One-pot, water-mediated, H2O2-HCl catalyzed synthesis of benzazepines

Article abstract of DOI:10.14233/ajchem.2020.22574

One-pot, multicomponent H2O2-HCl catalyzed system was employed for the synthesis of a series of benzazepine compounds. The implemented procedure oxidized the carbon-nitrogen bonds and produced benzazepines, while integrating diamines and substituted keton

Full text of DOI:10.14233/ajchem.2020.22574

Asian Journal of Chemistry; Vol. 32, No. 5 (2020), 1165-1168
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2020.22574
One-Pot, Water-Mediated, H2O2-HCl Catalyzed Synthesis of Benzazepines
*,
NIDHI SINGH and JAYA PANDEY
Amity School of Applied Sciences, Amity University Uttar Pradesh, Lucknow Campus, Lucknow-226028, India
*Corresponding author: E-mail: jpandey@lko.amity.edu
Received: 6 December 2019;
Accepted: 24 January 2020;
Published online: 29 April 2020;
AJC-19851
One-pot, multicomponent H2O2-HCl catalyzed system was employed for the synthesis of a series of benzazepine compounds. The
implemented procedure oxidized the carbon-nitrogen bonds and produced benzazepines, while integrating diamines and substituted
ketone. The advantage of the exercised synthetic route was that the reaction was water mediated and the completion time was quite
reduced compared to the time required by conventional methods.
Keywords: One-pot, Multicomponent reaction, Benzazepine, Diamines, Ketone, Water, H2O2-HCl system.
viewpoint, we have advanced to develop a greener, solventless,
one-pot synthetic route for benzazepine, catalyzed via H2O2-
HCl system. The idea for this synthesis was derived and
inspired from Bahrami’s work [22] on benzimidazole.
This work focuses on greener, high-yielding options for
benzazepine synthesis. o-Phenylenediamine and carbonyl
compound were used in the ratio of 1:2 and H2O2:HCl was
used in the ratio of 2:1 for this synthesis. Water has been used
as solvent providing a greener approach to this reaction. The
novelty of work lies in the catalytic system combined with
aqueous solvent system. The synthesized products (1a-h) have
been outlined in Scheme-I.
INTRODUCTION
Benzazepines are chemical compounds comprising of a
seven membered nitrogen heterocyclic ring fused to a six
membered benzene ring [1]. It is an important class of drug
compounds. The therapeutic value of benzazepine has been
explored through a number of current existing drugs, like
benazepril [2] used as oral medication in high blood pressure,
heart failure [3] and diabetic renal failure, fenoldopam [4]
functioning as antihypertensive agent [5], GSK-189,254 used
as H3 histamine receptor [6] inverse agonist in Alzheimer’s
disease, ivabradine used as antianginal agent or cardiotonic
agent [7,8], lorcaserin used as appetite controlling agent for
weight loss in obese patients [9], varenicline used for treating
narcotic addicted patients [10], mozavaptan used for treating
hyponatremia via vasopressin V2 receptor antagonistic action
[11,12]. The multiple therapeutic potential of benzazepines is
the reason for its exploration as important drug candidate.
Various synthetic routes have been suggested for benza-
zepine synthesis. The multipotent compound has been synthe-
sized via catalyzation by copper [13,14], lanthanide trichloride
[15], ytterbium trichloride [16], iron [17], rhodium [18] and
palladium [19,20]. Novel strategy of one-pot synthesis [21]
has also been applied to benzazepines. One-pot synthesis are
always considered to be better than multistep synthetic routes
as the yields are quite high and time consumption is low. It
is a greener and efficient approach in chemistry. With this
EXPERIMENTAL
The reagents used were of the make Sigma and Avra and
used without any further purification. The instrument used for
NMR analysis was JNM-ECZ500R. IR analysis was performed
on Perkin Elmer spectrum version 10.03.06. The synthesized
compounds were characterized by spectral analysis and yields
refer to the isolated products. The melting points were recorded
on automatic melting/boiling point apparatus Therm °Cal0.
The reactions were monitored viaTLC and the developed spots
were observed under ultraviolet light in UV cabinet.
General procedure: In a round bottom flask, o-phenylene-
diamine (1 mmol) and ketone (2 mmol) were taken.A magnetic
stirrer was placed in the same flask. To this flask, a solution of
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1166 Singh et al.
Asian J. Chem.
R1
R
H
N
NH2
NH2
O
H2O2-HCl
90-100 °C
R1
+
R1
R
N
R
1a-h
Compound
1a
CH3
H
1b
1c
1d
C6H5
H
1e
1f
4-Me-C6H4
H
1g
1h
4-NO2-C6H4
H
R
C2H5
H
C2H5
CH3
4-OMe-C6H4
H
4-Cl-C6H4
H
R1
Scheme-I: Synthesis of Benzazepine analogues (1a-h) catalyzed by H2O2-HCl (2:1) system
30% hydrogen peroxide (6 mmol) and 37% hydrochloric acid
(3 mmol) was added. The mixture was continuously stirred
at 90-100 °C for 90-180 min (Table-1). The completion of
reaction was monitored by TLC (hexane:ethyl acetate 6:4) and
observed in UV cabinet. The reaction mixture was extracted
with ethyl acetate. The extract was dried over sodium sulphate
and the filtrate was concentrated under vacuum and the crude
product was collected. The crude product was purified via
column chromatography in hexane-ethyl acetate system to gain
products in 82-95% yields.
128.2, 123.1, 118.2, 113.6, 57.9, 37.7, 30.3, 23.6, 8.7, 7.1;
MS (m/z): 244 (M+), 245 (M+1); Elemental anal. calcd. (%)
for C16H24N2: C, 78.64, H, 9.90, N, 11.46. Found (%) for
C16H24N2: C, 78.52, H, 9.96, N, 11.52.
2-Methyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1,4]-
diazepine (1d): Golden yellow solid; m.p.: 150-154 °C; yield:
90%; IR (KBr, νmax, cm-1): 3290 (-NH- str.), 1580 (-NH- bend.),
3035 (aromatic -C-H- str.), 1665 (-C-C- str.), 1490 (-C-C- str.),
1070 (in plane –C-H bend.), 765 (-C-H- bend.), 680 (-C-H-
str.); 1H NMR (CDCl3, 500 MHz, δ ppm): 7.13-7.18 (m, 5H),
7.29-7.52 (m, 5H), 6.40-7.10 (m, 4H), 4.3 (s, 1H), 1.80 (q,
2H), 1.61 (s, 3H); 13C NMR (CDCl3, 125 MHz, δ ppm): 165.1,
148.7, 137.0, 131.2, 130.8, 129.0, 128.6, 128.2, 127.8, 126.3,
125.7, 122.7, 118.7, 112.8, 51.0, 45.9, 28.7; MS (m/z): 312
(M+), 313 (M+1); Elemental anal. calcd. (%) for C22H20N2: C,
84.58, H, 6.45, N, 8.97. Found (%) for C22H20N2: C, 84.48, H,
6.55, N, 8.97.
2,4-Bis-(4-methoxy-phenyl)-2-methyl-2,3-dihydro-1H-
benzo[b][1,4]diazepine (1e): Yellow solid; m.p.: 152-157 °C;
yield: 89%; IR (KBr, νmax, cm-1): 3250 (-NH- str.), 1555 (-NH-
bend.), 3020 (aromatic -C-H- str.), 1640 (-C-C- str.), 1465 (-C-C-
str.), 1270 (-C-O- str.), 1055 (in plane –C-H bend.), 765 (-C-H-
bend.), 680 (-C-H-str.); 1H NMR (CDCl3, 500 MHz, δ ppm):
7.61 (d, 2H), 7.02 (d, 2H), 6.80 (d, 2H), 6.69 (d, 2H), 6.6-7.0
(m, 4H), 4.3 (s, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 1.92 (s, 2H),
1.66 (s, 3H); 13C NMR (CDCl3, 125 MHz, δ ppm): 164.6, 164.3,
159.2, 141.2, 137.0, 130.0, 127.9, 127.1, 123.2, 121.3, 118.2,
114.1, 113.6, 56.3, 51.0, 45.9, 28.7; MS (m/z): 372 (M+), 373
(M+1); Elemental anal. calcd. (%) for C24H24N2O2: C, 77.39,
H, 6.49, N, 7.52, O, 8.59. Found (%) for C24H24N2O2: C, 77.27,
H, 6.55, N, 7.55, O, 8.62.
2-Methyl-2,4-di-p-tolyl-2,3-dihydro-1H-benzo[b][1,4]-
diazepine (1f): Yellow coloured solid; m.p.: 150-155 °C; yield:
88%; IR (KBr, νmax, cm-1): 3268 (-NH- str.), 1568 (-NH- bend.),
3056 (aromatic -C-H- str.), 1668 (-C-C- str.), 1472 (-C-C- str.),
1280 (-C-O- str.), 1060 (in plane –C-H bend.), 755 (-C-H-
bend.), 670 (-C-H-str.); 1H NMR (CDCl3, 500 MHz, δ ppm):
7.50 (d, 2H), 7.09 (d, 2H), 7.01 (d, 2H), 6.98 (d, 2H), 6.6-7.0
(m, 4H), 4.0 (s, 1H), 2.35 (s, 3H), 2.26 (s, 3H), 1.80 (s, 2H),
1.61 (s, 3H); 13C NMR (CDCl3, 125 MHz, δ ppm): 164.9, 145.7,
140.0, 138.1, 134.9, 129.3, 128.9, 127.8, 126.2, 122.6, 118.4,
113.8, 51.2, 45.9, 20.9; MS (m/z): 340 (M+), 341 (M+1);
Elemental anal. calcd. (%) for C24H24N2: C, 84.67, H, 7.11, N,
8.23. Found (%) for C24H24N2: C, 84.47, H, 7.21, N, 8.33.
Spectral analysis and physical properties of selected
compounds
2,2,4-Trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine
(1a): Dark yellow solid; m.p.: 135-138 °C; yield: 95%; IR
(KBr, νmax, cm-1): 3290 (-NH- str.), 1580 (-NH- bend.), 3050
(aromatic -C-H- str.), 1665 (-C-C- str.), 1490 (-C-C- str.), 1060
(in plane –C-H bend.), 770 (-C-H- bend.); 1H NMR (CDCl3,
500 MHz, δ ppm): 6.6-7.0 (m, 4H), 4.2 (s, 1H), 1.56 (m, 2H),
1.28 (t, 6H), 0.9 (t, 3H); 13C NMR (CDCl3, 125 MHz, δ ppm):
164.6, 137.0, 132.4, 127.6, 122.8, 118.2, 113.7, 46.1, 44.3,
28.8, 27.6, 18.4; MS (m/z): 188 (M+), 189 (M+1); Elemental
anal. calcd. (%) for C12H16N2: C, 76.55, H, 8.57, N, 14.88.
Found (%) for C12H16N2: C, 76.35, H, 8.77, N, 14.88.
2,4-Diethyl-2-methyl-2,3-dihydro-1H-benzo[b][1,4]-
diazepine (1b): Pale yellow solid; m.p.: 140-143 °C; yield:
92%; IR (KBr, νmax, cm-1): 3285(-NH- str.), 1570 (-NH- bend.),
3035 (aromatic -C-H- str.), 1660 (-C-C- str.), 1490 (-C-C- str.),
1
1060 (in plane –C-H bend.), 760 (-C-H- bend.); H NMR
(CDCl3, 500 MHz, δ ppm): 6.5-7.1 (m, 4H), 4.0 (s, 1H), 1.56
(m, 2H), 1.48 (q, 2H), 1.40 (q, 2H), 1.33 (t, 3H), 1.10 (t, 3H),
0.9 (t, 3H); 13C NMR (CDCl3, 125 MHz, δ ppm): 164.4, 137.1,
133.2, 127.8, 122.4, 117.8, 112.9, 47.6, 41.1, 35.3, 26.3, 26.1,
8.2, 6.4; MS (m/z): 216 (M+), 217 (M+1); Elemental anal. calcd.
(%) for C14H20N2: C, 77.73, H, 9.32, N, 12.95. Found (%) for
C14H20N2: C, 77.53, H, 9.42, N, 13.05.
2,2,4-Triethyl-3-methyl-2,3-dihydro-1H-benzo[b][1,4]-
diazepine (1c): Yellow solid; m.p.: 143-147 °C; yield: 92%;
IR (KBr, νmax, cm-1): 3280 (-NH- str.), 1575 (-NH- bend.), 3030
(aromatic -C-H- str.), 1650 (-C-C- str.), 1480 (-C-C- str.), 1060
(in plane –C-H bend.), 765 (-C-H- bend.); 1H NMR (CDCl3,
500 MHz, δ ppm): 6.4-7.0 (m, 4H), 4.1 (s, 1H), 1.80 (q, 1H),
1.48 (q, 4H), 1.38 (q, 2H), 1.07 (d, 3H), 0.97 (t, 6H), 0.9 (t,
3H); 13C NMR (CDCl3, 125 MHz, δ ppm): 165.4, 138.2, 133.9,

Vol. 32, No. 5 (2020)
One-Pot, Water-Mediated, H2O2-HCl Catalyzed Synthesis of Benzazepines 1167
2,4-Bis-(4-chloro-phenyl)-2-methyl-2,3-dihydro-1H-
benzo[b][1,4]diazepine (1g): Lemon yellow solid; m.p.: 159-
162 °C; yield: 89%; IR (KBr, νmax, cm-1): 3272(-NH- str.), 1575
(-NH- bend.), 3062 (aromatic -C-H- str.), 1673 (-C-C- str.),
1478 (-C-C- str.), 1288 (-C-O- str.), 1058 (in plane –C-H bend.),
755 (-C-H- bend.), 720 (-C-Cl-str.), 672 (-C-H-str.); 1H NMR
(CDCl3, 500 MHz, δ ppm): 7.57 (d, 2H), 7.30 (d, 2H), 7.19
(d, 2H), 7.07 (d, 2H), 6.5-7.1 (m, 4H), 1.80 (s, 2H), 1.61 (s,
3H); 13C NMR (CDCl3, 125 MHz, δ ppm): 165.1, 146.8, 137.4,
136.1, 131.4, 130.7, 129.6, 129.0, 128.6, 127.8, 127.1, 122.8,
118.2, 113.6, 51.8, 45.5, 28.7; MS (m/z): 380 (M+), 381 (M+1);
Elemental anal. calcd. (%) for C22H18N2Cl2: C, 69.30, H, 4.76,
N, 7.35, Cl, 18.60. Found (%) for C22H18N2Cl2: C, 69.40, H,
4.70, N, 7.31, Cl, 18.60.
2-Methyl-2,4-bis-(4-nitro-phenyl)-2,3-dihydro-1H-
benzo[b][1,4]diazepine (1h): Corn yellow solid; m.p.: 159-
162 °C; yield: 90%; IR (KBr, νmax, cm-1): 3280 (-NH- str.),
1582 (-NH- bend.), 3075 (aromatic -C-H- str.), 1685 (-C-C-
str.), 1482 (-C-C- str.), 1290 (-C-O- str.), 1130 (-C-N-str.), 1058
(in plane –C-H bend.), 780 (-C-H- bend.), 690 (-C-H-str.); 1H
NMR (CDCl3, 500 MHz, δ ppm): 8.22 (d, 2H), 8.11 (d, 2H),
7.88 (d, 2H), 7.39 (d, 2H), 6.4-7.2 (m, 4H), 4.1 (s, 1H), 1.82
(s, 2H), 1.58 (s, 3H); 13C NMR (CDCl3, 125 MHz, δ ppm):
165.1, 146.8, 137.4, 136.1, 131.4, 130.7, 129.6, 129.0, 128.6,
127.8, 127.1, 122.8, 118.2, 113.6, 51.8, 45.5, 28.7; MS (m/z):
380 (M+), 381 (M+1); Elemental anal. calcd. (%) for
C22H18N4O4: C, 65.66, H, 4.51, N, 13.92, O, 15.90. Found (%)
for C22H18N4O4: C, 65.65, H, 4.52, N, 13.84, O, 15.98.
of HCl. This oxidative mechanism is responsible for one-pot
synthesis of benzazepine analogues.
To conclude, we have devised a new and efficient synthetic
route for synthesis of substituted benzazepines. Usage of water
as solvent, simple work-up and isolation, one-pot synthesis
and high yields, make this method a preferred synthetic route
for synthesis of benzazepines.
ACKNOWLEDGEMENTS
The authors are thankful toAmity University Uttar Pradesh,
Lucknow campus for providing laboratory facilities for
completion of this work. The authors are also thankful to
Council of Science and Technology, U.P. (UPCST) (Grant
registration #CST/D-2282/2016) and DST (Grant registration
#CS-176/2013) for their financial support in completion of
this work.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
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REACTION BETWEEN o-PHENYLENEDIAMINE
AND VARIOUS KETONES
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Compound
R
CH3
C2H5
C2H5
R1
H
H
CH3
H
H
H
H
H
Time (min)
90
Yield (%)
95
92
92
90
89
88
89
90
1a
1b
1c
1d
1e
1f
100
110
130
95
120
150
180
C6H5
4-OMe-C6H4
4-Me-C6H4
4-Cl-C6H4
4-NO2-C6H4
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The probable mechanistic route involves formation of
hypochlorous acid (HOCl) by reaction of hydrogen peroxide
and hydrochloric acid (H2O2:HCl 2:1), which further interacts
with o-phenylenediamine and 2 mol of carbonyl compound
for cyclizing the benzazepine product, followed by elimination
https://doi.org/10.1039/C7CC07027F

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