Synthesis and biological evaluation of novel methylene-bis-[1,5]- benzodiazepines

Article abstract of DOI:10.1002/jhet.5570450427

(Chemical Equation Presented) A series of novel methylene-bis-chalcones 3 was prepared by the reaction of 5-(3-formyl-4-hydroxybenzyl)-2-hydroxy benzaldehyde 2 with different acetophenones, subsequent treatment of compound 3 with an appropriate o-phenylen

Full text of DOI:10.1002/jhet.5570450427

Jul-Aug 2008
1115
Synthesis and Biological Evaluation of Novel Methylene-bis-[1,5]-
benzodiazepines
M. Raghu, A. Nagaraj and Ch. Sanjeeva Reddy*
Department of Chemistry, Kakatiya University, Warangal 506 009, India.
E-mail: chsrkuc@yahoo.co.in
Received October 17, 2007
CHO
OH
HO
OH
CHO
CHO
R'
1
2
O
R
R"
N
R
HN
HO
HO
OH
OH
H
N
R"
R'
O
3
4/5
N
R
R
A series of novel methylene-bis-chalcones 3 was prepared by the reaction of 5-(3-formyl-4-
hydroxybenzyl)-2-hydroxy benzaldehyde 2 with different acetophenones, subsequent treatment of
compound 3 with an appropriate o-phenylenediamine gave the corresponding methylene-bis-[1,5]-
benzodiazepines 4/5 in good yields. Characterization of the new compounds has been done by means of
1
IR, H NMR, MS and elemental analyses. The antibacterial and antifungal activity of the compounds has
also been evaluated.
J. Heterocyclic Chem., 45, 1115 (2008).
INTRODUCTION
pounds [15], ꢁ-haloketones [16] or ketones in presence of
BF3-OEt2 [17], NaBH4 [18], PPA or SiO2 [19], Sc(OTf)3
[20], MgO/POCl3 [21], Yb(OTf)3 [22], Al2O3/P2O5 [23],
AcOH/MWI [24], Ionic liquid [25], CAN [26] and InCl3
[27]. On the other hand, there are no reports on the
synthesis of bis-[1,5]-benzodiazepines from any
compound including ꢀ,ꢁ-unsaturated carbonyl
compounds and o-phenylenediamines.
Inspired with the biological profile of 1,5-benzodi-
azepines and increasing importance in pharmaceutical and
biological fields, and in continuation of our work on
biologically active heterocycles [28], it was considered
worthwhile to synthesize certain new chemical entities
incorporating two active 1,5-benzodiazepine moieties in a
single molecular framework in order to prepare molecules
having with potentially enhanced biological activities and
to have them evaluated for their antimicrobial activity.
1,5-Benzodiazepines have received special attraction
because of their pharmacological properties [1]. Many
members of this family are found to be active against a
variety of target types including peptide hormones (CCK)
[2], inter leukin converting enzymes (ICE) [3] and
potassium blockers (Ik) [4]. Nowadays the area of
biological interest of 1,5-benzodiazepines has been
extended to various diseases such as cancer [5], viral
infection (non nucleoside inhibitors of HIV-1 reverse
transcriptase) [6] and cardiovascular disorders [7]. In
addition, these compounds are also used as tranquilizing,
anticonvulsant, antidepressive, antibacterial, antifungal,
antifeedent, anti-inflammatory and analgesic agents [8].
1,5-Benzodiazepine derivatives are also used as dyes for
acrylic fiber in photography [9]. Moreover, these are
valuable synthons used for the preparation of other fused
ring systems such as trioxalo [10], oxadiazolo [11], oxa-
zino [12], triazolo [13] or furano-benzodiazepines [14].
Despite their wide range of pharmacological, industrial
and synthetic applications, synthesis of 1,5-benzodiaze-
pines has received little attention except a few monomeric
1,5-benzodiazepines. These include condensation of
o-phenylenediamines with ꢀ,ꢁ-unsaturated carbonyl com-
RESULTS AND DISCUSSION
In this article, we describe the synthesis of 1,5-benzo-
diazepines from methylene-bis-chalcones 3 and o-pheny-
lenediamines. For the synthesis of target compounds the
5-(3-formyl-4-hydroxybenzyl)-2-hydroxy benzaldehyde 2
was prepared by the reaction of salicylaldehyde 1 with

1116
M. Raghu, A. Nagaraj and Ch. Sanjeeva Reddy
Vol 45
Scheme 1
O
R
O
CHO
OH
HO
OH
HO
OH
R
Me
Trioxane
KOH/EtOH
H2SO4/AcOH
CHO
CHO
O
3
1
2
R
R'
NH2
NH2
Xylene/
reflux
Yield (%)
87
Yield (%)
R
R
R"
R'
C6H5
4a
4b
4c
4d
4e
4f
4g
4h
4i
C6H5
5a
5b
5c
5d
5e
5f
5g
5h
5i
R"
86
N
4-Br-C6H4
4-NO2-C6H4
4-Cl-C6H4
4-MeO-C6H4
2-OH-C6H4
2-Furyl
4-Br-C6H4
4-NO2-C6H4
4-Cl-C6H4
4-MeO-C6H4
2-OH-C6H4
2-Furyl
86
90
81
89
91
82
80
79
89
92
86
83
91
79
78
81
R
HN
HO
OH
H
N
2-Thienyl
2-pyridyl
R"
R'
2-Thienyl
2-pyridyl
4 (a-i) R' = R" = H
5 (a-i) R' = R" = Me
N
R
trioxane in presence of a mixture of acetic acid and conc.
sulfuric acid [29], followed by condensation of compound
2 with methyl ketones in the presence of 60% aqueous
KOH at room temperature [30] yields methylene-bis-
chalcones 3. The reaction times as well as the yields vary
depending on the corresponding reagents. The crude
product, contaminated by some starting materials, was
purified by extracting with ether. The methylene-bis-
chalcones 3 were reacted with an appropriate o-phenyl-
enediamine in xylene at reflux temperature for 8 h to get
methylene-bis-[1,5]-benzodiazepines 4/5 in good to excel-
lent yields (Scheme 1). The structure of the synthesized
active against E. coli and B.subtilis. Compounds 4d, 4g,
4i and 5d were highly active against B.subtilis and the
compound 5i was highly active against E. coli (Table 1).
The remaining compounds showed moderate to good
activity against all the organisms employed. It is
interesting to note that almost all the dimeric compounds
showed improved antibacterial activity than that of the
corresponding monomeric compounds.
Antifungal Activity. The compounds 4a-i and 5a-i
were also screened for their antifungal activity against A.
niger, C. albicans and E. vitae at a concentration of 500
μg using the cup plate method [31]. The compounds 4f
and 5c were highly active and the other compounds
showed moderate to good activity. The antifungal activity
of the compounds was compared with the standard drug
griseofulvin. The zones of inhibition formed were
measured in mm and are shown in table 1. The results
reveal that almost all the dimeric compounds showed
enhanced activity compared with that of their monomeric
compounds.
1
compounds was confirmed by IR, H NMR, MS and
elemental analyses.
Further, the compounds were
subjected to antibacterial and antifungal testing and
compared with the monomeric compounds prepared from
the literature method [26,27].
Antibacterial Activity. The compounds 4a-i and 5a-i
were screened for their antibacterial activity against
human pathogenic organisms Escherichia coli, Bacillus
subtilis and Staphylococcus typhi. The zone of inhibition
in mm at concentration 500 μg was determined using the
cup plate method [31]. DMF was used as solvent control.
Norfloxacin was used as antibacterial standard and the
results are given in table 1. It has been observed that the
compounds exhibited interesting biological activity
however, with a degree of variation.
In conclusion, we have evaluated a versatile method for
the synthesis of a series of novel methylene-bis[1,5]-
benzodiazepines in good to excellent yields. Some of the
synthesized compounds exhibited excellent antibacterial
and antifungal activity and they can be evaluated as
antimicrobial agents.
Compounds in the series 4 and 5, which contain 4-NO2,
4-Cl, thiophene or pyridine ring system displayed good
antibacterial activity against all the organisms.
Compounds 4h and 5h were highly active against B.
subtilis and S. typhi, compounds 5c and 5g were highly
EXPERIMENTAL
Melting points were determined on a Fisher-Johns melting
point apparatus and are uncorrected. The purity of the
compounds was checked using precoated TLC plates (Merck,

Jul-Aug 2008
Synthesis of Novel Methylene-bis-[1,5]-benzodiazepines
1117
Table 1
Antimicrobial activity of the compounds 4a-i and 5a-i.
Antibacterial activity
(zone of inhibition in mm)
E. coli
Antifungal activity
(zone of inhibition in mm)
Compound
B. subtilis
S. typhi
A. niger
C albicans
E. vitae
4a
15a (12)b
20 (14)
22 (17)
23 (17)
21 (16)
22 (19)
24 (22)
25 (20)
23 (19)
18 (14)
21 (16)
23 (21)
23 (20)
19 (11)
20 (10)
25 (19)
26 (20)
21 (19)
26
20a (12)b
18 (13)
22 (16)
21 (15)
15 (11)
21 (12)
22 (16)
22 (16)
22 (13)
21 (19)
19 (17)
24 (18)
21 (16)
21 (15)
21 (17)
23 (18)
22 (16)
24 (18)
28
18a (12)b
18 (14)
20 (16)
21 (15)
16 (11)
19 (13)
20 (15)
23 (17)
21 (17)
17 (11)
17 (11)
19 (13)
18 (14)
15 (10)
16 (10)
19 (16)
24 (16)
20 (15)
26
18a (14)b
20 (12)
23 (13)
25 (16)
18 (14)
24 (15)
26 (17)
26 (19)
24 (16)
18 (12)
18 (13)
25 (16)
24 (14)
18 (13)
24 (17)
19 (14)
24 (15)
26 (17)
-
18a (12)b
19 (14)
21 (13)
22 (15)
18 (14)
25 (17)
22 (14)
21 (12)
18 (11)
19 (11)
18 (12)
27 (19)
20 (14)
18 (13)
24 (17)
24 (15)
25 (14)
21 (13)
-
20a (12)b
19 (12)
18 (14)
24 (15)
22 (13)
25 (17)
23 (15)
24 (17)
20 (15)
18 (12)
19 (14)
23 (13)
23 (16)
19 (14)
22 (15)
18 (12)
20 (12)
23 (15)
-
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
5i
Norfloxacin
Griseofulvin
-
-
-
30
30
30
Note: <16mm, inactive; 17-23mm, moderately active; 23-26mm, highly active. aActivity of dimeric compounds; bActivity of their monomeric
compounds.
60F-254). IR spectra were obtained on a Perkin-Elmer FTIR 5000
General procedure for the synthesis of methylene-bis-
[1,5]-benzodiazepines (4/5). To a solution of 3 (0.01 mol) in 40
mL xylene, boiling solution of an appropriate o-phenylene-
diamine (0.02 mol) in 20 mL xylene was added in small portions
and the reaction mixture was refluxed for 8 h (TLC). During the
reaction, formed water was separated by using Dean-Stark
apparatus. The reaction mixture left for 24 h at room
temperature, and excess solvent was distilled off under reduced
pressure. The residual mass was triturated with light petroleum
ether; solid obtained was filtered and recrystallized from ethanol
to give pure 4/5.
spectrophotometer, using KBr pellets. 1H NMR spectra were
obtained with a Varian Gemini 300 MHz spectrometer and the
chemical shifts were reported as parts per million (ꢀ ppm) down
field using TMS as an internal standard. Mass spectra were
obtained on a VG micro mass 7070H spectrometer operating at
70 eV. UV spectra were obtained on a UV-2401 spectrometer.
Elemental analyses were performed on a Perkin-Elmer 240 CHN
elemental analyzer. All solvents and chemicals were purchased
from Sigma Aldrich chemical company and used without further
purification.
Synthesis of (E)-3-(4-bromophenyl)-1-(5,3-[(E)-3-(4-bromo
phenyl)-2-propenoyl]-4-hydroxy-benzyl-2-hydroxyphenyl)-2-
propen-1-one (3). A solution of 2 (2.56 g, 0.01 mol) and 4-
bromoacetophenone (0.02 mol) in 20 mL ethanol was slowly
treated with 20 mL 60% KOH solution at 5-10 °C. The reaction
was stirred at room temperature until TLC indicated complete
conversion (4 h). It was then diluted with 50 mL water and
extracted with 3x20 mL diethyl ether. The aqueous solution was
acidified with dilute HCl. The solid obtained was filtered,
washed thoroughly with water and dried. Crystallization of the
crude residue from toluene: MeOH (3:2) afforded 91% of 3 as a
yellow solid; mp 160-162 °C. UV (EtOH, nm) ꢁmax: 370.5,
304.9, 268.1; IR (KBr): 3440, 3056, 1640, 1571, 1482, 1224
4-[4-Hydroxy-3-(4-phenyl-2,3-dihydro-1H-1,5-benzodiaze-
pin-2-yl)benzyl]-2-(4-phenyl-2,3-dihydro-1H-1,5-benzodiaze
pin-2-yl)phenol (4a). This compound was obtained as yellow
solid; mp 80-82 °C; IR (KBr): ꢄ 3354, 3056, 1507, 1282, 1101,
1
742 cm-1; H NMR (DMSO-d6): ꢀ 3.16 (2H, dd, Jab = 13.5, Jax=
8.6 Hz, Ha), 3.41 (2H, dd, Jba = 13.5, Jbx = 3.2 Hz, Hb), 3.82 (2H,
s, -CH2), 4.01 (2H, bs, NH), 5.18 (2H, dd, Jxa = 8.6, Jxb = 3.2 Hz,
Hx), 6.37-7.32 (14H, m, ArH), 7.42-7.91 (10H, m, ArH). MS:
m/z 640 (M+). Anal. calcd. for C43H36N4O2: C, 80.60; H, 5.66; N,
8.74. Found: C, 80.75; H, 5.57; N, 8.69.
2-[4-(4-Bromophenyl)-2,3-dihydro-1H-1,5-benzodiazepin-
2-yl]-4-3-[4-(4-bromophenyl)-2,3-dihydro-1H-1,5-benzodiaze
pin-2-yl]-4-hydroxybenzylphenol (4b). This compound was
obtained as brown solid; mp 78-80 °C; IR (KBr): 3352, 3042,
1
cm-1; H NMR (DMSO-d6): ꢀ 3.84 (2H, s, -CH2), 6.84 (2H, d, J
1
= 15.2 Hz, ꢂ-H), 7.70 (2H, d, J = 15.2 Hz, ꢃ-H), 10.21 (2H, s,
OH), 7.18 (4H, d, J = 9.1 Hz, ArH), 8.05 (4H, d, J = 9.1 Hz,
ArH), 7.82-8.18 (6H, m, ArH); MS: m/z 616 (M+). Anal. calcd.
for C31H22O4Br2: C, 60.19; H, 3.67; Br, 25.78. Found: C, 60.12;
H, 3.59; Br, 25.61. The other chalcones 3 were prepared by the
similar procedure and confirmed their structures from the IR, 1H
NMR, MS and elemental analyses [30].
1500, 1281, 1110, 742 cm-1; H NMR (DMSO-d6): ꢀ: 3.21 (2H,
dd, Jab = 13.5, Jax = 8.6 Hz, Ha), 3.39 (2H, dd, Jba = 13.5, Jbx = 3.2
Hz, Hb), 3.82 (2H, s, -CH2), 4.0 (2H, bs, NH), 5.21 (2H, dd, Jxa =
8.6, Jxb = 3.2 Hz, Hx), 6.37-7.30 (14H, m, ArH), 7.41 (4H, d, J =
8.4 Hz, ArH),7.98 (4H, d, J = 8.4 Hz, ArH); MS: m/z 798 (M+).
Anal. calcd. for C43H34Br2N4O2: C, 64.67; H, 4.29; N, 7.02.
Found: C, 64.21; H, 4.17; N, 7.00.

1118
M. Raghu, A. Nagaraj and Ch. Sanjeeva Reddy
Vol 45
4-4-Hydroxy-3-[4-(4-nitrophenyl)-2,3-dihydro-1H-1,5-
(2H, s, ArH); MS: m/z 652 (M+). Anal. calcd. for C39H32N4O4:
C, 71.75; H, 4.94; N, 8.58. Found: C, 71.26; H, 4.83; N, 8.22.
4-4-Hydroxy-3-[4-(2-pyridyl)-2,3-dihydro-1H-1,5-benzo-
diazepin-2-yl]benzyl-2-[4-(2-pyridyl)-2,3-dihydro-1H-1,5-
benzodiazepin-2-yl]phenol (4i). This compound was obtained
as yellow-brown solid; mp 162-164 °C; IR (KBr): 3352, 3035,
1630, 1592, 1503, 1470, 1282, 1105, 742 cm-1; 1H NMR
(DMSO-d6): ꢀ 3.16 (2H, dd, Jab = 13.5, Jax = 8.6 Hz, Ha), 3.41
(2H, dd, Jba = 13.5, Jbx = 3.2 Hz, Hb), 3.84 (2H, s, -CH2), 4.01
(2H, bs, NH), 5.22 (2H, dd, Jxa = 8.6, Jxb = 3.2 Hz, Hx), 6.47-7.32
(16H, m, ArH), 7.50-7.60 (2H, m, ArH), 8.61 (2H, d, J = 8.32
Hz, ArH); MS: m/z 642 (M+). Anal. calcd. for C41H34N6O2: C,
76.62; H, 5.33; N, 13.07. Found: C, 76.31; H, 5.26; N, 12.87.
2-(7,8-Dimethyl-4-phenyl-2,3-dihydro-1H-1,5-benzodiaze-
pin-2-yl)-4-[3-(7,8-dimethyl-4-phenyl-2,3-dihydro-1H-1,5-ben-
zodiazepin-2-yl)-4-hydroxybenzyl]phenol (5a). This
compound was obtained as brown solid; mp 92-94 °C; IR (KBr):
3352, 3049, 1502, 1281, 1110, 742 cm-1; 1H NMR (DMSO-d6): ꢀ
2.20 (12H, s, CH3), 3.12 (2H, dd, Jab = 13.6, Jax = 8.7 Hz, Ha),
3.42 (2H, dd, Jba = 13.6, Jbx = 3.2 Hz, Hb), 3.82 (2H, s, -CH2),
4.01 (2H, bs, NH), 5.20 (2H, dd, Jxa = 8.7, Jxb = 3.2 Hz, Hx), 6.27
(2H, s, ArH), 6.78 (2H, d, J = 9.1 Hz, ArH), 6.96 (2H, s, ArH),
7.0 (2H, d, J = 9.1 Hz, ArH), 7.29-7.90 (12H, m, ArH); MS:
m/z 696 (M+). Anal. calcd. for C47H44N4O2: C, 81.01; H, 6.36;
N, 8.04. Found: C, 81.31; H, 6.21; N, 7.93.
2-[4-(4-Bromophenyl)-7,8-dimethyl-2,3-dihydro-1H-1,5-ben-
zodiazepin-2-yl]-4-3-[4-(4-bromophenyl)-7,8-dimeth-yl-2,3-
dihydro-1H-1,5-benzodiazepin-2-yl]-4-hydroxybenzylphenol
(5b). This compound was obtained as yellow-brown solid; mp
101-103 °C; IR (KBr): 3350, 3041, 1507, 1281, 1107, 742 cm-1;
1H NMR (DMSO-d6): ꢀ 2.20 (12H, s, -CH3), 3.12 (2H, dd, Jab =
13.6, Jax = 8.7 Hz, Ha), 3.42 (2H, dd, Jba = 13.6, Jbx = 3.2 Hz, Hb),
3.82 (2H, s, -CH2), 4.04 (2H, bs, NH), 5.20 (2H, dd, Jxa = 8.7, Jxb
= 3.2 Hz, Hx), 6.27 (2H, s, ArH), 6.78 (2H, d, J = 9.1 Hz, ArH),
6.96 (2H, s, ArH), 7.0 (2H, d, J = 9.1 Hz, ArH), 7.29-7.39 (6H,
m, ArH), 7.87 (4H, d, J = 8.2 Hz, ArH); MS: m/z 854 (M+).
Anal. calcd. for C47H42Br2N4O2: C, 66.05; H, 4.95; N, 6.56.
Found: C, 65.81; H, 4.86; N, 6.53.
benzodiazepin-2-yl]benzyl-2-[4-(4-nitrophenyl)-2,3-dihydro-
1H-1,5-benzodiazepin-2-yl]phenol (4c). This compound was
obtained as brown solid; mp 166-168 °C; IR (KBr): 3352, 3042,
1502, 1482, 1347, 1281, 1110, 743 cm-1; 1H NMR (DMSO-d6): ꢀ
3.16 (2H, dd, Jab = 13.5, Jax = 8.6 Hz, Ha), 3.41 (2H, dd, Jba
=
13.5, Jbx = 3.2 Hz, Hb), 3.82 (2H, s, -CH2), 4.0 (2H, bs, NH), 5.19
(2H, dd, Jxa = 8.6, Jxb = 3.2 Hz, Hx), 6.37-7.32 (14H, m, ArH), 8.1
(4H, d, J = 8.9 Hz, ArH), 8.32 (4H, d, J = 8.9 Hz, ArH); MS:
m/z 730 (M+). Anal. calcd. for C43H34N6O6: C, 70.67; H, 4.69;
N, 11.50. Found: C, 70.10; H, 4.52; N, 11.32.
2-[4-(4-Chlorophenyl)-2,3-dihydro-1H-1,5-benzodiazepin-
2-yl]-4-3-[4-(4-chlorophenyl)-2,3-dihydro-1H-1,5-benzodiaze
pin-2-yl]-4-hydroxybenzylphenol (4d). This compound was
obtained as pale brown solid; mp 99-101 °C; IR (KBr): 3351,
1
3051, 1502, 1280, 1100, 742, 686 cm-1; H NMR (DMSO-d6): ꢀ
3.16 (2H, dd, Jab = 13.5, Jax = 8.6 Hz, Ha), 3.40 (2H, dd, Jba
=
13.5, Jbx = 3.2 Hz, Hb), 3.84 (2H, s, -CH2), 4.0 (2H, bs, NH), 5.22
(2H, dd, Jxa = 8.6, Jxb = 3.2 Hz, Hx), 6.36-7.30 (14H, m, ArH),
7.39 (4H, d, J = 8.2 Hz, ArH), 7.91 (4H, d, J = 8.2 Hz, ArH);
MS: m/z 710 (M+). Anal. calcd. for C43H34Cl2N4O2: C, 72.78; H,
4.83; N, 7.89. Found: C, 71.90; H, 4.77; N, 7.61.
4-4-Hydroxy-3-[4-(4-methoxyphenyl)-2,3-dihydro-1H-
1,5-benzodiazepin-2-yl]benzyl-2-[4-(4-methoxyphenyl)-2,3-
dihydro-1H-1,5-benzodiazepin-2-yl]phenol (4e). This
compound was obtained as yellow solid; mp 77-79 °C; IR
1
(KBr): 3354, 3049, 1502, 1271, 1290, 1100, 742 cm-1; H NMR
(DMSO-d6): ꢀ 3.16 (2H, dd, Jab = 13.6, Jax = 8.6 Hz, Ha), 3.41
(2H, dd, Jba = 13.6, Jbx = 3.2 Hz, Hb), 3.82 (2H, s, -CH2), 3.90
(6H, s, CH3), 4.0 (2H, bs, NH), 5.20 (2H, dd, Jxa = 8.6, Jxb = 3.2
Hz, Hx), 6.36-7.30 (22H, m, ArH); MS: m/z 700 (M+). Anal.
calcd. for C45H40N4O4: C, 77.12; H, 5.75; N, 7.99. Found: C,
78.00; H, 5.67; N, 7.83.
4-4-Hydroxy-3-[4-(2-hydroxyphenyl)-2,3-dihydro-1H-
1,5-benzodiazepin-2-yl]benzyl-2-[4-(2-hydroxyphenyl)-2,3-
dihydro-1H-1,5-benzodiazepin-2-yl]phenol (4f). This
compound was obtained as orange solid; mp 110-112 °C; IR
(KBr): 3454-3357, 3032, 1502, 1280, 1102, 742 cm-1; 1H NMR
(DMSO-d6): ꢀ 3.08 (2H, dd, Jab = 13.5, Jax = 8.6 Hz, Ha), 3.52
(2H, dd, Jba = 13.5, Jbx = 3.2 Hz, Hb), 3.84 (2H, s, -CH2), 5.24
(2H, dd, Jxa = 8.6, Jxb = 3.2 Hz, Hx), 6.42 (2H, bs, NH), 6.52-
7.30 (22H, m, ArH); MS: m/z 672 (M+). Anal. calcd. for
C43H36N4O4: C, 76.77; H, 5.39; N, 8.33. Found: C, 75.61; H,
5.23; N, 8.27.
2-[7,8-Dimethyl-4-(4-nitrophenyl)-2,3-dihydro-1H-1,5-
benzodiazepin-2-yl]-4-3-[7,8-dimethyl-4-(4-nitrophenyl)-2,3-
dihydro-1H-1,5-benzodiazepin-2-yl]-4-hydroxybenzylphenol
(5c). This compound was obtained as orange solid; mp 173-175
°C; IR (KBr): 3350, 3042, 1502, 1487, 1344, 1281, 1110, 743
1
cm-1; H NMR (DMSO-d6): ꢀ 2.20 (12H, s, -CH3), 3.12 (2H, dd,
2-[4-(2-Furyl)-2,3-dihydro-1H-1,5-benzodiazepin-2-yl]-4-
3-[4-(2-furyl)-2,3-dihydro-1H-1,5-benzodiazepin-2-yl]-4-
hydroxybenzyl phenol (4g). This compound was obtained as
brown solid; mp 141-143 °C; IR (KBr): 3352, 3037, 1503, 1595,
Jab = 13.6, Jax = 8.7 Hz, Ha), 3.42 (2H, dd, Jba = 13.6, Jbx = 3.2 Hz,
Hb), 3.82 (2H, s, -CH2), 4.01 (2H, bs, NH), 5.21 (2H, dd, Jxa
=
8.7, Jxb = 3.2 Hz, Hx), 6.27 (2H, s, ArH), 6.77 (2H, d, J = 9.1 Hz,
ArH), 6.96-7.10 (4H, m, ArH), 7.27 (2H, s, ArH), 8.01 (4H, d, J
= 8.4 Hz, ArH), 8.27 (4H, d, J = 8.4 Hz, ArH); MS: m/z
786(M+). Anal. calcd. for C47H42N6O6:C, 71.74; H, 5.38; N,
10.68. Found:C,71.50; H, 5.26; N, 10.51.
2-[4-(4-Chlorophenyl)-7,8-dimethyl-2,3-dihydro-1H-1,5-
benzodiazepin-2-yl]-4-3-[4-(4-chlorophenyl)-7,8-dimeth-yl-
2,3-dihydro-1H-1,5-benzodiazepin-2-yl]-4-hydroxybenzyl-
phenol (5d). This compound was obtained as pale brown solid;
mp 121-123 °C; IR (KBr): 3351, 3036, 1502, 1284, 1107, 742,
686 cm-1; 1H NMR (DMSO-d6): ꢀ 2.20 (12H, s, -CH3), 3.12 (2H,
dd, Jab = 13.6, Jax = 8.7 Hz, Ha), 3.42 (2H, dd, Jba = 13.6, Jbx = 3.2
Hz, Hb), 3.82 (2H, s, -CH2), 4.01 (2H, bs, NH), 5.22 (2H, dd, Jxa
= 8.7, Jxb = 3.2 Hz, Hx), 6.27 (2H, s, ArH), 6.72 (2H, d, J = 9.1
Hz, ArH), 6.92-7.10 (4H, m, ArH), 7.28-7.32 (6H, m, ArH),
7.77 (4H, d, J = 8.3 Hz, ArH); MS: m/z 766 (M+). Anal. calcd.
1
1282, 1107, 1030, 742 cm-1; H NMR (DMSO-d6): ꢀ 3.16 (2H,
dd, Jab = 13.5, Jax = 8.6 Hz, Ha), 3.41 (2H, dd, Jba = 13.5, Jbx = 3.2
Hz, Hb), 3.84 (2H, s, -CH2), 4.01 (2H, bs, NH), 5.22 (2H, dd, Jxa
= 8.6, Jxb = 3.2 Hz, Hx), 6.19-7.32 (18H, m, ArH), 7.61 (2H, d, J
= 6.8 Hz, ArH); MS: m/z 620 (M+). Anal. calc. for C39H32N4O4:
C, 75.47; H, 5.20; N, 9.03. Found: C, 76.01; H, 5.05; N, 8.89.
4-4-Hydroxy-3-[4-(2-thienyl)-2,3-dihydro-1H-1,5-benzo-
diazepin-2-yl]benzyl-2-[4-(2-thienyl)-2,3-dihydro-1H-1,5-
benzodiazepin-2-yl]phenol (4h). This compound was obtained
as brown solid; mp 115-117 °C; IR (KBr): 3352, 3037, 1503,
1
1596, 1282, 1105, 1037, 742 cm-1; H NMR (DMSO-d6): ꢀ 3.12
(2H, dd, Jab = 13.5, Jax = 8.6 Hz, Ha), 3.46 (2H, dd, Jba = 13.5, Jbx
= 3.2 Hz, Hb), 3.84 (2H, s, -CH2), 4.01 (2H, bs, NH), 5.22 (2H,
dd, Jxa = 8.6, Jxb = 3.2 Hz, Hx), 6.49-7.30 (18H, m, ArH), 7.40

Jul-Aug 2008
Synthesis of Novel Methylene-bis-[1,5]-benzodiazepines
1119
for C47H42Cl2N4 O2: C, 73.72; H, 5.53; N,7.32. Found: C, 73.67;
H, 5.41; N, 7.30.
C45H42N6O2: C, 77.34; H, 6.06; N, 12.03. Found: C, 77.02; H,
6.00; N, 11.89.
4-4-Hydroxy-3-[4-(4-methoxyphenyl)-7,8-dimethyl-2,3-di-
hydro-1H-1,5-benzodiazepin-2-yl]benzyl-2-[4-(4-methoxy-
phenyl)-7,8-dimethyl-2,3-dihydro-1H-1,5-benzodiazepin-2-
yl]phenol (5e). This compound was obtained as yellow solid;
mp 94-96 °C; IR (KBr): 3352, 3036, 1502, 1287, 1271, 1107,
742 cm-1; 1H NMR (DMSO-d6): ꢀ 2.20 (12H, s, -CH3), 3.12 (2H,
dd, Jab = 13.6, Jax = 8.7 Hz, Ha), 3.42 (2H, dd, Jba = 13.6, Jbx = 3.2
Hz, Hb), 3.82 (2H, s, -CH2), 3.91 (6H, s, -CH3), 4.04 (2H, bs,
NH), 5.20 (2H, dd, Jxa = 8.7, Jxb = 3.2 Hz, Hx), 6.27 (2H, s, ArH),
6.78 (2H, d, J = 9.1 Hz, ArH), 6.85 (4H, d, J = 8.4 Hz, ArH),
6.96 (2H, s, ArH), 7.05 (6H, m, ArH), 7.32 (2H, s, ArH); MS:
m/z 756 (M+). Anal. calcd. for C49H48N4O4: C, 77.75; H, 6.39;
N, 7.40. Found: C, 78.01; H, 6.21; N, 7.32.
4-4-Hydroxy-3-[4-(2-hydroxyphenyl)-7,8-dimethyl-2,3-di-
hydro-1H-1,5-benzodiazepin-2-yl]benzyl-2-[4-(2-hydroxy-
phenyl)-7,8-dimethyl-2,3-dihydro-1H-1,5-benzodiazepin-2-
yl]phenol (5f). This compound was obtained as orange solid;
mp 134-136 °C; IR (KBr): 3452-3357, 3033, 1507, 1284, 1107,
742 cm-1; 1H NMR (DMSO-d6): ꢀ 2.20 (12H, s, CH3), 3.45 (2H,
dd, Jab = 13.6, Jax = 8.7 Hz, Ha), 3.66 (2H, dd, Jba = 13.6, Jbx = 3.2
Hz, Hb), 3.80 (2H, s, -CH2), 6.51 (2H, bs, NH), 5.22 (2H, dd, Jxa
= 8.7, Jxb = 3.2 Hz, Hx), 6.27 (2H, s, ArH), 6.76 (2H, d, J = 9.1
Hz, ArH), 6.97-7.32 (14H, m, ArH); MS: m/z 728 (M+). Anal.
calcd. for C47H44N4O4: C, 77.45; H, 6.09; N, 7.69. Found: C,
77.01; H, 6.01; N, 7.51.
Acknowledgements. The authors are grateful to the Director,
Indian Institute of Chemical Technology, Hyderabad, India, for
spectral analysis, to the Head, Department of Microbiology,
Kakatiya University, Warangal, India, for providing facilities for
the biological screening.
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2-[4-(2-Furyl)-7,8-dimethyl-2,3-dihydro-1H-1,5-benzodiaz-
epin-2-yl]-4-3-[4-(2-furyl)-7,8-dimethyl-2,3-dihydro-1H-
1,5-benzodiazepin-2-yl]-4-hydroxybenzylphenol (5g). This
compound was obtained as black solid; mp 151-153 °C; IR
1
(KBr): 3352, 3037, 1595, 1503, 1282, 1107, 1030, 742 cm-1; H
NMR (DMSO-d6): ꢀ 2.20 (12H, s, -CH3), 3.32 (2H, dd, Jab
=
13.6, Jax = 8.7 Hz, Ha), 3.49 (2H, dd, Jba = 13.6, Jbx = 3.2 Hz, Hb),
3.82 (2H, s, -CH2), 4.01 (2H, bs, NH), 5.22 (2H, dd, Jxa = 8.7, Jxb
= 3.2 Hz, Hx), 6.19-6.27 (4H, m, ArH), 6.76 (2H, d, J = 9.1 Hz,
ArH), 6.87-7.0 (6H, m, ArH), 7.27 (2H, s, ArH), 7.61 (2H, d, J =
8.3 Hz, ArH); MS: m/z 676 (M+). Anal. calcd. for C43H40N4O4:
C, 76.31; H, 5.96; N, 8.28. Found: C, 76.06; H, 5.81; N, 8.22.
2-[7,8-Dimethyl-4-(2-thienyl)-2,3-dihydro-1H-1,5-benzodi-
azepin-2-yl]-4-3-[7,8-dimethyl-4-(2-thienyl)-2,3-dihydro-1H-
1,5-benzodiazepin-2-yl]-4-hydroxybenzylphenol (5h). This
compound was obtained as brown solid; mp 119-121 °C; IR
(KBr): 3352, 3037, 2971, 1596, 1503, 1281, 1110, 1037, 742
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2000, 30, 1825.
1
cm-1; H NMR (DMSO-d6): ꢀ 2.20 (12H, s, -CH3), 3.21 (2H, dd,
[15] Stahlofen, P.; Ried, W. Chem. Ber. 1957, 90, 815.
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Jab = 13.6, Jax = 8.7 Hz, Ha), 3.41 (2H, dd, Jba = 13.6, Jbx = 3.2 Hz,
Hb), 3.84 (2H, s, -CH2), 4.05 (2H, bs, NH), 5.22 (2H, dd, Jxa
=
8.7, Jxb = 3.2 Hz, Hx), 6.27 (2H, s, ArH), 6.76-7.10 (12H, m,
ArH), 7.32 (2H, s, ArH); MS: m/z 708 (M+). Anal. calcd. for
C43H40N4O2S2: C, 72.85; H, 5.69; N, 7.90. Found: C, 73.06; H,
5.57; N, 7.79.
2-[7,8-Dimethyl-4-(2-pyridyl)-2,3-dihydro-1H-1,5-benzodi-
azepin-2-yl]-4-3-[7,8-dimethyl-4-(2-pyridyl)-2,3-dihydro-1H-
1,5-benzodiazepin-2-yl]-4-hydroxybenzylphenol (5i). This
compound was obtained as brown solid; mp 147-149 °C; IR
(KBr): 3352, 3035, 1630, 1592, 1503, 1470, 1282, 1105, 742
1
cm-1; H NMR (DMSO-d6): ꢀ 2.20 (12H, s, CH3), 3.14 (2H, dd,
Jab = 13.6, Jax = 8.7 Hz, Ha), 3.39 (2H, dd, Jba = 13.6, Jbx = 3.2 Hz,
Hb), 3.82 (2H, s, -CH2), 4.04 (2H, bs, NH), 5.22 (2H, dd, Jxa
=
8.7, Jxb = 3.2 Hz, Hx), 6.27 (2H, s, ArH), 6.80-7.0 (8H, m, ArH),
7.32 (2H, d, J = 8.3 Hz, ArH), 7.52-7.59 (4H, m, ArH), 8.62
(2H, d, J = 8.7 Hz, ArH); MS: m/z 698 (M+). Anal. calcd. for
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1120
M. Raghu, A. Nagaraj and Ch. Sanjeeva Reddy
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