Part 7: Synthesis of some new 1,5-benzodiazepines fused with different heterocyclic moieties

Article abstract of DOI:10.1080/10426500601087301

3-cyano-1,11-dihydro-4,5-diphenyl-2-thioxopyrido[2,3-b](1,5)benzodiazepine 2 and 3-(2′-cyano-1′-phenyl-2′-ethanethiocarboxamide)-4- phenyl-1(H)(1,5)benzodiazepin2-one 3 were prepared via the reaction of 1,3-dihydro-4-phenyl-(1,5)benzodiazepin-2-one 1 with benzylidenecyanothioacetamide. Compound 2 was treated with halo compounds to give the corresponding S-alkylated compounds 4_a-c, which underwent as intramolecular ring closure to thieno[3,2.5,6]pyrido[2,3-b](1,5)benzodiazepines 5_a-c under PTC conditions. One-pot syntheis of compounds 5a-c was achieved via the reaction of compound 2 with the appropriate halo compound under PTC conditions. Compound 1 and 1-ethyl-4-phenyl-(1,5)benzodiazepin-2-one 9 were treated with carbon disulfide or phenylisothiocyanate and active nitriles to afford 4-thioxothiopyrano[4,3-b](1,5)benzodiazepines 8 and 10-14. Treatment of compound 10 with pheny+lisothiocyanate or acetic anhydride yielded oxazino-and pyrimido[4,5-b]thiopyrano-[4′,3′-b′](1,5)benzodiazepine 15 and 17. The reaction of compound 1 with elemental sulfur and active nitriles yielded thieno[3,2-b](1,5)benzodiazepines 18-21, respectively. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500601087301

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Phosphorus, Sulfur, and Silicon
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Part 7: Synthesis of Some New
1,5-Benzodiazepines Fused
with Different Heterocyclic
Moieties
A. M. El-Sayed a , A. Khodairy a , H. Salah a & H.
Abdel-Ghany a
a Chemistry Department, South Valley University,
Sohag, Egypt
Version of record first published: 24 Feb 2007
To cite this article: A. M. El-Sayed, A. Khodairy, H. Salah & H. Abdel-Ghany (2007):
Part 7: Synthesis of Some New 1,5-Benzodiazepines Fused with Different Heterocyclic
Moieties, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:4, 711-722
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Phosphorus, Sulfur, and Silicon, 182:711–722, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601087301
Part 7: Synthesis of Some New 1,5-Benzodiazepines
Fused with Different Heterocyclic Moieties
A. M. El-Sayed
A. Khodairy
H. Salah
H. Abdel-Ghany
Chemistry Department, South Valley University, Sohag, Egypt
3-cyano-1,11-dihydro-4,5-diphenyl-2-thioxopyrido[2,3-b](1,5)benzodiazepine 2 and
3-(2ꢀ-cyano-1ꢀ-phenyl-2ꢀ-ethanethiocarboxamide)-4-phenyl-1(H)(1,5)benzodiazepin-
2-one 3 were prepared via the reaction of 1,3-dihydro-4-phenyl-(1,5)benzodiazepin-
2-one 1 with benzylidenecyanothioacetamide. Compound 2 was treated with
halo compounds to give the corresponding S-alkylated compounds 4a−c
,
which underwent as intramolecular ring closure to thieno[3,2.5,6]pyrido[2,3-
b](1,5)benzodiazepines 5a−c under PTC conditions. One-pot syntheis of compounds
5a−c was achieved via the reaction of compound
halo compound under PTC conditions. Compound
2
1
with the appropriate
and 1-ethyl-4-phenyl-
(1,5)benzodiazepin-2-one 9 were treated with carbon disulfide or phenylisothio-
cyanate and active nitriles to afford 4-thioxothiopyrano[4,3-b](1,5)benzodiazepines
8 and 10–14. Treatment of compound 10 with phenylisothiocyanate or acetic anhy-
dride yielded oxazino- and pyrimido[4,5-b]thiopyrano-[4ꢀ,3ꢀ-bꢀ](1,5)benzodiazepine
15 and 17. The reaction of compound 1 with elemental sulfur and active nitriles
yielded thieno[3,2-b](1,5)benzodiazepines 18–21, respectively.
Keywords 3-cyano-1,11-dihydro-4,5-diphenyl-2-thioxopyrido[2,3-b](1,5)benzodiazepine;
1-ethyl-1(H)-4-phenyl-1,5-benzodiazepin-2-one; PTC
INTRODUCTION
Benzodiazepines and their polycyclic derivatives are used in phar-
maceutical and biological chemistry,1 where they are used as antitu-
mor agents,2 nevirapine analgnes,3 and anti–HIV-1 (Human Immun-
odeficiency Virus) agents.3 They also are screened for in vitro cyto-
toxicity against a number of cancer cell lines,4 such as colon cancer,
breast cancer, lung cancer, and bladder cancer.5 For all these reasones,
we continue our laboratory work on the synthesis of fused and spiro
Received January 9, 2006; accepted March 14, 2006.
Address correspondence to H. Abdel-Ghany, Chemistry Department, Faculty of Sci-
ence, South Valley University, 82524 Sohag, Egypt. E-mail: khodairy@yahoo.com
711

712
A. M. El-Sayed et al.
benzodiazepines.6−11 So herein we report the synthesis of pyrido[2,3-
b]-,thiopyrano[4,3-b]-, and thieno[3,2-b](1,5)benzodiazepines.
RESULTS AND DISCUSSION
Recently, Khodairy10 reported that the reaction of 1,3-dihydro-4-
phenyl-1,5-benzodiazepin-2-one 112 with some ylidenecyanoth-
ioacetamides and sodium ethoxide gave corresponding 3-cyano-2-
thioxopyrido[2,3-b][1,5]-benzodiazepines. We report herein other trials
for the synthesis of 3-cyano-1,11-dihydro-4,5-diphenyl-2-thiopyrido
[2,3-b][1,5]benzodiazepine via the reaction of 1,3-dihydro-4-phenyl-
1,5-benzodiazepin-2-one 1 with benzylidenecyanothioacetamide and
piperidine as a basic catalyst, where a mixture of 3-cyano-1,11-dihydro-
4,5-diphenyl-2-thioxopyrido[2,3-b](1,5)-benzodiazepine 2 and 2-cyano-
3(4-phenyl-2-oxo-1,2-dihydro-3H-(1,5)benzodiazepin-3-ylidene)-3-phe-
nylpropanimidothioic acid 3 was obtained in a 20% and 70% yield,
respectively. The IR spectrum of compound 2 showed new absorption
bands at 3385 cm−1 and 2214 cm−1 corresponding to NH and CN
groups, respectively, while its 1H NMR spectrum revealed the presence
of multiplet signals at δ 8.70–7.00 ppm for the 14 H aromatic protons
and a singlet signal at δ 9.50 ppm for the new NH group.
Treatment of compound 2 with active halo compounds, namely ethyl
chloroacetate, chloroacetonitrile, and phenacyl bromide in the presence
of odium acetate as a catalyst, afforded 2-carbethoxymethylthio-3-
cyano-4,5-diphenyl-11(H)pyrido[2,3-b](1,5)benzodiazepine 4a, 3-cyano-
2-cyanomethy-Ithio-4,5-diphenyl-11(H)pyrido[2,3-b](1,5) benzodiaze-
pine 4b, and 2-benzoyl-methylthio-3-cyano-4,5-diphenyl-11(H)pyrido
[2,3-b](1,5)benzodiazepine 4c, respectively. Using the PTC technique
(dioxane/potassium carbonate/tetrabutyl-ammonium bromide [TBAβ]),
compounds 4a−c underwent intramolecular cyclization into 3-amino-2-
carbethoxy-4,5-diphenyl-11(H)thieno[2,3-b]pyrido-[2ꢀ,3ꢀ-bꢀ ](1,5)benzo-
diazepine 5a, 3-amino-2-cyano-4,5-diphenyl-11(H)thieno-[2,3-b]pyrido
[2ꢀ,3ꢀ-bꢀ](1,5)benzodiazepine 5b, and 3-amino-2-benzoyl-4,5-diphenyl-
11(H)thieno[2,3-b]pyrido[2ꢀ,3ꢀ-bꢀ](1,5)benzodiazepine 5c, respectively.
Compounds 5a−c
, 3-amino-2-carboxamido-4,5-diphenyl-11(H)thieno
[2,3-b]pyrido [2ꢀ,3ꢀ-bꢀ](1,5)benzodiazepine 5d, and 3-amino-2-phenyl-
carboxamido-4,5-diphenyl-11(H)thieno[2,3-b]pyrido[2ꢀ,3ꢀ-bꢀ ](1,5)benz-
odiazepine 5e were synthesized directly in a one-pot step via the
reaction of compound 2 with ethyl chloroacetate, chloroacetonitrile,
phenacyl bromide, chloroacetamide, and chloroacetanilide, respec-
tively, under PTC conditions (dioxane/potassium carbonate/TBAB). IR
spectra of compounds 5a−e showed characteristic absorption bands at
3463–3215 cm−1 due to the NH2 group and at 1721 cm−1 and 1671 cm−1

Synthesis of Some New 1,5-Benzodiazepines
713
for the CO groups, with disappearance of the absorption band for the
CN group. 1HNMR spectra of compounds 5a−e represented the charac-
teristic broad signal at δ 5.70–5.10 ppm due to the NH2 group along with
two singlet signals at δ 8.10 and δ 4.60 ppm due to the NH and CONH2
groups. The reaction of compound 2 with ethyl cyanoacetate under
PTC conditions yielded a mixture of ethyl 3-{[3-cyano-4,5-diphenyl-
11H-pyrido(2,3-b)(1,5)benzodiazepin-2-yl]thio}-3-iminopropanoate
6
and 4-amino-3-cyano-5,6-diphenyl-2-oxo-12(H)thiopyrano[2,3-b]pyrido
[2ꢀ,3ꢀbꢀ](1,5)benzo-diazepine 7, respectively (c.f. Scheme 1 and Table I).
SCHEME 1

714

715

716

Synthesis of Some New 1,5-Benzodiazepines
717
Compound 1 was allowed to react with carbon disulfide and
malononitrile in the presence of triethylamine as a basic catalyst
to afford 2-amino-1-cyano-11(H)-5-phenyl-4-thioxothiopyrano[4,3-
b](1,5)benzodiazepine 8. Moreover, the reaction of 1-ethyl-3H-
4-phenyl-1,5-benzodiazepin-2-one 910 with carbon disulfide and
active nitriles, namely malononitrile, cyanothioacetamide, cyanoac-
etamide, or ethyl cyanoacetate in the presence of triethylamine
as a basic catalyst, yielded 2-amino-1-cyano-11-ethyl-5-phenyl-4-
thioxothiopyrano[4,3-b](1,5)benzodiazepine 10, 2-amino-11-ethyl-5-
phenyl-4-thioxo-thiopyran[4,3-b](1,5)benzodiazepine-1-carboxamide
11,
and
1-cyano-11-ethyl-2-oxo-5-phenyl-4-thioxothiopyrano[4,3-
b](1,5)benzodiazepine 12, respectively. In analogy, compound 9 was
treated with a mixture of phenyl isothiocyanate and malononitrile or
cyanothioacetamide in presence of triethylamine as a basic catalyst
to give 2-amino-1-cyano-3,5-diphenyl-11-ethyl-4-thioxopyrido[4,3-
b](1,5)benzodiazepine 13 and 1-cyano-3,5-diphenyl-2,4-dithioxo-11-
ethyl-pyrido[4,3-b](1,5)benzodiazepine 14, respectively. The reaction
pathway was suggested to be a preliminary formation of carbanion of
the CH2 benzodiazepine group, which was added to the C=S bond followed
by a nucleophilic attack of the SH group or the NH group at the CN,
CO, and CS groups followed by condensation of the active methylene
and the C=Obenzodiazepine group with the eliminaton of H2S molecule in
case of cyanothioacetamide, water molecule in case of cyanoacetamide,
or ethanol molecule in case of ethyl cyanoacetate. The IR spectra of
compounds 8 and 10–14 exhibited new absorption bands at 3430–3163
cm−1 for the NH2 group and 2211–2202 cm−1 for the CN group. The
1HNMR spectra of these compounds showed the disappearance of
the signal corresponding to the CH2 benzodiazepine group and exihibted
multiplet signals at δ 8.00–7.00 for aromatic protons, a broad signal at
δ 5.20–4.30 ppm for the NH2 group, and a singlet signal at δ 4.1 for the
CH group, respectively.
Treatment of compound 10 with acetic anhydride along with pyridine
gave 2-acetylamino-1-cyano-11-ethyl-5-phenyl-4-thioxothiopyrano[4,3-
b](1,5)-benzodiazepine 15, which was converted into 13-ethyl-1-imino-
3-methyl-7-phenyl-6-thioxo(1,3)oxazino[4,5-b]thiopyrano[4ꢀ,3ꢀ-bꢀ ] (1,5)
benzodiazepine 16 in boiling pyridine. The cyclization of compound
10 into 2,7-diphenyl-3,6-dithioxo-13-ethyl-1-imino-4(H)-pyrimido[4,5-
b]thiopyrano[4ꢀ,3-b,](1,5)benzodiazepine 17 was achieved by treating
it with phenylisothiocyanate. The IR spectra of compounds 16 and 17
showed the absence of absorption bands corresponding to the NH2 and
CN groups and revealed a new absorption band at 3270–3140 cm−1
1
corresponding to NH groups. HNMR spectra were consistent of the
proposed structures.

718
A. M. El-Sayed et al.
Furthermore, the reaction of elemental sulfur and active methy-
lene, namely malononitrile, cyanothioacetamide, cyanoacetamide, or
ethyl cyanoacetate with compound 1 in presence of triethylamine
as a basic catalyst, gave 2-amino-1-cyano-4-phenyl-10(H)thieno[3,2-b]
(1,5)benzodiazepine 18,10 2-amino-1-carboxamido-4-phenyl-10(H)thi-
eno[3,2-b](1,5)benzodiazepine 19, 2-amino-1-carbethoxy-4-phenyl-10
(H)thieno[3,2-b](1,5)benzodiazepine 20, and 1-cyano-1, 10-dihydro-2-
oxo-4-phenylthieno[3,2-b](1,5)benzodiazepine 21, respectively. IR spec-
tra of compounds 18–21 exhibited new absorption bands at 3436–
3105 cm−1 for the NH2 group, 2201 and 2203 cm−1 for the CN group
in compounds 18 and 20, and 1700–1669 cm−1 for C=O groups in com-
pounds 19–21. 1HNMR spectra of these compounds showed the disap-
pearance of the signal specific for the CH2 benzodiazepine group.
EXPERIMENTAL
Synthesis of Compounds 2 and 3: General Procedure
A mixture of compound 1 (0.01 mol, 2.36 g), benzylidenecyano-
thioacetamide (0.01 mol, 1.88 g), and piperidine (1 mL) was refluxed
in dioxane (20 mL) for 4 h. On cooling, the formed precipitate was fil-
tered off and crystallized to give compound 3. The filtrate was poured
into a mixture of water and HCl (50: 3 v/v), and the solid product was
filtered off, washed with water, and crystallized to give compound 2 (cf.
Scheme 1, Table I).
Synthesis of Compounds 4a−c: General Procedure
A mixture of compound 2 (0.005 mol, 2.02 g); 0.005 mol of the appro-
priate halocompound; ethyl chloroacetate (0.54 mL), chloroacetonitrile
(0.31 mL), or phenacyl bromide (0.99 g); and sodium acetate (0.005 mol,
0.41 gm) in ethanol (20 mL) was refluxed for 2 h. The precipitate that
obtained on cooling was filtered off, washed with water, and crystallized
from the appropirate solvent (cf. Scheme 1, Table I).
Synthesis of Compounds 5a−c: Method A (General Procedure)
To a solution of the appropriate compound 4a−c (0.01 mol) in dioxane
(20 mL), anhydrous potassium carbonate (3 g), and TBAB (0.003 g)
were added. The reaction mixture was stirred for 5 h at 60◦C until the
completion of the reaction (TLC). The reaction mixture was filtered off,
and the filtrate evaporated in vacuo. The residual solid was washed
with water and crystallized from the appropriate solvent (cf. Scheme 1,
Table I).

Synthesis of Some New 1,5-Benzodiazepines
719
Synthesis of Compounds 5a−e: Method B (General Procedure)
A mixture of anhydrous potassium carbonate (3 g); dry dioxane
(30 mL); compound 2 (0.005 mol, 2.02 g); the appropirate halocompound;
ethylchloroacetate (0.54 mL), chloroacetonitrile (0.31 mL), phenacyl
bromide (0.99 g) chloroacetamide (0.46 g), or chloroacetanilide (0.85 g);
and TBAB (0.003 g) was stirred for 5 hr at 60◦C until the completion
of the reaction (TLC). The reaction mixture was filtered off, and the
filtrate evaporated in vacuo. The residual solid was washed with water
and crystallized from the appropriate solvent (cf. Scheme 1, Table I).
Synthesis of Compounds 6 and 7: General Procedure
A mixture of anhydrous potassium carbonate (3 g), dry dioxane (30 mL),
compound 2 (0.005 mol, 2.02 g), ethyl cyanoacetate (0.005 mol, 0.53 mL),
and TBAB (0.003 g) was stirred for 4 h at 60◦C until the completion of
the reaction (TLC). The reaction mixture was filtered off, and the filtrate
evaporated in vacuo. The residual solid was washed with water and
crystallized to give compound 6. The precipitate (carbonate layer) was
dissolved in water (50 mL) and acidified by HCl, and the solid product
was filtered off, washed with water, and crystallized to give compound
7 (cf. Scheme 1, Table I).
Synthesis of Compounds 8 and 10–14: General Procedure
An equimolar amount (0.01 mole) of compound 1 (2.36 g) or compound
9 (2.64 g) in ethanol (20 mL), carbondisulfide (1.14 mL), or phenylisoth-
iocyanate (1.3 mL), along with triethylamine (2 mL) were added. The
reaction mixture was stirred at r. t. for 2 h, and the suitable active
methylene, namely malononitrile (0.66 g), cyanothioacetamide (1 g),
cyanoacetamide (0.8 g), ethyl cyanoacetate (1.1 mL), and dimethylfor-
mamide (2 mL), was added. The reaction mixture was refluxed for 4 h.
After cooling, the reaction mixture was poured into water and HCl (100:
5 v/v). The solid product was filtered off, washed with water, and crys-
tallized from the appropirate sovent (cf. Scheme 2, Table I)
Synthesis of Compound 15
A mixture of compound 10 (0.001 mol, 0.388 g), acetic anhydride
(0.001 mol, 0.1 mL), and dry pyridine (20 mL) was refluxed for 1 h
The reaction mixture was poured into ice-cold water. The separated
solid was collected by filtration, washed with water, and crystallized
(cf. Scheme 2, Table I).

720
A. M. El-Sayed et al.
SCHEME 2

Synthesis of Some New 1,5-Benzodiazepines
721
SCHEME 3
Synthesis of Compound 16
A solution of compound 15 (0.001 mol, 0.43 g) in dry pyridine (20 mL)
was refluxed for 5 h. The reaction mixture was poured into ice-cold
water containing few drops of HCl. The separated solid was collected
by filtration and crystallized (cf. Scheme 2, Table I).
Synthesis of Compound 17
A mixture of compound 10 (0.001 mol, 0.388 g), phenyl isothiocyanate
(0.001 mol, 0.12 mL), and dry pyridine (20 mL) was refluxed for 10 h.
The reaction mixture was poured into ice-cold water. The separated
solid was collected by filtration and crystallized (cf. Scheme 2, Table I)
Synthesis of Compounds 18–21: General Procedure
To a stirred solution of compound 1 (0.01 mol, 2.36 g) in dry dioxane
(20 mL), sulphur (0.01 mol, 0.32 g) and triethylamine (0.4 mL) were
added. The reaction mixture was refluxed for 1 h, and then 0.01 mol
of the appropirate active methylene, namely malononitrile (0.66 g),

722
A. M. El-Sayed et al.
cyanothioacetamide (1 g), cyanoacetamide (0.88 g), or ethyl cyanoac-
etate (1.13 mL), was added. The reaction mixture was refluxed for 4 h.
After cooling, the solid precipitate was filtered off, washed with water,
and crystallized from the appropirate solvent. The filtrate was evapo-
rated in vacuo, and the residual solid was washed with water, filtered
off, dried, and crystallized to give compound 20 (cf. Scheme 2, Table I).
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