Mechanistic perspectives on piperidine-catalyzed synthesis of 1,5-benzodiazepin-2-ones

Article abstract of DOI:10.1016/j.mcat.2020.110774

This work introduced new members to the pharmaceutical family of 1,5-benzodiazepin-2-ones, 2_a–e. These compounds were synthesized in moderate yields via the reaction of 1,2-bifunctional substrates (α-cyanocinnamates) with o-phenylenediamine in

Full text of DOI:10.1016/j.mcat.2020.110774

MolecularCatalysis484(2020)110774
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Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Mechanistic perspectives on piperidine-catalyzed synthesis of 1,5-
benzodiazepin-2-ones
Hanaa Mansoura, Morad M. El-Hendawyb,*
a Department of Chemistry, Faculty of Science, Kafrelsheikh University, Kafrelsheikh 33516, Egypt
b Department of Chemistry, Faculty of Science, New Valley University, Kharga 72511, Egypt
A R T I C L E I N F O
A B S T R A C T
Keywords:
1,5-Benzodiazepin-2-one
Organocatalyst
Ethanol-assisted mechanism
Density functional calculations
This work introduced new members to the pharmaceutical family of 1,5-benzodiazepin-2-ones, 2a–e. These
compounds were synthesized in moderate yields via the reaction of 1,2-bifunctional substrates (α-cyanocinna-
mates) with o-phenylenediamine in xylene. The conduction of the above reaction in the presence of piperidine
has produced amazing product, N-alkenylimidazolone derivative (5), in addition to the traditional one, 1,5-
benzodiazepin-2-one (2a) in 3:1 ratio. The density functional theory (DFT) could successfully explain the role of
piperidine as an organic catalyst to produce both products in this ratio through ethanol-assisted mechanisms. It
is also amazing that we could obtain 5 solely by the dry fusion of 2a through the thermal contraction of dia-
zepinone ring into imidazolone one. The mechanism of diazepinone-imidazolone transformation was proposed
and validated by the DFT calculations. The findings showed that the precise proton transfer of primary amino
hydrogen of 2a is the play-maker in the reaction game. The proposed mechanisms of the three transformations
can be useful for investigation of the formation and deformation of other 1,5-diazepine systems.
1. Introduction
lactone within EtOH at reflux provided the 1,5-benzodiazepin-2-one
after amide formation, mediated by t-BuMgBr [29]. The most used
Design of privileged structures having valuable pharmacological
benefits such as 1,5-benzodiazepin-2-ones is a targeted strategy in
medicinal chemistry because they have a broad range of treatments
such as analgesic, anti-aggressive, psychotropic, anticonvulsive, and
anti-proliferative activities [1–7]. Fig. 1 shows some commercial drugs
based on 1,5-benzodiazepin-2-one scaffold include lofendazam, arfen-
dazam, and clobazam [5]. It is evident that there is an increasing need
in medicinal chemistry to introduce new scaffolds [3,8–19]; thus, our
goal herein was the addition of new members to this family.
procedure for the synthesis of 1,5-benzodiazepin-2-ones was conducted
by condensation of OPD with β-ketoesters [30,29–35]. The presence of
an active methylene segment played an essential role in the mechanism.
The novelty of the present work is the conduction of piperidine-cata-
lyzed synthesis via coupling of OPD with the 1,2-bifunctional substrate
(α-cyanocinnamate), i.e., with the absence of active methylene seg-
ment. On the other hand, we proposed reaction mechanisms to explain
these transformations, and the DFT method examined their validity.
Methods for the synthesis of benzodiazepines were formed mainly
via coupling of o-phenylenediamine (OPD) with a variety of ketones
[20] and chalcones [21], alkynes and other precursors [22–25]. The use
of an inexpensive substrate with a simple catalytic system for synthesis
of new members of benzodiazepine-based family with the formation of
multiple bonds (CeC/C]N/CeN), remains a highly desirable and
continuous goal in current organic synthesis [26,27]. Recently great
efforts have been made to develop new members in the 1,5-benzodia-
zepin-2-one family [28–35]. For instance, copper-catalyzed arylation of
2-azetidinone with 2-iodoaniline followed by transamidation promoted
by 50 mol% Ti(OiPr)4 in toluene at 110 °C provided 1,5-benzodiazepin-
2-one in excellent yield [28]. Also, the reaction of OPD with spiroepoxy
2. Results and discussions
2.1. Synthesis and characterization
According to the pathway shown in Scheme 1, a stepwise synthesis
of 1,5-benzodiazepin-2-ones 2a−e was carried out under simple reac-
tion conditions (Scheme 1). Firstly, and according to Knoevenagel
procedure [36], α-ethylcyanocinnamate derivatives (1a−e) were syn-
thesized from the condensation of ethylcyanoacetate and various al-
dehydes in ethanol with addition of few drops of piperidine at 0 °C.
Subsequently, 2a−e was successfully synthesized from mixing a molar
ratio of 1 and OPD in xylene. The mixture was refluxed with stirring for
⁎ Corresponding author.
E-mail address: morad.elhendawy@scinv.au.edu.eg (M.M. El-Hendawy).
https://doi.org/10.1016/j.mcat.2020.110774
Received 26 September 2019; Received in revised form 5 January 2020; Accepted 12 January 2020
2468-8231/©2020ElsevierB.V.Allrightsreserved.

H. Mansour and M.M. El-Hendawy
MolecularCatalysis484(2020)110774
Fig. 1. Some commercial drugs based on a 1,5−benzodiazepin−2−one scaffold [1,2, 4−7].
xylene with the elimination of one ethanol molecule as confirmed by
mass spectra and elemental analysis. IR absorption band of the cyano
group disappeared in the spectrum of 3, and instead, new bands ap-
peared around 3400 and 1590 cm−1, which assigned for stretching vi-
bration of the amino and > C]N groups, respectively. This could in-
dicate the addition reaction at the cyano group. The characteristic
bands at 1660 cm−1 assigned for stretching vibration of the amide
carbonyl group, which confirm the intramolecular cyclization reaction.
1H NMR spectrum of 3 exhibits a multiplet band around δ = 2.35 ppm
corresponding to the CH2 protons. The NH2 and NH protons were ob-
served at δ = 7.63−7.64 and 12.73−12.75 ppm (exchanged by D2O),
respectively. The characteristic aromatic protons were observed in the
region of δ = 7.22−7.61 ppm. N−methylation of 3 using methyl io-
dide, followed by subsequent condensation with the p-chlor-
obenzaldehyde in glacial acetic acid under boiling conditions, produced
the products, 1,5−benzodiazapin−2−ones (4a), Scheme 1. A com-
parison of this material with that obtained via methylation of 1,5-
benzodiazepin-2-ones 2c using methyl iodide showed identity by all
criteria evaluated. 1H and 13C NMR spectra of the methylated product,
4c, showed that both the primary and secondary amine nitrogen atoms
had been methylated. The NHCH3 and NCH3 bands in 4c are coming at
3.80 and 3.85 ppm in the 1H NMR spectrum and 31.5 and 33.4 ppm in
the 13C NMR spectrum, respectively.
Amazing product, N‒alkenylbenzimidazolone (5) in addition to the
expected product, 1,5-benzodiazepin-2-one derivative (2a) were ob-
tained by 1:3 ratio as a result to the piperidine-catalyzed reaction of 1a
and OPD, Scheme 2. It is worth mentioning that Kumar and Kapoor
have reported that this reaction under thermal conditions yielded ethyl
2−cyano-3−phenyl−propionoate, 2−phenyl benzimidazole, and
ethyl cyanoacetate without production of benzodiazepinone [38].
Interestingly, compound 5 was successfully prepared solely by ei-
ther of dry fusion (45 % yield) of the 2a or the reaction of 1a with OPD
in dilute hydrochloric acid (55 % yield), see Scheme 2 & Table 1. FD+
Scheme 1. Synthesis of the benzodiazepinones 2a-e: (i) EtOH / piperidine at
0 °C; (ii) xylene / reflux; (iii) methyl iodide; (iv) xylene / reflux; (v) methyl
iodide, (vi) glacial acetic acid.
different times (see experimental part), which led to the formation of
colorless to brown materials on cooling with about 50 % yield. Different
spectroscopic techniques, such as IR, 1H NMR, 13C NMR, and mass
spectrometry, were used to confirm the formation of 2a−e; see the
supporting information. The comparison of mass spectra of the products
with those of the reactants confirms the elimination of only one ethanol
molecule. IR absorption spectra of the enaminone group show a broad
band around 3426 cm−1 assigned for the NH groups. Also, the absence
of the stretching frequency of cyano groups refers to the addition to that
group. Characteristic bands were observed in the range of
1610−1627 cm−1, which may be assigned for the (NHeCOeC]C)
enaminone group [37]. Furthermore, the presence of the enaminone
group in the products has been also proved by the decolorization of
bromine in chloroform. 1H NMR spectra of 2a−e exhibit broad bands
around δ = 6.50 ppm (exchanged by D2O) for three protons, which
further confirm the presence of NH and NH2 groups.
To further prove the structures of 1,5-benzodiazepin-2-ones, 2a−e, a
different route has been conducted, as shown in Scheme 1. The first step
is the formation of 3 from the reaction of ethylcyanoacetate and OPD in
Scheme 2. Synthesis of N‒alkenylbenzimidazolone 5 via different conditions; i)
xylene; ii) EtOH / piperidine; iii) EtOH, dil. HCl; iv) dry fusion, 200 °C.
2

H. Mansour and M.M. El-Hendawy
MolecularCatalysis484(2020)110774
Table 1
Reaction conditions optimization.
+
Solvent
Catalyst
Temp.
Ar = ph
xylene
xylene
xylene
xylene
xylene
EtOH
EtOH
–
–
–
–
–
reflux
reflux
reflux
reflux
reflux
r.t.
50 %
–
–
–
–
Ar = p–OCH3–ph
Ar = p–Cl–ph
Ar = m–HO–ph
Ar = m–Cl–ph
Ar = ph
59 %
51 %
52 %
50 %
40 %
–
–
–
piperidine
HCl
–
35 %
55 %
45 %
Ar = ph
Ar = ph
r.t.
dry fusiona
a
Dry fusion of the 1,5-benzodiazepin-2-one.
mass (THF) of 5 exhibited peak at m/e = 263 corresponding to the
molecular ions peaks, [5]+. An IR broad band at 1920 and 840 cm−1
assigned for NH]CeC]C fragment, while the NH group appears at
3400 cm−1. A characteristic band at 1627 cm−1 assigned for the imide
carbonyl (NHC]O) group. Moreover, the 1H NMR spectrum of 5 is
coordinate for ethanol-assisted and thermal contraction mechanisms
are shown in the Supporting information.
2.2. Computational mechanistic investigations
characterized by the appearance of
a
broad band at
2.2.1. The first transformation: a piperidine-catalyzed synthesis of 1,5-
benzodiazepin-2-one, 2a
δ = 6.41−6.61 ppm that corresponds to the three protons of NH and
NH2 (exchanged by D2O). The α-styryl moiety was indicated by the
appearance of two vinyl proton signals, cis, and trans to the phenyl ring,
at δ = 5.50 and 5.81 ppm [39]. The mechanism of diazepinone-imida-
zolone conversion, shown in Scheme 2, was studied deeply by the DFT
method, as shown in the following section.
In order to study the reaction mechanisms and provide an ex-
planation for the different outcomes of the transformations shown in
Scheme 2, DFT calculations have been carried out. Ethanol, as a polar
solvent, should play an essential role in stabilization of different in-
termediates and transition states species, especially in the case of
proton transfer steps [40]. Thus, explicit consideration of one ethanol
molecule was involved in the modeling to simulate experimental con-
ditions. For simplicity, the ethanol molecules are not shown in Schemes
3 & 4 . The intermediates and transition states are denoted as Intn and
The proposed mechanism for the piperidine-catalyzed synthesis of
2a in EtOH is presented in Scheme 3, and its free energy profile is shown
in Fig. 2. The reaction initiates by a fast step (6.09 kcal/mol), i.e., nu-
cleophilic addition of the secondary amine (piperidine) to the carbonyl
group of 1a to form stable carbinolamine intermediate, Int1. Formation
of new C–NPIP bond between 1a and PPR is coupled with proton
transfer from the later to the former with the assist of one ethanol
molecule, as shown in Fig. 2. The next step is slightly endergonic by
0.48 kcal/mol, where the ethoxy group leaves the Int1 to afford Int2
and one ethanol molecule through TS1-2 with an activation barrier
16.02 kcal/mol. In this context, CeOEtOH single bond broke with in-
tramolecular proton transfer from hydroxyl oxygen to the ethoxy
oxygen atom. Int2 is essential species because it defines the direction of
the reaction. It possesses two active groups, > C]O, eC^N; thus, the
addition of OPD could occur on the electrophilic carbon of both of them
to afford both 2a and 5 in the reaction mixture by ratio 1: 3, respec-
tively, Schemes 3 & 4 . The carbon center of a nitrile is electrophilic;
TSn1-n2, respectively, where n1 and n2 refer to the initial and final
intermediates around the transition state, respectively. The Cartesian
coordinates of the optimized transition states located along the reaction
Scheme 3. Proposed mechanism for the piperidine-catalyzed synthesis of 1,5−benzodiazepin-2−one, 2a, in EtOH.
3

H. Mansour and M.M. El-Hendawy
MolecularCatalysis484(2020)110774
Scheme 4. The proposed mechanism for the piperidine−catalyzed the synthesis of N‒alkenylbenzimidazolone, 5, in EtOH. The structures from reactants until TS1-2
are shown in Scheme 3.
Fig. 2. Free energy profile of the piperidine-catalyzed synthesis of 1,5-benzodiazepin-2-one, 2a, in EtOH. The red dashed line shows the overall activation barrier.
(For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
4

H. Mansour and M.M. El-Hendawy
MolecularCatalysis484(2020)110774
Fig. 3. Free energy profile of the piperidine-catalyzed synthesis of N˗alkenylimidazolone derivative, 5, in EtOH.
hence it is susceptible to the nucleophilic addition of the amino group
of OPD. According to the calculations, the addition of OPD to the nitrile
group represents a concerted process where the formation of CeNOPD
bond and proton transfer occurred in one step. This step requires acti-
vation energy of 15.01 kcal/mol to produce exergonic intermediate,
Int3, by 3.65 kcal/mol. The fourth step is imine-amine tautomerism that
affords an endergonic species with an energy barrier of 19.27 kcal/mol.
The elimination of piperidine (TS4-p in Fig. 2) is the rate-limiting step
with an overall free energy barrier of 28.76 kcal/mol to afford the final
product, 2a, which is staying only 0.85 Kcal/mol above the initial re-
actants.
exocyclic carbonyl group to form a new CeNOPD bond to break CeCOPD
bond leading to imidazolone ring. In other words, the lifetime of the
high energetic species, Int7, is short because of the strain effect from the
four-membered ring. Thus, the ring-opening of the azetidinone ring is
an easy task for the sake of the formation of less strain five-membered
ring. This molecular adaptation could be explained by the low activa-
tion energy of 15.81 kcal/mol to furnish the externally exergonic pro-
duct, 5, by 33.88 kcal/mol. The rate associated with this process is
expected to be much higher than that leading to 2a, where the forma-
tion of 5 is 3.62 kcal/mol more favorable than that of 2a see Figs. 2 & 3 .
After all, according to DFT findings, it can be stated that the formation
of 2a and 5 can co-occur with the kinetic and thermodynamic preferable
formation of the later as the main product, in accord with the experi-
mental results.
2.2.2. The second transformation: a piperidine-catalyzed synthesis of N-
alkenylimidazolone (5)
On the other hand, the Int2 interacts with OPD differently where
the amino group of the later acts as a nucleophilic center to attack the
electrophilic carbon of carbonyl group in the Int2 to produce an iso-
energetic intermediate, Int5. In such a case, the formation of a new
CeN bond between OPD and Int2 is coupled with proton transfer from
the less electropositive N-atom toward the electronegative O-atom of
Int2 formed through TS2-5 with free energy barrier 12.28. It is evident
that the activation barrier of Int2→Int5 is more kinetically favorable
than that of Int2→Int3, by ca. 3 kcal/mol, see Figs. 2 & 3 . This could
explain the simultaneous attack of OPD on the nitrile and carbonyl
carbon of Int2, with the preferable production of the former.
The next step is the elimination of piperidine from Int5 to re-
generate carbonyl group again in Int6. To eliminate piperidine from
Int5, 13.78 kcal/mol is needed to break the CeN bond and to transfer
proton from the hydroxyl group to the piperidine nitrogen. The cycli-
zation step leading to 2-azetidinone ring formation, Int7, is a rate-de-
termining step for this reaction with an overall energy barrier of
25.14 kcal/mol. The formation of high endergonic Int7 (14.47 kcal/
mol) occurred in a concerted step as a result of concurrent proton
transfer from the secondary amine nitrogen to the imine nitrogen with
CeNOPD bond formation. The reaction ended by intramolecular nu-
cleophilic substitution, SN2, where the free primary amine attack the
2.2.3. The third transformation: thermal ring contraction of the
benzodiazepinones 2a
The proposed mechanism to account for the formation of
N−alkenylimidazolone 5 via thermal ring contraction of the benzo-
diazepinones 2a is depicted in Scheme 5. The calculations were per-
formed in the gas phase to simulate the dry fusion experimental con-
dition. The detailed theoretical analysis (Fig. 4) showed that the
thermal ring contraction reaction could be described as a sequential
three-step process. The initial step is the proton mediated amine/imine
tautomerization of 2a into Int8 that is exergonic by 2.52 kcal/mol). As
2a moves to Int8, significant structural changes occur through a four-
membered ring transition state, TS2-8, where N1eH1 and N3eH1 bonds
are elongated to 1.355 and 1.376 Å, respectively with a high activation
barrier, 20.56 kcal/mol. The formation of Int8 is followed by the in-
tramolecular nucleophilic addition of the secondary amine (eN1H1e)
on the carbonyl group (> C9]O1) to afford a highly endergonic spe-
cies, diazabicyclo[3.2.0]heptanol, Int9, i.e., 14.86 kcal/mol higher than
2a. In this step, the diazepine ring split into the bicyclic ring, where a
new C1eN9 bond is formed and proton transferred from the secondary
amine hydrogen into the carbonyl oxygen. The final step is the in-
tramolecular nucleophilic substitution, SN2, on the exocyclic C8]C10
5

H. Mansour and M.M. El-Hendawy
MolecularCatalysis484(2020)110774
Scheme 5. The thermal ring contraction mechanism of 1,5-benzodiazepin-2-one, 2a, into N−alkenylimidazolone derivative 5.
double bond, where the C8eC9 bond broke as a result of proton transfer
to C8 through TS9-p four-membered transition state, leading to the
scission of the azetidinone ring and furnished the final product, 5. The
depicted free energy profile in Fig. 4 shows that the intramolecular
nucleophilic addition in Int8 is the rate-limiting step along the reaction
path with a free energy of 26.70 kcal/mol. Careful analysis of potential
energy surface, Fig. 4, showed that the precise transfer of amino hy-
drogen (red-colored) through N1, O1, and eventually bonded to C8 atom
is the play-maker in the reaction game.
3. Conclusions and future work
A simple uncatalyzed method was employed to synthesize new
members of the 1,5-benzodiazepin-2-ones family (2a–e) via the reaction
of α-ethylcyanocinnamate derivatives with o-phenylenediamine in xy-
lene. The use of piperidine as a catalyst could successively lead to the
formation of N−alkenylimidazolone derivative (5) in addition to the
expected
product,
1,5-benzodiazepin-2-one
derivative
(2a).
Interestingly, 5 was successfully prepared solely by the fusion reaction
of 1,5−benzodiazepinones 2a. Reaction mechanisms were proposed to
explain these transformations and have been validated by DFT
Fig. 4. Free energy profile of the thermal ring
contraction mechanism of 1,5-benzodiazepin-
2-one, 2a, into N-alkenylimidazolone deriva-
tive 5. The optimized structure of transition
states is involved in the figure. All hydrogen
atoms are omitted for clarity except the inter-
esting ones. (For interpretation of the refer-
ences to colour in the text, the reader is re-
ferred to the web version of this article.)
6

H. Mansour and M.M. El-Hendawy
MolecularCatalysis484(2020)110774
theoretical analysis. The findings showed the piperidine-catalyzed re-
action 1a + OPD→5 is more kinetically and thermodynamically fa-
vorable than that of 1a + OPD →2a by ca. 3 kcal/mol. DFT could
successfully explain why 5 was the major product relative to 2a. We
proposed a valid mechanism to account for the formation of 5 via the
thermal ring contraction of the 2a. The calculated results are in
agreement with the experimental data. Besides, we are going to ex-
amine the pharmaceutical properties of the newly synthesized com-
pounds.
Ar−H); 7.69−7.71 (d, 3H; Ar−H, NH exchanged by D2O); 8.21−8.23
(d, 2H, Ar−H). 13C NMR (100 MHz, DMSO−d6): δ = 111.4 118.9,
121.7, 122.7, 128.1, 135.0, 143.7, 150.1. IR (KBr): ν = 3447(NeH),
3055(CeHarom), 2994(CeHaliph), 1605(C]CeC]O), 1477(C]N),
cm−1. Anal. %, Calcd. for C16H12N3OCl: C, 64.53; H, 4.03; N, 14.11;
Found: C, 64.28; H, 3.90; N, 14.10. MS (FD+, THF): m/z = 279 [M]+
4-amino−3−(m−hydroxy)phenylidine−1,5-benzodiazepin-2-
.
one (2d): It was obtained as colorless needles (52 % yield), m. p. 266 °C.
IR
(KBr):
ν = 3400(NeH),
3100(CeHarom),
2936(CeHaliph),
1584(C]CeC]O), 1466(C]N), cm−1
.
Anal. %, Calcd. for
4. Experimental and computational details
C
16H13N3O2: C, 68.81; H, 4.65; N, 15.05; Found: C, 68.90; H, 4.50; N,
15.68.
4-amino−3−(m−chloro)phenylidine−1,5-benzodiazepin-2-one
4.1. Instrumental measurements
(2e): It was obtained as colorless crystals (50
% yield), m. p.
All melting points are uncorrected; they were performed by the
open capillary using electrothermal melting MEL_TEMP II apparatus. IR
spectra were recorded a UNICAM SP 1200 spectrophotometer using
pellet technique KB discs. Micro-analysis was performed in the Faculty
of Science, Cairo University, Cairo, Egypt. 1H NMR spectra were re-
corded with Bruker AC spectrometer (200 MHz). 13C NMR spectra were
recorded Bruker AC spectrometer (200 MHz). TMS was used as an in-
ternal standard, and chemical shifts are expressed in δ ppm values. The
mass spectral data were obtained with micromass spectrometer model
7070F at an energy of 70 eV and inlet temperature 90 °C. All analytical
samples were homogenous by thin-layer chromatography, which was
performed on EM silica gel 60F254 sheet (0.2 mm) the compounds were
detected by UV light (254 nm). Ethylcyanoacetate was purchased from
Aldrich, and α-ethylcyanocinnamate derivatives (1a−e) were synthe-
sized as described in the literature using the Knoevenagel procedure
[37].
220−224 °C. 1H NMR (DMSO−d6): δ = 7.00−7.38 (m, 7H; NH2, ex-
changed by D2O, Ar−H, C−H arom.); 7.73−7.78 (m, 2H, Ar−H);
8.05−8.17 (m, 3H; Ar−H, NH exchanged by D2O). 13C NMR (100 MHz,
DMSO−d6): δ = 111.52, 115.5, 125.0, 126.0, 129.6, 131.0, 132.2,
133.8, 149.7. IR (KBr): 3424(NeH), 3038(CeHarom), 2957(CeHaliph),
1600(C]CeC]O), 1533(C]N), cm−1
.
Anal. %, Calcd. for
16H12N3OCl: C, 64.53; H, 4.03; N, 14.11; Found: C, 64.40; H, 4.13; N,
14.49.
C
4−amino−3-dihydro−1,5−benzodiazepin(1H)−2−one (3): A
mixture of o-phenylendiamine (1.08 g, 0.01 mole) and ethylcyanoace-
tate (1.59 ml, 0.015 mol) in 40 ml xylene was brought to boil and the
water, formed during the reaction, was separated by azeotropic dis-
tillation. Faint brown crystals began to separate after 2 h. The reaction
mixture was heated for 8 h in the course of which, faint brown crystals
formed. The product was collected by filtration and crystallized from
ethanol to give needle crystals (70 % yield), m. p. 200−205 °C. 1H NMR
(DMSO-d6): δ = 1.97–2.00 (m, 2H, CH2); 7.20–7.31 (m, 2H, Ar−H);
7.57–7.61 (m, 2H, Ar−H); 7.63–7.64 (b, 2H, NH2 exchanged by D2O);
12.73–12.74 (b, 1H, NH exchanged by D2O). IR (KBr): ν = 3400(NH2),
3051(CeHarom), 2946(CeHaliph), 1664(C]O), 1594(C]N) cm−1. Anal.
%, Calcd. for C9H9N3O: C, 61.70; H, 5.18; N, 23.99; Found: C, 61.90; H,
4.2. Synthetic methods
4.2.1. 4-Amino-3-arylidine-1,5-benzodiazepin-2-one derivatives (2a−e
)
4.2.1.1. General methods. A mixture of OPD (1.08 g, 0.01 mol) and α-
cyanocinnamate derivatives 1a-e (0.015 mol) in 40 ml xylene was
brought to boil, and the ethanol that formed during the reaction was
separated by distillation. Tan crystals began to form according to the
reaction mixture, and the mixture was further heated for an additional
6−8 h (TLC monitoring). The reaction mixture was cooled, and the
product was collected by filtration and crystallized twice from ethanol
5.00; N, 23.80. MS (FD+, THF): m/z = 175 [M]+
.
1-methyl-4-(N-methylamino−3−(p−chloro)phenylidine−1,5-
benzodiazepin-2-one (4c): A mixture of 2c (0.01 mole) and sodium
ethoxide (0.01 mmol) in absolute ethanol, was stirred at 0 °C. Methyl
iodide (0.02 mmol) was added dropwise, and the reaction mixture was
stirred for 3 h at room temperature. The resultant crystals were col-
lected, dried, and recrystallized to give 5 in 50 % yield. M. p. 206 °C.
1H NMR (DMSO−d6): δ = 8.11–7.98 (m, 1H, Ar−H); 7.88−7.76 (m,
3H, Ar−H); 7.67−7.60 (m, 3H, Ar−H); 7.20−7.16 (b, 1H, NH ex-
changed by D2O); 3.87–3.84 (s, 3H, NCH3); 3.80–3.75 (s, 3H,
NCH3).13C NMR (100 MHz, DMSO-d6): δ = 152.3, 150.8, 142.6, 136.6,
134.7, 131.5 130.4, 130.1, 138.10, 136.0, 127.7, 125.0, 123.3, 122.7,
119.9, 112.9, 109.1, 33.4 (NCH3), 31.5 (NCH3). IR (KBr):
to give needles crystals of 2a-e
.
4-amino−3−phenylidine−1,5-benzodiazepin-2-one (2a): It was
obtained as pale gray crystals (50 % yield); M. p. 290−291 °C. 1H NMR
(DMSO−d6): δ = 6.41−6.61 [b, 4H; NH2, NH (exchanged by D2O), 1H,
Ar−H]; 7.33−7.35 (t, 2H, Ar−H); 7.59 (s, 1H, C−Harom.); 7.69−7.70
(m, 4H, Ar−H); 8.27−8.29 (m, 2H, Ar−H). 13C NMR (100 MHz,
DMSO−d6): δ = 151.2, 130.1, 129.7, 128.9, 126.4, 122.0. IR (KBr):
ν = 3423(NeH), 3053(CeHarom), 2921(CeHaliph), 1604(C]CeC]O),
1492(C]N) cm−1. Anal. %, Calcd. for C16H13N3O: C, 73.00; H, 4.94; N,
15.96; Found: C, 73.90; H, 5.10; N, 15.10. MS (FD+, THF): m/z = 263
[M+].
ν = 3350(NH),
3049(CeHarom),
2929(CeHaliph),
1610(C]O),
1500(C]C) cm−1. Anal. %, Calcd. for C18H16ClN3O: C, 66.36; H, 4.95;
N, 12.90; Found: C, 66.90; H, 5.00; N, 11.98. MS (FD+, THF): m/
z = 325 [M]+
.
4-amino-3-(p-methoxy)phenylidine-1,5-benzodiazepin-2-one (2b):
It was obtained as yellowish crystals (59 % yield); M. p. 225−226 °C.
1H NMR (DMSO−d6): δ = 3.94 (s, 3H, OCH3); 7.20−7.32 (m, 6H,
Ar−H, NH2, NH exchanged by D2O); 7.65−7.69 (m, 3H; Ar−H, C−H
arom); 8.20−8.24 (d, 3H, Ar−H). 13C NMR (100 MHz, DMSO−d6):
δ = 55.3, 113.8, 114.3, 128.0, 130.1, 151.2, 160.6. IR (KBr):
ν = 3426(NeH), 3055(CeHarom), 2921(CeHarom), 1610(C]CeC]O),
1500(C]N), cm−1. Anal. %, Calcd. for C17H15N3O2, C, 69.62; H, 5.11;
N, 14.33; Found: C, 70.10, H, 5.40; N, 13.90. MS (FD+, THF): m/
4.2.2. 1-(1-Imino-3-phenylallyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one
(5)
4.2.2.1. Method A. A mixture of OPD (1.08 g, 0.01 mole) and α-
cyanocinnamate (1a) (0.015 mol) in 50 ml of absolute ethanol and a
catalytic amount of piperidine were heated under reflux for 3 h. The
reaction mixture was concentrated under reduced pressure, and the
products were collected by filtration. Fractional crystallization using
ethanol leads to the isolation of two products 2a and 5 in a 1:3 ratio.
z = 295 [M+2]+
4-amino−3−(p−chloro)phenylidine−1,5-benzodiazepin-2-one
.
4.2.2.2. Method B. 0.02 mol of compounds 2a in a test tube was
plunged in a hot sulfuric bath (∼260 °C). The colorless sublimate
material which formed above the heated area was repeatedly scraped
back into the melt. After 4 h, when sublimation had ceased, the tube
(2c): It was obtained as colorless crystals (51
% yield), m. p.
283−284 °C. 1H NMR (DMSO−d6): δ = 7.29−7.40 (m, 3H; NH2, NH
exchanged by D2O); 7.56−7.57 (d, 2H, Ar−H); 7.63−7.65 (d, 2H,
7

H. Mansour and M.M. El-Hendawy
MolecularCatalysis484(2020)110774
was removed from the bath and allowed to cool, the dark brown solid
product was loosened from the wall of the tube by triturating using
ethanol (6 ml). The products were collected and crystallized several
times from methanol to give brown crystals of 5 (43 % yield); M. p.
273 °C. 1H NMR (DMSO−d6): δ = 5.51 (2H, eHC]CHe), 6.42 (s, 1H;
Ar−H); 6.49–6.53 (d, 1H, Ar−H); 6.65–6.69 (d, 1H, Ar−H),
6.95−6.99 (d, 1H, Ar−H), 7.09−7.27 (m, 2H, Ar−H), 7.30−7.40
(m, 2H, Ar−H), 7.73−7.76 (d, 1H, Ar−H), 9.52−9.53 (b, 1H, NH
exchanged by D2O), 9.89−9.90 (b, 1H, NH exchanged by D2O). IR (KBr):
ν = 3338(NeH), 3053(CeHarom), 2928 (CeHaliph), 1627(C]Oamide),
1582(C]N) cm−1. Anal. %, Calcd. for C16H13N3O: C, 73.00; H, 4.94; N,
15.96; Found: C, 72.90; H, 5.10; N, 16.10. MS (FD+, THF): m/z = 263
c1cs15119c.
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All DFT calculations were performed using a Gaussian 09 software
package [41]. B3LYP functional [42,43] with 6-31G(d) basis set were
used for geometry optimization. The vibrational frequencies of the
optimized stationary points are calculated under the same level of
theory, to obtain the zero-point vibrational energy (ZPVE) and thermal
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CRediT authorship contribution statement
Hanaa Mansour: Investigation, Formal analysis, Resources, Data
curation, Writing
-
original draft. Morad M. El-Hendawy:
Conceptualization, Data curation, Formal analysis, Validation,
Investigation, Methodology, Project administration, Visualization,
Writing - original draft, Writing - review & editing.
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3529–3533, https://doi.org/10.1021/ja038565t.
[29] A. Otto, J. Liebscher, Synthesis 8 (2003) 1209–1214, https://doi.org/10.1055/s-
2003-39403.
Declaration of Competing Interest
There are no conflicts to declare.
Acknowledgment
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The authors are thankful to Dr. Mohamed Sadek, Tanta University,
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