A facile and efficient synthesis of arylsulfonamido-substituted 1,5-benzodiazepines and N-[2-(3-benzoylthioureido)aryl]-3-oxobutanamide derivatives

Article abstract of DOI:10.1002/hlca.200900364

A facile and efficient synthesis of 1,5-benzodiazepines with an arylsulfonamido substituent at C(3) is described. 1,5-Benzodiazepine, derived from the condensation of benzene-1,2-diamine and diketene, reacts with an arylsulfonyl isocyanate via an enamine intermediate to produce the title compounds of potential synthetic and pharmacological interest in good yields (Scheme 1). In addition, reaction of benzene-1,2-diamine and diketene in the presence of benzoyl isothiocyanate leads to N-[2-(3-benzoylthioureido)aryl]-3- oxobutanamide derivatives (Scheme 2). This reaction proceeds via an imine intermediate and ring opening of diazepine. The structures were corroborated spectroscopically (IR, ¹Hand ¹³C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme 3).

Full text of DOI:10.1002/hlca.200900364

Helvetica Chimica Acta – Vol. 93 (2010)
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A Facile and Efficient Synthesis of Arylsulfonamido-Substituted 1,5-
Benzodiazepines and N-[2-(3-Benzoylthioureido)aryl]-3-oxobutanamide
Derivatives
by Abdolali Alizadeh* and Nasrin Zohreh
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-88006631; fax: þ 98-21-88006544; e-mail: abdol_alizad@yahoo.com and
aalizadeh@modares.ac.ir)
A facile and efficient synthesis of 1,5-benzodiazepines with an arylsulfonamido substituent at C(3) is
described. 1,5-Benzodiazepine, derived from the condensation of benzene-1,2-diamine and diketene,
reacts with an arylsulfonyl isocyanate via an enamine intermediate to produce the title compounds of
potential synthetic and pharmacological interest in good yields (Scheme 1). In addition, reaction of
benzene-1,2-diamine and diketene in the presence of benzoyl isothiocyanate leads to N-[2-(3-
benzoylthioureido)aryl]-3-oxobutanamide derivatives (Scheme 2). This reaction proceeds via an imine
intermediate and ring opening of diazepine. The structures were corroborated spectroscopically (IR, 1H-
and 13C-NMR, and EI-MS) and by elemental analyses. A plausible mechanism for this type of cyclization
is proposed (Scheme 3).
1. Introduction. – Benzodiazepines [1] have been important pharmacophores in the
pharmaceutical industry. Therapeutically, benzodiazepines have found applications as
vasopressin antagonists [2a], HIV reverse-transcriptase inhibitors [2b], and cholecys-
tokinin antagonists [2c]. In this class of compounds, the 1,5-benzodiazepin-2-one
scaffolds possess a privileged substructure exhibiting a range of biological activities.
They exhibit interleukin-1b converting enzyme inhibition, delayed rectifier potassium
current blocking [3], antiarrhythmic [4], and CCK receptor antagonist (compound 1)
[5] activities. They are also found in compounds active against a variety of target types
such as protease inhibitors and 7-TM receptors [6 – 8]. Significantly less research has
been undertaken on the 1,5-benzodiazepin-2-ones, compared to the 1,4-benzodiazepin-
2-ones. Therefore, development of a synthetic method that could be used to prepare a
variety of these templates remains an important task.
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 93 (2010)
Due to the broad spectrum of biological activities of heterocycles with a
sulfonamido unit, including antibacterial, antiviral, antidiabetic, diuretic, and antithy-
roid activities [9], they are an interesting class of compounds. Thus, synthesis of 1,5-
benzodiazepines bearing a sulfonamido group is synthetically challenging and of
biological interest.
2. Results and Discussion. – Some of our previous works included the synthesis of
heterocycles from the reaction of various enamines and arylsulfonyl isocyanates [10].
In continuation, we describe in this article the synthesis of arylsulfonamido-substituted
1,5-benzodiazepines via diketene-based multicomponent reaction [11].
Our new synthetic method is outlined in Scheme 1. The reaction of 1,5-
benzodiazepin-2-one 7, which is formed in situ from the condensation of benzene-1,2-
diamine (2) and diketene (cf. Scheme 3) with arylsulfonyl isocyanate 3 proceeds in
CH2Cl2 at ambient temperature to give compounds 4a – 4e in good yield (Scheme 1).
Scheme 1
When benzene-1,2-diamines and diketene in dry CH2Cl2 were allowed to react in
the presence of benzoyl isothiocyanate (PhCONCS) at room temperature, compounds
5 was formed in nearly quantitative yield as yellow powder. This product type was
identified as N-[2-(3-benzoylthioureido)aryl]-3-oxobutanamide 5 (Scheme 2).
The structures of 4a – 4e, and 5a and 5b were deduced from their elemental analysis,
and IR, and 1H- and 13C-NMR spectra.
The mass spectrum of 4a showed the molecular-ion peak at m/z 357. Three sharp
bands in the IR spectrum (KBr) of 4a at 3315, 3270, and 3050 cmꢀ1 are due to the three
NH groups. The 1H-NMR spectrum of 4a exhibited four sharp singlets readily
recognized as arising from the Me group at the seven-membered ring (2.30 ppm) and
three NH groups (8.45, 8.10, and 12.31 ppm). The Ph moiety gave rise to characteristic
1
signals in the aromatic region of the spectrum, and 15 distinct signals in the H-
decoupled 13C-NMR spectrum of 4a are in agreement with the proposed structure.
The best evidences for the opening of the diazepine ring and formation of
compounds 5 are the appearance of a singlet at 3.62 ppm in the 1H-NMR spectrum of

Helvetica Chimica Acta – Vol. 93 (2010)
1223
Scheme 2
5a (related to CH2), and three signals at 49.59, 182.53, and 204.61 ppm in the 13C-NMR
spectrum of 5a attributed to CH2, C¼S, and COMe, respectively. It is important to note
1
that diazepine 7a (R ¼ H) has been synthesized and characterized by its H-NMR
spectrum1).
Although the mechanism of the reaction between 2, diketene, and arylsulfonyl
isocyanate 3 or benzoyl isothiocyanate has not yet been established in an experimental
manner, a proposal is presented in Scheme 3.
First, the reaction of benzene-1,2-diamine and diketene produces intermediate 6
that is readily converted to 1,5-benzodiazepine 7 via a condensation reaction. Probably,
1,5-benzodiazepine 7 reacts with arylsulfonyl isocyanate 3 via enamine intermediate 8
to produce 9. Subsequently, benzodiazepine 9 is converted to the product 4 by H shift.
On the other hand, the imine N-atom of 7 reacts with benzoyl isothiocyanate to
produce zwitterion 10, which is then transformed to aminal 11 by uptake of H2O. Cyclic
animal 11 is unstable, and it is converted, by ring opening, to product 5.
In summary, we have described a simple and efficient method for the synthesis of
arylsulfonamido-substituted 1,5-benzodiazepines and N-[2-(3-benzoylthioureido)ar-
yl]-3-oxobutanamides. This method is characterized by several unique advantages, such
as relatively short reaction times, simplicity in operation under neutral condition, high
yields of products, and no need of catalyst. The reaction is also relatively sensitive to the
type of cyanate.
Experimental Part
General. Benzene-1,2-diamines, diketene, arylsulfonyl isocyanates, and benzoyl isothiocyanate were
obtained from Merck (Germany) and Fluka (Switzerland), and were used without further purification.
M.p.: Electrothermal 9100 apparatus. IR Spectra (KBr): Shimadzu IR-460 spectrometer (˜n in cmꢀ1). 1H-
and 13C-NMR spectra: in CDCl3 or (D6)acetone with a Bruker DRX-500 AVANCE spectrometer at 500,
and 125 MHz, respectively. MS: FINNIGAN-MAT 8430 mass spectrometer operating at an ionization
potential of 20 eV. Elemental analyses: Herpes CHNꢀOꢀRapid analyzer.
1
1
)
4-Methyl-1,3-dihydro-2H-1,5-benzodiazepin-2-one (7a): H-NMR (500 MHz, CDCl3): 2.38 (s, 3 H);
2.13 (s, 2 H); 7.06 – 7.10 (m, 1 H); 7.16 – 7.18 (m, 2 H); 7.31 – 7.34 (m, 1 H); 9.59 (s, 1 H).

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Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 3
Compounds 4a – 4e: General Procedure (exemplified for 4a). To a magnetically stirred soln. of
benzene-1,2-diamine (2a; 0.11 g, 1 mmol) and diketene (0.08 g, 1 mmol) in CH2Cl2 (5 ml) was added after
1 h benzenesulfonyl isocyanate (3a; 0.18 g, 1 mmol). After completion of the reaction, the solvent was
removed, and the product 4a precipitated in Et2O. The product was filtered and washed with cool CH2Cl2
for further purification.
2,5-Dihydro-4-methyl-2-oxo-N-(phenylsulfonyl)-1H-1,5-benzodiazepine-3-carboxamide (4a). Yield
320 mg (90%). Yellow powder. M.p. 173 – 1758 (dec.). IR: 3315, 3270, 3050 (3 NH), 1664, 1651
(2 NC¼O), 1539, 1471 (2 Ar), 1329, 1153 (2 SO2). 1H-NMR ((D6)acetone): 2.30 (s, 3 H); 7.00 – 7.05 (m,
3 H); 7.13 – 7.15 (m, 1 H); 7.56 (t, J ¼ 7.3, 2 H); 7.64 (t, J ¼ 7.5, 1 H); 8.01 (d, J ¼ 7.3, 2 H); 8.45 (s, 1 H); 8.10
(s, 1 H); 12.31 (s, 1 H). 13C-NMR ((D6)acetone): 25.1; 100.3; 122.2; 122.3; 125.5; 126.8; 128.8; 129.4;
132.8; 133.8; 134.6; 141.6; 165.2; 173.5; 173.6. EI-MS: 357 (8, Mþ), 256 (12), 199 (5), 174 (22), 157 (28),
132 (83), 131 (40), 93 (25), 77 (100), 51 (45). Anal. calc. for C17H15N3O4S (357.38): C 57.13, H 4.23, N
11.76; found: C 57.19, H 4.26, N 11.75.
2,5-Dihydro-4-methyl-N-[(4-methylphenyl)sulfonyl]-2-oxo-1H-1,5-benzodiazepine-3-carboxamide
(4b). Yield 330 mg (90%). Yellow powder. M.p. 198 – 2008. IR: 3290, 3180, 3020 (3 NH), 1699, 1646
(2 NC¼O), 1522, 1408 (2 Ar), 1334, 1149 (2 SO2). 1H-NMR ((D6)acetone): 2.31 (s, 3 H); 2.39 (s, 3 H);
7.01 – 7.05 (m, 3 H); 7.13 – 7.15 (m, 1 H); 7.35 (d, J ¼ 7.9, 2 H); 7.90 (d, J ¼ 7.8, 2 H); 8.41 (s, 1 H); 9.10 (s,
1 H); 12.58 (s, 1 H). 13C-NMR ((D6)acetone): 21.4; 25.1; 105.4; 122.3; 125.5; 126.9; 128.0; 128.9; 130.0;
133.3; 138.8; 144.5; 165.8; 172.9, 173.0. EI-MS: 371 (5, Mþ), 311 (10), 197 (23), 174 (22), 155 (39), 132
(98), 131 (50), 91 (100), 65 (35), 39 (40). Anal. calc. for C18H17N3O4S (371.41): C 58.21, H 4.61, N 11.31;
found: C 58.29, H 4.64, N, 11.33.

Helvetica Chimica Acta – Vol. 93 (2010)
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2,5-Dihydro-4,7(or 8)-dimethyl-2-oxo-N-(phenylsulfonyl)-1H-1,5-benzodiazepine-3-carboxamide
(4c). Yield 320 mg (87%). Yellow powder. M.p. 197 – 1998 (dec.). IR: 3339, 3270, 3055 (3 NH), 1670,
1
1651 (2 NC¼O), 1512, 1431 (2 Ar), 1327, 1155 (2 SO2). H-NMR ((D6)acetone): 2.29 (s, 3 H); 2.81 (s,
3 H); 6.97 – 7.01 (m, 3 H); 7.58 (t, J ¼ 7.6, 2 H); 7.63 (t, J ¼ 7.5, 1 H); 8.02 (d, J ¼ 7.3, 2 H); 8.39 (s, 1 H);
9.19 (s, 1 H); 12.66 (s, 1 H). 13C-NMR (CDCl3): 20.7; 25.1; 100.4; 122.1; 126.0; 126.9; 128.6; 128.8; 129.4;
129.7; 133.8; 138.2; 141.7; 165.3; 172.3; 174.0. EI-MS: 302 (4), 157 (15), 141 (15), 93 (21), 84 (65), 77 (30),
66 (100), 46 (18). Anal. calc. for C18H17N3O4S (371.41): C 58.21, H 4.61, N 11.31; found: C 58.27, H 4.66, N
11.29.
2,5-Dihydro-4,7(or 8)-dimethyl-N-[(4-methylphenyl)sulfonyl]-2-oxo-1H-1,5-benzodiazepine-3-car-
boxamide (4d). Yield 330 mg (85%). Yellow powder. M.p. 160 – 1628 (dec.). IR: 3270, 3195, 3035
1
(3 NH), 1666, 1638 (2 C¼O), 1510, 1439 (2 Ar), 1334, 1153 (2 SO2). H-NMR ((D6)acetone): 2.21 (s,
3 H); 2.28 (s, 3 H); 2.39 (s, 3 H); 6.81 – 6.85 (m, 1 H); 6.90 – 6.97 (m, 2 H); 7.35 (d, J ¼ 7.9, 2 H); 7.89 (d,
J ¼ 7.8, 2 H); 8.38 (s, 1 H); 9.97 (s, 1 H); 12.57 (s, 1 H). 13C-NMR ((D6)acetone): 20.4; 21.4; 25.1; 99.5;
122.2; 122.6; 126.0; 128.5; 128.9; 129.9; 135.4; 135.2; 138.8; 144.63; 165.24; 173.3; 173.6. EI-MS: 385 (2,
Mþ), 202 (9), 188 (17), 171 (69), 155 (73), 146 (57), 107 (41), 91 (100), 77 (12), 65 (35). Anal. calc. for
C19H19N3O4S (385.43): C 59.21, H 4.97, N 10.90; found: C 59.25, H 4.99, N 10.95.
2,5-Dihydro-4,6(or 9)-dimethyl-N-[(4-methylphenyl)sulfonyl]-2-oxo-1H-1,5-benzodiazepine-3-car-
boxamide (4e). Yield 330 mg (85%). Yellow powder. M.p. 186 – 1898 (dec). IR: 3330, 3295, 3200
(3 NH), 1672, 1647 (2 NC¼O), 1571, 1402 (2 Ar), 1324, 1165 (2 SO2). 1H-NMR ((D6)acetone): 2.24 (s,
3 H); 2.30 (s, 3 H); 2.37 (s, 3 H); 6.81 – 6.95 (m, 3 H); 7.35 (d, J ¼ 7.9, 2 H); 7.88 (d, J ¼ 7.82, 2 H); 8.37 (s,
1 H); 8.97 (s, 1 H); 12.58 (s, 1 H). 13C-NMR ((D6)acetone): 20.4; 21.4; 25.1; 100.2; 122.2; 122.5; 126.0;
128.5; 128.90; 129.9; 134.6; 135.4; 138.8; 144.6; 165.2; 173.3; 173.6. EI-MS: 385 (10), 202 (7), 191 (15), 188
(15), 171 (52), 155 (61), 148 (23), 146 (41), 132 (9), 107 (51), 91 (100), 77 (10), 65 (41). Anal. calc. for
C19H19N3O4S (385.43): C 59.21, H 4.97, N 10.90; found: C 59.27, H 4.96, N 10.91.
N-({2-[(3-Oxobutanoyl)amino]phenyl}carbamothioyl)benzamide (5a). Yield 300 mg (86%). Yel-
low powder. M.p. 105 – 1078. IR: 3235, 3190, 3110 (3 NH), 1710, 1690, 1651 (3 C¼O), 1589, 1473 (2 Ar),
1
1317, 1150 (2 C¼S). H-NMR (CDCl3): 2.27 (s, 3 H); 3.62 (s, 2 H); 7.2 (t, J ¼ 7.5, 1 H); 7.38 (t, J ¼ 7.5,
1 H); 7.56 (t, J ¼ 7.7, 2 H); 7.60 (d, J ¼ 7.4, 1 H); 7.68 (t, J ¼ 7.4, 1 H); 7.93 (d, J ¼ 7.7, 2 H); 7.95 (d, J ¼ 7.8,
1 H); 9.25 (s, 1 H); 9.34 (s, 1 H); 12.15 (s, 1 H). 13C-NMR (CDCl3): 31.1; 49.6; 124.3; 125.8; 127.1; 127.6;
128.6; 129.2; 131.2; 131.8; 132.7; 133.7; 164.0; 167.9; 182.5; 204.6. EI-MS: 335 (5), 240 (17), 194 (21), 150
(20), 134 (29), 105 (100), 77 (89), 51 (41). Anal. calc. for C18H17N3O3S (355.41): C 60.83, H 4.82, N 11.82;
found: C 60.87, H 4.90, N 11.81.
N-({4-(or 5)Methyl-2-[(3-oxobutanoyl)amino]phenyl}carbamothioyl)benzamide (5b). Yield 330 mg
(90%). Yellow powder. M.p. 100 – 1028. IR (KBr): 3230, 3184, 3115 (3 NH), 1713, 1668, 1641 (3 NC¼O),
1511, 1412 (2 Ar), 1330, 1166 (2 C¼S). 1H-NMR ((D6)acetone): 2.24 (s, 3 H); 2.34 (s, 3 H); 3.61 (s, 2 H);
7.13 (d, J ¼ 7.8, 1 H); 7.57 – 7.62 (m, 3 H); 7.67 – 7.72 (m, 2 H); 8.08 (d, J ¼ 7.3, 2 H); 9.21 (s, 1 H); 10.32 (s,
1 H); 12.31 (s, 1 H). 13C-NMR ((D6)acetone): 20.9; 21.37; 49.6; 125.2; 128.2; 128.8; 129.10; 129.6; 131.3;
132.2; 133.3; 134.1; 135.8; 166.0; 168.5; 181.5; 203.4. EI-MS: 369 (9, Mþ), 336 (10), 285 (8), 252 (21), 164
(37), 146 (28), 105 (100), 77 (92), 51 (18). Anal. calc. for for C19H19N3O3S (369.44): C 61.77, H 5.18, N
11.37; found: C 61.81, H 5.21, N 11.39.
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Received October 14, 2009