A mixture of compound 1 (0.03 mol), dibromomalononitrile (0.03 mol),
and Et3N (0.06 mol) in dioxane (30 ml) was refluxed for 3 h. The reaction mixture was concentrated and filtered
off while hot. The precipitate was dried, washed with water, and crystallized from DMF–H2O.
Synthesis of Compounds 17a,b, 18 (General Procedure). Hydrazine hydrate, phenylhydrazine, or
mercaptoacetic acid (0.01 mol) were added to a solution of compound 16 (0.01 mol) in DMF (20 ml). The
reaction mixture was refluxed for 3 h. After cooling, the mixture was poured into ice-cold water (100 ml). The
separated solid was filtered off, washed with water, dried, and crystallized from the proper solvent.
Synthesis of Compounds 19-21 (General Procedure). Equimolar amounts (0.01 mol) of compound 1
and the proper ylidenemalononitrile or p-chlorobenzylidenecyanoacetamide were dissolved in dioxane (30 ml),
treated with two drops of Et3N, and refluxed for 4 h. The reaction mixture was concentrated, the separated solid
was filtered off, dried, and crystallized from the suitable solvent.
1083

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