Efficient synthesis of novel 1, 2, 3-triazole-based diazepam derivatives by click CuAAC reaction: Spectroscopic characterizations and DFT studies

Article abstract of DOI:10.1016/j.molstruc.2021.131206

A new family of 1, 2, 3-triazole-based benzodiazepines have been synthesized by the Huisgen [3+2] dipolar cycloaddition reaction of diazepam with O-propargyl salicylaldehydes in the aqueous medium. Mild reaction conditions, excellent yields (70–98%), envi

Full text of DOI:10.1016/j.molstruc.2021.131206

Journal of Molecular Structure 1246 (2021) 131206
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Efficient synthesis of novel 1, 2, 3-triazole-based diazepam derivatives
by click CuAAC reaction: Spectroscopic characterizations and DFT
studies
Zohreh Esmaeeli , Mohammad Reza Khodabakhshi , Zohreh Mirjafaryc,
Hamid Saeidian
a
b,∗
a,∗
a
Department of Science, Payame Noor University (PNU), P.O.Box 19395-3697, Tehran, Iran
b
Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
c
Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new family of 1, 2, 3-triazole-based benzodiazepines have been synthesized by the Huisgen [3+2] dipo-
lar cycloaddition reaction of diazepam with O-propargyl salicylaldehydes in the aqueous medium. Mild
reaction conditions, excellent yields (70–98%), environment-friendly method and easily prepared starting
materials are the key features of the protocol. Density functional theory calculations were also conducted
using the B3LYP functional and 6-31++G(d, p) basis set on the structure of the characterized structure
6a. Structural, electronic and thermodynamic data such as electrophilicity index, APT charge distribution
and electrostatic potential map were calculated by the computational method and interpreted.
© 2021 Elsevier B.V. All rights reserved.
Received 21 June 2021
Revised 25 July 2021
Accepted 27 July 2021
Available online 2 August 2021
Keywords:
[
1, 4]-Benzodiazepine
CuAAC Reaction
Anticonvulsant
Alkyne–Azide Cycloaddition Reaction
DFT Calculations
1. Introduction
sis of fused triazole derivatives has recently been reported through
Ugi reaction (Scheme 1, A) [19]. Novel fused-triazole benzodi-
Nitrogen containing seven-membered heterocyclic compounds
like 1, 4-benzodiazepines with various substituents show a wide
range of pharmacological activities such as analgesic, sedative, an-
tidepressive, anticonvulsant, antianxiety, anticancer, antimicrobial,
anti-HIV, muscle relaxant, antitumor antibiotics agents, etc. [1-5].
Also, the 1, 4-benzodiazepine cores such as Diazepam (Valium)
azepines have been synthesized by the Ma group (Scheme 1, B)
[20]. Zhang and co-workers illustrated a one pot-economy synthe-
sis involving sequential [3+2] cycloaddition of azomethine ylides,
N-propargylation, to synthesis triazole-based benzodiazepines [21].
This one-pot and three-step reaction has only two operation steps,
including the initial [3+2] cycloaddition of an azomethine ylide
and then followed by the addition of propargyl bromide. The
propargylated compound spontaneously undergoes the click reac-
tion at elevated temperature to form the final product.
(
[
Fig. 1) are found in numerous psychoactive pharmaceutical agents
6].
Among the triazoles, 1, 2, 3-triazoles are excellent hetero-
cyclic structures willing in various natural products and syn-
thetic pharmaceuticals [7]. Moreover, some studies display 1, 4-
benzodiazepines linked to 1, 2, 3-triazole core are considerable
skeletons have interesting biological properties such as antimi-
crobial, antifungal, anti-tubercular, anti-inflammatory, anticancer,
analgesic, anticonvulsant and anti-tyrosinase activities [8-10].
One of the multicomponent reactions for the synthesis 1, 2, 3-
triazoles is the click 1,3-dipolar cycloaddition between azides and
terminal alkynes [11-15]. The best known method for synthesis
Recently, our research group synthesized the β-hydroxy-1,4-
disubstituted-1,2,3-triazole-based benzodiazepinediones and 1,5-
bis(N-substituted 1,2,3–triazole) benzodiazepinediones by the
Huisgen [3+2] dipolar cycloaddition reaction under mild condi-
tions [22, 23]. Based on the background of the research group in
the synthesis of the 1,4-disubstituted 1,2,3-triazole derivatives [24-
32] and inspired by the promising therapeutic activities of 1,4-
benzodiazepines and 1, 2, 3-triazoles, we wish to design the syn-
thesis of a new category of 1,4-benzodiazepine-triazole compounds
based on diazepam scaffold, through a highly efficient click reac-
tion (Scheme 2). In the final section of this study, physicochemical
properties of the characterized structure of 6a were studied by us-
1,4-disubstituted 1,2,3-triazoles is via the copper-catalyzed azide
alkyne cycloaddition reaction (CuAAC) [16-18]. A two-step synthe-
∗
Corresponding authors.
https://doi.org/10.1016/j.molstruc.2021.131206
0
022-2860/© 2021 Elsevier B.V. All rights reserved.

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
Scheme 1. Synthesis of some 1, 2, 3-triazole-based benzodiazepine derivatives.
LC system. Elemental analyses were carried out by a CHN-O Rapid
Heraeus elemental analyzer (Wellesley, MA). Silica gel 60 (0.040–
Me
O
0.063 mm) were used for column chromatography. Thin layer chro-
matography (TLC) was performed using silica gel 60/Kieselguhr
F254 precoated on Aluminum sheets (thickness 0.2 mm), commer-
cially available from Merck. Visualization of spots on the TLC plate
was accomplished with UV light.
N
2
.2. Computational details
N
Cl
The geometry of the structure 6a was optimized at the
DFT/B3LYP level with 6-31++G(d, p) basis set using the Gaus-
sian 09 software [33]. In addition, the frequency calculations were
performed using the mentioned computational method to obtain
the thermodynamic data of enthalpy and Gibbs free energy of the
molecule 6a at a temperature of 298 K. Molecular electrostatic po-
tential (MEP) maps for 6a was calculated by applying B3LYP/6-
31++G(d, p) computational methods. Optimized Cartesian coordi-
nates and energies of all proposed structures are inserted into elec-
tronic supplementary material.
Ph
Fig. 1. Chemical structure of Diazepam (Valium).
ing the density functional theory (DFT) calculations in conjunction
with B3LYP/6-31++G (d, p) method.
2. Experimental
2
.1. General information
2.3. General procedure for the synthesis of O-propargyl
salicylaldehyde derivatives 2a-c
Diazepam was obtained from Hakim Pharmaceutical Co. and
all of the other commercially available reagents and solvents pur-
chased from Sigma–Aldrich and Merck and were used without fur-
ther purification. Melting points were determined with an Elec-
trothermal model 9100 apparatus and. IR spectra were recorded
with a Shimadzu IR-21 prestige spectrometer. 1H and 13CNMR
spectra were recorded on a Bruker DRX-500-Avance spectrome-
The O-propargyl salicylaldehydes 2a-c were prepared according
to the literature [34]. A solution of salicylaldehydes 1 (2.0 mmol)
and propargyl bromide (2.4 mmol, 286 mg) in DMF (15 mL) was
reacted in the presence of K CO3 (2.0 mmol, 276 mg) at room tem-
2
perature for 12 h. TLC followed the progress of the reaction. After
completion, the water was added, and the precipitated solid was
filtered and washed with water to give 2a-c.
ter in CDCl . LC-MS analysis was performed on an Agilent 1200
3
Scheme 2. General synthetic protocol for novel 1,2,3-triazole-based diazepam derivatives 6a-j.
2

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
2
.4. General procedure for the synthesis of 4a-d
114.4 (CH), 120.9 (C), 122.3 (C), 122.8 (CH), 123.8 (C), 127.0 (CH),
128.2 (CH), 128.3 (CH), 128.7 (2CH), 128.8 (CH), 128.9 (2CH),
A mixture of diazepam 3 (1 mmol) and O-propargyl salicylalde-
129.3 (CH), 130.3 (C), 130.8 (CH), 130.9 (2CH), 131.3 (CH), 132.0
(2CH), 136.7 (C), 138.1 (C), 139.4 (C), 141.1 (C), 141.4 (C), 163.7
(C), 167.2 (C=O), 170.7 (C=N). Anal. Calcd for C33H25ClN O : C,
hyde 2a-c (1 mmol) in t-BuOH (5 mL) was heated and treated
slowly with KOt-Bu/t-BuOH (1 mmol/ 5 mL). The reaction mixture
was refluxed for 3–6 h. The reaction was monitored by TLC. The
solvent was then removed under reduced pressure, and the mix-
ture was purified by silica gel column chromatography (n-hexane-
EtOAc, 3/1) to give the desired pure products 4a-d.
6
4
65.51; H, 4.16; N, 13.89, Found: C, 65.57; H, 4.20; N, 13.80. 3-
(2-((1-benzyl-1H-1, 2, 3-triazol-4-yl) methoxy)-5-bromobenzylidene)-
7-chloro-1-methyl-5-phenyl-1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-
2-one 6d: yellow powder, m.p.: 140-144°C; FT-IR (KBr): 3441, 3129,
−
1
1
3
067, 2922, 2855, 1661, 1609, 741, 694 cm
;
HNMR: δ = 3.36
(3H, s, Me), 5.12 (2H, d, 3J = 4.5, NCH2), 5.45 (2H, s, OCH2), 6.71
2
.5. General procedure for the synthesis of 1,2,3-triazole-based
diazepam 6a-j
(1H, s, CH), 7.19-7.22 (6H, m, 6CH), 7.27-7.31 (3H, m, 3CH), 7.38-
7
.47 (4H, m, 4CH), 7.53 (1H, s, CH), 7.76-7.80 (2H, m, 2CH), 7.92
(H, d, 3J = 4.5, CH); CNMR: δ = 35.7 (Me), 51.3 (NCH2), 61.6
(OCH2), 106.9 (C), 112.9 (CH), 114.2 (C), 122.3 (C), 122.4 (C), 122.9
(CH), 123.9 (CH), 124.0 (CH), 125.2 (2CH), 126.5 (2CH), 128.1 (2CH),
128.6 (2CH), 128.7 (CH), 129.1 (C), 129.9 (CH), 131.3 (CH), 131.4
(CH), 131.6 (CH), 133.3 (C), 134.1 (C), 137.0 (C), 140.8 (C), 149.5
13
NaN3 is toxic and potentially explosive material and therefore
the reaction should be carried out only by a trained professional
in an efficient chemical hood [35].
In a tube equipped with a magnetic stirring bar, 4a-d (1 mmol)
and benzyl bromide 5 (1 mmol) were added in water (15 mL).
Then sodium azide (1 mmol), Cu(OAc)2 (0.2 mmol), sodium ascor-
bate (0.2 mmol) were added to the reaction mixture, which was
stirred for 24 h at room temperature and subsequently extracted
with ethyl acetate (3 × 15 mL). The combined organic extracts
were dried over anhydrous Na SO , and the solvent was evapo-
+
(C), 150.3 (C), 161.3 (C=O), 166.4 (C=N); MS (ESI): 640 [M+H] ;
Anal. Calcd for C33H25BrClN5O2: C, 62.03; H, 3.94; N, 10.96, Found:
C, 62.00; H, 3.98; N, 10.93. 3-(5-bromo-2-((1-(4-bromobenzyl)-1H-1,
2, 3-triazol-4-yl) methoxy) benzylidene)-7-chloro-1-methyl-5-phenyl-
1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-one 6e: yellow powder,
m.p.; 139-143°C; FT-IR (KBr): 3437, 3129, 3069, 2922, 2864, 1659,
2
4
rated. Finally, the crude product was purified by silica gel column
chromatography ((n-hexane-EtOAc, 4/1) to afford the desired pure
products 6a-j as yellow powders.
−1
1
1605, 779, 691 cm
3
;
HNMR: δ = 3.36 (3H, s, Me), 5.13 (2H, dd,
J = 24.0, 7.0, NCH2), 5.40 (2H, s, OCH2), 6.72 (1H, s, CH), 6.80 (2H,
3
dd, J = 12.5, 6.0, CH), 7.06-7.11 (2H, m, 2CH), 7.19-7.22 (2H, m,
2CH), 7.25 (1H, s, CH), 7.25 (1H, d, 3J= 2.0, CH), 7.38-7.49 (4H, m,
2
.6. Spectral data of 1,2,3-triazole-based diazepam 6a-j
-(2-((1-benzyl-1H-1, 2, 3-triazol-4-yl) methoxy) benzylidene)-7-
3
4
CH), 7.57 (1H, s, CH), 7.76-7.80 (2H, m, 2CH), 7.89 (1H, d, J = 5.0,
CH); 13CNMR: δ = 35.7 (Me), 53.5 (NCH2), 63.2 (OCH2), 113.1 (CH),
113.6 (C), 114.3 (CH), 122.7 (CH), 122.9 (CH), 123.0 (C), 126.6 (C),
128.7 (2CH), 129.4 (C), 129.5 (CH), 129.8 (CH), 129.9 (2CH), 131.1
(C), 131.4 (CH), 131.5 (2CH), 131.6 (CH), 132.3 (2CH), 133.4 (C),
134.1 (CH), 137.2 (C), 140.8 (C), 141.7 (C), 144.3 (C), 155.2 (C), 164.4
(C=O), 170.8 (C=N); Anal. Calcd for C33H24Br2ClN5O2: C, 55.22;
H, 3.37; N, 9.76, Found: C, 55.13; H, 3.42; N, 9.81. 3-(5-bromo-2-
((1-(4-nitrobenzyl)-1H-1, 2, 3-triazol-4-yl) methoxy) benzylidene)-7-
chloro-1-methyl-5-phenyl-1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-
one 6f: yellow powder, m.p.: 147-150°C; FT-IR (KBr): 3437, 3138,
3
chloro-1-methyl-5-phenyl-1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-
one 6a: yellow powder; m.p.: 136-138°C; FT-IR (KBr): 3441, 3165,
−
1
1
3
024, 2920, 2850, 1660, 1601, 754, 698 cm
;
HNMR: δ = 3.53
(
3H, s, Me), 5.34 (2H, dd, 3J =12.0, 8.0, NCH ), 5.63 (2H, s, OCH ),
2
2
7
.02 (1H, s, CH), 7.31-7.40 (5H, m, 5CH), 7.42 (1H, d, 3J =2.5,
CH), 7.44-7.61 (9H, m, 9CH), 7.77 (1H, s, CH), 7.94-7.96 (2H, m,
2
CH); 13CNMR: δ = 35.6 (Me), 53.3 (NCH ), 62.0 (OCH ), 112.6
2
2
(
(
CH), 113.0 (CH), 121.3 (C), 123.8 (CH), 124.6 (C), 125.3 (CH), 128.4
CH), 128.5 (CH), 128.6 (2CH), 128.9 (CH), 129.2 (2CH), 129.3 (2CH),
−
1
1
129.8 (CH), 129.9 (2CH), 131.0 (CH), 131.1 (C), 131.9 (CH), 132.1
3075, 2924, 2859, 1650, 1607, 754, 694 cm
.
HNMR: δ = 3.41
(3H, s, Me), 5.18-5.27 (2H, dd, 3J = 19.0, 12.0, NCH2), 5.63 (2H, s,
OCH2), 6.78 (1H, s, CH), 6.87-6.89 (1H, d, 3J = 8.5, CH), 7.31 (2H,
s, 2CH), 7.40-7.42 (2H, m, 2CH), 7.48-7.55 (4H, m, 4CH), 7.76 (1H,
s, CH), 7.82-7.89 (4H, m, 4CH), 8.21-8.22 (2H, m, 2CH); 13CNMR:
δ = 35.2 (Me), 52.8 (NCH2), 63.0 (OCH2), 112.8 (CH), 114.0 (C),
114.1 (CH), 122.3 (CH), 122.7 (CH), 122.9 (C), 123.9 (C), 125.7 (2CH),
126.1 (C), 126.3 (CH), 128.3 (CH), 129.1 (2CH), 129.4 (C), 130.0
(CH), 130.9 (2CH), 131.1 (CH), 131.2 (2CH), 133.7 (C), 134.8 (C),
137.9 (C), 141.2 (C), 142.9 (C), 146.3 (C), 159.9 (C), 166.8 (C=O),
170.3 (C=N); Anal. Calcd for C33H24BrClN6O4: C, 57.95; H, 3.54; N,
12.29, Found: C, 58.01; H, 3.59; N, 12.27. 3-(2-((1-benzyl-1H-1, 2,
3-triazol-4-yl) methoxy)-5-methoxybenzylidene)-7-chloro-1-methyl-5-
phenyl-1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-one 6g: yellow
powder, m.p.: 137-139°C; FT- IR (KBr): 3447, 3136, 3069, 2926,
(
CH), 136.4 (C), 137.2 (C), 140.6 (C), 142.1 (C), 142.2 (C), 156.3
(
C), 164.6 (C=O), 170.4 (C=N). Anal. Calcd. for C33H26ClN O : C,
5
2
7
0.77; H, 4.68; N, 12.51, Found: C, 70.65; H, 4.87; N, 12.41. 3-(2-
((1-(4-bromobenzyl)-1H-1, 2, 3-triazol-4-yl) methoxy) benzylidene)-7-
chloro-1-methyl-5-phenyl-1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-
one 6b: yellow powder, m.p.: 137-139°C; FT-IR (KBr): 3443, 3138,
−
1
1
3
065, 2924, 2859, 1661, 1599, 752, 696 cm
;
HNMR: δ = 3.35
(
3H, s, Me), 5.17 (2H, dd, 3J = 24, 6.5, NCH ), 5.41 (2H, s, OCH ),
2
2
6
.84 (1H, s, CH), 6.91-6.94 (2H, m, 2CH), 7.07-7.19 (5H, m, 5CH),
7
.37-7.47 (6H, m, 6CH), 7.56 (1H, dd 3J = 3.5, 13, CH), 7.62 (1H, s,
CH), 7.75-7.79 (2H, m, 2CH); 13CNMR: δ = 35.6 (Me), 53.3 (NCH ),
2
6
3.2 (OCH2), 112.7 (CH), 114.6 (CH), 121.2 (C), 122.7 (C), 122.8
(
CH), 122.9 (C), 124.6 (CH), 128.6 (CH), 129.1 (CH), 129.2 (2CH),
29.3 (CH), 129.7 (2CH), 131.2 (CH), 131.4 (C), 132.3 (CH), 133.6
1
−1
1
(
(
2CH), 137.2 (CH), 139.9 (2CH), 141.9 (C), 142.5 (C), 144.9 (C), 151.4
2857, 1661, 1605, 754, 702 cm
.
HNMR: δ = 3.36 (3H, s, Me),
3.77 (3H, s, OMe), 5.13 (2H, dd, 3J = 25.0, 58.0, NCH2), 5.46 (2H,
s, OCH2), 6.77-6.80 (2H, m, 2CH), 6.94-7.09 (2H, m, 2CH), 7.16-7.23
(6H, m, 6CH), 7.25-7.27 (1H, m, 1 CH), 7.37-7.48 (4H, m, 4CH), 7.74-
7.78 (2H, m, 2CH), 7.97 (1H, s, CH); 13CNMR: δ = 33.1 (Me), 55.8
(OMe), 57.6 (NCH2), 67.2 (OCH2), 108.4 (C), 111.5 (CH), 115.2 (CH),
118.3 (CH), 122.8 (C), 123.8 (C), 123.9 (CH), 125.3 (CH), 125.4 (CH),
126.1 (2CH), 128.2 (2CH), 128.4 (2CH), 128.6 (2CH), 128.9 (CH),
129.2 (C), 129.8 (CH), 130.4 (CH), 131.4 (2CH), 132.2 (C), 132.9 (C),
137.2 (C), 140.5 (C), 144.9 (C), 152.6 (C=O), 158.8 (C=N); MS (ESI):
C), 151.5 (C), 156.3 (C), 163.9 (C=O), 171.1 (C=N). Anal. Calcd
for C
H BrClN O : C, 62.03; H, 3.94; N, 10.96, Found: C, 62.14;
25 5 2
33
H, 3.86; N, 10.90. 7-chloro-1-methyl-3-(2-((1-(4-nitrobenzyl)-1H-1,
, 3-triazol-4 yl) methoxy) benzylidene)-5-phenyl-1, 3-dihydro-2H-
2
benzo[e] [1, 4] diazepin-2-one 6c: yellow powder, m.p.: 142.145°C;
FT-IR (KBr): 3426, 3138, 3069, 2928, 2862, 1661, 1601, 746, 700
cm 1. 1HNMR: δ = 3.41 (3H, s, Me), 5.26 (2H, dd, J = 17.5, 12,
−
3
NCH ), 5.64 (2H, s, OCH ), 6.89 (1H, s, CH), 6.99- 7.01 (2H, m,
2
2
2
CH), 7.27-7.32 (1H, m, CH), 7.39-7.49 (6H, m, 6CH), 7.54- 7.57
+
(
1H, m, CH), 7.68- 7.71 (4H, m, 4CH), 7.81-7.83 (3H, m, 3CH);
590 [M+H] ; Anal. Calcd for C34H28ClN5O3: C, 69.21; H, 4.78; N,
1
3
CNMR: δ = 35.1 (Me), 52.7 (NCH ), 67.7 (OCH ), 112.6 (CH),
11.87, Found: C, 69.11; H, 4.73; N, 11.91. 3-(2-((1-(4-bromobenzyl)-
2
2
3

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
Table 1
Solvent, temperature and time efficacy in the synthesis of 4aa
Entry
Base
Solvent
T (°C)
Time (h)
Yield b (%)
1
2
3
4
5
6
7
8
KOH
EtOH
r.t
3
10
25
45
23
-
KOH
EtOH
reflux
reflux
reflux
120
24
24
24
24
24
24
5
KOH
THF
KOH
Toluene
DMSO
CH3CN
Ac2O
KOH
TEA
reflux
reflux
reflux
-
NaOAc
KOt-Bu
-
t-BuOH
85
a
Diazepam 3 (1 equiv.); O-propargyl salicylaldehyde 2a (1 equiv.); base (1 equiv.); solvent (10 ml)
Isolated yield.
b
Scheme 3. Synthesis of O-propargyl salicylaldehydes 2a-c.
Scheme 4. Chemical structures of the synthesized 1,4-disubstituted-1,2,3-triazole-based diazepam 6a-i.
4

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
Scheme 5. Synthesis of 1,2,3-triazole-based diazepam 6j.
Scheme 6. Proposed mechanism for the synthesis of 6a-i.
1
H-1, 2, 3-triazol-4-yl) methoxy)-5-methoxybenzylidene)-7-chloro-1-
dihydro-2H-benzo[e] [1, 4] diazepin-2-one 6i: yellow powder, m.p.:
118-121°C; FT-IR (KBr): 3433, 3204, 3075, 2926, 2857, 1661, 1605,
methyl-5-phenyl-1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-one 6h:
yellow powder, m.p.: 144–148°C; FT-IR (KBr): 3441, 3136, 3069,
−1
1
752, 696 cm
.
HNMR: δ = 3.38 (3H, s, Me), 3.87 (3H, s, OMe),
−1
1
5.31 (2H, dd, 3J = 12.5, 62.5, NCH ), 5.62 (2H, s, OCH ), 6.83-6.86
2
926, 2857, 1659, 1605, 752, 694 cm
;
HNMR: δ = 3.35 (3H, s,
2
2
Me), 3.79 (3H, s, OMe), 5.18 (2H, dd, 3J = 25.5, 58.5, NCH ), 5.41
(2H, m, 2CH), 7.02 (2H, m, 2CH), 7.27-7.30 (1H, m, 1CH), 7.40 -
7.59 (7H, m, 7CH), 7.79-7.81 (2H, m, 2CH), 8.10 (2H, m, 2CH), 8.21
2
(
2H, s, OCH ), 6.78 (1H, s, CH), 6.93-7.20 (6H, m, 6CH), 7.25 (1H, m,
2
1
CH), 7.34-7.48 (6H, m, 6CH), 7.74-7.78 (2H, m, 2CH), 8.07 (1H, s,
(1H, s, CH); 13CNMR: δ = 34.9 (Me), 52.6 (NCH ), 55.4 (OMe), 66.4
2
CH); 13CNMR: δ = 35.5 (Me), 53.4 (NCH ), 55.8 (OMe), 67.0 (OCH ),
(OCH ), 111.9 (CH), 115.1 (C), 122.3 (CH), 122.5 (CH), 123.4 (CH),
2
2
2
112.3 (CH), 115.5 (C), 116.6 (CH), 122.8 (CH), 123.0 (CH), 123.9
123.6 (C), 127.9 (C), 128.2 (2CH), 128.4 (C), 128.7 (CH), 128.9 (CH),
129.0 (2CH), 129.3 (C), 130.8 (CH), 130.9 (2CH), 131.0 (CH), 136.6
(2CH), 139.6 (C), 141.3 (CH), 141.5 (C), 144.8 (C), 145.4 (C), 147.4 (C),
152.1 (C), 163.9 (C=O), 170.7 (C=N); Anal. Calcd for C34H27ClN O :
(
(
C), 128.7 (C), 129.2 (2CH), 129.3 (C), 129.8 (CH), 131.2 (CH), 131.3
2CH), 131.5 (C), 132.1 (CH), 133.9 (2CH), 134.8 (CH), 135.1 (2CH),
137.2 (C), 140.3 (CH), 141.8 (C), 143.2 (C), 146.0 (C), 152.6 (C), 161.3
6
5
+
(
C), 164.2 (C=O), 164.6 (C=N); MS (ESI): 670 [M+H] ; Anal. Calcd
C, 64.30; H, 4.29; N, 13.23, Found: C, 64.18; H, 5.64; N, 13.33. 3-
(4-((1-benzyl-1H-1, 2, 3-triazol-4-yl) methoxy) benzylidene)-7-chloro-
1-methyl-5-phenyl-1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-one 6j:
yellow powder, m.p.: 131-136°C; 1HNMR: δ = 3.14 (3H, s, Me),
for C
H BrClN O : C, 61.04; H, 4.07; N, 10.47, Found: C, 61.09;
27 5 3
34
H, 4.02; N, 10.44. 7-chloro-3-(5-methoxy-2-((1-(4-nitrobenzyl)-1H-
, 2, 3-triazol-4-yl) methoxy) benzylidene)-1-methyl-5-phenyl-1, 3-
1
5

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
Fig. 2. The B3LYP/6-31++G(d, p) optimized geometry of 6a and 6aˊ.
Fig. 3. Possible intramolecular C-H...N and C-H...O hydrogen bond interactions in the optimized structure 6a. Dashed lines represent hydrogen bonds. The bond distances are
in ( A˚ ).
Table 2
(
6H, m, 6CH), 7.54-7.58 (1H, m, CH), 7.63 (1H, s, CH), 7.75-7.80 (2H,
The representative B3LYP/6-31++G(d, p) calculated bond lengths and bond
angles for 6a.
m, 2CH), 7.98 (1H, s, CH); 13CNMR: δ = 35.5 (Me), 54.9 (NCH ),
2
6
6.0 (OCH ), 113.6 (CH), 114.8 (CH), 119.9 (C), 121.3 (2CH), 123.9
2
Atom groupsa
Bond lengths (A)
˚
Atom groups
Bond angles (o)
(CH), 126.2 (CH), 127.6 (C), 127.8 (2CH), 128.1 (2CH), 128.3 (2CH),
129.4 (CH), 129.7 (2CH), 129.8 (C), 130.7 (2CH), 131.5 (CH), 132.4
(CH), 132.9 (C), 134.5 (C), 134.9 (C), 135.8 (C), 140.9 (C), 148.9 (C),
O20-C11
N14-C11-C12
1.226
1.289
1.308
1.756
1.405
1.078
1.4275
1.082
117.6
120.0
109.7
120.4
121.9
120.6
115.7
108.2
N15-C13
N51-N52
C6-Cl10
C1-C2
C49-H50
C45-O44
C45-O44-C35
H17-C15-H19
C38-C39-C36
O20-C11-C12
H27-O23-H26
C33-C32-H43
H46-C45-H47
1
62.4 (C=O), 165.2 (C=N); Anal. Calcd for C33H26ClN O : C, 70.77;
5
2
H, 4.68; N, 12.51, Found: C, 70.70; H, 4.61; N, 12.55.
C34-H37
3. Results and discussion
a
For numbering of atoms refer Fig. 3.
3
.1. Synthesis and spectroscopic characterization of
1,2,3-triazole-based diazepam 6a-j
5
.17 (2H, dd, 3J= 24.0, 6.5, NCH ), 5.40 (2H, s, OCH ), 6.84 (1H,
The starting compounds 3-(2-(prop-2-yn-1-yloxy) benzylidene)-
1, 3-dihydro-2H-benzo[e] [1, 4] diazepin-2-one 4a-c are readily
2
2
s, CH), 6.90-6.95 (2H, m, 2CH), 7.07-7.19 (5H, m, 5CH), 7.37-7.49
6

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
Fig. 4. Frontier orbitals (HOMO and LUMO) and Eg for 6a resulted from the B3LYP/6-31++G(d, p) method.
Table 3
dition reaction 4a-c to the synthesis of 1,4-disubstituted-1,2,3-
triazole-based diazepam 6a-j. The desired 1,2,3-triazole 6a-j were
prepared by treatment of 4 (1 equiv.), benzyl bromide derivatives 5
The calculated electronic data of 6a by B3LYP/6-31++G(d, p)
method.
Parameter
Value
derivation
(
1 equiv.), NaN3 (1 equiv.), Cu(OAc)2 (0.2 equiv.) and sodium ascor-
Energy (Hartree)
2157.6
5.52
-
bate (0.2 equiv.) in water. The crude product was purified using
silica gel column chromatography to afford the desired products
μ
D (Debye)
-
EHOMO (eV)
−5.74
−2.32
3.42
-
6a-j in pure form. As shown in Scheme 4, using copper (II) acetate
ELUMO (eV)
-
in the presence of sodium ascorbate for an in situ reduction, the
desired products 6a-j were formed under mild condition. A diverse
range of benzyl bromide derivatives 5 reacted successfully with the
propargyl benzodiazepine derivatives 4a-c, and the corresponding
desired 1,2,3-triazole-based diazepam 6a-j were obtained in excel-
lent yields (70-98%). Structures of all the synthesized compounds
6a-j were fully characterized by FT-IR, 1HNMR, 13CNMR, MS (ESI)
and CHN analysis (Experimental section and electronic supplemen-
tary information). As a representative example, the spectral analy-
sis of 6a is discussed below.
Eg (eV)
ELUMO – EHOMO
(ELUMO+EHOMO)/2
(ELUMO–EHOMO)/2
Chemical potential (μ) (eV)
Chemical hardness (η) (eV)
Electrophilicity (ω) (eV)
−4.03
1.71
2
4.75
ω = μ /2η [45]
synthesized from the commercially available materials in high
yield and excellent purity in house. O-propargyl salicylaldehyde
derivatives 2a-c were prepared from the corresponding substituted
salicylaldehydes 1. Treatment of salicylaldehydes 1 with propar-
gyl bromide in the presence of K CO in DMF at room tempera-
The experimental 1HNMR spectrum of 6a in CDCl3 revealed a
singlet peak at δ = 3.53 ppm for CH3 and a doublet of doublet
resonance at δ = 5.34 ppm for the NCH2 group (electronic sup-
plementary material). The vinylic proton was observed at δ = 5.40
ppm as a distinct singlet signal. The methylene protons of OCH2
group in 6a appeared at δ = 5.63 ppm as a singlet line. The pro-
tons on aromatic rings were appeared at δ = 7.02–7.96 ppm. The
characteristic triazole proton was observed at δ = 7.77 ppm as
a singlet resonance. The 1H–decoupled CNMR spectrum of 6a
showed 29 signals, which is in accord with the proposed struc-
ture that the corresponding signals of Me, NCH2 and OCH2 groups
appeared at 35.6, 53.3 and 62.0 ppm, respectively. The sp2 carbon
2
3
ture for 12 h gave O-propargylbenzaldehyde 2a-c in 70–98% yields
(
Scheme 3) [34].
In the next step, diazepam 3 was subjected to condensation
with O-propargyl salicylaldehyde derivatives 2a-c under different
conditions (Table 1). The results showed that the best condition
and yield (85%) was obtained in the presence of KOt-Bu as a base
in refluxing t-BuOH for 5 h. Using the optimization condition, the
Knoevenagel adducts 4b, 4c and 4d (Scheme 4) were also synthe-
sized with high yields 87%, 81% and 90%, respectively.
13
With the propargyl benzodiazepine derivatives 4a-c in hand, at-
tention was focused on copper (I)-catalyzed azide-alkyne cycload-
7

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
Scheme 7. Possible nucleophilic carbon centers in 6a, based on APT charge analysis and electrophilicity index.
atoms were observed at 112.6–170.4 ppm, with the amide carbon
appearing at δ = 164.6 ppm and imine carbon (C=N) at δ = 170.4
ppm.
actions. Strong intramolecular hydrogen bonding was observed in
6a [H43…O44, 2.300 A] with the hydrogen atom (H43) as a donor
and the oxygen atom (O44) as an acceptor site. Analogous type of
these interactions has been discussed in the literature [43, 44].
The representative calculated bond lengths and bond angles of
6a are tabulated in Table 2. All bond lengths and bond angles
are in the normal range. The bond between C=O and C=N were
˚
The method’s applicability is further extended by performing
the [3 + 2] cycloaddition reaction of 4-O-propargyl benzaldehyde
derivative of 4d (1 mmol) with benzyl bromide 5 (1 mmol) and
NaN3 (1 mmol) (Scheme 5). The reaction was performed well, and
the desired product 6j is synthesized in good yield (74%).
A proposed mechanism for the domino condensation-click re-
action is illustrated in Scheme 6. The first step is condensation be-
tween diazepam and O-propargyl salicylaldehyde 2a–c. Next, a Cu
˚
found to be 1.226 and 1.289 A, respectively. Carbonyl group in 6a
has a resonance structure that emphasizes the pi-donor proper-
ties of the amine group. This bonding arrangement is confirmed
by a short C10–N31 distance (1.394 A) and the planarity of the
O20-C11 -C14 core (120.3°). Thus, the molecule 6a has two planar
˚
(
II) ion is enhanced to the reaction that in the presence of sodium
N14 C11 =O and C
20
13 15
N
=C groups lying in the plane with C(sp )-
12
2
ascorbate reduced to the Cu (I). The triple bond is activated with
Cu (I) through the formation of a copper acetylide complex, after-
ward coordination of organic azides to the acetylide, initiates an
azide-alkyne 1,3-dipolar cycloaddition to form the desired products
3
H and C(sp )-H bonds. The noncovalent intramolecular hydrogen
bonds stabilize such arrangement (Fig. 3).
The calculated total energy, dipolar moment (μ ) and electronic
D
6
a-j. In the end, the Cu (I) is separated from the reaction medium
data such as electrophilicity and nucleophilicity index of 6a are
inserted in Table 3. The all electronic data are reactivity descrip-
tors, which obtained from the HOMO and LUMO energies of 6a.
The dipole moment is an important physical parameter of the elec-
tronic distribution in a molecule, which can be related to the in-
teraction strength of the molecule with metal ions. The calculated
dipole moment value of 6a is 5.52 D, which reveals high dipolar
properties. The presence of polar functional groups such as amide
moiety and the asymmetric chemical structure of 6a are the main
reasons for this high dipolar moment value.
[
36, 37].
3
.2. Theoretical studies on the characterized 1,2,3-triazole-based
diazepam 6a
Quantum computational modelling methods such as DFT can be
utilized in chemistry to get the structural/electronic properties of
chemical systems. With the encouraging experimental data of 6a-i,
our attention was turned on DFT calculations to investigate physic-
ochemical properties of the synthesized compounds such as struc-
tural parameters (bond lengths and bond angles) and electronic
data (electrophilicity and nucleophilicity index, APT charge distri-
bution, and molecular electrostatic potential analysis). It should be
mentioned that nowadays, the DFT method in connection with the
hybrid functional B3LYP (DFT-B3LYP) is utilized by chemists as a
robust method for a variety of chemical quantum calculations [38-
The gap between the highest occupied molecular orbital
(HOMO, π donor) and lowest unoccupied molecular orbital (LUMO,
π acceptor) energy levels (Eg) is a helpful hint to determine the
chemical reactivity of an organic compound. As the Eg value de-
creases, the reactivity of the compound increases [45]. Fig. 4 shows
the graphical sketches of HOMO and LUMO orbitals for 6a. The
HOMO and LUMO orbitals are mainly localized on the diazepam
framework.
4
2]. The DFT-B3LYP computational method supplies a good balance
between placed and localized bond structures. This method has
been used here for performing the related computations. It should
be noted that structure 6a can exist in two geometric forms of Z-
and E-isomers, due to C=C. The B3LYP/6-31++G(d, p) optimized
structures of 6a (Z-isomer) and 6aˊ (E-isomer) are shown in Fig. 2.
Electrophilicity index (ω, eV) as a trustable and valuable de-
scriptor for quantitative classification of the electrophilic nature
of the organic molecules is calculated as 4.75 (eV). Electrophilic-
ity can be categorized based on Domingo’ scale [46]. Based on
this scale, electrophiles are divided into three groups based on
the electrophilic index: strong, mild and weak. When the elec-
trophilic index ω is more than 1.5 eV, the electrophile is strong;
in the range of 0.8 to 1.5 eV, it is mild and less than 0.8 eV the
electrophile is weak. Based on this scale, compound 6a is strong
electrophile and can easily interact with a nucleophile. The atomic
polar tensor (APT) charge distribution for the structure of 6a is
−1
The Z-isomer is 93.48 kJ mol more stable than the corresponding
E-configuration. In this study, attention was focused on Z-isomer
(
6a). It should be mentioned that the Z-isomer (6a) can be stabi-
lized by some favorable intramolecular interactions between acid
and base groups (Fig. 3). As shown in Fig. 3, the stabilization of 6a
is due to intramolecular C–H...N and C–H...O hydrogen bond inter-
8

Z. Esmaeeli, M.R. Khodabakhshi, Z. Mirjafary et al.
Journal of Molecular Structure 1246 (2021) 131206
Fig. 5. Molecular electrostatic potential map for 6a.
shown in Fig. 33S (electronic supplementary material). According
to APT charge distribution analysis there is a remarkable excess
of positive charge (1.230e) on the carbon atom of the carbonyl
group (C11 =O20). The study also indicates that the carbon atom
of the imine unit (N1 =C13), C32 and C45 bear a positive charge
energies) and molecular electrostatic potential map for the synthe-
sized compound 6a were also calculated by applying DFT-B3LYP/6-
31++G(d, p) method.
5
Declaration of Competing Interest
0
.670, 0.145 and 0.735e, respectively. APT charge analysis and elec-
trophilicity index of 6a show that a nucleophile can attack to these
positive carbon centers (Scheme 7).
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
The molecular electrostatic potential (MEP) maps can also be
used to identify the sites for the electrophilic and nucleophilic at-
tack in 6a [47]. The MEP map for 6a is represented in Fig. 5. In the
MEP map, red shows areas of most negative electrostatic poten-
tial, the minimum electrostatic potential and act as electrophilic
attack, while blue corresponds to areas of most positive electro-
static potential, the maximum of electrostatic potential and act as
nucleophilic attack. As shown in Fig. 5, the most negative charge
on the MEP map of 6a is associated with the nitrogen atoms of
triazole ring. The MEP pattern also shows negative region (yellow)
around the oxygen of the carbonyl unit (C=O). Oxygen and nitro-
gen atoms can interact through hydrogen bonding with amino and
hydroxyl groups on a biological molecule and electron-deficient
sites. The C11 , C13, C32 and C45 atoms in MEP maps of 6a are posi-
tive (pale blue region), and a nucleophile can be approached these
sites more readily than other atoms, according to the above expla-
nations (Scheme 7).
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.131206.
CRediT authorship contribution statement
Zohreh Esmaeeli: Formal analysis, Investigation, Resources,
Software, Validation, Visualization. Mohammad Reza Khod-
abakhshi: Conceptualization, Formal analysis, Investigation,
Resources, Software, Validation, Visualization, Writing – review
& editing. Zohreh Mirjafary: Writing – review & editing. Hamid
Saeidian: Conceptualization, Formal analysis, Investigation, Re-
sources, Software, Validation, Visualization, Writing – review &
editing.
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