Mukaiyama's reagent promoted mild protocol for one-pot metal-free synthesis of dihydro quinazolinones

Article abstract of DOI:10.1016/j.tetlet.2020.152791

We have developed a fast and convenient method to prepare dihydroquinazolin-4(1H)-ones from anthranilamide and different aromatic aldehydes by using the Mukaiyama reagent. The reactions proceeded smoothly with a broad scope of substrates providing the expected products in good to excellent yields under with a low environmental factor and high atom economy. The metal-free condition and the ease of product isolation are the highlighted advantages in solving the issue of trace metal contamination in synthesized pharmaceuticals.

Full text of DOI:10.1016/j.tetlet.2020.152791

Tetrahedron Letters 65 (2021) 152791
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Tetrahedron Letters
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Mukaiyama’s reagent promoted mild protocol for one-pot metal-free
synthesis of dihydro quinazolinones
b
a
a
Chatrasal S. Rajput a, , Shweta Srivastava , Ashish Kumar , Arunendra Pathak
⇑
a Jubilant Biosys Limited, B-34, Sector-58, Noida, UP 201301, India
b Department of Chemistry, Gautam Buddha University, Greater Noida, UP 20130, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a fast and convenient method to prepare dihydroquinazolin-4(1H)-ones from
anthranilamide and different aromatic aldehydes by using the Mukaiyama reagent. The reactions pro-
ceeded smoothly with a broad scope of substrates providing the expected products in good to excellent
yields under with a low environmental factor and high atom economy. The metal-free condition and the
ease of product isolation are the highlighted advantages in solving the issue of trace metal contamination
in synthesized pharmaceuticals.
Received 6 November 2020
Revised 15 December 2020
Accepted 17 December 2020
Available online 7 January 2021
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Mukaiyama’s reagent
Dihydroquinazolin-4(1H)-ones
3-Phenyl-dihydroquinazolin-4(1H)-one
Anthranilamide
The Mukaiyama reagent (2-chloro-1-methylpyridinium iodide,
CMPI) was introduced as a useful reagent for the synthesis of car-
boxylic esters by Teruaki Mukaiyama in 1975 [1]. CMPI is one of
the most valuable reagent for activation of hydroxyl groups of car-
boxylic acids and alcohols [2]. This important reagent can be easily
synthesized from 2-chloropyridine and methyliodide [3,4]. It is
widely used for the synthesis of esters [5], lactones [6], amides
[7], ketenes [8] lactams [9], from the corresponding carboxylic
acids. Furthermore, it is also helpful in conversion of thioureas into
carbodiimides [10], and alcohols into the corresponding alkyl thio-
cyanates [11]. The Mukaiyama reagent also play significant role in
peptide synthesis [12]. Inspired with the above results, our group
has recently used this reagent for one-pot two-step synthesis of
isatoic anhydrides from anthranilic acid and di-tert-butyl dicar-
bonate [13] (Scheme 1). The Mukaiyama reagent also used for
CAN bond formation, for synthesis of 3-alkylquinazolin-4-ones
[14]. Very recently, a mild and general method for preparation of
acyl sulphonamides from carboxylic acids and sulphonamides by
using the Mukaiyama reagent was also reported [15].
moiety is a building block for many drugs [16] like Quinethazone,
Metolazone, Methaqualone and Diuretic (Fig. 1). Among these
compounds, quinazolinone derivatives have become especially
noteworthy in recent years owing to their broad spectrum of bio-
logical activity including anti-inflammatory [17–19] antitumor
[20–23,55] antibacterial [24–26] antimalarial [27] antiviral [28–
30] anti-fungal [31] anticonvulsant [32] activities.
Thus, due to the diverse range of the pharmacological activities
of quinazolinones and their derivatives, there are numerous proto-
cols available for their synthesis and naturally occurring quinazoli-
none synthesis. Most of the synthetic protocols for quinazolinone
[33–42] reported so far suffer from harsh reaction conditions
[35], prolonged time period [36], use of hazardous acid catalysts
[42], high catalyst loading [38], and expensive methods [40], and
yields are oftentimes low due to poor selectivity in such condi-
tions. Several nonacidic transition metal catalyzed [38,41],
nanoparticle catalyzed [43], and ionic liquid mediated [44] synthe-
ses of these molecules have also been reported. More recently, effi-
cient, cost-effective and greener process of one-pot metal free
conditions also reported [56–58]. Therefore, development of a
new catalytic metal free condition route is an active area of
research. We herein report an efficient modular one-pot metal free
method for the synthesis of 2,3-dihydroquinazolin-4(1H)-one.
Here, we describe an innovative one-pot highly selective syn-
thesis of quinazolinones catalyzed by Mukaiyama reagent. The
reaction takes place through a cascade comprising (i) a novel and
mild Mukaiyama reagent mediated activation of the carbonyl
group of an aldehyde or ketone, which is further attacked by the
Furthermore, the importance of heterocyclic compounds has
long been recognized in the field of synthetic organic chemistry.
Currently, heterocyclic compounds have been extensively studied
due to their important properties and applications. It is well known
that a number of nitrogen containing heterocyclic compounds
exhibited a wide variety of biological activity. The quinazolinone
⇑
Corresponding author. Tel.: +91 120 409 3340; fax: +91 120 258 6776.
E-mail address: chatrasal.rajput@jubilantbiosys.com (C.S. Rajput).
https://doi.org/10.1016/j.tetlet.2020.152791
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

C.S. Rajput, S. Srivastava, A. Kumar et al.
Tetrahedron Letters 65 (2021) 152791
Table 1
O
COOH
Optimization of catalyst loading.
Boc2O, TEA, ACN, DMAP, rt
2-Chloro-1-methylpyridinium iodide
NH
R
R
Entry
Amount of CMPI (Eq.)
Yield (%) isolated
NHR'
N
H
O
1
2
3
4
1.0
0.3
0.5
0.7
93
59
94
94
Mukaiyama reagent promoted one-pot two-step synthesis of isatoic anhydrides13
Scheme 1. Mukaiyama reagent promoted one-pot two-step synthesis of isatoic
anhydrides [13].
Table 2
Optimization of solvent.
N
Entry
Solvents
THF
Time (h)
Yield (%)a
O
O
S
O
O
O
H2N
H2N
S
S
1.
2.
3.
4.
5.
6.
8
47
39
48
50
94
74
NH
N
N
O
O
2-Methyltetrahydrofuran
10
12
10
0.5
16
Cl
N
H
Cl
N
H
N
H
NH2
CH3CH2OH
1,4-Dioxane
ACN
Quinethazone
Nolatrexed
Metolazone
H2O
O
N
N
O
0.5 eq of CMPI, rt.
O
a
Purified yield.
H2N
N
N
N
N
F
N
O
Methaqualone
Afloqualone
Diuretic
results of the solvents optimization experiments are summarized
in Table 2.
Fig. 1. Structures of biologically important quinazolinones.
With the optimized parameters in hand we have also performed
[59] wide substrate study with different aromatic aldehydes hav-
ing electron-donating and electron withdrawing substituents to
form a series of dihydroquinazolin-4(1H)-ones derivatives (3a-k).
The electronic effects have no significant impact on reaction rate;
nevertheless, in ortho-substituted aldehydes the reaction time
was long, which directly reflects its steric property. Substituted
(naphthalen-1-yl/2-yl)benzaldehyde was also readily introduced
into the quinazolinone skeleton at the 2-position, and desired
products (3j and 3k) were formed in good yield. To demonstrate
the utility of this method, 2,3-disubstituted quinazolinones (3l-
3s) were also synthesized with aliphatic and aromatic amines.
The reaction of anilines with isatoic anhydride led to the synthesis
of N-substituted benzamide (3t), which have poor nucleophilicity
toward the cyclocondensation reaction in the synthesis of 3-substi-
tuted quinazolinones. We screened CMPI as catalyst in such cyclo-
condensation reactions, and the results obtained are good (3i-3s,
Table 3). These 3-substituted quinazolinones are also important
molecules in pharmacological aspects. As only few methods are
available for the synthesis of these 3-substituted quinazolinones,
our methodology can serve as a useful tool in synthesis of these
pharmacologically active scaffolds, with good to excellent yield
of desired products.
A plausible mechanism for the formation of these quinazoli-
nones is proposed in Scheme 3. Being an electron deficient system,
CMPI (0.5 eq) might activate the carbonyl group of aldehyde, which
is simultaneously attacked by anthranilamide to form the interme-
diate with 0.5 equivalent amount of HCl. The so produced HCl
might further catalyse the reaction to form the Schiff base after
the elimination of the bulky 1-methylpyridin-2-one group, and
finally intramolecular cyclization affords the desired product in
quantitative yield. The isolation of the intermediates in the given
course of reaction is not possible as the CMPI-aldehyde adduct
may be unstable or short-lived, and in next step the elimination
of 1-methylpyridin-2-one group might be very fast.
amine functionality of anthranilamide to generate the imine and,
(ii) intramolecular cyclocondensation of imine to furnish the final
quinazolinones. (Scheme 2).
In the current protocol, we have used 2-aminobenzamide (1)
and 4-methoxy-benzaldehyde (2a) as model substrates for the
optimization of the reaction conditions as shown in Scheme 2.
The reaction conditions were optimized with respect to the quan-
tity of catalyst (Table 1) and the solvent (Table 2) by studying the
condensation of 2-aminobenzamide (1) with 4-methoxybenzalde-
hyde (2a).
To determine the catalyst loading, a model reaction of 2-
aminobenzamide and 4-methoxybenzaldehyde with different
equivalent of CMPI in acetonitrile were carried out. The reaction
completed smoothly in the presence of (0.5 eq.) CMPI as a catalyst
and Acetonitrile as a solvent at room temperature, affording a sin-
gle product in 94% yield. Increasing or decreasing the amount of
catalyst, more than 0.3 equivalent showed no significant improve-
ment in the yield (Table 1). In absence of CMPI, the reaction in ace-
tonitrile was incomplete even after an extended reaction time.
In order to determine effect of solvent on the reaction conver-
sion using 0.5 eq. of CMPI as catalyst at room temperature, various
solvents like THF, 2-Methyltetrahydrofuran, CH3CH2OH, 1,4-diox-
ane, ACN and water was examined. Among these solvents (Table 2,
entries 1–6), Acetonitrile (ACN) was selected to be the best reac-
tion media for its higher yielding and shorter reaction time (Table 2,
entry 5). Interestingly, in water the reaction proceeds very
smoothly but requires a long reaction time, which might be attrib-
uted to the poor solubility of the starting substrates in water. The
O
O
O
2-Chloro-1-methylpyridinium iodide
ACN, RT, 30-60 mins
NH2
NH2
NH
In conclusion, we have successfully developed a practical and
operationally simple method for the synthesis of 2,3-dihydro-
quinazolin-4(1H)-one by using CMPI from 2-aminobenzamide
and benzaldehyde in Acetonitrile medium at room temperature.
This mild transformation would provide a simple, compatible,
and potentially powerful method for the modular construction of
quinazolinones. Furthermore, the moderate reaction conditions,
N
H
O
2a
1
O
3a-3k
Effective approach for the one-pot synthesis of 2,3-dihydroquinazolin-4(1H)-one
Scheme 2. Effective approach for the one-pot synthesis 2,3-dihydroquinazolin-4
(1H)-one.
2

C.S. Rajput, S. Srivastava, A. Kumar et al.
Tetrahedron Letters 65 (2021) 152791
Table 3
Scope of the reaction with different aromatic and aliphatic aldehydes.
Entry
aldehyde
R1
H
Dihydroquinazolinones
Yield %a
94%
Melting point °C (reported)
3a
186–188 (187–189) [45]
3b
3c
3d
H
H
H
95%
88%
99%
221–222 (218–220) [41]
185–189 (188–189) [46]
170–172
3e
H
84%
192–193 (190–193) [47]
3f
H
H
H
89%
99%
92%
203–205 (202–204) [48]
3g
3h
150–152
205–208
3i
H
65%
172–174 (171–172) [49]
(continued on next page)
3

C.S. Rajput, S. Srivastava, A. Kumar et al.
Tetrahedron Letters 65 (2021) 152791
Table 3 (continued)
Entry
aldehyde
R1
H
Dihydroquinazolinones
Yield %a
86%
Melting point °C (reported)
3j
>250
3k
3l
H
72%
65%
198–200
Ph
204–207 (202–205) [50]
3m
3n
Ph
Ph
78%
68%
210–213 (212–214) [51]
191–193 (188–190) [43]
3o
Ph
87%
220–223 (222–224) [52]
3p
3q
3r
3s
Ph
Ph
Ph
Ph
62%
72%
73%
57%
239–241 (236–238) [53]
218–220 (222–224) [53]
194–196
163–166 (165–167) [54]
a
Isolated yield.
4

C.S. Rajput, S. Srivastava, A. Kumar et al.
Tetrahedron Letters 65 (2021) 152791
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N
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The authors declare that they have no known competing finan-
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We would like to sincerely thank Jubilant management in facil-
itating this research work and also the analytical team for generat-
ing the spectral data.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152791.
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