Synthesis of 4-amino-3-cyano-2-methylsulfanyl-1 H-[1,5]benzodiazepine, benzo[1,3]azole, and pyrazolobenzo[1,3]azole derivatives via a new utility of bis(methylsulfanyl)methylene derivatives

Article abstract of DOI:10.1002/hc.20031

Novel polysubstituted 1,5-benzodiazepine 5, 2,2-bis(methylthio)benzoxazoles 8a-d, 2,2-bis-(acetyl)benzoxazole 8e, 2-(3-methyl-1-phenylpyrazolo4-yl) benzoazole derivatives 16a-c, as well as the previously reported 2-di[cyano(acetyl)-methylene]benzothiazole

Full text of DOI:10.1002/hc.20031

Heteroatom Chemistry
Volume 15, Number 5, 2004
Synthesis of 4-Amino-3-cyano-2-
methylsulfanyl-1H-[1,5]benzodiazepine,
Benzo[1,3]azole, and Pyrazolobenzo[1,3]azole
Derivatives via a New Utility
of Bis(methylsulfanyl)methylene Derivatives
Eman A. El-Rady, Mohamed A. Khalil, and Fawi M. Abd El Latif
Chemistry Department, Aswan Faculty of Science, South Valley University, Aswan, Egypt
Received 25 November 2003; revised 28 January 2004
RESULTS AND DISCUSSION
ABSTRACT: Novel polysubstituted 1,5-benzodiaze-
pine 5, 2,2-bis(methylthio)benzoxazoles 8a–d, 2,2-bis-
(acetyl)benzoxazole 8e, 2-(3-methyl-1-phenylpyrazolo-
4-yl)benzoazole derivatives 16a–c, as well as the pre-
viously reported 2-di[cyano(acetyl)-methylene]benzo-
thiazoles 7a,b have been obtained via a new utility of
ketene dithioacetals 1a,b and 12 with aniline deriva-
tives 2. Rationales for the reactions pathways are pre-
sented. 2004 Wiley Periodicals, Inc. Heteroatom Chem
15:407–412, 2004; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20031
The bis(methylsulfanyl)methylene malononitrile 1a
reacted with 1,2-phenylenediamine 2a in ethanol
solution containing catalytic amount of piperi-
dine at reflux temperature to yield the cor-
responding 4-amino-3-cyano-2-methylsulfanyl-1H-
[1,5]benzodiazepine 5. The structure assignment
of product 5 is based on spectral and elemental
analysis. The MS (70 eV) spectrum of compound
5 showed molecular ion corresponding to the for-
mula C11H10N4S (231, M + 1, 35%), 182 (M-CH3SH,
30), 154 (182-HCN, 9), 127 (154-N2, 22), 102 (127-
CH CH, 20), 98 (100). The IR spectrum revealed ab-
sorption bands at ν 3100, 3121, 3250, and 2215 as-
signed for imino, amino, and cyano function groups,
respectively. The 1H NMR spectrum of 5 showed two
singlets at δ 3.4 ppm assigned for thiomethyl protons
and a downfield absorption at δ 12.9 ppm assigned
for amine protons, respectively. The 13C NMR spec-
trum of 5 showed signals at δ 56.5 assignable for one
carbon of thiomethyl (SCH3) and at δ 118.2 also as-
signed for only one cyano carbon (CN), 110.2 (C-3),
140.4 (C-4), 145.5 (C-2), in addition to the aryl car-
bons. A rationale for formation of the product 5 is
presented in Scheme 1.
ꢀ
C
INTRODUCTION
The ketene dithioacetals 1 were successfully used
in heterocyclic synthesis [1–7]. To the best of our
knowledge, the ketene dithioacetal 1 was not used to
prepare seven-membered ring systems so far; how-
ever, some other related derivatives were used [8,9].
The remarkable biological and pharmaceutical prop-
erties of 1,5-benzodiazepine derivatives [10–13] are
behind our interest [14–18] to prepare such seven-
membered ring systems.
It assumes that the amine function of 2a attacks
exclusively the activated double bond of the ketene
dithioacetal 1a at the more electrophilic carbon bear-
ing the two thiomethyl groups to give the adduct
Dedicated to Professor Dr. Dietrich Doˆpp on the occasion of his
65th birthday.
Correspondence to: Eman A. El-Rady; e-mail: emanelradi@
hotmail.com.
c
ꢀ
2004 Wiley Periodicals, Inc.
407

408 El-Rady, Khalil, and Abd El Latif
SCHEME 1
3. Elimination of one molecule of thiomethyl alco-
hol from 3 affords the intermediate 4, which may
also be obtained directly from losing thiomethyl al-
cohol from 1 and 2. Cyclization of 4 via a nucle-
ophilic attack by the lone pair electrons of the second
amine group into the cyano function finally yielded
the 1,5-benzodiazepine compound 5 (Scheme 1).
The reaction of 1a with 2b and 2c failed to pro-
duce any of the desired benzothiazepine or benzox-
azepine derivatives. Hypothetically, the amine func-
tion might attack C(CN)2) carbon; this would lead
to elimination of HCN and CH3SH, respectively, to
afford benzopyrazine 11 via the plausible interme-
diate 10. Formation of 11 is ruled out on the ba-
sis of the spectroscopic and elemental data obtained
(Scheme 2).
on spectral and elemental analysis and compared
with the data was reported [5]. The MS of com-
pound 7a gave a correct molecular ion at m/z 199
(M+, 100%) as base peak. The IR spectrum showed
characteristic bands at 3170 and 2212, 2210 assigned
1
for imino and nitrile functions, respectively. The H
NMR spectrum showed absorption at δ 7.1–7.9 ppm
attributed for aromatic protons and at 9.2 assigned
for NH proton only, with the lack of any absorption
due to thiomethyl protons. 13C NMR spectrum of 7a
shows signals at δ 117.5, 118.4 (CN), 145.2 (C-2a),
and 152.2 (C-2), in addition to aryl carbons.
Contrarily, 2-aminophenol 2c reacts with ketene
dithioacetals 1a,b in a different mode, as is shown in
Scheme 1. Elimination of one molecule of malonon-
itrile from the adduct 3 affords 2,2-bis[methylthio-
(acetyl)]-2,3-dihydrobenzoxazole 8a–e. The MS of 8a
showed exact molecular ion at m/z 213 (M+, 15) cor-
responding for C9H11NOS2. The IR spectrum showed
On the other hand, reaction of 2-aminothio-
phenol 2b with the ketene dithioacetals 1a,b under
the same reaction conditions yielded the previously
reported benzothiazole derivatives 7a,b via the inter-
mediate 6. The structure of compounds 7a,b based
1
no absorption due to cyano function. The H NMR
spectrum showed one singlet at δ 3.4 ppm integrated

4-Amino-3-cyano-2-methylsulfanyl-1H-[1,5]benzodiazepine, Benzo[1,3]azole, and Pyrazolobenzo[1,3]azole Derivatives 409
SCHEME 2
for six protons of two SCH3. The 13C NMR spec-
trum of 8a showed signals at 45.5 and 56.7 ppm
assigned for C-2 and 2(SCH3). These spectral data
prompted us to propose that the reaction may pro-
ceeds via the key intermediate 3, which transformed
via a five-endo-trig pathway with the elimination of
one molecule of malononitrile to yield the benzoxa-
zole derivatives 8 (Scheme 1).
EXPERIMENTAL
Melting points have been determined on a Gallen–
Kamp melting point apparatus and are uncorrected.
The IR spectra (potassium bromide, ν in cm−1)
were recorded on a Pye-Unicam SP-1100 spec-
trophotometer. 1H NMR spectra (deuterochloroform
and deuterodimethyl sulfoxide, δ in ppm) were run
on a Varian EM-390 spectrometer using tetram-
ethylsilane as internal standard. Mass spectra were
recorded (70 eV) on a Varian MAT 311 A spectrom-
eter, and the elemental analyses were determined at
the Microanalytical Center, Cairo University, Egypt.
On the other hand, 3-methyl-1-phenylpyrazole-
4-methylenedithioacetal-5-one 12 was reacted
with aniline derivatives 2a–c in ethanol contain-
ing piperidine at reflux temperature to afford
2-(1-methyl-1-phenylpyrazole-5-one-4-yl)benzazole
derivatives 16a–c in moderated yields. The mass
spectrum of 16b showed m/z at 307 (M+, 100),
174 (37), 133 (13), 105 (13), 103 (3), and 77 (15).
The IR spectrum revealed absorption bands at ν
3215 and 1675 and 1628 cm−1 assigned for NH,
C O and C C groups, respectively. The 1H NMR
spectrum of 16b showed signals at δ 2.1, 7.2–7.9,
and 9.2 ppm attributed for methyl, aromatic, and
NH protons, respectively. The 13C NMR of 16b
showed characteristic signals at 172.5 and 185.2
ppm assigned for carbonyl and C-2 of thiazole ring,
respectively. Formation of 16 may be proceeded as
described in Scheme 3. Elimination of one molecule
of thiomethyl alcohol from the adduct 13 afforded
the intermediate 14, which transformed to the
intermediate 15. The latter loses another molecule
of thiomethyl alcohol to finally yield the product
16. Formation of the expected 1,5-benzodiazepine
derivatives 17 was ruled out.
4-Amino-3-cyano-2-methylsulfanyl-
1H-[1,5]benzodiazepine 5
A solution of 1 (1.7 g, 10 mmol), 1,2-phenylene-
diamine2a (1.0 gm, 10 mmol), and 0.1 mL of piperi-
dine in 30 mL of dry ethanol was warmed to reflux
for 3 h and concentrated under vacuum. The solid
compound formed after two hours of reflux was col-
lected by filtration, washed with 5 mL of methanol,
and crystallized from dimethylformamide to give 5.
This compound was isolated (1.4 g, 63%), mp
>300◦C. IR: ν 3100 (NH), 3121–3250 (NH2), 2215
(CN). 1H NMR (DMSO-d6): δ 3.4 (s, 3H, SCH3), 12.9
(s, 2H, NH2), 7.1–7.9 (m, 5H, Ar H, NH). 13C NMR
(DMSO-d6): δ 56.5 (SCH3), 110.2 (C-3), 118.2 (CN),
123.5, 124.3, 127.2, 128.3 (aryl-C), 140.4 (C-4), 145.5
(C-2). MS m/z (%): 231 (M + 1, 35), 182 (30), 154 (9),
127 (22), 102 (20), 98 (100). Anal calcd for C11H10N4S

410 El-Rady, Khalil, and Abd El Latif
SCHEME 3
(230.29): C, 57.37; H, 4.38; N, 24.33; S, 13.92. Found:
C, 57.19; H, 4.21; N, 24.14; S, 13.80.
2-Di(acetylmethylenyl)-
2,3-dihydrobenzothiazole 7b
This was crystallized from ethanol in 60% yield, mp
160–161◦C (lit. 158.5–159.5◦C). IR: ν 3145 (NH), 1610
(C O). 1H NMR (CDCl3): δ 2.4 (s, 6H, 2CH3), 7.2–7.8
(m, 4H, Ar H), 14.9 (s, 1H, NH). MS: m/z = 233 (M+,
100%). Anal calcd for C12H11NO2 S (233.29): C, 61.78;
H, 4.75; N, 6.00; S, 13.74. Found: C, 61.50; H, 4.63;
N, 5.87; S, 13.55.
2-Di(cyanomethylenyl)-
2,3-dihydrobenzothiazole 7a
To 30 mL of ethanol, 1.7 g (10 mmol) of 1, 2-
aminothiolphenol 2b (1.2 g, 10 mmol), and 0.1 mL
of piperidine was refluxed for 5 h. The solid com-
pound formed on heating was collected by filtration,
washed with 5 mL of methanol, and crystallized from
a mixture of equal volumes of dimethylformamide
and ethanol. This compound was isolated (1.0 mg,
52%), mp 292◦C (lit. 290◦C). IR: ν 3170 (NH), 2212,
General Procedure for 2,2-Bis[methylsulfanyl-
(acetyl)]-2,3-dihydrobenzoxazoles 8a–e
1
2210 (CN). H NMR: (DMSO-d6): δ 7.1–7.9 (m, 4H,
A mixture of 1a (1.7 g, 10 mmol), 2-aminophenol
2c (1.2 g, 1 mmol), and 0.1 mL of piperidine in 30
mL of dry ethanol was refluxed for five hours and
then concentrated under vacuum till dryness. The
solid formed was triturated with cold methanol and
collected by filtration, washed with 5 mL of methanol
and crystallized from ethanol.
Ar H), 9.2 (s, 1H, NH). 13C NMR: δ 117.5, 118.4 (CN),
121.2, 123.5, 126.7, 128.5 (aryl-C), 145.2 (C-2a), 152.2
(C-2). MS: m/z = 199 (M+, 100%), 172 (25), 146 (19),
109 (6), 77 (5). Anal calcd for C10H5N3S (199.23): C,
60.29; H, 2.53; N, 21.09; S, 16.09. Found: C, 60.10; H,
2.42; N, 20.88; S, 15.98.

4-Amino-3-cyano-2-methylsulfanyl-1H-[1,5]benzodiazepine, Benzo[1,3]azole, and Pyrazolobenzo[1,3]azole Derivatives 411
Compound 8a. This compound was isolated
(0.39 g) and 2c (0.39 g) reacted with 12 under the
same conditions to yield 16a and 16c, respectively.
1
(1.2 g, 60%), mp 240◦C. IR: ν 3170 (NH). H NMR
(CDCl3): δ 3.4 (s, 6H, 2SCH3), 7.2–7.9 (m, 4H, Ar H),
10.3 (s, 1H, NH). 13C NMR: δ 45.5 (C-2), 56.7 (SCH3),
110.2, 120.3, 124.2, 125.2, 140.1, 150.3 (aryl-C). MS:
m/z (%) 213 (M+, 15%), 185 (66), 120 (2), 108 (2),
92 (13), 77 (8), 64 (80), 52 (17). Anal calcd for
C9H11NOS2 (213.31): C, 50.68; H, 5.20; N, 6.57; S,
30.06. Found: C, 50.52; H, 5.05; N, 6.33; S, 29.86.
2-(1-Methyl-1-phenylpyrazole-5-one-4-yl)-benzi-
midazole 16a. Yield: 0.3 g (65%), mp 100◦C. IR:
1
ν 1700 (C O), 3177 (NH). H NMR (DMSO): δ 2.1
(s, 3H, CH3), 7.1–7.9 (m, 9H, Ar H), 9.8 (s, 2H,
2NH). MS: m/z (%) 290 (M+, 25%). Anal calcd for
C17H14N4O (290.33): C, 70.33; H, 4.86; N, 19.30.
Found: C, 70.20; H, 4.64; N, 19.11.
Compound 8b. This was isolated (EtOH) in
0.4 g (57%), mp 295◦C. IR: ν 3180 (NH). H NMR
1
2-(1-Methyl-1-phenylpyrazole-5-one-4-yl)-benzo-
thiazole 16b. Yield: 0.4 g (72%), mp 195◦C. IR:
ν 1628 (C C), 1675 (C O), 3215 (NH). 1H NMR
(DMSO): δ 2.1 (s, 3H, CH3), 7.2–7.9 (m, 9H, Ar H),
9.2 (s, 1H, NH). 13C NMR (DMSO): 15.2 (CH3),
121.2–130.3 (aryl-C), 142.6 (C-3-pyrazole), 145.2
(C-4-pyrazole), 172.5 (C-5-pyrazole), 185.2 (C-2-
thiazole). MS: m/z (%) 307 (M+, 100%). Anal calcd
for C17H13N3OS (307.37): C, 66.43; H, 4.26; N, 13.67.
Found: C, 66.25; H, 4.03; N, 13.55.
(CDCl3): δ 3.5 (s, 6H, 2SCH3), 7.2–7.9 (m, 3H, Ar H),
9.2 (s, 1H, NH). MS: m/z (%) 247 (M+, 17%). Anal
calcd for C9H10ClNOS2 (247.76): C, 43.64; H, 4.07; N,
5.66; S, 25.88; Cl, 14.31. Found: C, 43.36 ; H, 4.27; N,
5.44; S, 25.74; Cl, 14.01.
Compound 8c. This was isolated (MeOH) in
1
0.5 g (66%), mp 280◦C. IR: ν 3172 (NH). H NMR
(CDCl3): δ 3.2 (s, 6H, 2SCH3), 7.1–7.9 (m, 3H, Ar H),
10.2 (s, 1H, NH). MS: m/z (%) 258 (M+, 25%). Anal
calcd for C9H10N2O3S2 (258.31): C, 41.85; H, 3.90; N,
10.85; S, 24.82. Found: C, 41.63; H, 3.76; N, 10.46; S,
24.66.
2-(1-Methyl-1-phenylpyrazole-5-one-4-yl)-benzo-
xazole 16c. Yield: 0.3 g (60%), mp 95◦C. IR: ν 1850
1
(C O), 3185 (NH). H NMR (CDCl3): δ 1.6 (s, 3H,
CH3), 7.1–7.9 (m, 9H, Ar H), 10.5 (s, H, NH). MS:
m/z (%) 291 (M+, 35%). Anal calcd for C17H13N3O2
(291.31): C, 70.10; H, 4.50; N, 14.42. Found: C, 69.90;
H, 4.26; N, 14.22.
Compound 8d. This was isolated (MeOH) in
1
0.5 g (58%), mp 210◦C. IR: ν 3175 (NH). H NMR
(CDCl3): δ 3.5 (s, 6H, 2SCH3), 7.1–7.9 (m, 8H, Ar H),
11.3 (s, 1H, NH). MS: m/z (%) 289 (M+, 19%). Anal
calcd for C15H15NOS2 (289.41): C, 62.25; H, 5.22; N,
4.84; S, 22.16. Found: C, 62.06; H, 5.01; N, 4.63; S,
22.01.
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Compound 8e. This was isolated (Dioxan/H2O)
in 0.2 g (40%), mp 110◦C. IR: ν 1710 (C O), 3180
(NH). H NMR (CDCl3): δ 1.4 (s, 6H, 2CH3), 7.1–
7.9 (m, 4H, Ar H), 12.5 (s, 1H, NH). MS: m/z (%)
205 (M+, 15%). Anal calcd for C11H11NO3 (205.21):
C, 64.38; H, 5.40; N, 6.83. Found: C, 64.17; H, 5.23;
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General Procedure for 2-(1-Methyl-1-phenylpyra-
zole-5-one-4-yl)-benzazole derivatives 16a–c
Equimolar amounts (1 mmol) of 12 (1.0 g) and 2-
aminothiophenol 2b (0.45 g) were refluxed in 30
mL ethanol for 10–12 h in the presence of 0.5 mL
of piperidine. The solid product isolated during re-
flux was filtered, and the residue was concentrated
under vacuum till dryness and triturated with 3
mL methanol, and the solid formed was filtered
and crystallized together with the first portion from
DMF/ethanol to afford 16b. Similarly, each of 2a

412 El-Rady, Khalil, and Abd El Latif
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[17] Abd El Latif, F. M. Phosphorus Sulfur Silicon 2000,
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[18] Barsy, M. A.; Elrady, E. A.; Hassan, M. E.; Abd El
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[15] El-Rady, E. A. J Heterocycl Chem 2002, 39, 1109.