Urea/thiourea as ammonia surrogate: A catalyst-free synthesis of 2-substituted 2,3-dihydroquinazolin-4(1 H)-ones/quinazoline-4(3 H)-ones

Article abstract of DOI:10.1080/00397911.2013.862551

Urea/thiourea have been identified as an effective ammonia surrogate in the construction of quinazolin-4(3H)-one ring. This strategy afforded a simple and catalyst-free synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones via the reaction of isatoic anhydride and aryl aldehydes in the presence of urea or thiourea in ethanol. The reaction proceeded well to afford the quinazolin-4(3H)-one or its dihydro derivative, depending on the nature of carbonyl compounds employed.

Full text of DOI:10.1080/00397911.2013.862551

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Urea/Thiourea as Ammonia Surrogate: A
Catalyst-Free Synthesis of 2-Substituted
2,3-Dihydroquinazolin-4(1H)-ones/
Quinazoline-4(3H)-ones
P. Paradesi Naidu a b , Akula Raghunadh a , K. Raghavendra Rao a ,
Ramamohan Mekala a , J. Moses Babu c , B. R. Rao a , V. Siddaiah b &
Manojit Pal d
a Process Research and Development, Dr. Reddy's Laboratories ,
Andhra Pradesh , India
b Organic Research Labs, Department of Organic Chemistry , Andhra
University , Visakhapatnam , India
c Analytical Research , Custom Pharmaceutical Services, Dr. Reddy's
Laboratories , Hyderabad , India
d Dr. Reddy's Institute of Life Sciences, University of Hyderabad
Campus , Hyderabad , India
Published online: 29 Apr 2014.
To cite this article: P. Paradesi Naidu , Akula Raghunadh , K. Raghavendra Rao , Ramamohan Mekala ,
J. Moses Babu , B. R. Rao , V. Siddaiah & Manojit Pal (2014) Urea/Thiourea as Ammonia Surrogate: A
Catalyst-Free Synthesis of 2-Substituted 2,3-Dihydroquinazolin-4(1H)-ones/Quinazoline-4(3H)-ones,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:10, 1475-1482, DOI: 10.1080/00397911.2013.862551
To link to this article: http://dx.doi.org/10.1080/00397911.2013.862551
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Synthetic Communications1, 44: 1475–1482, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.862551
UREA/THIOUREA AS AMMONIA SURROGATE:
A CATALYST-FREE SYNTHESIS OF 2-SUBSTITUTED
2,3-DIHYDROQUINAZOLIN-4(1H)-ONES/
QUINAZOLINE-4(3H)-ONES
P. Paradesi Naidu,1,2 Akula Raghunadh,1
K. Raghavendra Rao,1 Ramamohan Mekala,1 J. Moses Babu,3
B. R. Rao,1 V. Siddaiah,2 and Manojit Pal4
1Process Research and Development, Dr. Reddy’s Laboratories,
Andhra Pradesh, India
2Organic Research Labs, Department of Organic Chemistry, Andhra
University, Visakhapatnam, India
3Analytical Research, Custom Pharmaceutical Services, Dr. Reddy’s
Laboratories, Hyderabad, India
4Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract Urea/thiourea have been identified as an effective ammonia surrogate in the
construction of quinazolin-4(3H)-one ring. This strategy afforded a simple and catalyst-
free synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3-
H)-ones via the reaction of isatoic anhydride and aryl aldehydes in the presence of urea
or thiourea in ethanol. The reaction proceeded well to afford the quinazolin-4(3H)-one
or its dihydro derivative, depending on the nature of carbonyl compounds employed.
Keywords Aldehyde; isatoic anhydride; quinazolin-4(3H)-one; urea
Received October 5, 2013.
Address correspondence to Manojit Pal, Dr. Reddy’s Institute of Life Sciences, University of
Hyderabad Campus, Hyderabad 500046, India. E-mail: manojitpal@rediffmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1475

1476
P. P. NAIDU ET AL.
INTRODUCTION
The development of new and efficient synthetic methods for the construction of
nitrogen-containing heterocyclic rings is an important area of synthetic and
medicinal chemistry, as many bioactive agents or drugs belong to this class of hetero-
cycle. Quinazoline-4(3H)-ones, because of their wide spectrum of biological and
pharmacological activities, are one of the more extensively studied heterocyclic com-
pounds in medicinal=pharmaceutical chemistry.[1] For example, some quinazolinone-
based natural products (e.g., febrifugine and isofebrifugine) have been identified as
potential antimalarial agents. The 2,3-dihydroquinazolin-4(1H)-ones, on the other
hand, have also showed a broad range of pharmacological properties.[2]
Various synthetic methods have been reported for the synthesis of quinazolin-
4(3H)-ones.[3–8] Thus quinazolines can be prepared from 2-aminobenzaldehyde,
2-aminophenyl ketones, or anthranilic acids. For example, quinazolin-4(3H)-ones
are prepared from an anthranilic acid or its derivative, for example, 2-aminobenzo-
nitrile and an amide in the presence of an acid catalyst at 200 ꢀC (the Niementowski
synthesis). Recently, a Yb(OTf)3-catalyzed, one-pot, synthesis of quinazolin-4(3H)
-ones from anthranilic acid, anilines, and orthoesters (or formic acid) has been
reported under solvent-free conditions.[9] A number of synthetic methods have been
reported for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones that include the use
of iridium,[10] citric acid,[11] [bmim]HSO4,[12] iodine,[13] ammonium chloride,[14] gal-
lium trifluoromethanesulfonate,[15] ionic liquids,[16] Broonsted acids,[17] phosphoric
acid,[18] copper chloride,[19] tetra butyl ammonium bromide,[20] and TiCl4=Zn.[21]
While many of these methods are useful in various degrees, some of them still suffer
from limitations such as unsatisfactory or variable yields, lengthy reaction time,
unsatisfactory substrate tolerance, and more importantly the use of expensive or
complex catalysts and reagents. Thus, development of an operationally simple,
straightforward, and catalyst-free method is highly desirable. While the use of urea=
thiourea as a reactant is common in organic synthesis (e.g., Biginelli reaction[22]),
their uses as ammonia surrogate is not common in the literature. Because of our
continuing interest in quinazolinone derivatives,[23] we now report the use of urea=
thiourea as an effective ammonia surrogate in the construction of quinazolin-4(3H)
-one ring, affording a simple and inexpensive synthesis of 2-substituted 2,3-
dihydroquinazolin-4(1H)-ones=quinazoline-4(3H)-ones (3 or 4) from isatoic
anhydride 1 and aldehyde 2 in the presence of urea or thiourea (Scheme 1). To
the best of our knowledge, this strategy has not been explored for the synthesis of
3 previously.
Scheme 1. Catalyst-free synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones=quinazoline-
4(3H)-ones (3 or 4).

UREA/THIOUREA AS AMMONIA SURROGATE
1477
RESULTS AND DISCUSSION
In our initial study, isatoic anhydride (1) was reacted with 2-bromobenzalde-
hyde (2a) and urea in the absence of any catalyst in dimethylformamide (DMF) at
80–85 ꢀC for 6 h under open air when the corresponding 2,3-dihydroquinazolin-4(1H)
-one (3a) was obtained in 90% yield (Table 1, entry 1). Notably, formation of any
quinazoline-4(3H)-one was not observed in the present case. We then examined the
use of other solvents such as ethanol, methanol, and water (Table 1, entries 2, 3,
and 4), among which ethanol was found to be most effective as 3a was isolated in
90% yield (Table 1, entry 2). While 3a was isolated in poor yield in MeOH, the reac-
tion did not proceed in water. The use of acetic acid, toluene, o-xylene, and acetone
was also examined but found to be less or ineffective in terms of product yield
(Table 1, entries 5–8). While urea was used as a reactant in all these reactions, the
use of thiourea was also found to be equally effective as the reaction afforded 3a in
88% yield when urea was replaced by thiourea (Table 1, entry 9). Nevertheless, being
an inexpensive and safer solvent, EtOH was chosen as a preferred solvent for further
study. It is worth mentioning that while the formation of the corresponding
quinazoline-4(3H)-one was not observed in the present case, its formation was noted
in case of other aldehydes.
We then examined the generality and scope of this methodology. Accordingly,
a variety of aryl aldehydes (2) were reacted with isatoic anhydride (1) in EtOH under
the conditions of entry 2 of Table 1, and the results are summarized in Table 2. The
reaction afforded the corresponding 2,3-dihydroquinazolin-4(1H)-ones (3) in excel-
lent yields when aldehydes 2a–d were employed (Table 2, entries 1–4). In the case
Table 1. Reaction of 1 with 2a under various conditionsa
Entry
Solvent
DMF
EtOH
Yieldb (%)
1
2
3
4
5
6
7
8
9
90
90
55
0
MeOH
H2O
Acetic acid
Toluene
O-Xylene
Acetone
EtOH
20
0
0
10
88c
aReaction conditions: All the reactions were carried out using isatoic anhy-
dride (0.003 mol), 2-bromobenzaldehyde 2a (0.0033 mol), and urea
1
(0.0033 mol) in EtOH (4 mL) at 80–85 ꢀC under open air.
bIsolated yield.
cThiourea (0.0033 mol) was used in place of urea.

1478
P. P. NAIDU ET AL.
Table 2. Synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones=quinazoline-4(3H)-ones (3 or 4)a
Yieldb (%) Yieldb,c (%)
Entry
Aldehyde (2)
Product (3 or 4)
1
90
85
2
92
80
3
4
5
6
90
90
95
83
86
88
82
76
(Continued )

UREA/THIOUREA AS AMMONIA SURROGATE
1479
Table 2. Continued
Entry
Aldehyde (2)
Product (3 or 4)
Yieldb (%)
Yieldb,c (%)
7
87
88
90
75
80
85
8
9
10
90
82
11
85
88
aReaction conditions: All the reactions were carried out using isatoic anhydride 1 (0.003 mol), aldehyde
2 (0.0033 mol), and urea (0.0033 mol) in EtOH (4 mL) at 80–85 ꢀC under open air.
bIsolated yield.
cThiourea (0.0033 mol) was used in place of urea.

1480
P. P. NAIDU ET AL.
Scheme 2. Proposed reaction mechanism.
of aldehydes 2e–k, the reaction seemed to proceed one step further, affording the
quinazoline-4(3H)-ones (4) in good yields (Table 1, entries 5–11). While the reasons
for these observations are not clearly understood, the participation of areal oxygen[24]
in these cases perhaps caused the formation of 4. Notably, a similar observation has
been reported by Gao et al. while performing the synthesis of 2,3-dihydroquinazolin-
4(1H)-one derivatives under their reaction conditions.[25] Nevertheless, in addition to
aryl aldehydes, the 1H-indole-3-carbaldehyde (2 h) also participated well in the
present reaction, affording the product 3 h in 88% yield (Table 2, entry 8). The reac-
tion did not proceed when ketones were employed in place of aldehydes (2), indicat-
ing the limitation of the present synthesis. The reaction was also not successful when
aliphatic aldehyde (e.g., acetaldehyde) was used. While urea was used in all these
reactions, we also examined the use of thiourea, which, like urea, afforded compara-
ble yields of products 3 or 4 (Table 2).
A plausible mechanism for the present catalyst-free transformation is depicted
in Scheme 2. The reaction seemed to proceed via the generation of intermediate E-1,
which tautomerizes to the enol E-2 stabilized by the intramolecular H-bonding in a
six-membered cyclic form. The amino group of E-2 then reacts with the aldehyde 2
to give the imine E-3, which on intramolecular cyclization afforded the intermediate
=
E-4. The cleavage of ꢁNꢁC X)- bond aided by EtOH at elevated temperature
afforded 3. As shown in Table 2, 2,3-dihydroquinazolin-4(1H)-ones 3 formed in
some of the cases underwent oxidation in the presence of air to give quinazoline-4(3H)
-ones 4. To gain further evidence, the isatoic anhydride 1 was reacted with urea under
the conditions of entry 2 of Table 1 when quinazoline-2,4(1H,3H)-dione was isolated
as the only product (Scheme 3).
Scheme 3. Reaction of isatoic anhydride 1 with urea in the absence of aldehyde.

UREA/THIOUREA AS AMMONIA SURROGATE
1481
CONCLUSIONS
In conclusion, urea=thiourea has been identified as an effective ammonia
surrogate in the construction of quinazolin-4(3H)-one ring for the first time. The
methodology afforded 2-substituted 2,3-dihydroquinazolin-4(1H)-ones and quinazo-
lin-4(3H)-ones via the reaction of isatoic anhydride and aryl aldehydes in the
presence of urea or thiourea in ethanol. The methodology is operationally simple
and does not involve the use of any metal,[26,27] other toxic, expensive catalysts=
reagents,[28] and inert atmosphere. The limitations of this methodology are also dis-
cussed. Overall, the methodology is amenable for the generation of library of small
molecules based on 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones of
potential pharmacological interest.
EXPERIMENTAL
Typical Method for the Synthesis of 2-(2-Bromophenyl)-2,3-
dihydroquinazolin-4(1H)-one[24] (3a)
A mixture of isatoic anhydride 1 (3.0 mmol), 2-bromobenzaldehyde 2a
(3.3 mmol), and urea (3.3 mmol) in EtOH (4.0 mL) was stirred at reflux for 6 h under
open air. The progress of the reaction was monitored by thin-layer chromatography
(TLC). After completion of the reaction, the mixture was concentrated under
reduced pressure. The crude product obtained was crystallised from methanol to give
the analytically pure compound as a colorless solid; 1H NMR (400 MHz, DMSO-d6)
d 8.19 (s, 1H, NH), 7.69–7.65 (m, 3H), 7.45 (t, J ¼ 8.0 Hz, 1H), 7.35 (t, J ¼ 8.0 Hz,
1H), 7.28 (t, J ¼ 6.8 Hz, 1H), 6.98 (s, 1H, NH), 6.77 (d, J ¼ 7.6 Hz, 1H), 6.74 (t,
J ¼ 8.0 Hz,1H), 6.09 (s, 1H, CH); 13C NMR (DMSO-d6, 100 MHz) 163.6, 147.7,
139.1, 133.4, 132.8, 130.7, 129.1, 128.1, 127.4, 122.2, 117.5, 114.7, 114.6, 66.4;
HRMS (ESI): calcd. for C14H12N2OBr, (MþH)þ 303.0133; found 303.0140.
ACKNOWLEDGMENTS
Help from the analytical department for the analytical data is appreciated. We
thank Dr. Vyass and Kavi Raj for their helpful discussions.
FUNDING
We thank Dr. Reddy’s Laboratories Ltd. for the financial support and encour-
agement.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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