An efficient one-pot synthesis, structure, antimicrobial and antioxidant investigations of some novel quinolyldibenzo[b,e][1,4]diazepinones

Article abstract of DOI:10.1016/j.bmcl.2012.03.100

A highly improved one-pot procedure for the synthesis of diazepinones, which incorporate a bioactive quinoline nucleus, under catalyst-, and solvent-free environment has been developed. The method allowed us to achieve the products in high yields without requiring a chromatographic separation. All new quinolyldibenzo[b,e][1,4]diazepinones 6a-h thus obtained were further treated to achieve N10-allylated products 7a-h by a simple allylation. The structure of all new synthesized compounds was established based on elemental analysis, mass, ¹H NMR, ¹³C NMR, IR spectral data, 2D NMR experiments, and single crystal X-ray study. From in vitro antimicrobial activity studies it revealed all are active against Gram positive (Streptococcus pneumoniae, Clostridium tetani, and Bacillus subtilis), Gram negative (Salmonella typhi, Vibrio chlolerae and Escherichia coli), M. Tuberculosis H37RV bacteria, and fungus like Candia albicans and Aspergillus fumigatus. All were also found to display good antioxidant activity of a ferric reducing power.

Full text of DOI:10.1016/j.bmcl.2012.03.100

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3816–3821
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An efficient one-pot synthesis, structure, antimicrobial and antioxidant
investigations of some novel quinolyldibenzo[b,e][1,4]diazepinones
Narsidas J. Parmar a, , Hitesh A. Barad a, Bhavesh R. Pansuriya a, Shashikant B. Teraiya a,
⇑
Vivek K. Gupta b, Rajni Kant b
a Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar-388120, Dist. Anand, Gujarat, India
b Post Graduate Department of Physics, University of Jammu, Jammu Tawi-180006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly improved one-pot procedure for the synthesis of diazepinones, which incorporate a bioactive
quinoline nucleus, under catalyst-, and solvent-free environment has been developed. The method
allowed us to achieve the products in high yields without requiring a chromatographic separation. All
new quinolyldibenzo[b,e][1,4]diazepinones 6a–h thus obtained were further treated to achieve N10–ally-
lated products 7a–h by a simple allylation. The structure of all new synthesized compounds was estab-
lished based on elemental analysis, mass, 1H NMR, 13C NMR, IR spectral data, 2D NMR experiments, and
single crystal X-ray study. From in vitro antimicrobial activity studies it revealed all are active against
Gram positive (Streptococcus pneumoniae, Clostridium tetani, and Bacillus subtilis), Gram negative (Salmo-
nella typhi, Vibrio chlolerae and Escherichia coli), M. Tuberculosis H37RV bacteria, and fungus like Candia
albicans and Aspergillus fumigatus. All were also found to display good antioxidant activity of a ferric
reducing power.
Received 3 February 2012
Revised 26 March 2012
Accepted 28 March 2012
Available online 13 April 2012
Keywords:
1,4-Diazepines
Solvent-free method
Antimicrobial agents
Quinoline derivatives
Antitubercular agents
Ó 2012 Elsevier Ltd. All rights reserved.
1,4-Diazepines continue to receive an overwhelming impor-
tance in medicinal chemistry due to their promising and potential
pharmaceutical properties.1 Examples include chlorodiazepoxide
and diazepam in the treatment of anxiety,2 clozapines from the
piperidinyldibenzodiazepine family in schizophrenia, as well as
the muscarinic receptor (M1) antagonist pirenzepines, and the
platelet activating factor inhibitor apafant.3 After their entry as a
tranquilizer in 1970’s, there has been increasing therapeutic use
and demand of class of these compounds, which broadened their
scope such as sedative, hypnotic, muscular relaxant and anticon-
vulsant. Moreover, as antipsychotic drugs4a,b in the treatment of
schizophrenia, and possessing antianaphylactic activity,4c these
compounds have attracted interest of many researchers. According
to the criterion of pharmacological value, tricyclic systems incor-
eton would generate a novel molecular template which likely to
exhibit interesting properties. Both benzodiazepine and quinoline
units have promising pharmaceutical properties. Diazepine sub-
structure has been evaluated as antioxidants and lipid peroxida-
tion inhibitors in vitro.8 In the same way, quinoline as
antioxidant, anti-inflammatory and anticancer activities, as a key
structure feature.9,10 The presence of 3,4-double bond and 2-oxo
functionality in quinolone is known to exhibit hydroxyl radical
scavenging properties.10a For example, rebamipide is an effective
antioxidant and antiulcer agent.10b Therefore, we planned the syn-
thesis and biological investigations of quinolyldiazepines, which is
not only desirable but may open interesting new area in medicinal
research. Furthermore, an alkylation in general, and allylation in
particular, at benzodiazepine nitrogen reported to improve the
affinity towards the cholecystokinin (CCK2) receptor that is in-
volved in many pathological situations.11 Those, which include
anxiety12a and panic12b particularly are relevant targets to thera-
peutic interventions.
Various routes have been intentional for the synthesis of class of
these compounds.6,13 Common one is a cyclization of an enami-
none derived from diketones and o-phenylenediamine, with an
aldehyde. Raboisson et al. and Eduardo et al. used a two-step pro-
cedure wherein, an enaminone formed in the first step undergoes
cyclization with an aldehyde in the presence of acetic acid under
ethanol reflux.6a,b Formation of intermediate Michael adduct from
aldehyde and diketone, and its subsequent reaction with diamines
porating
a 1,4-diazepine unit into their structure is a key
derivative.5
Acid catalyzed cyclization of an enaminone with an aldehyde is
a key step to afford these heterocycles. Various aldehydes such as
benzaldehyde, 2,3,4-pyridinecarbaldehydes, and 2-thiophene car-
baldehydes have been employed.6 To the best of our knowledge
however; there is no report on quinoline-3-carbaldehydes. Incor-
poration of this biologically potential unit7 into the diazepine skel-
⇑
Corresponding author. Tel.: +91 2692 226858; fax: +91 2692 236475.
E-mail address: njpchemdeptspu@yahoo.co.in (N.J. Parmar).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.03.100

N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3816–3821
3817
Table 1
is another way to assess these compounds, well studied by Orlov
Optimization of the reaction conditions
et al. A rarely existing route so far is the in situ cyclization of
enaminone with aldehyde.6c This approach however, suffers from
a longer reaction time, usage of excess organic solvents, and lower
yields. Even, an enaminone sometime requires a chromatographic
separation.6f So, it would be much more efficient and green ap-
proach, if one could design a new synthetic approach which elim-
inate an intermediate isolation step, and the use of solvents, and of
course taking less reaction time.
Keeping in mind so-called synthetic and biological, we report
here more efficient solvent- and catalyst-free method for the syn-
thesis of new quinolyldibenzodiazepinones. Besides affording new
biologically active scaffolds, this new approach also promised
advantages like less reaction time, no isolation step, no chromato-
graphic separation, and no use of toxic solvent.
Entry
Solvent
Catalyst
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
Ethanol
Ethanol
None
None
None
AcOH
AcOH
—
—
—
Reflux
Refluxa
50a
80
100
14
4b
4b
10
6
62
75
—
55
69
90
None
—
120
2.5
a
Microwave irradiation.
Time in minute.
b
and second one at d 1.14 assigned to methyl protons attached to
C-3. A singlet appeared at d 2.20 was consistent with C-2 methy-
lene protons. A C-4 methylene protons gave two doublet signals;
one at d 2.58 (J = 16.0 Hz) and second one at d 2.76 (J = 16.0 Hz).
In present work, we describe a catalyst-, and solvent-free
procedure for one-pot synthesis of novel N1-allylated quin-
olyldibenzo[b,e][1,4]diazepin-1-ones from qunoline-3-carbaldehy-
des, 1,3-cyclohexadione and o-phenylenediamine. The method14 is
simple and highly efficient one.
A
doublet that appeared at d 5.56 with coupling constant,
J = 5.2 Hz, is assigned to N-10 proton. In the allylated product 7a,
its disappearance showed that N-10 nitrogen is involved in the
allylation. Another doublet that appeared at
d 5.76 with
Quinolines 2a–d, obtained by Vilsmeier–Haack reaction,15
when treated with AcOH16 or HCl17 followed by allylation16–18 they
gave corresponding quinolones 3a–d as shown in Scheme 1.
In our first attempt, we examined an acetic acid catalyzed reac-
tion taking a mixture of an equimolar o-phenylenediamine 4, 1,3-
cyclohexadione 5a and quinolone aldehyde 3a in refluxing ethanol
for 14 h to effect dibenzodiazepine 6a. However, it gave no good
yield (Table 1, entry 1). Instead, it proceeded via different possibil-
ities as confirmed by TLC. Next, we tested the reaction in absence
and presence of ethanol under microwave irradiation. Again, there
was no improvement in the yield of 6a (Table 1, entries 2, 3). Final-
ly, we employed a solvent-free thermally induced reaction. Ini-
tially, we could not succeed but upon increasing temperature
with an increment of 20 °C, raising it up to 100 °C, we found a very
low yield due to incomplete reaction (Table 1, entries 4–5). But ris-
ing to 120 °C, surprisingly, we got desired product 6a in 90% yield
with an excellent purity. There was no chromatographic separation
needed to purify the product. Simply upon washing the crude reac-
tion mass by ethanol, we could get almost pure products. Further
increase in the temperature could not improve the yield. Thus,
other products were prepared by this same optimal condition.
Accordingly, we have synthesized a series of compounds 6a–h19
(Scheme 2, Table 2).
J = 5.6 Hz, is due to C-11 methine proton. N-5 proton gave a singlet
at d 8.93. Methyl protons at C-3 in 7a resonate as a two singlet; one
at d 1.10 and second at d 1.12. A C-11 methine proton gave singlet
at d 5.88. A singlet that appeared at d 8.88 is due to N-5 proton.
The stereochemistry of the compounds were confirmed by 2D
NMR experiments; COSY (double quantum filtered correlation
spectroscopy) and NOESY (nuclear Overhauser effect spectroscopy)
of representative 6a (Fig. 1) and a single crystal X-ray data22 of rep-
resentative 7c (Figs. 2 and 3). The data are fully agreed with their
proposed structures.
All new mono 6a–h, and diallylated 7a–h quinolyldibenzo
[b,e][1,4]diazepin-1-ones were screened in vitro for their antibac-
terial and antifungal activity by the macro-broth dilution as-
say.23,24 Table 4 summarizes the test results.
Ampicillin, norfloxacin, chloramphenicol, ciprofloxacin, griseo-
fulvin and nystatin were used as standard reference drugs to com-
pare the present tests results. Besides, we have determined ferric-
reducing antioxidant power (FRAP) and antitubercular activity of
the compounds employing Benzie and Strain’s modified method25
and L.J. Medium respectively. FRAP values are expressed as ascor-
bic acid equivalent (mmol/100 g) (Table 5). Percent growth inhibi-
tion of M. Tuberculosis H37RV bacteria was measured by a test
solution containing 250
(Table 5).
lg/mL of respective compounds in DMSO
Allylated products 7a–h were obtained by allylating com-
pounds 6a–h with allyl bromide in DMF in the presence of K2CO3
for 12 h (Table 3). Out of three possibilities of allylation i.e. either
at N-5 and/or N-10 positions, a close examination of spectroscopic
data showed that an allylation took place at N-10. The same was
also supported by a literature.13c,20 Thus, the present method
exclusively give a single allylated product.
From antimicrobial test results, it follows that compounds are
active against Gram-positive (Clostridium tetani and Bacillus subtil-
is) bacteria, and fungi Candia albicans, with their MICs values close
to reference drug ampicillin (100
lg/mL), and an antifungal drug
griseofulvin (500 g/mL) respectively. While compounds 6c, 6h
l
and 7d are relatively more potent than ampicillin against Cl. tetani,
others 6a, 6b, 6d, 6e, 7e, 7g, and 7h have similar effect against
these bacteria. However, majority of compounds are active against
B. subtilis. It includes 6a, 6b, 6d, 6e, and 7e. Though the results are
not so impressive against Streptococcus pneumonia, there exist only
Structures of the compounds; 6a–h and 7a–h, were established
by spectral data (1H NMR, 13C NMR, DEPT-135, IR and mass spec-
trometry) that are summarized in the experimental section.21 1
H
NMR of 6a showed two signals (2 Â 3H); one singlet at d 1.12
R2
R2
R1
CHO
O
R2
CHO
Cl
(i)
(ii)
(iii)
R1
NHCOCH3
R1
N
2a-d
2
N
3a-d
1a-d
1
2
1
1
2
1
2
1a
1b
1c
1d
, R =Cl, R =H; , R =Me, R =H; , R ,R = H; , R =H, R =Me
Scheme 1. Reagents and conditions: (i) DMF, POCl3, 75–80 °C, 8 h; (ii) aq AcOH, reflux, 4 h; (iii) allyl bromide, K2CO3, DMF, 12h, room temperature.

3818
N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3816–3821
R1
O
N
R2
R1
CHO
O
R2
O
NH2
NH2
(i)
H
N
O
N
R
HO
R
N
H
5a,b
4
R
3a-d
R
5a
: R = CH3
5b
: R = H
6a-h
(ii)
R1
N
R2
O
N
O
N
H
R
R
7a-h
Scheme 2. Reagents and conditions: (i) 120 °C, 2.5–3.0 h; (ii) allyl bromide, K2CO3, DMF, 12 h, room temperature.
Table 2
Cl
Synthesis of dibenzodiazepinones 6a–h
Product
R
R1
R2
Time (h)
Yield (%)
Mpa (°C)
6a
6b
6c
6d
6e
6f
Me
H
Me
H
Me
H
Me
H
Cl
Cl
H
H
H
H
H
H
H
Me
Me
2.5
2.7
2.6
2.8
2.6
3.0
2.5
3.0
90
90
83
88
80
80
92
75
270–272
276–278
214–215
173–175
175–177
274–276
175–177
270–273
N
H
H
O
H
H
O
H
Me
Me
H
N
H
6g
6h
H
N
H
a
H
Uncorrected.
H
Figure 1. Characteristic NOE’s of 6a.
Table 3
Synthesis of N10-allylated dibenzodiazepinones 7a–h
Product
R
R1
R2
Yield (%)
Mpa (°C)
7c, and 7f more active against C. albicans. MICs of others 6c, 6b, 6d,
7d, 6e and 7e, were observed in the same range. As shown in Ta-
ble 4, none of the compounds except 6f and 7b have inhibitory ef-
fect against E. coli. However, compounds 7b and 6f with a MIC
7a
7b
7c
7d
7e
7f
Me
H
Me
H
Me
H
Me
H
Cl
Cl
H
H
H
H
H
H
H
Me
Me
95
92
93
90
91
87
90
92
150–152
118–121
192–194
151–153
160–163
140–142
148–150
156–158
H
value 62.5
exhibited by a standard drug ampicillin. While compound 7d hav-
ing an MIC of 100 g/mL, was active against Gram positive bacteria
B. subtilis, compound 6h with MIC of 100 g/mL was relatively ac-
tive against Gram positive bacteria C. tetani compared to ampicil-
lin. Similarly compounds 6g and 7h (MIC-200 g/mL) showed
good activity against Gram positive bacteria B. subtilis. Compounds
6c and 7d (MIC-200 g/mL) remained excellent against C. tetani.
Also compounds 7b, 7d, 6f, 6g, 7g and 7h (MIC-250 g/mL) showed
an excellent activity against fungal pathogen C. albicans as com-
pared to griseofulvin. The MIC of 6d (200 g/mL) against Vibrio
lg/mL showed a good activity which is very near to that
Me
Me
H
7g
7h
l
H
l
a
Uncorrected.
l
l
7d which is more potent against all three Gram-positive bacteria.
Similarly, 6f has good activity against all three Gram-negative bac-
teria with a lower MIC particularly in case of Escherichia coli,
against which MICs of 7b and 6f were recorded less than standard
while similar in case of others 7b and 7g. From the antifungal test
results, it revealed that a major span of compounds is active
against fungi particularly C. albicans. Surprisingly, none of the com-
pounds found active against Aspergillus fumigatus. Comparison of
these results with a standard drug griseofulvin makes compounds
l
l
cholera showed a moderate activity as compared to Ampicillin.
When tested against M. tuberculosis H37RV bacteria following a
conventional L.J. Medium method, it was found that compounds
6a, 6e, 6f, 6g, 6h, 7b, 7f and 7d showed more than 50% growth inhi-
bition. Among them 6e and 6g have a better performance than

N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3816–3821
3819
Figure 2. ORTEP view of the compound 7c.
Figure 3. The packing arrangement of compound 7c.
standard drugs Metronidazole (>256
l
g/mL), Fluconazole
In conclusion, the present work demonstrates the synthesis of a
series of new quinolyldibenzo[b,e][1,4]diazepin-1-ones showing
good biological activities. While the compounds 6f and 7b exhib-
ited good activity against E. coli. bacteria, more than half of the
compounds showed more than 50% growth inhibition against M.
(>256 g/mL) and Miconazole (>256 g/mL). Table 5 summerize
l
l
the test results. The measurement of ferric reducing power (FRAP
value) that ranging from 265 to 499 mmol/100 gm of compound
indicates that the compounds are good antioxidant.

3820
N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3816–3821
Table 4
Antibacterial and antifungal test results (MIC, lg/mL)
Compound
Gram-positive bacteria
Gram-negative bacteria
Fungi
S.p.
C.t.
B.s.
S.t.
V.c.
E.c.
A.f.
Ca.
MTCC
1936
MTCC
449
MTCC
441
MTCC
98
MTCC
3906
MTCC
443
MTCC
3008
MTCC
227
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
7c
7d
7e
7f
7g
7h
[A]
[B]
[C]
[D]
[E]
[F]
>250
250
>250
200
>250
>250
250
>250
>250
>250
>250
100
250
>250
250
>250
100
10
250
250
200
250
250
500
500
100
500
500
500
200
250
500
250
250
250
50
250
250
>250
250
250
200
200
250
>250
250
>250
100
250
250
>250
200
250
100
50
100
250
>250
250
250
100
250
250
>250
200
>250
250
250
200
200
250
100
10
>250
250
>250
200
>250
100
250
500
500
250
>250
100
>250
100
>250
250
100
10
250
100
200
200
250
62.5
>250
250
>250
62.5
250
>250
200
>250
100
250
100
10
>250
>250
>250
>250
>250
250
250
>250
>250
>250
>250
250
>250
>250
250
250
—
>250
>250
>250
>250
>250
>250
>250
>250
>250
>250
250
>250
>250
250
>250
>250
—
—
—
—
100
100
—
—
—
500
50
50
—
—
50
100
—
50
25
—
—
50
25
—
—
50
25
—
—
50
—
—
—
100
S.p.: Streptococcus pneumoniae, C.t.: Clostridium tetani, B.s.: Bacillus subtilis, S.t.: Salmonella typhi, V.c.: Vibrio cholerae, E.c.: Escherichia coli, A.f.: Aspergillus fumigatus, C.a.: Candida
albicans, [A]: Ampicillin, [B]: Norfloxacin,[C]: Chloramphenicol, [D]: Ciprofloxacin, [E]: Griseofulvin, [F]: Nystatin, MTCC: Microbial Type Culture collection.
Table 5
facilities. Three of us (H.A.B.; B.R.P. and S.B.T.) are grateful to the
UGC, New Delhi for financial support under the UGC scheme of
RFSMS. We also acknowledge the help rendered by the Vaibhav
Analytical Laboratories, Ahmadabad.
Antitubercular and antioxidant test results
Compound
Growth of inhibitiona (%)
Antioxident activityb
OD (593 nm)
FRAP valued
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
7c
7d
7e
7f
7g
62%
<50%
<50%
<50%
91%
75%
96%
58%
<50%
76%
1.628
1.338
1.609
2.291
1.99
1.317
1.775
1.446
2.43
2.474
1.719
2.474
1.791
1.931
1.895
2.474
2.474
328.20
489.88
324.37
346.54
269.75
498.75
461.86
498.75
401.18
361.06
265.50
389.28
357.83
382.03
291.51
498.75
–
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.bmcl.2012.03.100.
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Chiarini, A.; Spampinato, S.; Melchiorre, C. J. Med. Chem. 1994, 37, 3363.
64%
<50%
<50%
99%
7h
Standardc
a
Concentration of compounds used against M. Tuberculosis H37RV bacte-
ria = 250 g/mL.
Antioxidant activity: Concentration = 200
(A.A.) = 176 g/mL.
Standard antimicrobials used: Metronidazole (>256
(>256 g/mL), Miconazole (>256 g/mL).
A.A. mm/100 gm sample.
l
b
l
g/mL, cStandard: Ascorbic Acid
l
c
l
g/mL), Fluconazole
l
l
d
tuberculosis H37RV bacteria. All the compounds except 7f are active
against C. albicans. Compound 7f showed good activity against A.
fumigatus. All the compounds are comparatively good antimicro-
bial. Besides this, FRAP values showed a good antioxidant power
of the compounds.
Acknowledgments
Authors sincerely express their thanks to the Head, Department
of Chemistry, S. P. University for providing necessary research

N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3816–3821
3821
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21. Spectroscopic data of some selected compounds: Compound 6a: Yield: 90%,
yellow crystals; mp = 270–272 °C; IR (KBr):
mmax = 770, 925, 1330, 1375, 1585,
1645, 3245, 3290, 3325 cmÀ1 1H NMR (400 MHz, DMSO-d6): dH = 1.12 (s, 3H,
;
3-CH3), 1.14 (s, 3H, 3-CH3), 2.20 (s, 2H, 2-H), 2.58 (d, 1H, J = 16.0 Hz, 4-Ha), 2.76
(d, 1H, J = 16.0 Hz, 4-Hb), 4.69 (d, 1H, J = 17.2 Hz, 22-Ha), 1.80 (d, 1H,
J = 16.8 Hz, 22-Hb), 5.09 (d, 2H, J = 10.4 Hz, 20-H), 5.56 (d, 1H, J = 5.2 Hz, 10-
H), 5.76 (d, 1H, J = 5.6 Hz, 11-H), 5.89 (m, 1H, 21-H), 6.43–7.51 (m, 8H, Ar-H),
8.93 (s, 1H, 5-H) ppm. 13C NMR (100 MHz, DMSO-d6): dC = 28.10, 29.02, 32.33,
42.92, 44.23, 44.61, 49.98, 54.08, 107.58, 115.02, 116.37, 118.60, 120.70,
121.10, 122.73, 123.30, 130.84, 131.59, 132.53, 133.55, 134.46, 135.04, 138.45,
139.13, 156.27, 161.14, 192.76 ppm; ESI-MS: m/z: 459 (M+); Anal. Calcd for
8. (a) Neochoritis, C. G.; Tsoleridis, C. A.; Stephanatou, J. S.; Kontogiorgis, C. A.;
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Mol. Cell Biochem. 2003, 245, 51.
C
27H26ClN3O2: C, 70.55; H, 5.71; N, 9.15. Found: C, 70.25; H, 5.55; N, 9.02.
Compound 6e: Yield: 80%, yellow crystals; mp = 175-177 °C; IR (KBr):
max = 770, 905, 1400, 1600, 1650, 3175, 3265, 3470 cmÀ1 1H NMR
m
;
9. (a) Faber, K.; Kappe, T. J. Heterocycl. Chem. 1984, 21, 1881; (b) Ukrainets, I. V.;
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Tiamkao, S. J. Pharm. Pharmacol. 2002, 54, 827.
(400 MHz, DMSO-d6): dH = 1.12 (s, 3H, 3-CH3), 1.15 (s, 3H, 3-CH3), 2.21 (s,
2H, 2-H), 2.34 (s, 3H, 23-H), 2.60 (d, 1H, J = 16.0 Hz, 4-Ha), 2.75 (d, 1H,
J = 16.4 Hz, 4-Hb), 4.73 (d, 1H, J = 16.8 Hz, 22-Hb), 4.80 (d, 1H, J = 4 Hz, 22-Ha),
5.08 (d, 2H, J = 10.8 Hz, 20-H), 5.58 (d, 1H, J = 5.6 Hz, 10-H), 5.78 (d, 1H,
J = 5.2 Hz, 11-H), 5.9 (m, 1H, 21-H), 6.43-7.32 (m, 8H, Ar-H), 8.92 (s, 1H, 5-H)
ppm. 13C NMR (100 MHz, DMSO-d6): dC = 22.04, 28.31, 28.72, 32.32, 44.08,
44.63, 50.00, 54.19, 107.84, 115.19, 116.36, 117.59, 120.59, 120.98, 121.07,
123.23, 123.75, 128.94, 131.53, 132.75, 132.79, 133.97, 138.34, 138.59, 140.47,
156.20, 161.41, 192.76 ppm; ESI-MS: m/z: 440.2 (M+H+); Anal. Calcd for
C
28H29N3O2: C, 76.51; H, 6.65; N, 9.56. Found: C, 76.59; H, 6.60; N, 9.62.
Compound 7a: Yield: 95%, yellow crystals; mp = 150–152 °C; IR (KBr):
max = 760, 925, 1350, 1395, 1580, 1650, 3295 cmÀ1 1H NMR (400 MHz,
12. (a) Bain, E. E.; Candillis, P. J. Expert Opin. Ther. Patents 2000, 10, 389; (b) Tullio,
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m
;
13. (a) Hasvold, L. A.; Wang, L.; Przytulinska, M.; Xiao, Z.; Chen, Z. Bioorg. Med.
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19. General procedure for the synthesis of 6a–h: In a round-bottom flask, a solvent-
free equimolar (2 mmol) mixture of o-phenylenediamine 4, 1,3-
cyclohexadione 5a–b and quinolone-3-carbaldehyde 3a–d heated at 120 °C
till the completion of the reaction as confirmed by the TLC (2.5–3.0 h). The
crude products obtained were purified by washing with ethanol and dried at
room temperature. Entire products 6a–h were received quantitatively with an
excellent purity.
DMSO-d6): dH = 1.09 (s, 3H, 3-CH3), 1.12 (s, 3H, 3-CH3), 2.13 (s, 2H, 2-H), 2.57 (s,
1H, 4-Ha), 2.74 (d, 1H, J = 16.0 Hz, 4-Hb), 3.97 (dd, 1H, J = 3.2 Hz & J = 3.2 Hz,
22-Ha), 4.24 (dd, 1H, J = 6.0 Hz & J = 6.0 Hz, 22-Hb), 4.65 (d, 1H, J = 17.2 Hz, 25-
Hb), 4.73 (d, 1H, J = 15.6 Hz, 25-Ha), 4.99 (m, 4H, 20 & 23-H), 5.76 (m, 2H, 21 &
24-H), 5.88 (s, 1H, 11-H), 6.53-7.39 (m, 8H, Ar-H), 8.88 (s, 1H, 5-H) ppm. 13C
NMR (100 MHz, DMSO-d6): dC = 27.71, 29.16, 32.42, 44.23, 44.34, 49.98, 56.37,
57.16, 109.27, 114.69, 116.02, 116.87, 118.60, 120.49, 121.31, 122.28, 122.35,
123.54, 130.50, 132.65, 134.21, 134.31, 134.95, 135.93, 137.00, 139.10, 140.39,
156.51, 161.15, 192.20 ppm; ESI-MS: m/z: 499 (M+); Anal. Calcd for
C30H30ClN3O2: C, 72.06; H, 6.05; N, 8.40. Found: C, 72.20; H, 5.98; N, 8.52.
22. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.
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