A new and facile synthesis of N-benzyl-N′-acylureas via reaction of dibenzoylhydrazine carboxamide and benzylamines

Article abstract of DOI:10.1080/00397911.2021.1960376

Herein, we report a new method of synthesis of N-acylureas (E1–5) via reaction of dibenzoylhydrazine carboxamide (N,2-bis(4-methoxybenzoyl)hydrazine-1-carboxamide) (C) and various benzylamines. Preparation of dibenzoylhydrazine carboxamide (C) was perform

Full text of DOI:10.1080/00397911.2021.1960376

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A new and facile synthesis of N-benzyl-N′-
acylureas via reaction of dibenzoylhydrazine
carboxamide and benzylamines
Mehdi Valipour, Ann M. Chippindale, Aynaz Kouzeli & Hamid Irannejad
To cite this article: Mehdi Valipour, Ann M. Chippindale, Aynaz Kouzeli & Hamid
Irannejad (2021): A new and facile synthesis of N-benzyl-N′-acylureas via reaction of
dibenzoylhydrazine carboxamide and benzylamines, Synthetic Communications, DOI:
10.1080/00397911.2021.1960376
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https://doi.org/10.1080/00397911.2021.1960376
A new and facile synthesis of N-benzyl-N0-acylureas via
reaction of dibenzoylhydrazine carboxamide and
benzylamines
Mehdi Valipoura , Ann M. Chippindaleb , Aynaz Kouzelia , and
Hamid Irannejada
aDepartment of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences,
b
Sari, Iran; Department of Chemistry, University of Reading, Whiteknights, Reading, Berks, UK
ABSTRACT
ARTICLE HISTORY
Received 11 April 2021
Herein, we report a new method of synthesis of N-acylureas (E1–5)
via reaction of dibenzoylhydrazine carboxamide (N,2-bis(4-methoxy-
benzoyl)hydrazine-1-carboxamide) (C) and various benzylamines.
Preparation of dibenzoylhydrazine carboxamide (C) was performed
by the treatment of 5,6-diaryl-3-methylthio-1,2,4-triazine (B) with
Oxone which leads to oxidation and triazine ring cleavage in high
yield (82%). Five benzylamine derivatives containing different elec-
tron donating and withdrawing substituents were used in this study.
Yields for the conversion of dibenzoylhydrazine carboxamide (C) to
N-acylureas (E1–5) were in the range of 40–55%. The structures of
the intermediates and final products were characterized and con-
firmed by NMR, mass spectrometry and single-crystal X-ray crystal-
lography.
KEYWORDS
Carbamoylbenzamide; N-
benzyl-N0-acylurea; Ureide;
X-ray crystallography
GRAPHICAL ABSTRACT
Introduction
N-Benzyl-N0-acylureas are a class of N-acylureas in which both amide nitrogen atoms
have been substituted. N-acylureas are attractive substructures or scaffolds in drug dis-
covery. Due to their resemblance in structure to peptidic bonds and their high hydrogen
bonding potential,[1] they have a wide range of biological activities, such as antidiabetic
effects by inhibiting human liver glycogen phosphorylase,[2] anticonvulsant,[3] anticancer
and Hedgehog inhibiting[1] and histone deacetylase inhibitor effects[4] (Fig. 1). Various
synthetic routes reported in the literature for the preparation of the N-acylurea deriva-
tives are represented in Scheme 1. As shown in Scheme 1a, N-Acylureas can routinely
be prepared either by reaction of N-acylisocyanates with amines or by reaction of
CONTACT Hamid Irannejad
irannejadhamid@gmail.com
Department of Medicinal Chemistry, Faculty of
Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
Supplemental data for this article is available online at publisher’s website
ß 2021 Taylor & Francis Group, LLC

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M. VALIPOUR ET AL.
Figure 1. Some of the N-acylurea derivatives reported to have pharmacological activities.
(a)
(b)
(c)
(d)
(e)
Scheme 1. Previous synthetic routes for the preparation of N-acylurea derivatives. For reactions (a)
to (e), see references,[5–9] respectively.
isocyanates with amides under harsh conditions.[5] A recent method has reported the
preparation of N-acylureas using dicyclohexylcarbodiimide (DCC) and various carbox-
ylic acids using a copper-oxide nanocatalyst, but the urea-substituted alkyl side chains
were only limited to the cyclohexyl group (Scheme 1b).[6] Interestingly, acyl carbamates
are useful intermediates and can react with amines to produce N-acylureas (Scheme
1c).[7] Here the acyl carbamates are prepared from diphenyl carbonate and sodium

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Scheme 2. Representation of the synthetic route for the preparation of the N-benzyl-N0-acylurea
derivatives (E1–5) described in this study.
hydride. Both the preparation of diphenyl carbonate and its reactions with benzamides
in the presence of sodium hydride need a critically dry condition. An extensive study
has also reported the synthesis of N-acylureas by solid-phase techniques using resin-
bound urea derivatives and acylchlorides in which complicated, expensive and very
reactive reagents have been utilized (Scheme 1d).[8] N-acylureas were also synthesized
recently in a one-pot, four-component reaction with very reactive aminonitrones and
isocyanide dibromides (Scheme 1e).[9]
Herein, we report a new and facile four-step preparation of a series of N-acylureas
((N-benzyl)carbamoylbenzamides (E1–5)), starting from 1,2-bis(4-methoxyphenyl)ke-
tone and adding benzylamine derivatives at the final stage (Scheme 2).
Results & discussion
In our ongoing program to prepare benzylamines substituted at position 3 in the 5,6-
diaryl-1,2,4-triazine derivatives, 3-methylthio-5,6-diaryl-1,2,4-triazine (B) was reacted
with potassium hydrogen monopersulfate (Oxone) (Scheme 3). The reaction was
expected to proceed via steps (iii) and (v) in which leaving group 3-methylsulfonyl
group would have to be replaced with various benzylamines in nucleophilic addition
reactions to afford 3-benzylamine substituted 1,2,4-triazines.[10,11] However, the reaction
of compound B with Oxone did not occur as planned, proceeding via steps (iii) and
1
(iv). Characterization of the purified products by H, 13C-NMR, mass spectrometry and
X-ray crystallography confirmed the structures of compounds C and D (Scheme 3 and
Fig. 2). Subsequently, the reaction of N,2-bis(4-methoxybenzoyl)hydrazine-1-carboxa-
mide (C) with various benzylamines yielded (N-benzyl)carbamoylbenzamides (E1–5)
1
(Table 1), which were fully characterized by H, 13C-NMR, mass spectrometry and, in
the case of E2, single-crystal X-ray diffraction (Fig. 3 and Supplementary material). For

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M. VALIPOUR ET AL.
Scheme 3. Synthetic route for the preparation of N-Benzyl-N’-acylureas, E1–5. (i) thiosemicarbazide,
H2O, EtOH, MW, 130 ꢀC, 20 min. (ii) MeI, MeOH, Et3N, rt. (iii) Oxone, THF, H2O, MeOH, rt. (iv) benzyl-
amine deriv., CH3CN, Et3N, reflux.
the details of procedures used for the preparation of compounds A and B, please refer
to our previously published articles.[12,13]
The molecular weights and formulae of N-acylureas E1–5, together with their isola-
tion yields (conversion of B to E1–5), are presented in Table 1. Plausible mechanisms
for the reactions to afford C, D and E1–5 are illustrated in Schemes 4 and 5. In order
to confirm and prove the hypothesis, the starting material 5,6-bis(4-methoxyphenyl)-
1,2,4-triazin-3-ol was also treated with Oxone under the same conditions and also pro-
duced compounds C and D.
The production of either the 3-methylsulfonyl or 3-hydroxy derivatives of 5,6-bis(4-
methoxyphenyl)-1,2,4-triazin and their subsequent conversion to the C and D products
seems feasible under acidic and oxidative conditions in the presence of Oxone. At the
first step, protonation of N1 and N4 atoms of the triazine ring facilitates nucleophilic
attack of water at positions C3, C5 and C6 of the triazine ring due to the strong elec-
tron withdrawing nature of the 1,4-protonated nitrogen atoms. Subsequently, oxidation
of sulfur to sulfonyl and then its replacement as a leaving group by hydroxyl, as long as
nucleophilic attack of water occurs at positions C5 and C6, results in the breakdown of
the C5-C6 bond of the triazine ring and oxidation to compound C (Scheme 4 and Fig.

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Figure 2. ORTEP structures showing (a) the two molecules of compound C in the asymmetric unit
(which are held together by a network of H bonding) and (b) the asymmetric unit of compound D,
as determined by single-crystal X-ray diffraction. Displacement ellipsoids for non-hydrogen atoms are
shown at 50% probability level. Crystallographic details are given in Tables S6 and S7 and have
Cambridge Crystallographic Data Center deposit codes CCDC2076143 and CCDC 2076150, respectively.
Table 1. Details for N-acylureas E1–E5.
Compd. code
Ar
Molecular weight
Molecular Formula
Yield%a
E1
E2
E3
E4
E5
3-Pyridyl
4-Pyridyl
Phenyl
4-Methoxyphenyl
3,4,5-Trimethoxyphenyl
285
285
284
314
374
C15H15N3O3
C15H15N3O3
C16H16N2O3
C17H18N2O4
C19H22N2O6
35
35
45
44
33
aYields are for the conversion of compound B to E1–5 (two steps).
2a). A plausible mechanism for the formation of compound D is depicted in Scheme 5.
Accordingly, oxidation of the sulfur atom at position 3 and its replacement by a
hydroxyl group, together with nucleophilic attack of the persulfate oxygen atom at C5
of the triazine ring, initiates the conversion. This is followed by migration of the 4-
methoxyphenyl ring from C5 to the oxygen atom of persulfate and hence release of the
sulfate anion. This arrangement leaves the terminal oxygen atom of the persulfate in the
structure bearing 4-methoxyphenyl while attached to the C5 of the triazine ring. In the
next step, attack of a water molecule at the electrophilic C5 atom results in the 4-
methoxy phenol group leaving and the production of compound D. Compound D was
isolated and purified then characterized by NMR, mass spectrometry and X-ray crystal-
lography (Fig. 2b). The production of compounds E1–5 was accomplished by the reac-
tion of C with various benzylamines. The structure of one of the products, E2, is
discussed below.
X-ray analysis of a single crystal of compound E2 showed that there are two mol-
ecules of the N-acylurea in the unit cell (Fig. 3). The bond lengths and bond angles

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M. VALIPOUR ET AL.
Scheme 4. Proposed mechanisms for the reactions leading to the formation of Compounds C and
E1–5. Red arrows indicate positions attacked by water and where oxidation occurs.
Scheme 5. Possible mechanism for the formation of compound D.
are as expected for the particular organic groups (Table S3). The angle between the
mean planes of the two benzene rings in the molecule is ꢁ 81ꢀ. The molecules pack
together as shown in Figure S1. Hydrogen bonding interactions occur between adja-
cent molecules and run parallel to the b axis (N(10) – H(101) … O(3) and N(8) –
H(81) … O(2) at 2.8624(16) and 2.9829(16) Å, respectively) (Fig. S2 and Table S4).
An intramolecular H-bonding interaction (N(8) – H(81) … O(2)) also occurs at
2.6946(16) Å.

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Figure 3. ORTEP structure of the asymmetric unit of compound E2, as determined by single-crystal X-
ray diffraction, showing the labeling scheme. Displacement ellipsoids for non-hydrogen atoms are
shown at 50% probability level (see Tables S1–S5). Cambridge Crystallographic Data Center deposit
code CCDC1853114.
In summary, N-Acylurea substructures are becoming attractive and potentially useful
scaffolds in medicinal chemistry for drug development projects, especially in peptidomi-
metic science. The new synthetic method described here should help the development
of new N-acylurea derivatives.
Experimental section
General procedure for the preparation of N-acyl ureas (E1–5)
To a mixture of N,2-bis(4-methoxybenzoyl)hydrazine-1-carboxamide (C) (0.29 mmol, 1
eq) in acetonitrile and triethylamine (1 eq), was added benzylamine derivative
(0.32 mmol, 1.1 eq) and the resulting mixture was refluxed for 24–48 hours. The reac-
tion progress was checked by TLC. After cooling the reaction mixture to room tempera-
ture, it was concentrated under vacuum and was chromatographed through silica gel
(230–400 mesh) eluting with chloroform/methanol (5%) to give the pure product.
Single crystals were prepared by the slow evaporation of dissolved compounds E1–5 in
absolute ethanol. Full characterization data for E1–5 are provided in the
Supplementary Material.
1
Full experimental detail including synthetic routes, H and 13C-NMR, Mass spectrom-
etry and X-ray crystallographic data are given in the Supplementary material.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Acknowledgments
We thank the University of Reading for access to the Chemical Analysis Facility (CAF) and Mr.
Nick Spencer for help with X-ray data collection.

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M. VALIPOUR ET AL.
Funding
This work was supported by a grant [Grant no. 91-53] from Research Council of Mazandaran
University of Medical Sciences, Sari, Iran.
ORCID
Mehdi Valipour
Ann M. Chippindale
http://orcid.org/0000-0001-6689-3743
http://orcid.org/0000-0002-5918-8701
Aynaz Kouzeli
Hamid Irannejad
http://orcid.org/0000-0002-0422-5245
http://orcid.org/0000-0001-7513-6162
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