Synthesis of new fused 1,5-benzodiazepines, part 3

Article abstract of DOI:10.1080/104265090889611

1,3-Dihydro-4-phenyl-1,5-benzodiazepin-2-one 1_a was treated with some ylidenecyanothioacetamides to give the corresponding pyrido(2,3-b) benzodiazepines 3-6. Treatment of compound 1_a with a mixture of thiophen-2-aldehyde and thiourea

Full text of DOI:10.1080/104265090889611

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Synthesis of New Fused 1,5-
Benzodiazepines, Part 3
A. Khodairy a
a Chemistry Department, Faculty of Science, Sohag,
Egypt
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Part 3, Phosphorus, Sulfur, and Silicon and the Related Elements, 180:8, 1893-1907
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Phosphorus, Sulfur, and Silicon, 180:1893–1907, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090889611
Synthesis of New Fused 1,5-Benzodiazepines, Part 3∗
A. Khodairy
Chemistry Department, Faculty of Science, Sohag, Egypt
1,3-Dihydro-4-phenyl-1,5-benzodiazepin-2-one
1
was treated with some yli-
a
denecyanothioacetamides to give the corresponding pyrido(2,3-b)benzodiazepines
3–6. Treatment of compound 1 with a mixture of thiophen-2-aldehyde and
a
thiourea or guanidine gave the corresponding 1,3-thiazino- and pyrimido(4,5-
b)benzodiazepines
7
and 8. 3-Arylidene derivatives
9
and 10 were
a–e
synthesized. Compound 10 was subject to react with 2-(1-methylthio-1ꢀ-
anilinomethylidene)malononitrile to give oxazino-benzodiazepine 11. Thieno(3,2-
b)benzodiazepines 12
and 13 were synthesized via the reaction of compound
with sulfur and some active nitriles. [1,3-Dihydro-4-phenyl(1,5)-benzodiazepin-
a,b
1
b
2-ylidene]malononitrile 15 was used as synthon to obtain novel pyrido-, pyrano-,
benzo-, and thienobenzodiazepines 16–20, respectively. The reaction of compound 1
b
with CS or PhNCS along with 1,1,3-tricyano-2-aminoprop-1-ene, 2-(1-methylthio-
2
1ꢀ-anilinomethylidene)malononitrile, or 1,3-dibromopropane gave the correspond-
ing polyfused benzodiazepines 21–23, respectively.
Keywords
1,3-Dihydro-4-phenyl-1,5-benzodiazepin-2-one; pyridobenzodiazepines;
pyrimidobenzodiazepines; thiazinobenzodiazepines; oxazinobenzodiazepines; thienoben-
zodiazepines
INTRODUCTION
Benzodiazepines have been widely employed in clinical prac-
tices as anxiolytics,1 sedative-hypnotics,2 anticonvulsant vasopressin
antagonists,3 and anticipated CNS-depressants.4 Interestingly, ben-
zothienobenzodiazepine (Y-931), dibenzo[b,f]diazepine (clozapine), and
thienobenzodiazepine (olanzapine) are known as typical effective
antipsychotics.5,6
This prompted us to continuate our previous work7,8 to synthesize
some new fused and spiro benzodiazepines. So, we report herin the
synthesis of novel pyridine, pyran, thiophene, pyrimidine, oxazine, thi-
azine, and naphthyridine rings fused with benzodiazepine moiety.
Received June 6, 2004; accepted September 7, 2004.
∗For Part 1 and Part 2, see references 7 and 8.
Address correspondence to A. Khodairy, Chemistry Department, Faculty of Science,
Sohag, 82524 Egypt. E-mail: khodairy@yahoo.com
1893

1894
A. Khodairy
SCHEME 1
RESULTS AND DISCUSSION
9
The reaction of 1,3-dihydro-4-phenyl-1,5-benzodiazepin-2-one 1a with
a variety of arylidenecyanothioacetamides namely; benzo[b]-3,4-
dioxolmethylidene-, p-fluorobenzylidene-, thien-2-ylidene-, or pyrrol-
2-ylidenecyanothioacetamide in the presence of piperidine as a cata-
lyst, afforded the corresponding 3-substituted benzodiazepines 2a–d
,
which in turn were cyclized in the presence of sodium ethoxide to
afford 3-cyano-pyrido[2,3-b][1,5]benzodiazepine–2-thione derivatives
3
a–d. Compounds 3a–d and 4 were also prepared in one step via the
reaction of compound 1a with the same arylidenecyanothioacetamides
or cyclohexylidenecyano thio-acetamide in alcoholic sodium ethoxide.
IR spectra of compounds 2a–d showed the absorption bands correspond-
ing to NH2, CN, and C O groups at 3320, 3200, 2210, and 1690 Cm−1
,
respectively, whereas IR spectra of compounds 3a–d and 4 showed the
disappearance of the absorption bands corresponding to NH2 and C O
groups and the appearance of the absorption bands corresponding to
NH groups (cf. Scheme 2, Table I). Compound 3a was treated with some
active halo compounds, namely ethyl chloroacetate, chloroacetonitrile,
phenacyl bromide, or chloroacetanilide, in the presence of sodium ac-
etate, to afford the corresponding S-alkylated derivatives 5a–d. Com-
pound 5a underwent intramolecular cyclization,10 affording the corre-
sponding thieno[3ꢀ,2ꢀ:5,6]pyrido[2,3-b]-1,5-benzodiazepine derivative 6
on refluxing with sodium ethoxide. IR spectrum of compound 6 showed
the disappearance of the absorption band corresponding to the CN
1
group and H-NMR spectrum revealed a broad signal at δ 5.4–5.0 of
the NH2 group, which was exchangeable with deuterium on addition of
D2O (c.f. Scheme 2, Table I).
Treatment of compound 1a with a mixture of thiophen-2-aldehyde
and thiourea or guanidine in the presence of sodium methoxide11
gave the corresponding 1,3-thiazino- and pyrimido[4,5-b][1,5]benzodi-
azepine derivatives 7 and 8, respectively (c.f. Scheme 2, Table I).

New Fused 1,5-Benzodiazepines
1895
SCHEME 2
3-Arylidene-1,5-benzodiazepine derivatives 9a–e and 10 were syn-
thesized through the reaction of compound 1a with some aromatic
carbonyl reagents including o-, m-, and p-chlorobenzaldehyde; p-
nitrobenzaldehyde; p-N,N-dimethylaminobenzaldehyde; or isatine in
glacial acetic acid and fused sodium acetate as a catalyst. Com-
pound 10 was subjected to react with 2-(1-methylthio-1ꢀ-anilinomethyl-
idene)malononitrile12 in tert. butanol to afford the corresponding
1,3-oxazine[6,5-b](1,5)benzodiazepine derivative 11. IR spectrum of

1896

1897

1898

1899

1900

New Fused 1,5-Benzodiazepines
1901
compound 11 showed an absorption band corresponding to the CN
group at 2219 Cm−1 (c.f. Scheme 2, Table I).
13
1,3-Dihydro-1-ethyl-4-phenyl-1,5-benzodiazepin-2-one 1b was al-
lowed to react with elemental sulfur along with malononitrile, ethyl
cyanoacetate, or 1,1,3-tricyano-2-aminoprop-1-ene to yield the cor-
responding thieno[3,2-b]benzodiazepines 12a,b and 13, respectively.
Treatment of compound 13 with phenyl isothiocyanate14 in the pres-
ence of triethylamine as a base gave the corresponding 2-amino-3-
pyrimidinyl thieno(3,2-b)-1,5-benzodiazepine derivative 14. The reac-
tion pathway for the formation of compound 14 was assumed to proceed
via a nucleophilic attack of the ethylenic NH2 group to the C S group
followed by a nucleophilic addition of the formed NH group to the CN
group (c.f. Scheme 3, Table I).
SCHEME 3
[1,3-Dihydro-4-phenyl(1,5)benzodiazepin-2-ylidene]malononitrile
158 was treated with phenyl isothiocyanate,15 benzoyl isothio-
cyanate, benzoyl chloride,15 or benzaldehyde15 in pyridine to
give the corresponding pyrido(4,3-b)benzodiazepinethiones 16a,b
,
pyrido(4,3-b)benzodiazepinone 17, or pyrano(4,3-b)benzodiazepine
18, respectively. Moreover, treatment of compound 15 with p-chloro-
benzylidenemalononitrile12 in the presence of triethylamine afforded
the corresponding 3-amino-2,4-dicyanobenz[b]-(1,5)benzodiazepine

1902
A. Khodairy
derivative 19. Thieno[3,2-b]benzodiazepine 20 was synthesized
through the reaction of compound 15 with elemental sulfur in the
presence of triethylamine (c.f. Scheme 4, Table I).
SCHEME 4
Compound 1b was allowed to react with a mixture of CS2 or
PhNCS and 1,1,3-tricyano-2-aminoprop-1-ene under PTC condi-
tions (dioxane/K2CO3/tetrabutylammonium bromide [TBAB]) to
afford pyridothiopyrano[4,3-b]-1,5-benzodiazepine 21a and [1,5]-
benzodiazepino[6,5-c][1,8]naphthyridine 21b, respectively. The
reaction pathway16 was indicated in Scheme 5. Also, treatment
of compound 1b with a mixture of CS2 or PhNCS and 2(1-methylthio-
1ꢀ-anilinomethyl-idene)malononitrile12 under PTC conditions afforded
the corresponding 1,3-thiazino(4,5-b)-1,5- benzodiazepine 22a and

New Fused 1,5-Benzodiazepines
1903
pyrimido-1,5-benzodiazepine 22b derivatives, respectively. Morever,
the reaction of compound 1b with CS2 and 1,3-dibromopropane in
a 1:1:1 molar ratio under the same PTC conditions afforded the
corresponding 3[1,3-dithi-2-ylidene]benzodiazepin-2-one derivative 23
(c.f. Scheme 5, Table I).
SCHEME 5
EXPERIMENTAL
All melting points were determined on a Koffler melting points appa-
ratus and are uncorrected. IR spectra were obtained on a Nicolet 710

1904
A. Khodairy
1
FT-IR spectrometer. H-NMR spectra were recorded on a Varian EM
360 at 60 MHz using TMS as an internal reference and DMSO-d6 as a
solvent. Elemental analyses were performed on a perkin-Elmer CHN-
2400◦C analyzer model.
Synthesis of Compounds 2a–d
A mixture of compound 1a (0.01 mol, 2.36 gm), the appropriate
arylidenecyanothioacetamide (0.01 mol), including benz[b]-3,4-dioxol-
methylidene- (2.32 g), p-fluorobenzylidene- (2.06 g), thiene-2-ylidene-
(1.94 g), or pyrrol-2-ylidenecyanothioacetamide (1.77 g), and catalytic
amount of piperidine (0.2 mL) was refluxed in dioxane (20 mL) for 2 h.
The formed precipitate was filtered off and crystallized from an appro-
priate solvent to give compounds 2a–d (cf. Scheme 2, Table I).
Synthesis of Compounds 3a–d (Method A)
The appropriate compound 2a–d (0.01 mol) was suspended in sodium
ethoxide solution (0.23 g Na in 30 mL absolute ethanol) and refluxed
for 3 h. The solid that formed after cooling was collected by filteration,
washed with water, and crystallized from the suitable solvent to give
the compounds 3a–d ( cf. Scheme 2, Table I).
Synthesis of Compounds 3a–d and 4 (Method B)
A mixture of compound 1a (0.01 mol, 2.36 gm), the appropriate yli-
denecyanothioacetamide (0.01 mol), and sodium ethoxide (0.23 g of Na
in 40 mL absolute ethanol) was refluxed for 2 h. The formed precip-
itate was filterd off, dried, washed with water, and crystallized from
an appropriate solvent to give compounds 3a–d and 4, respectively (cf.
Scheme 2, Table I).
Synthesis of Compounds 5a–d
A mixture of compound 3a (0.005 mol, 4.48 gm), (0.005 mol) from the ap-
propriate halo compound (chloroacetonitrile [0.31 mL], ethyl chloroac-
etate [0.54 mL], phenacyl bromide [0.93 g] or chloroacetanilide [0.85 g])
and sodium acetate (0.005 mol, 0.41 gm) in ethanol (20 mL) was refluxed
for 2 h. The precipitate that was obtained was filtered off, washed with
water, and crystallized from the appropriate solvent to give the com-
pounds 5a–d, respectively (cf. Scheme 2, Table I).

New Fused 1,5-Benzodiazepines
1905
Synthesis of Compound 6
Compound 5a (0.01 mol, 5.34 g) was suspended in sodium ethoxide solu-
tion (0.35 g Na in 30 mL absolute ethanol) and refluxed for 3 h. The solid
that formed after cooling was filtered off, washed with water, and crys-
tallized from the ethanol to give the compound 6 (cf. Scheme 2, Table I).
Synthesis of Compounds 7 and 8: General Procedure
To a stirred solution of compound 1a (0.003 mol, 0.7 g) in methanol
(25 mL), thiophene-2-aldehyde (0.003 mol, 0.28 mL), thiourea
(0.003 mol, 0.22 g) or guanidine hydrochloride (0.003 mol, 0.28 g) and
sodium methoxide (0.23 g Na in 5 mL methanol) were added. The
reaction mixture was refluxed for 2 h, evaporated in vacuo and the
residue was triturated with pet. ether (60–80◦C). The solid product
was collected by filtration and crystallized (cf. Scheme 2, Table I).
Synthesis of Compounds 9 and 10: General Procedure
A mixture of compound 1a (4.72 g, 0.005 mol); the appropirate carbonyl
reagent (0.005 mol), including o-chloro- (0.7 g), m-chloro- (0.7 g), p-hloro-
(0.7 g), p-nitro- (o.75 g), p N,N-dimethylaminobenzaldehyde (0.73 g), or
isatin (0.73 g); and fused sodium acetate (2.3 g) in glacial acetic acid
(20 mL) was refluxed for 4 h. On cooling, the precipitated solid was
filtered, dried, washed with water, and crystallized from appropirate
solvent (cf. Scheme 2, Table I).
Synthesis of Compound 11
Equimolar amount (0.003 mol) of compound 10 (0.28 g) and 2(1-
methylthio-1ꢀ-anilinomethylidene)malononitrile (0.64 g) were dissolved
in tert. butanol (30 mL) containing few drops of triethyl amine. The re-
action mixture was refluxed until the evolution of MeSH ceased (12 h),
evaporated in vacuo, and the remaining residue was triturated with
pet. ether (40–60◦C). The solid formed was collected by filtration and
crystallized (cf. Scheme 2, Table I).
Synthesis of Compounds 12 and 13: General Procedure
A mixture of compond 1b (0.002 mol, 0.53 g); elemental sulfur
(0.002 mol, 0.096 g); the appropirate active methylene (0.003 mol) in-
cluding malononitrile (0.1 g), ethyl cyanoacetate (0.23 mL), or 1,1,3-
tricyano-2-aminoprop-1-ene (0.26 g), and triethylamine (0.003 mol,

1906
A. Khodairy
0.32 mL) in dioxane (20 mL) was refluxed for 3 h. The solid that formed
on cooling was filtered off and crystallized from an appropirate solvent
(cf. Scheme 3, Table I).
Synthesis of Compound 14
A mixture of compound 13 (0.002 mol, 0.82 g), phenyl isothiocyanate
(0.002 mol, 0.23 mL), and a catalytic amount of triethylamine was re-
fluxed in dimethylformamide (20 mL) for 2 h. The formed precipitate
was filtered off and crystallized to give compound 14 (cf. Scheme 3,
Table I).
Synthesis of Compounds 16a,b–18: General Procedure
Equimolar amounts (0.003 mol) of compound 15 (0.89 g) and phenyl
isothiocyanate (0.35 mL), benzoyl isothiocyanate (0.4 mL), benzoyl chlo-
ride (0.34 mL) or benzaldehyde (0.32 mL) in pyridine (20 mL) was re-
fluxed for 5 h. After cooling, the reaction mixture was poured into a
mixture of ice water (100 mL) and HCl (5 mL). The separated solid was
then collected by filtration, washed with water, and crystallized from
appropirate solvent (Scheme 4, Table I).
Synthesis of Compounds 19
(0.003 Mol) of compound 15 (0.89 g), p-chlorobenzylidene-malononitrile
(0.7 g), and triethylamine (0.2 mL) in dioxane (20 mL) was refluxed
for 4 h. On cooling, the precipitated solid was filtered off, dried, and
crystallized (cf. Scheme 4, Table I).
Synthesis of Compound 20
A mixture of compound 15 (0.003 mol, 0.89 g), elemental sulfur
(0.003 mol, 0.1 g), and a catalytic amount of triethylamine was refluxed
in dioxane (20 mL) for 2 h. The formed precipitate was filtered off and
crystallized to give compound 20 (cf. Scheme 3, Table I).
Synthesis of Compounds 21–23: General Procedure
A mixture of anhydrous potassium carbonate (3 g), dry dioxane (30 mL),
compound 1b (0.003 mol, 0.79 g), carbon disulfide (0.003 mol, 0.22 mL)
or phenyl isothiocyanate (0.003 mol, 0.36 mL) and TBAB (0.003 g) was
stirred for 2 h. at room temperature and stirred for 2 h at 60◦C. To the

New Fused 1,5-Benzodiazepines
1907
reaction mixture, the appropirate reagent (0.003 mol), namely, 1,1,3-
tricyano-2-aminoprop-1-ene (0.39 g), 2(1-methylthio-1‘-anilinomethyl-
idene)malononitrile (0.64 g), or 1,3-dibromopropane (0.6 mL), was
added. The reaction mixture was stirred for 5 h at 60◦C until the com-
pletion of the reaction (TLC). The reaction mixture was filtered off and
the filtrate evaporated in vacuo. The residual solid was washed with
water and then crystallized from the appropriate solvent (cf. Scheme 5,
Table I).
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