Application of privileged molecular framework of 7-fluoro-1,4- benzodiazepin-2-one-5-methylcarboxylate to the synthesis of its 1- and 5-disubstituted analogs of medicinal interest

Article abstract of DOI:10.1002/jhet.1621

Synthetic potential of the privileged molecular framework of 7-fluoro-1,4-benzodiazepin-2-one containing a methyl carboxylate substituent at its 5-position was exploited to develop efficient protocols to the synthesis of several novel 5-(1′,3′,4′)oxadiazole ring incorporated analogs of medicinal interest, appended with the Mannich's base motifs at the nitrogen atom in its seven-membered ring.

Full text of DOI:10.1002/jhet.1621

July 2014
Application of Privileged Molecular Framework of 7-Fluoro-1,4-
benzodiazepin-2-one-5-methylcarboxylate to the Synthesis of Its
1- and 5-Disubstituted Analogs of Medicinal Interest
991
,*
Pragati Devi Aarti Gupta, and Dharma Kishore
Department of Chemistry, Banasthali University, Banasthali, Rajasthan 304022, India
*
E-mail: pragati.banasthali@gmail.com
Received October 17, 2011
DOI 10.1002/jhet.1621
Published online 16 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
Synthetic potential of the privileged molecular framework of 7-fluoro-1,4-benzodiazepin-2-one
containing a methyl carboxylate substituent at its 5-position was exploited to develop efficient protocols
to the synthesis of several novel 5-(10,30,40)oxadiazole ring incorporated analogs of medicinal interest,
appended with the Mannich’s base motifs at the nitrogen atom in its seven-membered ring.
J. Heterocyclic Chem., 51, 991 (2014).
INTRODUCTION
functionally and structurally discrete biological receptors. This
study resulted in the design and development of efficient
molecular probes for biological evaluation from this nucleus.
It has been observed that incorporation of five-membered
heterocyclic rings to the seven-membered azepine core of
benzodiazepines exerted a profound influence in conferring
novel biological activities in these molecules [3]. The discovery
of anticancer activity in many antibiotics containing pyrrolo
[2,1-c][1,4]-benzodiazepine nucleus and anti-HIV activity in
tetrahydroimidazo[4,5,1-jkj][1,4]benzodiazepin-2(1H)one and
-thione (TIBO) [4] (A, Fig. 1) containing an imidazole ring,
in 1,4-benzodiazepine nucleus, and in FDA approved nevira-
pine [5] (B, Fig. 1) containing a dipyrido-1,4-diazepine nucleus
is among the few examples that illustrate this phenomenon.
Ever since Waldmann et al. [1,2] have carried out a
quantitative analysis of physiologically active natural products
and showed that the ones with two or three rings were most
often found in active natural products, the interest on the
various facets of the chemistry of small molecules has
expanded exponentially thereafter. This led the exploration
of the synthetic processes that lead to the development of
small molecules of medicinal interest, by telescoping the
multicomponent operations to a single step. Recently, the
privileged molecular frameworks of bicyclic and tricyclic
derivatives of benzodiazepines have been actively studied in
view of their ability to provide ligands to a number of
© 2013 HeteroCorporation

992
P. Devi, A. Gupta, and D. Kishore
Vol 51
premise that their presence in tandem in the same molecu-
lar framework was in all probability expected to contribute
significantly to provide an additive effect on the overall
bioefficacy in the resulting materials. In exercise of this
premise, in this communication, we report the preliminary
results of our study focused in the direction of incorporat-
ing the Mannich’s base fragments and oxadiazole ring on
1- and 5-positions of 1,4-benzodiazepine nucleus substi-
tuted with a fluorine atom in the arene ring of its molecule.
Figure 1. Structures of TIBO and nevirapine.
RESULTS AND DISCUSSION
In recent years [6], molecules containing an oxadiazole
nucleus have emerged as versatile lead structures in the
design and development of potential anti-HIV agents.
The attachments of Mannich’s base fragments in
chemotherapeutically useful materials have often been found
to induce novel bioactivity. Their role, as intermediates in drug
synthesis and in imparting such activities as analgesic, anti-
spasmodic, anesthetic, antimalarial, and others, has been well
documented in the literature [7–15] and reviewed recently [16].
In recent years, active research has been pursued on
halogen-containing heterocycles, particularly fluorine-
containing heterocycles. The incorporation of fluorine has
been reported [17,18] to increase the lipid solubility thereby
enhancing the rate of absorption and transport of drug
in vivo. Although fluorine has a greater size than hydrogen,
several studies have demonstrated [19] that fluorine is a
reasonable hydrogen mimic that exerts only a minor steric
demand at receptor sites. This observation stimulated us to
synthesize the 1,4-benzodiazepine analogs containing a
fluorine atom in its core nucleus (Scheme 1).
For our synthetic plan (Scheme 1) to succeed to give the
5-oxadiazolyl substituted analog of 7-fluoro-1,4-benzodiazepine
(4), we required a good synthesis of 5-carbomethoxy substi-
tuted derivative of 7-fluoro-1,4-benzodiazepine (2). Consid-
eration of factors on reactivity of starting material and
simplicity in operational procedure led us to favor the use
of 5-fluoroisatin (1) for its synthesis. Ogata and Motsumoto
[20] in 1976 developed a highly innovative technique for
the synthesis of 1,4-benzodiazepine nucleus and its 7-chloro
analog from the corresponding 1-chloroacetylisatin through
its treatment with methanolic solution of hexamine. An
attractive feature of this process was that it provided a very
convenient one-pot synthetic entry to the 1,4-benzodiazepine
nucleus substituted with a carbomethoxy group at 5-position.
We applied this methodology on 5-fluoro-1-chloroacetylisa-
tin to obtain 7-fluoro-5-carbomethoxy substituted analog of
1,4-benzodiazepin-2-one (2) in good yield. The ester func-
tion of 2 reacted smoothly with hydrazine hydrate [21,22]
to form the acid hydrazide (3) in excellent yield. Reaction
of 3 with CS2 + KOH followed by treatment with acid
[23,24] formed the 10,30,40-oxadiazole derivative 4. Mass
spectrum of 4 exhibited M+ peak at m/z 278.26 (86%) and
a base peak at m/z 245.19 (100%) (because of the loss of
SH group) that was consistent to its structure.
Encouraged by the impressive bioactive profiles of
the privileged template of 1,4-benzodiazepines, oxadiazole
nucleus, and the Mannich’s base fragments, it was consid-
ered of interest to explore the possibility of incorporating
these moieties together, in the same molecule, on this
In view of obvious reasons (as apparent from Scheme 2),
the depicted strategies were allowed to operate in three parts.
In the first part, reaction of 4 with 2-chloro-N,N-dimethy-
lethanamine [25,26] was carried out to append an aminoalkyl
chain on the SH group of 4 to give compound 5, which, on
treatment with cyclic secondary amines in presence of
formaldehyde, formed the Mannich’s bases (8a–h). Structural
assignments to these compounds were based on elemental
analysis, IR, 1H-NMR, and mass spectral data.
Scheme 1
Subsequent desulphurization of 4 with Raney Ni [27]
led to the formation of 6 whose reaction with different
cyclic secondary amines and formaldehyde [25,26]
produced another series of Mannich’s base derivatives
(9a–h). The structures of these compounds were estab-
lished on the basis of their spectral data.
A further study involved the conversion of 4 to 7
through the reaction of the former with CH3I [28]. The
resulting lactim thioether function of 7 underwent facile
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Application of Privileged Molecular Framework of 7-Fluoro-1,4-benzodiazepin-2-one-5-
methylcarboxylate to the Synthesis of Its 1- and 5-Disubstituted Analogs of Medicinal Interest
993
Scheme 2
solvent. Chemical shifts are expressed in d parts per million
relative to the signal for TMS as internal standard.
Preparation of methyl-7-fluoro-2-oxo-2,3-dihydro-1H-1,4-
benzodiazepin-5-carboxylate (2).
5-Fluoroisatin (1, 3.40 g,
0.02 mol) was vigorously refluxed with chloroacetyl chloride
(4.48 g, 0.04 mol) for 5 h, and the mixture was cooled for 2 h
in an ice bath. The precipitated product was filtered, washed
with 30 mL portion of ether, then air-dried, and recrystallized
from ethyl acetate to give 5-fluoro N-chloroacetyl isatin.
5-Fluoro N-chloroacetyl isatin (2.95 g, 0.012 mol) and
hexamethylenetetramine (hexamine) (2.8 g, 0.02 mol) in 50 mL
dry methanol were refluxed for 10–11 h. Progress of the
reaction was monitored through TLC. After completion of the
reaction, the solvent was removed under reduced pressure, and
the solid was chromatographed over alumina (neutral) in C6H6/
MeOH (9.5:0.5) as the eluant. The product obtained was
recrystallized from benzene to give 2, 2.50 g, yield (85%),
mp, 230–232ꢀC. IR (KBr) cmꢁ1: 3400 (NH), 1660, 1700
(C═O), 2970, 1430 (—CH2 next to C═O), 1050 (CF), 1630
(C═N), 2970 (C—H), 1590 (C═C); 1H-NMR (300 MHz,
CDCl3 + DMSO-d6) d ppm: 7.84 (1H, d, J = 8.5 Hz, Ar—CH),
7.34 (1H, d, J = 8.7 Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.18
(2H, s, CH2 of benzodiazepine ), 3.68 (3H, s, methyl), 8.00
(1H, s, NH); MS: m/z (%) 236.20 (M+ 75%), 205.17 (100%),
177.16 (35%); Analytical data: Calcd/found for C11H9FN2O3,
C: 55.93/55.65, H: 3.84/3.82, N: 11.86/11.80.
Preparation of 7-fluoro-2-oxo-2,3-dihydro-1H-1,4-benzodiazepin-
5-carbohydrazide (3). To a solution of 2 (2.15g, 0.013mol) in
ethanol (30mL), hydrazine hydrate (1.7 mL, 0.053 mol) was added.
The mixture was refluxed for 12h and cooled, and the obtained
product was recrystallized from ethanol to give 3, 2.00 g, yield
(85%), mp, 210–212ꢀC. IR (KBr) cmꢁ1: 3410 (NH), 1644, 1670
(C═O), 3315, 3123 (NH, NH2), 1610 (C═N), 2980 (C—H),
2965, 1425 (—CH2 next to C═O), 1580 (C═C), 1055 (C—F);
1H-NMR (300 MHz, CDCl3 +DMSO-d6) d ppm: 7.84 (1H, d,
J = 8.5 Hz, Ar—CH), 7.34 (1H, d, J = 8.7Hz, Ar—CH), 7.78 (1H,
s, Ar—CH), 4.18 (2H, s, CH2 of benzodiazepine ), 2.00 (2H, s,
NH2), 8.00 (1H, s, NH of CONHNH2), 8.05 (1H, s, NH); MS:
m/z (%) 236.20 (M+ 72%), 177.25 (25%), 149.1 (100%);
Analytical data: Calcd/found for C10H9FN4O2, C: 50.85/50.60, H:
3.84/3.82, N: 23.72/23.60.
nucleophilic displacements with a wide variety of cyclic
secondary amines [29] to give compounds 10a–h.
Compounds 10a–h were characterized on the basis of their-
spectral data. Physical data of the compounds 8a–10h have
been summarized in Table 1.
Preparation of 7-fluoro-5-(50-mercapto-10,30,40-oxadiazol-
20-yl)-1H-1,4-benzodiazepin-2(3H)-one (4). To a solution of
carbohydrazide (3, 0.472 g, 0.002 mol) in dry ethanol (20 mL),
carbon disulfide (0.76 g, 0.01 mol) and potassium hydroxide
(0.112 g, 0.002 mol) were added at 0ꢀC. The resulting solution
was refluxed for 40 h with the addition of 0.5 mL of CS2 in four
installments after each 10 h. After the completion of the
reaction, the solvent was evaporated, and the product was
dissolved in water and then brought to neutral point by addition
of dil. HCl. The solid obtained was filtered and recrystallized
with methanol to give 4, 0.400 g, yield (72%), mp, 115–117ꢀC.
IR (KBr) cmꢁ1: 3400 (NH), 1627, 1415 (C═N), 1660 (C═O),
3010 (C—H), 1600 (C═C), 1370, 1245 (C═S), 1168 (C—O—C),
2970, 1420 (—CH2 next to C═O), 1056 (C—F); 1H-NMR
(300 MHz, CDCl3 + DMSO-d6) d ppm: 7.84 (1H, d, J = 8.5 Hz,
Ar—CH), 7.34 (1H, d, J = 8.7 Hz, Ar—CH), 7.78 (1H, s,
Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine ), 8.00 (1H, s,
NH), 13.05 (1H, s, aromatic C—SH); MS: m/z (%) 278.26
(M+ 86%), 245.19 (100%), 180.09 (37%); Analytical data:
Calcd/found for C11H7FN4O2S, C: 47.48/47.24, H: 2.54/2.52,
N: 20.13/20.03, S: 11.52/11.46.
CONCLUSION
In view of the positive impact that the presence of an
oxadiazole nucleus and the Mannich’s base motifs produced
on the bioefficacy of the biologically active materials, we
developed an expedient protocol to the synthesis of
5-oxadiazolyl -substituted-7-fluoro -1,4-benzodiazepine-2-one
and their Mannich’s base derivatives to study their biological
activity, which is in progress.
EXPERIMENTAL
Melting points were determined in open glass capillaries and are
uncorrected. Progress of the reaction was monitored by TLC on silica
gel “G” coated plates using benzene/methanol (9:1). IR spectra on
KBr were recorded on FTIR-8400S, CE (Shimadzu, Nakagyo-
ku-Kyoto, Japan). Mass spectra were taken on 3000 LC/MS System
(McKinley Scientific, Sparta, NJ). 1H-NMR spectra were recorded on
model AC-300F (Bruker, Billerica, MA) using CDCl3 /DMSO-d6 as
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

994
P. Devi, A. Gupta, and D. Kishore
Vol 51
Table 1
Physical data of compounds 8a–10h.
Yield (%)
Entry
no.
R
mp (ꢀC)
Conventional method
Microwave method
Molecular formula (MW)
C20H25FN6O2S (432.51)
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
Pyrrolidinyl
Piperidinyl
Morpholinyl
101–103
107–109
112–114
122–124
130–132
147–149
156–158
177–179
105–107
115–117
138–140
152–154
165–167
144–146
171–173
190–192
128–130
133–135
159–161
178–180
188–190
190–192
198–200
215–217
75
82
85
73
75
86
92
79
71
82
85
77
74
80
92
79
75
70
80
75
85
81
77
79
79
85
87
77
78
89
96
85
76
85
90
83
80
86
97
82
90
78
86
79
98
94
84
87
C21H27FN6O2S (446.54)
C20H25FN6O3S (448.51)
C21H28FN7O2S (461.56)
C22H30FN7O2S (475.58)
C27H32FN7O2S (537.65)
C23H30FN7O4S (519.59)
C22H28FN7O4S (505.57)
C16H16FN5O2 (329.33)
C17H18FN5O2 (343.36)
C16H16FN5O3 (345.33)
C17H19FN6O2 (358.37)
C18H21FN6O2 (372.4)
C23H23FN6O2 (434.47)
C19H21FN6O4 (416.41)
C18H19FN6O3 (386.38)
C15H14FN5O2 (315.3)
C16H16FN5O2 (329.33)
C15H14FN5O3 (331.3)
C16H17FN6O2 (344.34)
C17H19FN6O2 (358.37)
C22H21FN6O2 (420.44)
C18H19FN6O4 (402.38)
C17H17FN6O3 (372.35)
N-Methyl piperazinyl
N-Ethyl piperazinyl
N-Benzyl piperazinyl
N-Ethoxy carbonyl piperazinyl
N-Acetyl piperazinyl
Pyrrolidinyl
Piperidinyl
Morpholinyl
N-Methyl piperazinyl
N-Ethyl piperazinyl
N-Benzyl piperazinyl
N-Ethoxy carbonyl piperazinyl
N-Acetyl piperazinyl
Pyrrolidinyl
9f
9g
9h
10a
10b
10c
10d
10e
10f
10g
10h
Piperidinyl
Morpholinyl
N-Methyl piperazinyl
N-Ethyl piperazinyl
N-Benzyl piperazinyl
N-Ethoxy carbonyl piperazinyl
N-Acetyl piperazinyl
Preparation of (E)-5-(5-(2-(dimethylamino)ethylthio)-1,3,4-
oxadiazol-2-yl)-7-fluoro-1H-benzo[e][1,4]diazepin-2(3H)-one
Ar—CH), 7.78 (1H, s, Ar—CH), 4.18 (2H, s, CH2 of
benzodiazepine), 8.00 (1H, s, NH), 5.95 (1H, s, methine of
oxadiazole ring); MS: m/z (%) 246.20 (M+ 87%), 176.15
(100%), 148.14 (29%); Analytical data: Calcd/found for
C11H7FN4O2, C: 53.66/53.49, H: 2.87/2.85, N: 22.76/22.66.
(5).
Potassium hydroxide (1.12 g, 0.02 mol) was added to a
solution of 4 (2.95 g, 0.012 mol) in ethanol (25 mL), and the
mixture was heated under reflux for 30 min. 2-Chloro-N,N-
dimethylethanamine (1.07 g, 0.01 mol) was added, and the
reaction mixture was heated under reflux for 10 h. The solvent
was distilled under vacuo. The obtained residue was washed
with water and recrystallized from methanol to give 5, 2.50 g,
yield (70%), mp, 95–97ꢀC. IR (KBr) cmꢁ1: 3058 (NH), 1612,
1415 (C═N), 1670 (C═O), 3010 (C—H), 1560 (C═C), 1254
(C—O—C), 2975, 1425 (—CH2 next to C═O), 1056 (C—F),
2915, 2850 (CH3, CH2, CH); 1H-NMR (300 MHz,
CDCl3 +DMSO-d6) d ppm: 7.84 (1H, d, J=8.5Hz, Ar—CH),
7.34 (1H, d, J=8.7Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 2.26
[6H, s, —N(CH3)2], 3.41 (2H, t, J=6.2Hz, NCH2), 2.65 (2H, t,
J=5.4Hz, SCH2), 4.19 (2H, s, CH2 of benzodiazepine), 8.00 (1H,
s, NH); MS: m/z (%) 349.38 (M+ 80%), 245.19 (100%), 175.68
(46%); Analytical data: Calcd/found for C15H16FN5O2S, C: 51.55/
51.29, H: 4.62/4.60, N: 20.04/19.95, S: 9.18/9.13.
Preparation of (E)-7-fluoro-5-(5-(methylthio)-1,3,4-oxadiazol-2-
yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (7).
A mixture of 4
(2.95 g, 0.01 mol), methyl iodide (0.08 mol) in ethyl acetate
(60 mL) was stirred at room temperature with the addition of
extra amount of methyl iodide (about 1 mL) in four installments
in 25 h. The precipitate formed was isolated by filteration to give
7, 2.30 g, yield (75%), mp, 145–147ꢀC. IR (KBr) cmꢁ1: 3050
(NH), 1610, 1415 (C═N), 1675 (C═O), 3010 (C—H), 1575
(C═C), 1256 (C—O—C), 2975, 1420 (—CH2 next to C═O),
1060 (C—F), 1475 (C—H str. CH3); 1H-NMR (300MHz,
CDCl3 +DMSO-d6) d ppm: 7.84 (1H, d, J=8.5Hz, Ar—CH), 7.34
(1H, d, J = 8.7Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H, s,
CH2 of benzodiazepine), 8.00 (1H, s, NH), 2.53 (3H, s, CH3);
MS: m/z (%) 292.29 (M+ 85%), 245.20 (100%), 175.14 (23%);
Analytical data: Calcd/found for C12H9FN4O2S, C: 49.31/49.20,
H: 3.10/3.008, N: 19.17/19.11, S: 10.97/10.90.
Preparation of (E)-7-fluoro-5-(1,3,4-oxadiazol-2-yl)-1H-
benzo[e][1,4]diazepin-2(3H)-one (6). Raney Ni (5g) was added
to a solution of 4 (2.95 g, 0.012 mol) in ethanol (100mL), and the
mixture was heated at 60–70ꢀC for 6 h. After the completion of
reaction (monitored by TLC), Raney Ni was filtered off, and the
solvent was evaporated off. The product obtained was recrystallized
from ethanol to give 6, 2.40 g, yield (95%), mp, 125–127ꢀC. IR
(KBr) cmꢁ1: 3060 (NH), 1610, 1412 (C═N), 1670 (C═O), 3015
(C—H), 1565 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2 next
Preparation of (E)-5-(5-(2-(dimethylamino)ethylthio)-1,3,4-
oxadiazol-2-yl)-7-fluoro-1-((pyrrolidin-1-yl)methyl)-1H-benzo
[e][1,4]diazepin-2(3H)-one (8a)
Conventional method. A mixture of 5 (1.75 g, 0.005 mol),
pyrrolidine (0.35 g, 0.005 mol), and 37% formaldehyde solution
(0.75 mL) in ethanol (15 mL) was stirred at room temperature
for 5 h and allowed to stand overnight. The precipitated product
was filtered, washed with water, and recrystallized from ethanol
to give 8a, 1.20 g, yield (75%), mp, 101–103ꢀC. Other products
8 (b–h) were prepared using the same procedure.
1
to C═O), 1060 (C—F); H-NMR (300 MHz, CDCl3 +DMSO-d6)
d ppm: 7.84 (1H, d, J=8.5Hz, Ar—CH), 7.34 (1H, d, J=8.7Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Application of Privileged Molecular Framework of 7-Fluoro-1,4-benzodiazepin-2-one-5-
methylcarboxylate to the Synthesis of Its 1- and 5-Disubstituted Analogs of Medicinal Interest
995
Microwave-assisted method.
Equimolar quantities of 5
C21H28FN7O2S, C: 54.65/54.52, H: 6.11/6.09, N: 21.24/21.13, S:
(1.75 g, 0.005 mol), pyrrolidine (0.35 g, 0.005 mol), and 37%
formaldehyde (2.5 mL) were taken in ethanol (50 mL) and
placed in 100 mL flask fitted with a funnel and a loose top. The
reaction mixture was subjected to microwave irradiation at
360 W microwave power for 5 min and then at 720 W for 4 min
at short interval of 1 min to avoid the excessive evaporation of
solvent. The completion of the reaction was checked by TLC.
The solution obtained after the reaction had completed was kept
at 0ꢀC for 1 h, and the resulting solid obtained was filtered and
recrystallized from ethanol to give compound 8a, 1.50 g, yield
(79%), mp, 101–103ꢀC. Other products 8 (b–h) were prepared
using the same procedure.
8a. IR (KBr) cmꢁ1: 1625, 1415 (C═N), 1670 (C═O), 3010 (C—H),
1570 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2 next to
C═O), 1065 (C—F), 2912, 2865 (CH3, CH2, CH); 1H-NMR
(300 MHz, CDCl3 + DMSO-d6) d ppm: 1.68[4H, m, (CH2)2 of
pyrrolidine], 2.51 [4H, m, (CH2)2 of pyrrolidine], 2.26 [6H, s, —
N(CH3)2], 2.65 (2H, t, J = 5.4 Hz, SCH2 ), 3.41 (2H, t, J = 6.2Hz,
NCH2), 4.45 (2H, s, N—CH2—N linkage), 7.41 (1H, d,
J = 8.3Hz, Ar—CH), 7.30 (1H, d, J = 8.6Hz, Ar—CH), 7.78
(1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine); MS:
m/z (%) 432.51 (M+ 90%), 328.32 (100%), 258.27 (68%);
Analytical data: Calcd/found for C20H25FN6O2S, C: 55.54/55.39,
H: 5.83/5.80, N: 19.43/19.35, S: 7.41/7.37.
8b. IR (KBr) cmꢁ1: 1627, 1415 (C═N), 1670 (C═O), 3010 (C—H),
1575 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2 next to
C═O), 1065 (C—F), 2920 (CH3, CH2, CH); 1H-NMR (300 MHz,
CDCl3 + DMSO-d6) d ppm: 1.59 (2H, m, CH2 of piperidine),
1.53 [4H, m, (CH2)2 of piperidine], 2.45 [4H, m, (CH2)2
of piperidine], 2.26 [6H, s, —N(CH3)2], 2.65 (2H, t,
J = 5.4Hz, SCH2), 3.41 (2H, t, J = 6.2Hz, NCH2), 4.45 (2H, s,
N—CH2—N linkage), 7.41 (1H, d, J =8.3 Hz, Ar—CH), 7.30
(1H, d, J = 8.6Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H, s,
CH2 of benzodiazepine); MS: m/z (%) 446.54 (M+ 76%), 342.35
(100%), 272.30 (50%); Analytical data: Calcd/found for
C21H27FN6O2S, C: 56.48/56.30, H: 6.09/6.07, N: 18.82/18.77,
S: 7.18/7.13.
6.95/6.90.
8e. IR (KBr) cmꢁ1: 1610, 1445 (C═N), 1665 (C═O), 3010 (C—H),
1585 (C═C), 1243 (C—O—C), 2975, 1425 (—CH2 next to C═O),
1
1065 (C—F), 2906, 2847 (CH3, CH2, CH); H-NMR (300 MHz,
CDCl3 + DMSO-d6) d ppm: 1.02 (3H, t, CH3 ), 2.38 (2H, q, CH2
), 2.35[8H, t, J = 5.0 Hz, (CH2)4 of N-ethylpiperazine], 2.26
[6H, s, —N(CH3)2 ], 2.65 (2H, t, J =5.4 Hz, SCH2), 3.41
(2H, t, J = 6.2Hz, NCH2), 4.45 (2H, s, N—CH2—N linkage),
7.41 (1H, d, J =8.3 Hz, Ar—CH), 7.30 (1H, d, J = 8.6Hz,
Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzodiaze-
pine); MS: m/z (%) 475.58 (M+ 65%), 371.39 (100%), 342.37
(34%); Analytical data: Calcd/found for C22H30FN7O2S, C: 55.56/
55.42, H: 6.36/6.34, N: 20.62/20.53, S: 6.74/6.69.
8f. IR (KBr) cmꢁ1: 1609, 1440 (C═N), 1670 (C═O), 3016 (C—H),
1570 (C═C), 1248 (C—O—C), 2975, 1425 (—CH2 next to
C═O), 1065 (C—F), 2905. 2851 (CH2, CH); 1H-NMR
(300MHz, CDCl3 + DMSO-d6)
d ppm: 2.35–2.48 [8H, t,
J = 5.0 Hz, (CH2)4 of piperazine], 2.26 [6H, s, —N(CH3)2 ], 2.65
(2H, t, J = 5.4Hz, SCH2), 3.41 (2H, t, J = 6.2Hz, NCH2), 3.66
(2H, s, —N—CH2—C linkage), 4.45 (2H, s, N—CH2—N linkage),
7.23–7.33 (5H, m, C—H, benzene), 7.41 (1H, d, J = 8.3Hz,
Ar—CH), 7.30 (1H, d, J = 8.6 Hz, Ar—CH), 7.78 (1H, s,
Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine); MS: m/z (%)
537.65 (M+ 77%), 433.46 (100%), 363.41 (15%); Analytical data:
Calcd/found for C27H32FN7O2S, C: 60.32/60.25, H: 6.00/5.98,
N: 18.24/18.13, S: 5.96/5.91.
8g. IR (KBr) cmꢁ1: 1625, 1415 (C═N), 1685, 1650 (C═O),
3010 (C—H), 1570 (C═C), 1254 (C—O—C), 2975, 1425
(—CH2 next to C═O), 1065 (C—F), 2995, 2925, 2855 (CH3,
CH2, CH); 1H-NMR (300 MHz, CDCl3 + DMSO-d6) d ppm:
1.29 (3H, t, CH3), 4.13 (2H, q, CH2), 2.51[4H, t, J = 5.0 Hz,
(CH2)2 of piperazine], 3.20 [4H, t, J = 5.5 Hz, (CH2 )2 of pipera-
zine], 2.26 [6H, s, —N(CH3)2], 2.65 (2H, t, J = 5.4 Hz, SCH2),
3.41 (2H, t, J = 6.2 Hz, NCH2), 4.45 (2H, s, N—CH2—N
linkage), 7.41 (1H, d, J = 8.3 Hz, Ar—CH), 7.30 (1H, d,
J = 8.6 Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.18 (2H, s, CH2
of benzodiazepine); MS: m/z (%) 519.59 (M+ 87%), 415.40
(100%), 370.34 (48%); Analytical data: Calcd/found for
C23H30FN7O4S, C: 53.17/53.05, H: 5.82/5.80, N: 18.87/18.76,
S: 6.17/6.13.
8c. IR (KBr) cmꢁ1: 1615, 1412 (C═N), 1665 (C═O), 3015 (C—H),
1565 (C═C), 1256 (C—O—C), 2975, 1425 (—CH2 next to C═O),
1065 (C—F), 2917 (CH3, CH2, CH); 1H-NMR (300 MHz,
CDCl3 + DMSO-d6) d ppm: 2.50 [4H, t, J = 5.0 Hz, (CH2)2 of
tetrahydro1,4-oxazine], 3.65 [4H, t, J = 6.0Hz, (CH2)2 of
tetrahydro1,4-oxazine], 2.26 [6H, s, —N(CH3)2], 2.65 (2H, t,
J = 5.4Hz, SCH2 ), 3.41 (2H, t, J = 6.2Hz, NCH2), 4.45
(2H, s, N—CH2—N linkage), 7.41 (1H, d, J = 8.3Hz, Ar—CH),
7.30 (1H, d, J = 8.6Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.17
(2H, s, CH2 of benzodiazepine); MS: m/z (%) 448.51 (M+ 74%),
344.32 (100%), 274.27 (43%); Analytical data: Calcd/found for
C20H25FN6O3S, C: 53.56/53.45, H: 5.62/5.60, N: 18.74/18.64,
S: 7.15/7.10.
8h. IR (KBr) cmꢁ1: 1608, 1458 (C═N), 1680, 1665 (C═O),
3015 (C—H), 1578 (C═C), 1243 (C—O—C), 2975, 1425
(—CH2 next to C═O), 1065 (C—F), 2904, 2832 (CH3, CH2,
1
CH); H-NMR (300 MHz, CDCl3 + DMSO-d6) d ppm:3.68 (3H,
s, CH3), 2.51[4H, t, J = 5.0 Hz, (CH2)2 of piperazine], 3.20 [4H,
t, J = 5.5 Hz, (CH2
) of piperazine], 2.26 [6H, s, —N(CH3)2],
2
2.65 (2H, t, J = 5.4 Hz, SCH2), 3.41 (2H, t, J = 6.2 Hz, NCH2),
4.45 (2H, s, N—CH2—N linkage), 7.41 (1H, d, J = 8.3 Hz,
Ar—CH), 7.30 (1H, d, J = 8.6 Hz, Ar—CH), 7.78 (1H, s,
Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine); MS: m/z (%)
505.57 (M+ 90%), 401.19 (100%), 370.35 (54%); Analytical data:
Calcd/found for C22H28FN7O4S, C: 53.97/53.84, H: 5.76/5.74,
N: 20.03/19.94, S: 6.55/6.51.
8d. IR (KBr) cmꢁ1: 1605, 1445 (C═N), 1675 (C═O), 3015 (C—H),
1570 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2 next to C═O),
1
1068 (C—F), 2907, 2850 (CH3, CH2, CH); H-NMR (300 MHz,
Preparation
((pyrrolidin-1-yl)methyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (9a)
Conventional method. A mixture of 6 (2.46 g, 0.01 mol),
pyrrolidine (0.71 g, 0.01 mol), and 37% formaldehyde solution
(1.5 mL) in ethanol (20 mL) was stirred at room temperature for
8 h and allowed to stand overnight. The precipitated product
was filtered, washed with water, and recrystallized from ethanol
of
(E)-7-fluoro-5-(1,3,4-oxadiazol-2-yl)-1-
CDCl3 +DMSO-d6) d ppm: 2.35 [8H, t, J=5.0Hz, (CH2)4 of N-
methylenepiperazine], 2.26 (3H, s, CH3 ), 2.26 [6H, s, —N(CH3)2],
2.65 (2H, t, J=5.4Hz, SCH2), 3.41 (2H, t, J=6.2Hz, NCH2), 4.45
(2H, s, N—CH2—N linkage), 7.41 (1H, d, J=8.3Hz, Ar—CH),
7.30 (1H, d, J=8.6Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H,
s, CH2 of benzodiazepine); MS: m/z (%) 461.56 (M+ 68%), 357.37
(100%), 342.35 (25%); Analytical data: Calcd/found for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

996
P. Devi, A. Gupta, and D. Kishore
Vol 51
to give 9a, 2.00 g, yield (71%), mp, 105–107ꢀC. Other products 9
(b–h) were prepared using the same procedure.
C═O), 1065 (C—F), 2906, 2847 (CH3, CH2, CH); 1H-NMR
(300MHz, CDCl3 + DMSO-d6) d ppm: 1.02 (3H, t, CH3 ),
2.38 (2H, q, CH2), 2.35[8H, t, J = 5.0 Hz, (CH2)4 of N-ethylpipera-
zine], 4.45 (2H, s, N—CH2—N linkage), 7.41 (1H, d,
J = 8.3 Hz, Ar—CH), 7.30 (1H, d, J = 8.6 Hz, Ar—CH), 7.85
(1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine), 5.95
(1H, s, methine of oxadiazole ring); MS: m/z (%) 372.4
(M+ 89%), 302.35 (100%), 273.79 (62%); Analytical data:
Calcd/found for C18H21FN6O2, C: 58.05/57.93, H: 5.68/5.66,
N: 22.57/22.44.
Microwave-assisted method.
Equimolar quantities of 6
(2.46 g, 0.01 mol), cyclic secondary amine (0.71 g, 0.01 mol),
and 37% formaldehyde (5 mL) were taken in ethanol (100 mL)
and placed in 250 mL flask fitted with a funnel and a loose top.
The reaction mixture was subjected to microwave irradiation at
360 W microwave power for 8 min and then at 720 W for 5 min
with short interval of 1 min to avoid the excessive evaporation
of solvent. The completion of the reaction was checked by
TLC. The solution obtained after the reaction had completed
was kept at 0ꢀC for 2 h, and the resulting solid obtained was
filtered and recrystallized from ethanol to give compound 9a,
2.20 g, yield (76%), mp, 105–107ꢀC. Other products 9 (b–h)
were prepared using the same procedure.
9f. IR (KBr) cmꢁ1: 1609, 1440 (C═N), 1670 (C═O), 3016 (C—H),
1570 (C═C), 1248 (C—O—C), 2975, 1425 (—CH2 next to
C═O), 1065 (C—F), 2905. 2851 (CH2, CH); 1H-NMR (300 MHz,
CDCl3 + DMSO-d6) d ppm: 2.35–2.48 [8H, t, J = 5.0 Hz, (CH2)
of piperazine], 3.66 (2H, s, —N—CH2—C linkage), 4.45
4
(2H, s, N—CH2—N linkage), 7.23–7.33 (5H, m, C—H,
benzene), 7.41 (1H, d, J = 8.3 Hz, Ar—CH), 7.30 (1H, d,
J = 8.6 Hz, Ar—CH), 7.86 (1H, s, Ar—CH), 4.19 (2H, s, CH2
of benzodiazepine), 6.05 (1H, s, methine of oxadiazole ring);
MS: m/z (%) 434.47 (M+ 75%), 343.47 (100%), 273.37 (28%);
Analytical data: Calcd/found for C23H23FN6O2, C: 63.58/
63.46, H: 5.34/5.32, N: 19.34/19.26.
9a. IR (KBr) cmꢁ1: 1627, 1415 (C═N), 1670 (C═O), 3010 (C—H),
1570 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2 next to
C═O), 1065 (C—F); 1H-NMR (300 MHz, CDCl3 + DMSO-d6)
d ppm: 1.68 [4H, m, (CH2)2 of pyrrolidine], 2.51 [4H, m,
(CH2)2 of pyrrolidine], 4.45 (2H, s, N—CH2—N linkage), 7.41
(1H, d, J = 8.3Hz, Ar—CH), 7.30 (1H, d, J =8.6 Hz, Ar—CH),
7.85 (1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine), 6.00
(1H, s, methine of oxadiazole ring); MS: m/z (%) 329.33
(M+ 92%), 259.28 (100%), 231.27 (63%); Analytical data:
Calcd/found for C16H16FN5O2, C: 58.35/58.25, H: 4.90/4.88,
N: 21.27/21.20.
9g. IR (KBr) cmꢁ1: 1625, 1412 (C═N), 1710, 1670 (C═O),
3012 (C—H), 1570 (C═C), 1254 (C—O—C), 2975, 1425
(—CH2 next to C═O), 1065 (C—F), 2995, 2925, 2855 (CH3,
1
CH2, CH); H-NMR (300 MHz, CDCl3 +DMSO-d6) d ppm: 1.29
(3H, t, CH3), 4.13 (2H, q, CH2), 2.51[4H, t, J = 5.0Hz, (CH2)2 of
piperazine], 3.20 [4H, t, J = 5.5Hz, (CH2 )2 of piperazine], 4.45
(2H, s, N—CH2—N linkage), 7.41 (1H, d, J = 8.3Hz, Ar—CH),
7.30 (1H, d, J = 8.6 Hz, Ar—CH), 7.86 (1H, s, Ar—CH), 4.19
(2H, s, CH2 of benzodiazepine), 5.95 (1H, s, methine of oxadiazole
ring); MS: m/z (%) 416.41 (M+ 87%), 371.35 (100%), 343.39
(43%); Analytical data: Calcd/found for C19H21FN6O4, C: 54.80/
54.68, H: 5.08/5.06, N: 20.18/20.10.
9h. IR (KBr) cmꢁ1: 1608, 1458 (C═N), 1695, 1650 (C═O),
3015 (C—H), 1578 (C═C), 1243 (C—O—C), 2975, 1425
(—CH2 next to C═O), 1065 (C—F), 2904 (CH3, CH);
1H-NMR (300 MHz, CDCl3 + DMSO-d6) d ppm: 2.35 (3H, s,
CH3), 2.51 [4H, t, J = 5.0 Hz, (CH2)2 of piperazine], 3.45 [4H, t,
J = 5.5 Hz, (CH2)2 of piperazine], 4.45 (2H, s, N—CH2—N
linkage), 7.41 (1H, d, J = 8.3 Hz, Ar—CH), 7.30(1H, d,
J = 8.6 Hz, Ar—CH), 7.85 (1H, s, Ar—CH), 4.19 (2H, s, CH2
of benzodiazepine), 5.98 (1H, s, methine of oxadiazole ring);
MS: m/z (%) 386.38 (M+ 90%), 371.30 (100%), 343.78 (66%);
Analytical data: Calcd/found for C18H19FN6O3, C: 55.95/55.84,
H: 4.96/4.94, N: 21.75/21.66.
9b. IR (KBr) cmꢁ1: 1628, 1412 (C═N), 1675 (C═O), 3016 (C—H),
1578 (C═C), 1255 (C—O—C), 2975, 1426 (—CH2 next to C═O),
1065 (C—F); 1H-NMR (300 MHz, CDCl3 + DMSO-d6) d ppm:
1.59 (2H, m, CH2 of piperidine), 1.53 [4H, m, (CH2)2 of
piperidine], 2.45 [4H, m, (CH2)2 of piperidine], 4.45 (2H, s,
N—CH2—N linkage), 7.41 (1H, d, J = 8.3 Hz, Ar—CH), 7.30
(1H, d, J = 8.6 Hz, Ar—CH), 7.85 (1H, s, Ar—CH), 4.18 (2H,
s, CH2 of benzodiazepine), 5.95 (1H, s, methine of oxadiazole
ring); MS: m/z (%) 343.36 (M+ 79%), 273.31 (100%), 245.34
(30%); Analytical data: Calcd/found for C17H18FN5O2, C:
59.47/59.39, H: 5.28/5.26, N: 20.40/20.31.
9c. IR (KBr) cmꢁ1: 1615, 1412 (C═N), 1665 (C═O), 3015 (C—H),
1565 (C═C), 1256 (C—O—C), 2975, 1425 (—CH2 next to C═O),
1065 (C—F); 1H-NMR (300 MHz, CDCl3 + DMSO-d6) d ppm:
2.50[4H, t, J =5.0Hz, (CH2)2 of tetrahydro1,4-oxazine], 3.65
[4H, t, J= 6.0 Hz, (CH2)2 of tetrahydro1,4-oxazine], 4.45 (2 H, s,
N—CH2—N linkage), 7.41 (1H, d, J =8.3Hz, Ar—CH), 7.30
(1H, d, J =8.6Hz, Ar—CH), 7.85 (1H, s, Ar—CH), 4.19 (2H, s,
CH2 of benzodiazepine), 5.90 (1H, s, methine of oxadiazole ring);
MS: m/z (%) 345.33 (M+ 74%), 275.28 (100%), 247.98 (38%);
Analytical data: Calcd/found for C16H16FN5O3, C: 55.65/55.51, H:
4.67/4.65, N: 20.28/20.18.
Preparation of (E)-7-fluoro-5-(5-(pyrrolidin-1-yl)-1,3,4-
oxadiazol-2-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (10a)
9d. IR (KBr) cmꢁ1: 1600, 1439 (C═N), 1675 (C═O), 3015 (C—H),
1570 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2 next to
C═O), 1068 (C—F), 2906 (CH3, CH); 1H-NMR (300 MHz,
CDCl3 + DMSO-d6) d ppm: 2.35 (8H, t, J = 5.0 Hz, (CH2)4 of
N-methylenepiperazine ), 2.26 (3H, s, CH3), 4.45 (2H, s,
N—CH2—N linkage), 7.41 (1H, d, J = 8.3 Hz, Ar—CH), 7.30
(1H, d, J = 8.6Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H, s,
CH2 of benzodiazepine), 5.95 (1H, s, methine of oxadiazole ring);
MS: m/z (%) 358.37 (M+ 68%), 288.32 (100%), 273.30 (18%);
Analytical data: Calcd/found for C17H19FN6O2, C: 56.98/56.85,
H: 5.34/5.32, N: 23.45/23.38.
Conventional method.
A mixture of 7 (1.46 g, 0.005 mol),
5.0 mL of pyrrolidine, 1 mL AcOH, and 20 mL of xylene was
heated at reflux temperature for 45 h. The reaction mixture was
concentrated, and the residue was diluted with H2O and filtered.
The product was stirred with 30 mL of 2N AcOH, and the insoluble
material was collected. The filtrate was treated with 9 mL of
concentrated NH4OH and extracted with CH2Cl2. The CH2Cl2
layer was washed with H2O, dried over MgSO4, and concentrated
to remove the solvent. The residue was recrystallized from ethyl
acetate to give 10a, 1.00 g, yield (75%), mp, 128–130ꢀC. Other
products 10 (b–h) were prepared using the same procedure.
9e. IR (KBr) cmꢁ1: 1610, 1440 (C═N), 1695 (C═O), 3010 (C—H),
1586 (C═C), 1246 (C—O—C), 2975, 1425 (—CH2 next to
Microwave-assisted method.
Equimolar quantities of 7
(1.46 g, 0.005 mol) and pyrrolidine (0.35 g, 0.005 mol) were
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Application of Privileged Molecular Framework of 7-Fluoro-1,4-benzodiazepin-2-one-5-
methylcarboxylate to the Synthesis of Its 1- and 5-Disubstituted Analogs of Medicinal Interest
997
taken in ethanol (50 mL) and placed in 100 mL flask fitted with a
funnel and a loose top. The reaction mixture was subjected to
microwave irradiation at 360 W microwave power for 6 min and
then at 720 W for 4 min with short interval of 1 min to avoid the
excessive evaporation of solvent. The completion of the reaction
was checked by TLC. The solution obtained after the reaction
had completed was kept at 0ꢀC for 1 h, and the resulting solid
obtained was filtered and recrystallized from ethanol to give
compounds 10a, 1.30 g, yield (90%), mp, 128–130ꢀC. Other
products 10 (b–h) were prepared using the same procedure.
(100%), 245.90 (25%); Analytical data: Calcd/found for
C17H19FN6O2, C: 56.98/56.85, H: 5.34/5.32, N: 23.45/23.36.
10f. IR (KBr) cmꢁ1: 1609, 1440 (C═N), 1670 (C═O), 3016 (C—H),
1570 (C═C), 1248 (C—O—C), 2975, 1425 (—CH2 next to C═O),
1065 (C—F), 2851 (CH2, CH); 1H-NMR (300 MHz, CDCl3 +
DMSO-d6) d ppm: 2.62 [4H, t, J = 5.0 Hz, (CH2)2 of piperazine],
3.15 [4H, t, J = 5.3Hz, (CH2)2 of piperazine], 3.66 (2H, s, —N—
CH2—C linkage), 7.23–7.33 (5H, m, C—H, benzene),
7.34 (1H, d, J = 8.7 Hz, Ar—CH), 7.85 (1H, d, J = 8.4 Hz,
Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine),
8.00 (1H, s, NH); MS: m/z (%) 420.44 (M+ 78%), 335.59 (100%),
268.21 (56%); Analytical data: Calcd/found for C22H21FN6O2, C:
62.85/62.72, H: 5.03/5.01, N: 19.99/19.90.
10a. IR (KBr) cmꢁ1: 1625, 1415 (C═N), 1675 (C═O), 3015
(C—H), 1579 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2
next to C═O), 1065 (C—F); 1H-NMR (300 MHz, CDCl3 +
DMSO-d6) d ppm: 1.92 [4H, m, (CH2)2 of pyrrolidine], 3.59
[4H, m, (CH2)2 of pyrrolidine], 7.84 (1H, d, J = 8.4 Hz,
Ar—CH), 7.34 (1H, d, J = 8.7 Hz, Ar—CH), 7.78 (1H, s,
Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine), 8.00 (1H, s,
NH); MS: m/z (%) 315.3 (M+ 89%), 245.20 (100%), 175.14
(38%); Analytical data: Calcd/found for C15H14FN5O2, C:
57.14/57.05, H: 4.48/4.46, N: 22.21/22.14.
10g. IR (KBr) cmꢁ1: 1625, 1412 (C═N), 1710, 1670 (C═O),
3012 (C—H), 1570 (C═C), 1254 (C—O—C), 2975, 1425
(—CH2 next to C═O), 1065 (C—F), 2995, 2925, 2855 (CH3,
CH2, CH); 1H-NMR (300 MHz, CDCl3 + DMSO-d6) d ppm:
1.29 (3H, t, CH3), 4.13 (2H, q, CH2), 3.33 [4H, t, J = 5.6 Hz,
(CH2)2 of piperazine], 3.31 [4H, t, J = 5.6 Hz, (CH2)2 of pipera-
zine], 7.86 (1H, d, J = 8.4 Hz, Ar—CH), 7.34 (1H, d, J = 8.7 Hz,
Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzodiaz-
epine), 8.00 (1H, s, NH); MS: m/z (%) 402.38 (M+ 87%), 357.35
(100%), 329.56 (38%); Analytical data: Calcd/found for
C18H19FN6O4, C: 54.80/54.68, H: 4.76/4.74, N: 20.89/20.81.
10h. IR (KBr) cmꢁ1: 1608, 1458 (C═N), 1695, 1650 (C═O),
3015 (C—H), 1578 (C═C), 1243 (C—O—C), 2975, 1425 (—
CH2 next to C═O), 1065 (C—F), 2904 (CH3, CH); 1H-NMR
(300 MHz, CDCl3 + DMSO-d6) d ppm: 2.35 (3H, s, CH3), 3.31
[4H, t, J = 5.5 Hz, (CH2)2 of piperazine], 3.57 [4H, t, J = 5.8 Hz,
(CH2)2 of piperazine], 7.85 (1H, d, J = 8.4 Hz, Ar—CH), 7.34
(1H, d, J = 8.7 Hz, Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H,
s, CH2 of benzodiazepine), 8.00 (1H, s, NH); MS: m/z (%)
372.35 (M+ 92%), 341.32 (100%), 313.67 (58%); Analytical data:
Calcd/found for C17H17FN6O3, C: 54.84/54.71, H: 4.60/4.58, N:
22.57/22.48.
10b. IR (KBr) cmꢁ1: 1628, 1412 (C═N), 1675 (C═O), 3016
(C—H), 1578 (C═C), 1255 (C—O—C), 2975, 1426 (—CH2
next to C═O), 1065 (C—F); 1H-NMR (300 MHz, CDCl3 +
DMSO-d6) d ppm: 1.59 [2H, m, CH2 of piperidine], 1.53[4H,
m, (CH2)2 of piperidine], 3.71 [4H, m, (CH2)2 of piperidine],
7.84 (1H, d, J = 8.4 Hz, Ar—CH), 7.35 (1H, d, J = 8.7
Hz,Ar—CH), 7.78 (1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzo-
diazepine), 8.00 (1H, s, NH); MS: m/z (%) 329.33 (M+ 76%),
245.69 (100%), 177.65 (19%); Analytical data: Calcd/found for
C16H16FN5O2, C: 58.35/58.21, H: 4.90/4.89, N: 21.27/21.17.
10c. IR (KBr) cmꢁ1: 1615, 1416 (C═N), 1665 (C═O), 3014
(C—H), 1576 (C═C), 1256 (C—O—C), 2975, 1425 (—CH2
next to C═O), 1065 (C—F); 1H-NMR (300 MHz, CDCl3 +
DMSO-d6) d ppm: 3.57 [4H, t, J = 5.6 Hz, (CH2)2 of tetrahy-
dro1,4-oxazine], 3.65 [4H, t, J = 6.0 Hz, (CH2)2 of tetrahy-
dro1,4-oxazine], 7.84 (1H, d, J = 8.4 Hz, Ar—CH), 7.34 (1H, d,
J = 8.7 Hz, Ar—CH), 7.76 (1H, s, Ar—CH), 4.19 (2H, s, CH2
of benzodiazepine), 8.00 (1H, s, NH); MS: m/z (%) 331.3
(M+ 74%), 258.67 (100%), 180.67 (20%); Analytical data:
Calcd/found for C15H14FN5O3, C: 54.38/54.29, H: 4.26/4.24, N:
21.14/21.07.
Acknowledgment. The authors are thankful to the Director, CDRI
Lucknow, SAIF-Chandigarh, and Arbro Pharmaceutical Ltd-Delhi
(India), for providing the microanalyses and spectral data of the
compounds and to the Department of Science and Technology,
New Delhi (India), for granting project to “Banasthali Centre of
Education for Research in Basic Sciences” under their CURIE
(Consolidation of University Research for Innovation and
Excellence in Women Universities) program.
10d. IR (KBr) cmꢁ1: 1600, 1439 (C═N), 1675 (C═O), 3015
(C—H), 1570 (C═C), 1254 (C—O—C), 2975, 1425 (—CH2
next to C═O), 1068 (C—F), 2906 (CH3, CH); 1H-NMR
(300 MHz, CDCl3 + DMSO-d6) d ppm: 2.36 [4H, t, J = 5.0 Hz,
(CH2)2 of N-methylenepiperazine], 3.15 [4H, t, J = 5.8 Hz,
(CH2)2 of N-methylenepiperazine], 2.26 (3H, s, CH3), 7.84
(1H, d, J = 8.4 Hz, Ar—CH), 7.34 (1H, d, J = 8.7 Hz, Ar—CH),
7.78 (1H, s, Ar—CH), 4.19 (2H, s, CH2 of benzodiazepine),
8.00 (1H, s, NH); MS: m/z (%) 344.34 (M+ 87%), 329.35
(100%), 257.89 (54%); Analytical data: Calcd/found for
C16H17FN6O2, C: 55.81/55.70, H: 4.98/4.96, N: 24.41/24.33.
10e. IR (KBr) cmꢁ1: 1612, 1446 (C═N), 1695 (C═O), 3010
(C—H), 1586 (C═C), 1248 (C—O—C), 2975, 1425 (—CH2
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