Studies on synthesis and evaluation of quantitative structure-activity relationship of 10-methyl-6-oxo-5-arylazo-6,7-dihydro-5H-[1,3]azaphospholo[1,5- d][1,4]benzodiazepin-2-phospha-3-ethoxycarbonyl-1-phosphorus dichlorides

Article abstract of DOI:10.1016/j.bmcl.2006.01.080

A new series of 10-methyl-6-oxo-5-arylazo-6,7-dihydro-5H-[1,3] azaphospholo[1,5-d][1,4]benzodiazepin-2-phospha-3-ethoxycarbonyl-1-phosphorus dichlorides 11a-p has been synthesized and evaluated as antimicrobial agents. Structures of all the synthesized co

Full text of DOI:10.1016/j.bmcl.2006.01.080

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2484–2491
Studies on synthesis and evaluation of quantitative
structure–activity relationship of 10-methyl-6-oxo-5-arylazo-6,
7-dihydro-5H-[1,3]azaphospholo[1,5-d][1,4]benzodiazepin-
2-phospha-3-ethoxycarbonyl-1-phosphorus dichlorides
Ashok Kumar,* Pratibha Sharma, V. K. Gurram and Nilesh Rane
School of Chemical Sciences, Devi Ahilya University, Indore 452 017, India
Received 5 December 2005; revised 19 January 2006; accepted 20 January 2006
Available online 7 February 2006
Abstract—A new series of 10-methyl-6-oxo-5-arylazo-6,7-dihydro-5H-[1,3]azaphospholo[1,5-d][1,4]benzodiazepin-2-phospha-3-eth-
oxycarbonyl-1-phosphorus dichlorides 11a–p has been synthesized and evaluated as antimicrobial agents. Structures of all the syn-
thesized compounds were established on the basis of elemental analysis and spectroscopic data. Quantitative structure–activity
relationship (QSAR) investigations were applied to find out the correlation between the experimentally evaluated activity with var-
ious parameters of the compounds studied. QSAR equations showed that the molecular refractivity correlates significantly with the
antimicrobial activity.
Ó 2006 Elsevier Ltd. All rights reserved.
Benzodiazepines (BDZs) and their derivatives are well
known to the chemists mainly because of the broad-
spectrum biological properties exhibited by this class
of compounds.1–5 Interest in the chemistry, synthesis
and biology of this pharmacophore continues to be
fuelled by their activity against a variety of CNS disor-
ders as well as due to wide biological properties such as
antianxiety, anticonvulsant, sedative/hypnotic, muscle
relaxing and tranquilizing.6–8 Many drugs incorporat-
ing BDZ core nucleus which extensively binds to plas-
ma and tissue proteins have been developed over the
past two decades and they became the most commonly
prescribed group of psychotherapeutic drugs world-
wide.9,10 After the discovery of benzodiazepine recep-
tors in the CNS and peripheral tissues11,12 many
attempts have also been made to correlate the molecu-
lar structure with the biological activity of these com-
pounds.13 In an attempt to prepare even more potent
drugs, the ability of BDZ analogues to adjoin with
another four- or five-membered ring has been investi-
gated.14–16 It has been reported that the introduction
of an additional five-membered heterocyclic ring to sev-
en-membered azepine nucleus tends to exert profound
influence in conferring novel biological activities in
these molecules.17 The attachment of a five-membered
ring often produces potent anti-HIV active com-
pounds.11–13 These compounds exert their biological
activity by covalently binding to the N-2 of guanine
in the minor groove of DNA through the imine or
equivalent functionality at N10–C11 of the BDZ. The
aminal linkage thus interferes with DNA function.18
Furthermore, these molecules have been shown to
interact with DNA in a sequence-selective manner as
a result they may have the potential to inactivate par-
ticular genes.19
Hence, in view of the variegated importance associated
with the five-membered phosphole ring system, we
decided to link up this moiety with the benzodiazepine
nucleus in order to frame the novel molecular architec-
ture of annulated heterophospholobenzodiazepines.
Keeping this in mind and in continuation of our endur-
ing research on the synthesis of biologically significant
compounds,20–25 we have attempted the synthesis of
hitherto unknown, 10-methyl-6-oxo-5-arylazo-6,7-dihydro-
5H-[1,3]azaphospholo[1,5-d][1,4]benzodiazepin-2-phos-
pha-3-ethoxycarbonyl-1-phosphorus dichlorides 11a–p
with fascinating structural features.
Keywords: 1,4-Benzodiazepine; Azaphohole; Intramolecular cyclocon-
densation; Antimicrobial activity; QSAR; Molecular refractive index
(MR).
*
Corresponding
drashoksharma2001@yahoo.com
author.
Tel.:
+91
731
2460208; e-mail:
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.01.080

A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2484–2491
2485
Moreover, to find a role of this nucleus against the prob-
lem of multidrug-resistant pathogens, the constructed
molecules were screened for their antimicrobial activity.
preparation of precursor, viz., chloroacetamidoacetoph-
enone26 3 as the representative of B-ring fragment. Sub-
sequently, this was allowed to reflux in ammonia/
methanol for 24 h, which leads to cyclization to give
5,7-dimethyl-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one
4 in an excellent yield (80%). Moreover, stereochemical
asymmetry at C11a of 5a–p was accessible by introduc-
ing a diazonium fragment in an electrophilic substitu-
tion mode which resulted in the formation of
Additionally, the systematic quantitative structure–ac-
tivity relationship (QSAR) studies have also been car-
ried out to reach a thorough understanding of the
effect of substituents on the observed activities of the
synthesized compounds.
compound
(3S)-3-arylazo-5,7-dimethyl-1,3-dihydro-
The synthetic route to the desired target molecule 10-
methyl-6-oxo-5-arylazo-6,7-dihydro-5H-[1,3]azaphos-
pholo[1,5-d][1,4]benzodiazepin-2-phospha-3-ethoxycar-
bonyl-1-phosphorus dichlorides 11a–p includes the
cyclization (3 ! 4) (Scheme 1) to generate the imine
moiety of the B-ring. The approach involves the initial
2H-1,4-benzodiazepin-2-one 5a–p.27 This in turn was al-
lowed to react with an equimolar quantity of a pertinent
alkyl halide in THF and stirred for 36 h at room temper-
ature to give the N-alkylated product 6a–p in good
yield.28
Condensation of 6a–p with phosphors trichloride
(2 equiv) in the presence of triethylamine (3 equiv.) in
toluene yielded intermediate synthesis of 5-bis(dic-
hlorophosphino)-ylidene-(3S)-N-ethoxycarbonyl-7-
methyl-3-arylazo-2-oxo-1,2,3,5-tetrahydro-5H-1,4-ben-
zodiazepine 9a–p.29 The initially formed mono
dichlorophosphino derivative 7a–p is highly activated
and undergoes instantaneous substitution by phosphorus
trichloride to provide the bis(dichlorophosphino) deriva-
tive 9a–p. Further, the absence of any 1H NMR signal at d
6.00 ppm, which is characteristic of a C-5 methine pro-
ton, also supports the formation of 9a–p. This was cyc-
lized to give 10a–p on heating with an additional
amount of triethylamine in acetonitrile (Scheme 2).
NH
2
H C
C O
3
2
CH
3
(i)
COCH Cl
NH
2
H C
3
C O
CH
3
(ii)
3
24 hr
The polarity of the solvent influences the progress of the
above reaction. In non-polar solvents such as toluene
and xylene, the reaction stops at stage 9a–p, whereas
in polar solvents, viz., acetonitrile, ethylacetate the ini-
tially formed bis(dichlorophosphino) derivative 9a–p
undergoes intramolecular cyclocondensation to form
species10a–p and finally 10-methyl-6-oxo-5-arylazo-6,
7-dihydro-5H-[1,3]azaphospholo[1,5-d][1,4]benzodiaze-
pin-2-phospha-3-ethoxycarbonyl-1-phosphorus dichlo-
rides 11a–p.30
H
N
O
CH
2
H C
N
3
CH
3
4
(iii)
H
N
O
C
R1
H
Structures of all the newly obtained compounds have
been ascertained on the basis of their consistent IR,
NMR and mass spectral assignments.31–34
N
N
H C
N
3
5a-p
CH3
The newly obtained derivatives were evaluated for
in vitro antibacterial activity against Escherichia coli
ATCC 6633, Bacillus subtilis ATCC 16404 and anti-
fungal activity against Aspergillus niger ATCC 16404
and Candida albicans ATCC 10231. Nutrient agar and
saboured dextrose agar were employed for bacterial
and fungal growth, respectively. Minimum inhibitory
concentrations (MIC) were determined by means of
standard 2-fold serial dilution method using agar med-
ia.35 Stock solutions of test compounds were prepared
in DMSO at a concentration of 1 mg/mL. Suspension
containing approximately 107 CFUs/mL of bacteria
and 106 CFUs/mL of fungi was prepared from broth
cultures. Bacterial and fungal plates were made in tripli-
cate and incubated at 37 °C for 16–47 h for bacteria and
48–72 h for fungi. Ampicillin trihydrate and clotrima-
zole were also screened under similar conditions as
(iv)
H
N
R1
O
H
C
+
N
N
N
H C
3
Cl
CH
R
2
CH
3
6a-p
Where R = COOC2H5
R1 = as reported in Table 1
Scheme 1. Reagents and conditions: (i) 1,4-di-oxan, ClCH2COCl, 3 N
NaOH, CH2Cl2, 30 min; (ii) NH3/CH3OH; (iii) RC6H4NH2, NaNO2/
HCl, 0–5 °C; (iv) ClCH2COOC2H5,THF, 36 h.

2486
A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2484–2491
6a-p
(v)
H
N
O
H
N
O
R1
H
R1
H
C
N+
N
N
C
N
N
N
H C
3
H C
3
CH R
CH R
2
2
CH
C
Cl P
2
Cl P
2
9a-p
PCl
2
7a-p
(vi)
(vi)
H
N
O
C
R1
H
N
O
H
R1
H
N
N
C
N
N
N
H C
3
R
N
H C
3
H
R
Cl P
PA
Cl
2
B
H
P
10a-p
8a-p
(vii)
H
N
O
R1
H
C
N
N
N
H C
3
R
Cl P
P
2
A
B
Where , R as shown in Scheme 1
R1 as reported in Table 2
11a-p
Scheme 2. Reagents and conditions: (v) CH2COOC2H5CH3, PCl3, Et3N, 4–6 h; (vi) CH3CN, PCl3, Et3N, 2–4 h, Et3NH+Clꢀ; (vii) PCl3, Et3N,
40 min.
reference drugs, respectively. The screening results re-
veal that reported compounds showed a remarkable
effect on the bactericidal potency. However, these com-
pounds have been found to show least to moderate
activity on the growth of C. albicans. The deduced
pattern followed by tested compounds is in the order
E. coli > B. subtilis > A. niger > C. albicans.
and LUMO energies were calculated by semiempirical
PM338 studies using MOPAC 6.0 package.38 Energy min-
imized geometry of the parent molecule 11a is shown in
Figure 1. The Hammett substituent constant (r) values
were obtained from the literature.39
A correlation analysis was performed on all the descrip-
tors, depending on the inter-correlation among the inde-
pendent descriptors and also their individual correlation
with biological activity. Different possible combinations
of parameters were subjected to multiple regression
analyses. Calculated parameters and correlation matrix
needed for regression analysis are elicited in Tables 2
and 3, respectively.
In order to identify substituent effect on the antimicrobial
activity, quantitative structure–activity relationship
(QSAR)36 studies of title compounds were preformed.
Biological activity data (MIC) were calibrated to their
logarithmic values (ꢀlogMIC) and are listed in Table 1.
The congener series possesses the substitution on the aro-
matic ring system at 30 and 40 positions. QSAR studies
were performed by multiple regression analysis (MRA)
approach. The calculated parameters used in present
studies include molar refractivity (MR), vander Waals
volume (VDW), Connolly accessible area (CAA),
Connolly molecular area (CMA), Connolly Solvent
Excluded Area (CSEV), and partition coefficient (logP).
These parameters were calculated by using Chem 3D 6.0
Software.37 Further, electronic parameters like HOMO
It has been observed that molar refractivity (MR) tends
to correlate with biological activity exclusively. The sta-
tistical quality of the resulting models, as depicted in
Eqs. 1–4, is determined by r (coefficient of correlation),
s (standard error of estimate) and F (F-statistics) values.
It is noteworthy that all these equations were derived
using entire data set of compounds (n = 16) and no out-
liers were identified.

A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2484–2491
2487
Table 1. The in vitro antimicrobial activity of substituted [1,3]azaphospholo-[1,5-d][1,4]benzodiazepin-3-ethoxycarbonyl-1-phosphorus dichlorides
Compound
R1
ꢀlogMIC (lg/mL)
Gram negative bacteria
Gram positive bacteria
Fungi
Escherichia coli
Bacillus subtilis
Aspergillus niger
Candida albicans
ATCC 445
ATCC 6633
ATCC 16404
ATCC 10231
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
A
H
4.05
4.22
4.36
4.58
4.54
4.74
4.73
4.30
4.26
4.39
4.11
5.04
4.88
4.17
4.20
4.61
4.60
—
4.05
4.25
4.37
4.64
4.46
4.83
4.55
4.28
4.29
4.41
4.17
4.96
4.68
4.22
4.22
4.52
4.61
—
4.12
4.31
4.48
4.64
4.68
4.74
4.56
4.56
4.39
4.51
4.18
4.89
4.82
4.22
4.25
4.45
—
4.10
4.17
4.32
4.52
4.47
4.59
4.50
4.39
4.24
4.36
4.06
4.78
4.61
4.09
4.11
4.32
—
3-CH3
3-COOH
4-C2H5
3-Cl
4-OC2H5
3-NO2
3-OCH3
4-OCH3
4-Cl
4-OH
3-OC2H5
3-C2H5
4-CH3
3-OH
4-NO2
—
C
—
3.23
3.13
A, ampicillin; C, clotrimazole.
QSAR model for activity against A. niger
ꢀ log BA ¼ 4:04209ðꢁ0:148464Þꢂ
þ MR½0:630564ðꢁ0:191937Þꢂ
n ¼ 16; r ¼ 0:884; s ¼ 0:112; F ¼ 50:355 ð3Þ
QSAR model for activity against C. albicans
ꢀ log BA ¼ ½3:94185ðꢁ0:141714Þꢂ
þ MR½0:580462ðꢁ0:18321Þꢂ
n ¼ 16; r ¼ 0:877; s ¼ 0:106; F ¼ 46:833 ð4Þ
The F-value obtained in Eqs. 1–4 is found statistically
significant at 99% level since all the calculated F values
are higher as compared to tabulated values. Similarly,
cross validation of the obtained equations was subse-
quently checked by employing the leave-one-out
(LOO) method40 and on the basis of related cross-vali-
dation parameters viz. PRESS (predicted residual sum
of squares), SPRESS (uncertainty of prediction), SDEP
(standard error of prediction), r2CV (cross-validated cor-
relation coefficient) and r2bsp (bootstrapping r2). The cal-
culated and predicted activities of the synthesized
compounds were in good accordance with the observed
activities as shown in Figures 2 and 3.
Figure 1. The ORTEP drawing (PM3 optimized geometry) of 10-
methyl-6-oxo-5-phenylazo-6,7-dihydro-5H-[1,3]azaphospholo[1,5-d]-
[1,4]benzodiazepin-2-phospha-3-ethoxycarbonyl-1-phosphorus dichlo-
ride 11a with atom numbering.
QSAR model for activity against E. coli
ꢀ log BA ¼½3:91423ðꢁ0:217073Þꢂ
PRESS is a good estimate of the real prediction error
of the model. Its value less than SSY indicate that
the proposed model has good predictive power. Thus,
in view of this, all the four models proposed by us
(Eqs. 1–4) are statistically significant. Further, to be
a reasonable QSAR model, PRESS/SSY ratio should
be lesser than 0.4. The data presented in Table 4 indi-
cate that for all the four proposed models this ratio is
<0.38 there by suggesting all of them to be good mod-
els. Moreover, the values of bootstrapping r2 are
þ MR½0:756708ðꢁ0:280636Þꢂ
n ¼ 16; r ¼ 0:841; s ¼ 0:163; F ¼ 33:921 ð1Þ
QSAR model for activity against B. subtilis
ꢀ log BA ¼ ½3:93497ðꢁ0:143867Þꢂ
þ MR½0:702574ðꢁ0:185994Þꢂ
n ¼ 16; r ¼ 0:908; s ¼ 0:108; F ¼ 66:572 ð2Þ

2488
A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2484–2491
Table 2. Physicochemical parameters data for the compounds 11a–p
Compound
HOMO
LUMO
VDW
r
logP
2.868
CSEV
CMA
CAA
MR
11a
11b
11c
11d
11e
11f
11g
11h
11i
ꢀ9.238
ꢀ9.237
ꢀ9.408
ꢀ9.234
ꢀ9.266
ꢀ9.292
ꢀ11.256
ꢀ9.263
ꢀ9.205
ꢀ9.292
ꢀ9.228
ꢀ9.275
ꢀ9.243
ꢀ9.228
ꢀ9.284
ꢀ11.095
ꢀ1.223
ꢀ1.118
ꢀ1.225
ꢀ1.148
ꢀ1.273
ꢀ0.873
ꢀ5.006
ꢀ1.243
ꢀ1.203
ꢀ1.271
ꢀ1.215
ꢀ1.177
ꢀ1.154
ꢀ1.110
ꢀ1.260
ꢀ4.870
12.468
12.485
11.219
11.219
11.860
11.219
10.009
15.086
13.366
12.468
11.219
11.219
11.219
11.219
11.219
16.520
0
379.232
404.848
393.415
417.372
398.187
424.025
254.775
403.284
401.887
393.397
393.415
382.741
415.268
404.503
379.232
392.361
413.253
433.343
427.675
447.339
423.807
458.399
306.438
439.247
439.183
427.66
722.538
743.104
745.492
769.975
730.163
794.785
578.755
753.337
753.337
745.483
745.492
731.697
743.104
740.377
722.538
744.605
0.103
0.565
0.693
1.030
0.603
1.247
0.736
0.787
0.787
0.603
0.285
1.247
1.03
ꢀ0.07
0.37
6.090
2.867
2.867
3.152
2.867
ꢀ0.234
3.152
3.152
2.868
2.868
2.867
2.867
2.868
2.868
ꢀ0.423
ꢀ0.15
0.37
ꢀ0.24
0.71
0.12
ꢀ0.27
0.23
11j
11k
11l
ꢀ0.37
0.1
427.675
418.023
446.336
433.523
413.253
426.51
11m
11n
11o
11p
ꢀ0.07
ꢀ0.17
0.12
0.565
0.285
0.736
0.78
Table 3. Correlation matrix of molecular descriptors calculated for 11a–p
EC
BS
AN
CA
HOMO
LUMO
VDW
r
LOGP
CSEV
CMA
CAA
MR
EC
BS
1
0.962
0.921
0.946
0.309
0.271
0.174
0.303
0.352
0.138
0.123
0.130
0.841
1
AN
CA
0.915
0.938
0.174
0.126
0.204
0.147
0.244
0.013
0.033
0.055
0.909
1
0.980
0.049
0.012
0.13
1
HOMO
LUMO
VDW
r
logP
CSEV
CMA
CAA
MR
0.126
0.087
0.168
0.211
0.201
0.049
0.031
0.032
0.877
1
0.995
0.226
0.790
0.835
0.707
0.696
0.661
0.044
1
0.268
0.787
0.834
0.704
0.695
0.667
0.005
1
0.179
0.126
0.066
0.081
0.065
0.885
0.274
0.158
0.284
0.302
0.312
0.065
1
0.658
0.581
0.595
0.570
0.026
1
0.570
0.546
0.502
0.090
1
0.996
0.975
0.181
1
0.985
0.216
1
0.221
1
4.8
4.7
4.6
4.5
4.4
4.3
4.2
4.1
4.8
4.7
4.6
4.5
4.4
4.3
4.2
4.1
4.0
3.9
4.0
3.9
4.0
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.0
4.1
4.2
4.3
4.4
4.5
4.6
4.7
CALCULATED
PREDICTED
Figure 2. Plots of observed versus calculated and observed versus predicted activity of compounds 11a–p screened against Escherichia coli (Eq. 1).
further in support of the predictive power of these
explaining models (Eqs. 1–4).
to steric interaction in polar spaces. All the synthesized
compounds bearing substituents 30-NO2, 30-Cl and 30-
OH have been found to be more active than 40-NO2,
40-Cl, indicating that compounds having electron-at-
tracting groups on the para position of the ring decrease
the activity, whereas, if they are present on the meta
Biological activity was found to have a good correlation
with molar refractivity (MR). The positive contribution
of molar refractivity towards the activity is possible due

A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2484–2491
2489
5.0
4.9
4.8
4.7
4.6
4.5
4.4
4.3
4.2
4.1
4.9
4.8
4.7
4.6
4.5
4.4
4.3
4.2
4.1
4.0
4.0
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
5.0
CALCULATED
PREDICTED
Figure 3. Plots of observed versus calculated and observed versus predicted activity of compounds 11a–p screened against Aspergillus niger (Eq. 3).
Table 4. Cross-validation parameters
Equation
Compound
PRESS
SSY
PRESS/SSY
SPRESS
SDEP
r2bsp
Eq. 1
Eq. 2
Eq. 3
Eq. 4
16
16
16
16
0.273
0.208
0.214
0.206
0.909
0.785
0.632
0.535
0.300
0.264
0.338
0.385
0.184
0.122
0.124
0.121
0.172
0.114
0.116
0.113
0.700
0.814
0.765
0.768
4. Sternbach, L. H. J. Med. Chem. 1961, 26, 4936.
position they tend to increase the activity to a greater
extent. In general, it has been concluded that the antimi-
crobial results follow the pattern:
5. Bock, M. G.; Di Pardo, R. M.; Evans, B. E.; Rittle, K. E.;
Whitter, W. L.; Veber, D. F.; Anderson, P. S.; Friedinger,
R. M. J. Med. Chem. 1989, 32, 13.
6. Hester, J. B.; Ludens, J. H. D.; Emmest, D. E.; West, B. E.
J. Med. Chem. 1989, 32, 1157.
7. Hester, J. B.; Rudzik, A. D.; Von Voigtlander, P. F. J.
Med. Chem. 1980, 44, 842.
11l > 11m > 11g > 11e > 11h > 11c > 11b > 11o > 11a >
11f > 11d > 11p > 11j > 11i > 11n > 11k
Thus, we have successfully constructed a tricyclic het-
erocyclic system comprising of benzodiazepine and het-
erophosphole nuclei in an unprecedented manner. All
the synthesized compounds have shown the remarkable
in vitro inhibitory activity on the growth of tested bac-
terial and fungal strains. Further, the QSAR studies
using the conventional Hansch approach have revealed
that the antimicrobial activity exhibited by these mole-
cules is mainly governed by the polarizability parameter,
that is, MR. Since molar refractive index represents the
influence of size and polarity of the group, the com-
pounds with different substituent in the newly generated
nucleus will be designed, synthesized and will subse-
quently be tested for their potential as antimicrobial
agents.
8. Roma, G.; Grossi, G. C.; Di Braccio, M.; Mattioli, F. Eur.
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References and notes
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2. Sharp, J. T.. In Katrizky, A. R., Rus, C. W., Wowski, W.
L, Eds.; Comprehensive Heterocyclic Chemistry; Perg-
amon: New York, 1984; Vol. 7, p 593.
17. Roberte, B. A.; Andries, K.; Desayter, J. S.; Kukla, D.;
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R.; Janseen, J. K.; Clerq, M. A.; De, E.; Janseen, P.
Nature 1990, 343, 470.
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Res. 1986, 19, 230.
3. Mohiuddin, G.; Reddy, P. S. N.; Kamal, A.; Ratnam, C.
V. Heterocycles 1986, 24, 3489.
19. Thurston, D. E.; Morris, S. J.; Hartley, J. A. J. Chem.
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dron 2005, 61, 4237.
21. Sharma, P.; Kumar, A.; Sharma, S.; Rane, N. Bioorg.
Med. Chem. Lett. 2005, 5, 937.
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residue was concentrated to 25 mL and left in refrigerator
overnight, when yellow to reddish yellow coloured solid was
deposited which was filtered and dried in vacuum.
30. General procedure for the synthesis of 10-methyl-6-oxo-5-
arylazo-6,7-dihydro-5H-[1,3]azaphospholo[1,5-d][1,4]ben-
zodiazepin-2-phospha-3-ethoxycarbonyl-1-phosphorus
dichlorides (11a–p): To 5-bis(dichlorophosphino)-ylidene-
(3S)-N-ethoxycarbonyl-7-methyl-3-arylazo-2-oxo-1,2,3,5-
tetrahydro-5H-1,4-benzodiazepine (0.01 M), which was
cooled to 0–5 °C under stirring acetonitrile (40 mL) was
added. To this a solution of triethylamine (4.04 g, 0.04 M)
was also added slowly to the reaction mixture till the
development of yellow colour. After stirring for 30 min a
solution of PCl3 (1.37 g, 0.01 M) was added drop wise till
the reaction mixture turns pale yellow to brown. The
reaction mixture was allowed to attain the room temper-
ature and stirring was continued for 10 h. Now the solvent
was evaporated in vacuum and the white shiny crystals of
11a–p were obtained.
26. Sternbach, L. H.; Reeder, E. J. Org. Chem. 1961, 26, 4936.
27. Experimental: Analytical grade chemicals and solvents
were always employed. Solvents were distilled under
nitrogen atmosphere prior to use. Standard syringe and
separation techniques were used for transferring the
reactants and the product mixture. All reactions were
carried out under nitrogen atmosphere. The product
mixtures were analyzed by thin-layer chromatography
(TLC) on silica gel sheets (Merck silica gel-G). IR spectra
(in cmꢀ1) were recorded on Perkin Elmer 377 spectropho-
31. Analytical data of compound 5b: mp 151–152 (°C), yield
72%; IR KBr (m cmꢀ1) 3350 (N–H), 3050 (C–H, sp2), 2850
(C–H, sp3), 2020 (N@N), 1710 (C@O), 1620 (C@C/C@N),
1
tometer. H NMR and 31P NMR spectra were recorded
1580, 1490, 1450 (
, ring str), 920, 850, 740 (sub
……
C
C
on JEOL EX400 and on Bruker DRX 300 MHz spec-
trometers, respectively in DMSO-d6 or CDCl3 chemical
phenyl), 1H NMR (d) ppm 0.92 (s, 3H, CH3, azepine ring),
1.11 (q, 2H, –CH2CH3), 2.35 (s, 3H, CH3-u), 2.52 (s, CH,
azepine ring), 3.41 (t, 3H, –CH2CH3), 3.82 (s, 2H, CH2–
N), 7.12 (d, H8), 7.25 (s, H6), 7.42 (d, H9), 7.59 (s, 5H,
C6H5), 8.20 (s, NH), MS (FAB): M+H+ peak at m/z 305.
Elemental analyses, found (calcd) (%) C, 70.57 (70.66); H,
5.92 (6.05); N, 18.29 (18.32).
1
shifts are given in d ppm using TMS (for H NMR) as an
internal standard and 85% H3PO4 (for 31P NMR) as an
external standard. Mass spectral analysis was performed
using FAB technique. General procedure for the synthesis
of (3S)-3-arylazo-5,7-dimethyl-1,3-dihydro-2H-1, 4-ben-
zodiazepin-2-one (5a–p): To a stirred, cooled (10 °C)
solution of 0.1 M of the 2-aminoacetophenone in 40 mL
of 1,4-dioxan, 0.13 M of chloroacetylchloride and an
equivalent amount of 3 N sodium hydroxide solution was
added in small portions. The reactants were introduced
alternatively at such a rate as to keep the temperature
below 10 °C and the mixture neutral or slightly alkaline.
The reaction was completed after 30 min. The neutral
mixture was diluted with ice and water, and extracted with
methylene chloride. The extract was washed with water,
filtered, dried concentrated in vacuum, and the residue
crystallized. Thus, obtained chloroacetamidoacetophe-
none 2 (0.01 M) in 200 mL of a 20% (w/v) solution of
ammonia in methanol was stirred for 24 h at room
temperature. The methanolic ammonia filtrate obtained
after the separation of 3 was concentrated to dryness in
vacuum, and residue recrystallized to give cyclized ben-
zodiazepin-2-one nucleus 4, which was further, allowed to
react with benzene diazonium chloride (0.01 M) under
thorough stirring for 3–4 h to obtain 5a–p.
32. Analytical data of compound 6a: mp 162–163 (°C), yield
78%;IR KBr (m cmꢀ1) 3350 (N–H), 3050 (C–H, sp2), 2850
(C–H, sp3), 2020 (N@N), 1710 (C@O), 1620 (C@C/C@N),
……
1580, 1490, 1450 (
, ring str), 920, 850, 740 (sub
C
C
phenyl), 1H NMR (d) ppm 1.05 (s, 3H, CH3, azepine ring),
1.21 (q, 2H, –CH2CH3), 2.25 (s, 3H, CH3-u), 2.63 (s, CH,
azepine ring), 3.30 (t, 3H, –CH2CH3), 3.94 (s, 2H, CH2–
N), 7.09 (d, H8), 7.30 (s, H6), 7.46 (d, H9), 7.75 (s, 5H,
C6H5), 8.05 (s, NH), MS (FAB): M+H+ peak at m/z 290.
Elemental analyses, found (calcd) (%) C, 66.47 (66.59); H,
6.11 (6.18); N, 14.77 (14.85).
33. Analytical data of compound 9a: mp (°C) 146–147, yield
68%; IR KBr (m cmꢀ1) 3330 (N–H), 3050 (C–H, sp2), 2840
(C–H, sp3), 1980 (N@N), 1710 (C@O), 1630 (C@C/C@N),
……
1580, 1490, 1470 (
, ring str), 1430 (C–P), 930, 820,
C
C
1
710 (sub. phenyl), 570 (P–Cl), H NMR (d) ppm 1.12 (t,
3H, –CH2CH3), 2.25 (s, 3H, CH3-u), 3.40 (s, CH, azepine
ring), 4.05 (s, 2H, CH2–N), 4.60 (q, 2H, –CH2CH3), 6.85
(d, H8), 7.20 (s, 4H, C6H4), 7.30 (d, H6), 7.60 (d, H9), 9.5
(s, NH), 31P NMR 145.6 (dPA), MS (FAB): M+H+ peak at
m/z 595. Elemental analyses, found (calcd) (%) C, 57.01
(57.13); H, 5.47 (5.51); N, 12.66 (12.78).
28. General procedure for the synthesis of N-ethoxycarbonyl-
5,7-dimethyl-2-oxo-3-arylazo-2,3-dihydro-1H-1,4-benzo-
diazepinium chlorides (6a–p): In a 250 mL round bottom
flask to a solution of alkyl halide (0.1 M) in tetrahydrofu-
ron (50 mL), (3S)-3-arylazo-5,7-dimethyl-1,3-dihydro-2H-
1,4-benzodiazepin-2-one 5a–p (0.01 M) was added and
reaction mixture was stirred for 24–48 h at room temper-
ature. The white precipitate obtained was filtered, washed
with diethyl ether (30 mL), dried in vacuum and were used
without further purification.
29. General procedure for the synthesis of 5-bis(dic-
hlorophosphino)-ylidene-(3S)-N-ethoxycarbonyl-7-meth-
yl-3-arylazo-2-oxo-1,2,3,5-tetrahydro-5H-1,4-benzodiaze-
pine (9a–p): In a closed vessel containing compound 6a–p
(0.01 M) in 40 mL toluene, triethylamine (2.02 mL) was
added at room temperature and the reaction mixture was
stirred for 1–2 h. To this mixture a solution of PCl3 (1.37 g,
0.01 M) was added slowly and allowed to stir further for
24 h. The solvent was thereafter removed in vacuum and
34. (a) Analytical data of compound 11a: mp (°C) 256–257,
yield 72%; IR KBr (m cmꢀ1) 3274 (N–H), 3010 (C–H, sp2),
2118 (C–Hasym, sp3), 2852 (C–Hsym, sp3), 1735 (C–O,
ester), 1710 (C@O), 1555 (N@N), 1500, 1464, 1377
……
(
, ring str), 1308 (C–P), 722, 700 (sub phenyl), 550
C
C
(P–Cl),1H NMR (d) ppm 1.42 (t, 3H, CH3), 2.30 (s, 3H,
CH3-u), 4.76 (q, 2H, CH2), 7.33 (m, 3H, Ar-H), 7.49 (s,
5H, C6H5), 9.50 (s, NH), 31P NMR 36.5 (dPA) 166.7 (dPB),
MS (FAB): M+H+ peak at m/z 506. Elemental analyses,
found (calcd) (%) C, 49.72 (49.85); H, 3.58 (3.60); N, 11.05
(11.13).; (b) Analytical data of compound 11b: mp (°C)
232–233, yield 82%; IR KBr (m cmꢀ1) 3250 (N–H), 3040
(C–H, sp2), 2920, (C–Hasym, sp3), 2852 (C–Hsym, sp3), 1735
……
(C@O), 1620 (C@C/C@N), 1600, 1466, 1376 (
, ring
C
C
str), 1540 (N@N), 1118 (C–P), 909, 736 (sub phenyl), 649
(P–Cl), 1H NMR (d) ppm 1.12 (t, 3H, –CH2CH3), 2.15 (s,
3H, CH3-u), 3.15 (s, CH, azepine ring), 4.36 (q, 2H,

A. Kumar et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2484–2491
2491
–CH2CH3), 6.90 (d, 1H, H8), 7.35 (s, 5H, C6H5), 7.65 (d,
H6), 7.95 (s, H9), 9.51 (s, NH), 31P NMR 41.3 (dPA) 173.8
(dPB), MS (FAB): M+H+ peak at m/z 520. Elemental
analyses, found (calcd) (%) C, 50.69 (50.72); H, 3.87 (3.96);
N, 10.75 (10.88).
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39. Hansch, C.; Leo, A.; Hoekman, D. In Exploring QSAR:
Hydrophobic, Electronic and Steric Constants; ACS:
Washington, DC, 1995.
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