Efficient Access to 2,3-Dihydroquinazolin-4(1 H)-ones by Environmentally Benign l -Proline Nitrate as Recyclable Catalyst

Article abstract of DOI:10.1055/s-0035-1560483

An l-proline nitrate assisted protocol is described for the construction of 2,3-dihydroquinazolin-4(1H)-ones. The catalyst can be recovered easily and is reusable for at least six cycles without significant loss of catalytic efficiency.

Full text of DOI:10.1055/s-0035-1560483

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2575–2577
letter
2575
S. P. Bahekar et al.
Letter
Synlett
Efficient Access to 2,3-Dihydroquinazolin-4(1H)-ones by Environ-
mentally Benign L-Proline Nitrate as Recyclable Catalyst
Sandeep P. Bahekar
Nityanand D. Dahake
Prashant B. Sarode
Hemant S. Chandak*
O
O
L-proline nitrate (10 mol%)
MeCN, r.t.
NH
O
NH2
NH2
+
N
H
R
R
up to 96%
Department of Chemistry, G. S. Science, Arts and Commerce College,
Khamgaon 444303, India
chemants@gmail.com
* no column chromatography
* high AE and RME
* low E factor and PMI
* clean reaction profile
Received: 10.07.2015
Accepted after revision: 24.08.2015
Published online: 15.09.2015
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones is usual-
ly achieved with a variety of acid catalysts18 and certain
ionic liquids.19 In continuation of our endeavors in the de-
velopment of clean and green synthetic protocols,3
we herein disclose an efficient method for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones by an intramolecular
one-pot cyclocondensation of anthranilamide with alde-
hydes employing inexpensive, recyclable L-proline nitrate
(10 mol%) as an efficient catalyst (Scheme 1).
DOI: 10.1055/s-0035-1560483; Art ID: st-2015-d0532-l
Abstract An L-proline nitrate assisted protocol is described for the
construction of 2,3-dihydroquinazolin-4(1H)-ones. The catalyst can be
recovered easily and is reusable for at least six cycles without significant
loss of catalytic efficiency.
Key words 2,3-dihydroquinazolin-4(1H)-one, L-proline nitrate, ionic
liquid, cyclocondensation reaction
O
O
Organic chemists from academia and industry are in-
creasingly aware of the goals of sustainable and green
chemistry.1 With this view, green chemistry metrics such
as the E-factor and atom-economy concept have played a
significant role in the assessing of synthetic protocols. Mon-
itoring these metrics proves to be helpful in minimizing
waste generation during organic synthesis.2 In this context,
ionic liquids (ILs) have played a crucial role in avoiding the
entry of waste chemical streams in the environment. Thus,
catalysis by ILs is proving to be a means of achieving organ-
ic transformations in a green manner.3 Amino acids and
their derivatives are considered as a prevalent natural
source of quaternary nitrogen and ILs derived from these
amino acids, being fully green, serve as an alternative to the
traditional ILs derived from imidazole or pyridine.4
Quinazoline derivatives display activities of biological
and pharmaceutical importance such as plant-growth regu-
lation5 as well as antihistaminic,6 vasodilating,7 antianxi-
ety,8 tranquilizing,9 antitumor,10 antidepressant,11 antide-
fibrillatory,12 antihypertensive,13 CNS stimulant,14 and anal-
gesic15 properties. Quinazoline derivatives have also proven
effective as insecticides, fungicides, and bactericides.16 In
addition to this, quinazolinone scaffolds have also found
application in organic electroluminescence devices.17
L-proline nitrate
MeCN, r.t.
NH2
NH2
NH
O
+
R
N
H
R
1
2
3
Scheme 1 Efficient access to 2,3-dihydroquinazolin-4(1H)-ones using
L-proline nitrate
The reaction of anthranilamide (1) and benzaldehyde
(2a) was opted for model studies. Gratifyingly, the desired
product 3a was achieved in 96% of yield; the presence of 10
mol% of L-proline nitrate proving vital in conjunction with
acetonitrile as solvent at ambient temperature in 20 min-
utes (Table 1, entry 10). In the absence of catalyst, the prod-
uct was only obtained in low yield (Table 1, entry 1). A cata-
lyst loading of 10 mol% proved sufficient for nearly com-
plete transformation (96%; Table 1, entry 10), while
increasing the catalyst loading to 20 mol% neither improved
the yield nor reduced the reaction time (Table 1, entry 11).
Classical ILs are effective in the sense of catalytic reusability
but require harsh reaction conditions (Table 1, entries 3 and
4).
We then tested various solvents such as methanol, wa-
ter, dichloromethane, toluene, and acetonitrile, out of
which acetonitrile proved to be most suitable for this trans-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2575–2577

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S. P. Bahekar et al.
Letter
Synlett
formation giving higher yields with easier workup (Table 1,
entry 10). The workup involved simple filtration of the
crude reaction mass to afford sufficiently pure product that
could be recrystallized from hot ethanol if necessary.
Table 2 L-Proline Nitrate Catalyzed Synthesis of 2,3-Dihydroquinazolin-
4(1H)-one Derivatives
O
O
O
L-proline nitrate (10 mol%)
MeCN, r.t.
NH
NH2
+
Table 1 Optimization for the Synthesis of 2,3-Dihydroquinazolin-
4(1H)-one
R
N
H
R
NH2
2a–o
3a–o
O
O
O
Product
R
Yield (%)a mp (°C)
Observed
NH
catalyst
NH2
Lit.
+
solvent, r.t.
N
H
Ph
NH2
3a
3b
3c
3d
3e
3f
Ph
96
88
75
72
86
77
87
76
74
75
87
90
90
85
70
218–219
192–193
206–208
200–202
198–199
220–222
168–170
200–202
167–168
219–221
210–211
208–210
280–281
200–202
165–166
219–22018b
189–19018b
205–20618b
199–20018b
195–19725
228–22918b
162–16426
193–19427
1
2a
3a
4-MeOC6H4
4-ClC6H4
4-FC6H4
Entry
Catalyst (mol%)
Solvent
Time
Yield (%)a
1
2
–
MeCN
MeCN
[bmim]PF6
–
15 h
2 h
34
4-BrC6H4
p-TsOH (30)
80
4-Me2NC6H4
b
3
–
35 min
1.5 h
5 h
8919a
8219b
60
3g
3h
3i
4-i-PrC6H4
4
TBABc
3,4,5-(MeO)3C6H2
2-furyl
5
L-proline nitrate (10)
L-proline nitrate (10)
L-proline nitrate (10)
L-proline nitrate (10)
L-proline nitrate (5)
L-proline nitrate (10)
L-proline nitrate (20)
toluene
H2O
167.2–168.518b
226–22718a
206–20825
20928
6
3 h
20
3j
3-MeO-4-HO C6H3
2-HO
7
CH2Cl2
MeOH
MeCN
MeCN
MeCN
2.5 h
1 h
45
3k
3l
8
67
3-HO
9
1 h
72
3m
3n
3o
4-HO
279–28118b
212.5–214.818b
162–16429
10
11
20 min
20 min
96
4-O2N
96
n-Pr
a Isolated yields.
b Reaction carried out at 75 °C.
c Reaction carried out at 100 °C under N2 atmosphere.
a Isolated yield.
Thus, we present L-proline nitrate as a green and effi-
cient catalyst for the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones via one-pot cyclocondensation of anthranil-
amides and substituted aromatic/aliphatic aldehydes under
mild conditions.
The filtrate containing IL was evaporated under reduced
pressure. The residue was washed with water to give an
aqueous solution of the catalyst. The bulk of the water was
removed under reduced pressure, and the last traces of wa-
ter were eliminated azeotropically with toluene to recover
the catalyst ready for the next cycle. Even after the 6th cycle
the recovered catalyst gave the desired product in >90%
yield. This protocol has favorable green chemistry metrics
such as a small E-factor (0.175) and process mass intensity
(PMI = 4.375), higher atom economy (AE = 92.49%) and re-
action mass efficiency (RME = 85.09%).
With the optimum reaction conditions established, we
next explored the scope of substrates in the synthesis of
2,3-dihydroquinazolin-4(1H)-ones (Table 2).20 Aromatic al-
dehydes with electron-donating as well as electron-with-
drawing substituents reacted smoothly, affording good to
excellent yields of 2,3-dihydroquinazolin-4(1H)-ones. A va-
riety of aromatic aldehydes with different substituent at
the 2-, 3-, or 4-positions reacted readily to afford product
formation with better yields.21–24 Aliphatic aldehydes also
reacted smoothly and gave good yields of products (Table 2,
product 30).
Acknowledgment
This research was supported by UGC New Delhi, India (F. no. 41-335/
2012 (SR) dt.13.07.2012).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560483.
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2575–2577

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S. P. Bahekar et al.
Letter
Synlett
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2575–2577