Oxone-mediated annulation of 2-aminobenzamides and 1,2-diaminobenzenes with: Sec -amines via imine- N -oxides: New syntheses of 2,3-dihydroquinazolin-4(1 H)-ones and 1 H -benzimidazoles

Article abstract of DOI:10.1039/c7nj04939k

An efficient and mild method for the preparation of 2,3-dihydroquinazolin-4(1H)-ones and 1H-benzimidazoles by the oxone-mediated reaction of sec-amines via imine-N-oxides with 2-amino-N-substituted benzamides and 1,2-diaminobenzenes respectively in THF-wa

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Oxone mediated annulation of 2-aminobenzamides and 1,2-
diaminobenzenes with a sec-amine via imine-N-oxide: New
syntheses of 2,3-dihydroquinazolin-4(1H)-ones and 1H-
benzimidazoles
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Vinodkumar Sriramoju, Srinivas Kurva and Sridhar Madabhushi*
www.rsc.org/
Efficient and mild method for preparation of 2,3- amino-N-substituted benzamides with aldehydes using Lewis or
dihydroquinazolin-4(1H)-ones and 1H-benzimidazoles by oxone Bronsted acid catalyst (eq. 1, Scheme 1),21 ii) by intramolecular
mediated reaction of a sec-amine via imine-N-oxide with 2-amino- cyclization of 2-amino-N-alkyl-N-allenyl benzamides using Pd(OAc)2
N-substituted benzamides and 1,2-diaminobenzenes respectively as the catalyst (eq. 2, Scheme 1)22 and iii) by reductive
in THF-water (2:1) at ambient temperature is described.
desulfurization of 2-thioxo-2,3-dihydroquinazolinones
with
NiCl2/NaBH4 (eq. 3, Scheme 1).23 The methods described in
literature for preparation of 1H-benzimidazoles are: i) by
condensation of 1,2-diaminobenzenes with aldehydes using a Lewis
or Bronsted acid catalyst (eq. 4, Scheme 1),24 ii) by condensation of
1,2-diaminobenzenes with formaldehyde generated by reaction of a
N,N-dialkyl formamide with poly(methylhydrosiloxane) (PMHS)
under Zn(OAc)2 catalysis (eq. 5, Scheme 1)25 and iii) by reaction of
1,2-diaminobenzene with a β-diketone using p-toluenesulfonic acid
as the catalyst (eq. 6, Scheme 1).26
2,3-Dihydroquinazolin-4(1H)-ones and their derivatives occur in a
variety of natural products1 and in synthetic drugs which found
applications as anticancer,2 diuretic,3 anti-inflammatory,4
antidepressant,5 CNS stimulant,6 antianxietic,7 antihistamine,8
antiviral,9 antibiotic,10 vasodilatory,11 anticonvulsant12 and anti-
defibrillator13 agents. They are also important as plant-growth
regulators.14 1H-benzimidazoles and their derivatives also have
similar importance in medicinal chemistry for
a variety of
pharmacological applications as antitumor,15 cardiotonic,16
antiulcer,17 antihypertensive,18 anthelmintic19 agents and also as
pesticides.20 Some of the important commercial drugs with 2,3-
dihydroquinazolin-4(1H)-one and 1H-benzimidazole core structures
are shown in Figure 1.
In literature, so far three methods are known for preparation of 2,3-
dihydroquinazolin-4(1H)-ones and they are: i) by condensation of 2-
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Despite these methods, there has been a long-standing interest in Next, we studied the scope of the present reaction using a
the development of new methods for their synthesis owing to their variety of N-alkyl and N-aryl substituted 2-amino benzamides
high importance in drug discovery studies. In our laboratory, we 1a-1i, which were reacted with secondary amines 2a-2e in the
are interested in study of oxidative transformations using oxone,27 presence of oxone at ambient temperature in THF-H2O (2:1).
which is a mild, inexpensive and environmentally benign solid In this study, acyclic sec-amines 2a-2d gave corresponding 2,3-
oxidant. In the course of work, we found new methods by dihyroquinazolin-4(1H)-one derivatives 3a-3l in 78-92%.
serendipity for preparation of 2,3-dihydroquinazolin-4(1H)-ones
Table 2: Synthesis of 2,3-dihydroquinazolin-4(1H)-ones
and 1H-benzimidazoles and here, we report one-pot method for
syntheses of 2,3-dihydroquinazolin-4(1H)-ones and 1H-
O
O
R
R
Oxone
N
N
benzimidazoles from 2-amino-N-substituted benzamides and 1,2-
diaminobenzenes respectively which were reacted with secondary
amines via imine-N-oxides using oxone as an oxidant at ambient
temperature in tetrahydrofuran (THF)-water (2:1) as the reaction
medium as shown in Scheme 2. The existing methods are all
catalytic processes and most of them involve metal catalysts and
high reaction temperatures. However, the present methods are
efficient non-catalytic processes with mild reaction conditions.
H
R'
N
H
R'
THF-H2O (2:1), r.t.
N
H
R'
NH2
1a-1i
2a-2e
3a-3m
1a (R= Ph); 1b (R= Bn); 1c (R= furfuryl); 1d (R= 2-ClPh); 1e (R= 4-MePh); 1f (R= 4-OMePh);
1g (R= 3,4-methylenedioxy Ph); 1h (R= cyclopropyl); 1i (R= cyclohexyl) and
2a (R'= Ph); 2b (R'= Me); 2c (R'= Et); 2d (R'= Pr); 2e (piperidine)
Product
3
Substrate sec-amine Time
% Yielda
mp (oC)
Entry
1
2
(h)
3
O
N
Ph
Ph
a
1a
2a
5
89
92
86
205-208
N
H
O
O
O
R
R
Oxone
N
N
Ph
R'
R'
N
H
R'
R'
N
H
b
c
1a
1a
2b
2c
4
4
163-165
149-151
THF-H2O (2:1), r.t.
N
H
R'
NH2
N
H
O
(R, R'= alkyl, aryl)
65-92%
Ph
Et
NH2
NH2
N
N
Oxone
R
R
R'
N
H
N
H
O
THF-H2O (2:1), r.t.
N
H
Ph
Pr
56-65%
N
1a
1b
1c
1d
1e
2d
2b
2b
2b
2b
5
5
5
5
5
84
85
84
89
87
113-116
160-162
91-93
d
e
Scheme 2: Synthesis of 2,3-dihydroquinazolin-4(1H)-ones/1H-benzimidazoles
N
H
O
In our preliminary experiments, we found that N-benzyl-1-
phenylmethanimine oxide (imine-N-oxide), which was in situ
generated by oxidation28 of dibenzylamine 2a with oxone in THF-
H2O (2:1), reacts with 2-amino-N-phenylbenzamide 1a at ambient
temperature to give annulated product 2,3-diphenyl-2,3-
dihydroquinazolin-4(1H)-one 3a in 89% yield. The results of the
solvent screening study of this reaction are summarized in Table 1.
N
Ph
N
H
O
O
N
f
N
H
O
N
g
h
163-164
155-157
Cl
N
H
O
Table 1: Solvent screening study for preparation of 3a
N
N
H
OMe
O
i
j
N
1f
2b
4
88
177-180
N
H
O
O
O
N
1g
1h
2b
2b
6
5
81
81
159-162
122-124
N
H
O
N
k
l
N
H
O
N
1i
2b
2e
5
6
78
65
165-167
oil
N
H
O
Ph
mb
1a
N
COOH
N
3
H
aIsolated yields. All products gave satisfactory 1H, 13C NMR, IR and Mass spectral data.
bReflux conditions.
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In our study, unlike acyclic sec-amines, cyclic sec-amines such reaction pathway, N-benzylhydroxylamine is expected to form as
as piperidine, morpholine and pyrrolidine found to behave the by-product. In our study, however, we observed only formation
differently and with these substrates, reaction proceeded only of benzaldoxime, which possibly generated by oxidation of N-
up to the formation of corresponding imine-N-oxide, which did benzylhydroxylamine under the reaction conditions.29
not react with 1a-1i to give an annulated product. However,
N
Ph
under reflux condition, piperidine 2e was found to react with
1a producing 4-(4-oxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-
2-yl)butanoic acid 3m in 65 % yield (entry m, Table 2) while
morpholine and pyrrolidine did not show similar reactivity.
In our study, 1,2-diaminobenzenes 4a-4d were also found to
undergo annulation reactions with secondary amines 2a-2d via
imine-N-oxides in the presence of oxone to give corresponding 1H-
benzimidazole derivatives 5a-5i in 56-65% yields as shown in Table
3. Here also annulation products were not formed with a cyclic sec-
amine such as piperidine, morpholine and pyrrolidine.
Ph
H
Oxone
O
O
H
N
Ph
Ph
O
Ph
N
Ph
Ph
N
H
N
H
NH2
N
1a
A
Ph
HO
O
O
Ph
Table 3: Synthesis of 1H-benzimidazoles
N
Ph
Ph
N
H
N
Ph NHOH
Oxone
N
H
Ph
3a
OH
Ph
N
Scheme 3: Plausible mechanism for the formation of dihydroquinazolinones
In conclusion, we showed new method for syntheses of
substituted 2,3-dihydroquinazolin-4(1H)-ones and 1H-
benzimidazoles in high yields by reaction of secondary amines
via imine-N-oxides, with 2-amino-N-substituted benzamides
and 1,2-diaminobenzenes respectively using oxone as the
oxidant.
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
Authors V.S. and S.K. are thankful to UGC, New Delhi for the award
of Senior Research Fellowship.
Notes and references
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In this
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