A facile and rapid access towards the synthesis of 2,3-dihydroquinazolin- 4(1H)-ones

Article abstract of DOI:10.1016/j.tetlet.2013.08.037

An efficient synthetic route for 2,3-dihydroquinazolin-4(1H)-ones using 2-morpholinoethanesulfonic acid as a potential and new organocatalyst is described. The developed synthetic protocol represents a novel and very simple route for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. In addition, microwave irradiation technique is successfully implemented for carrying out the reactions in shorter reaction times.

Full text of DOI:10.1016/j.tetlet.2013.08.037

Accepted Manuscript
A facile and rapid access towards the synthesis of 2,3-dihydroquinazo‐
lin-4(1H)-ones
Vilas B. Labade, Pravin V. Shinde, Murlidhar S. Shingare
PII:
S0040-4039(13)01390-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.037
TETL 43399
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 June 2013
7 August 2013
9 August 2013
Please cite this article as: Labade, V.B., Shinde, P.V., Shingare, M.S., A facile and rapid access towards the synthesis
of 2,3-dihydroquinazolin-4(1H)-ones, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.
2013.08.037
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A facile and rapid access towards the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones
Vilas B. Labade, Pravin V. Shinde and Murlidhar S. Shingare*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad -
431004, Maharashtra, India
*Corresponding author. Tel.: +91 2402403311; fax: +91 2402403113.
E-mail address: prof_msshingare@rediffmail.com
___________________________________________________________________________
__
Abstract: An efficient synthetic route for 2,3-dihydroquinazolin-4(1H)-ones using 2-
morpholinoethanesulfonic acid as a potential and new organocatalyst is described. The
developed synthetic protocol represents novel and very simple route for the preparation of
2,3-dihydroquinazolin-4(1H)-one derivatives. In addition, microwave irradiation technique is
successfully implemented for carrying out the reactions in shorter reaction times.
Keywords:
2-Morpholinoethanesulfonic
Acid,
2,3-Dihydroquinazolin-4(1H)-ones,
Organocatalyst, Microwave irradiations, Aqueous medium.
___________________________________________________________________________
__

Quinazoline represents a significant heterocyclic core of many organic molecules endowed
with diverse biological activities.1 Various quinazolin-4-ones, quinazolin-2,4-diones and their
derivatives are well known to possess an array of physiological activities. 2,3-
Dihydroquinazolinones exhibit a wide range of biological activities, such as antitumor,
antibiotic, antidefibrillatory, antipyretic, analgesic, diuretic, antihistamine, antidepressant,
and vasodilating behavior.2 Furthermore, quinazolinone skeleton is frequently found in
various natural products. Some examples include the anticancer compound trimetrexate, the
sedative methaqualone, the alpha adrenergic receptor antagonist such as doxazosin and the
antihypertensive agent ketanserin. Quinazolinones have also been reported as potent
chemotherapeutic agents in the treatment of tuberculosis.3,4 In particular, 2,3-
dihydroquinazolin-4(1H)-ones are owned with antihyperlipidemic,5 antiviral,6 anti-
parkinsonism,7 antimicrobial,8 anti-inflammatory,9 bronchodilator10 and antihypertensive11
activities. As a consequence of these biodynamic and pharmacological properties 2,3-
dihydroquinazolin-4(1H)-ones have been very attractive targets in synthetic chemistry in
recent years.
Development of novel synthetic methodologies to facilitate preparation of the desired
molecule is an intense area of research. In this regard, efforts have been made constantly to
introduce new methodologies that are efficient and more compatible with the environment.
In the recent years, there has been a growing demand for the development of more
sustainable chemistry, particularly in the synthesis of value added materials, in order to
minimize the great amounts of waste and consecutive treatment.12 In performing the majority
of organic transformations, thermal activation plays a crucial role in making the reaction
homogeneous and allowing molecular interactions to be more efficient. One of the key
principles of green chemistry is the elimination of excessive and wasteful heating during
chemical operations or the replacement of conventional thermal equipments such as oil bath,
heating mantle, etc. by non- conventional sources like microwave irradiations.13
A variety of methods have been developed for the synthesis of quinazolinone
scaffolds with their own merits and demerits.14,15 Of these, the condensation of 2-
aminobenzamide with aldehydes or ketones is one of the simplest and direct methods for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones. Number of acid catalysts, such as p-
TSA/NaHSO3,16a TiCl4/Zn,16b CuCl2,16c ionic liquid-water,16d TFA,16e ammonium chloride16f
and chiral phosphoric acids17 have been utilized to accomplish this transformation. Moreover,

very recently heteropolyacid (H3PW12O40),18a silica-bonded N-propylsulfamic acid18b and
cellulose-SO3H18c have been reported to catalyze this reaction. Many of the reported synthetic
protocols are associated with the use of expensive reagents, extended reaction times, high
reaction temperatures, and also involve tedious work-up procedures.
Considering the above discussed significance of 2,3-dihydroquinazolin-4(1H)-ones,
and in continuation of our endeavor towards the development of ecofriendly synthetic
protocols for heterocyclic compounds, it was thought worthwhile to develop a novel, simple,
greener, and expeditious synthetic route for obtaining 2,3-dihydroquinazolin-4(1H)-one
derivatives.
As literature reveals that the quinazolinone derivatives are best synthesized in the
presence of catalysts bearing sulphonic acid functionality, our efforts were directed for
finding out sulphonic acid based organocatalysts, which should be water soluble, mild in
nature and resists pH change during reaction, i.e. it should act as catalyst as well as buffer. In
this endeavor, 2-(N-morpholino)ethanesulfonic acid perfectly stood out as mild acid catalyst
meeting most of the abovementioned requirements. 2-(N-morpholino)ethanesulfonic acid,
well known as MES is commonly used as a buffering agent in biology and biochemistry. It
has pH 2.5-4.0 (1% sol. at 25 °C) and its useful pH range is 5.5-6.7 with pKa value of 6.2 at
20 °C. MES is highly soluble in water and thermally stable organic molecule (higher melting
point -approx. 300 °C).
As per the literature and to the best of our knowledge, till date there are no reports on
the use of MES as a catalyst for carrying out any organic transformation. In view of unique
properties of MES and its ability to act as acidic organocatalyst, herein we wish to disclose
MES as a potential organocatalyst for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
(Scheme 1). The developed synthetic protocol represents novel and very simple route for the
preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. In addition, microwave
irradiation technique is successfully implemented for carrying out the reactions in shorter
reaction times.
O
O
C
SO3H
N
O
O
NH
NH2
+
R
H
Aq. Ethanol
60 oC / MWI
R
N
H
NH2
2(a-o)
1
3(a-o)
Scheme 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones.

In search of the best experimental reaction conditions for the preparation of 2,3-
dihydroquinazolin-4(1H)-ones, reaction of 2-amino benzamide 1 and benzaldehyde 2a was
selected as a model reaction (Scheme 2). During the initial study, various acid catalysts
bearing sulphonated functionalities were screened, owing to their widespread catalytic
applications in organic synthesis. For this purpose, sulphamic acid, sulphanilic acid, zinc
sulphate and 2-morpholinoethanesulfonic acid were screened.
Scheme 2. Standard model reaction.
During optimization studies, all the aforementioned catalysts were examined using
ethanol as solvent at reflux temperature. When sulphamic acid and zinc sulphate were used as
catalyst, reaction rate was very slow and product was obtained in lower yield (Table 1, entries
1-2). While sulphanilic acid afforded the desired compound in acceptable yield, the time
required for the completion of the reaction was much longer (Table 1, entry 3). In
comparison, 2-morpholinoethanesulfonic acid (MES) proved as an excellent catalyst
furnishing the product in excellent yield (Table 1, entry 4) and therefore, it was chosen as a
catalyst of choice for further optimization studies.
For evaluation of the effect of solvents on model reaction, various solvents such as
toluene, 1,4-dioxane, acetonitrile, methanol and aqueous ethanol (50%) were tested at their
respective reflux temperatures (Table 1, entries 5-10). Among the solvents tested, aqueous
ethanol was superior over the other solvents in terms of both product yield and reaction time
(Table 1, entry 10).
In further attempts, to reduce the reaction time and increase the product yield, model
reaction was tested at different temperatures like RT, 45 ºC, 60 ºC, 80 ºC and reflux
condition. Surprisingly, increase in product yield was observed along with decrease in the
reaction temperature up to 60 ºC (Table 2, entries 1-5).
To establish the appropriate amount of the catalyst, we investigated the model
reaction using varied concentrations of 2-morpholinoethanesulfonic acid such as 5, 10, 15, 20
and 25 mol%. In this study, formation of the product was observed in 65%, 93%, 91% and

83% yield, respectively. This indicated that 10 mol% of 2-morpholinoethanesulfonic acid is
sufficient to carry out the reaction smoothly.
Table 1. Screening of the catalysts and solventsa
Entry Catalyst
Solvent
Sulphamic acid Ethanol
Zinc sulphate Ethanol
Sulphanilic acid Ethanol
Time (h) Yieldb (%)
1
2c
8
8
42
49
63
78
39
26
48
63
67
84
3
6
4
MES
MES
MES
MES
MES
MES
MES
Ethanol
4
5
Toluene
4
6
1,4-Dioxane
Acetonitrile
Methanol
4
7
4
8
4
9
Water
4
10
Aq. ethanol (50%)
2.5
aReaction conditions: 1 (1 mmol), 2a (1 mmol), catalyst (20 mol%) and
solvent (10 mL) at reflux temperature; bIsolated yields.
Reasons behind the excellent catalytic reactivity of 2-morpholinoethanesulfonic acid
may be due to - (i) presence of sulphonic acid functionality which plays the role of acid
catalyst thereby enhancing the electrophilicity of carbonyl carbon of aldehydes; (ii) MES
being buffering agent and it may be minimizing the formation of the side products, caused by
polymerization of the aldehydes, under the mild buffered conditions; (iii) organic nature of 2-
morpholinoethanesulfonic acid and its good solubility in aqueous ethanol. Thus it forms
homogeneous solution with reacting species and enhances the rate of reaction by shifting
equilibrium of the reaction towards product giving excellent yield in shorter reaction times.
In further set of experiments, model reaction was performed using non-classical
activation energy source, i.e. microwave irradiations. In this experiment, model reaction was
found to proceed effectively within very short reaction time delivering the desired product in
excellent yield. Inspired by this, it was decided to synthesize number of derivatives following
developed reaction conditions by classical as well as non-classical method.

Table 2. Screening of temperature and catalyst concentrationa
Entry
Temperature (°C)
Catalyst Conc. (mol%)
Yieldb (%)
1
2c
3
4
5
6
7
8
9
RT
45
20
20
20
20
20
5
30
63
88
87
84
65
93
91
83
60
80
Reflux
60
60
10
15
25
60
60
aReaction conditions: 1 (1 mmol), 2a (1 mmol) and MES in Aq. ethanol
(50%) (10 mL) for 2.5 h; bIsolated yields.
To further establish the scope of optimized reaction conditions and in order to
generalize the synthetic procedure,19 variety of electronically divergent aromatic aldehydes
were treated with 2-amino benzamide under conventional and microwave irradiation method.
The presence of electron-withdrawing and electron-releasing groups on the aromatic rings
does not affect yield of the product. More importantly, various hetero aryl aldehydes were
observed to be well tolerated under optimized conditions furnishing the product in good
yields. All the results are compiled in Table 3. Formation of the desired product was
confirmed with the help of 1H NMR, 13C NMR and mass spectroscopic data.20
In summary, we have developed an exceedingly simple and novel synthetic protocol
for 2,3-dihydroquinazolin-4(1H)-one derivatives. To the best our knowledge, application of
2-morpholinoethanesulfonic acid is reported for the first time to carry out any organic
transformation under conventional as well as non-conventional method. Remarkable
advantages of this synthetic strategy over the others are (i) higher product yields, (ii)
utilization of microwave irradiations, (iii) decreased reaction times, (iv) simplified work-up
procedure, and (v) most importantly introduction of newer organic catalyst, which may act as
a key catalyst for achieving various organic transformations.

Table 3. Synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives 3(a-o)a
Time
(min)
Yielda (%)
Entry Compound
R
M.P.c ( C)
A/B
A/B
1
2
3a
3b
3c
3d
3e
3f
Ph
150/10
93/95
224-226
220-221
191-192
192-194
200-201
166-168
202-204
208-210
>300
2-OH-Ph
2-NO2-Ph
3-NO2-Ph
4-NO2-Ph
2-OMe-Ph
2-Cl-Ph
150/8
120/5
150/5
120/5
120/8
120/8
90/6
93/95
88/89
85/88
91/93
96/95
86/94
92/94
89/86
91/93
93/96
89/92
86/88
88/90
81/83
3
4
5
6
7
3g
3h
3i
8
4-N(Me)2-Ph
4-OH-Ph
4-Me-Ph
9
120/8
180/15
120/5
180/12
180/12
120/10
180/20
10
11
12
13
14
15
3j
232-233
177-178
197-198
211-213
227-228
166-167
3k
3l
4-OMe-Ph
4-Cl-Ph
3m
3n
3o
3,4-OMe-Ph
4-OH-3-OMe-Ph
Furfuryl
aReaction conditions: 1 (1 mmol), 2 (1 mmol) and 2-morpholinoethanesulfonic
b
c
acid (10 mol%) in 50% aq. ethanol (10 mL); Isolated Yields; Melting points
matches with literature values; A=Conventional method and B=MWI method.

References
1. (a) Hess, H. J.; Cronin, T. H.; Sciabine, A. J. Med. Chem. 1968, 11, 130; (b) Hori, M.;
Iemura, R.; Hara, H.; Ozaki, A.; Sukamoto, T.; Ohtaka, H. Chem. Pharm. Bull. 1990, 38,
681; (c) Srivastava, B.; Shukla, J. S.; Prabhakar, Y. S.; Saxena, A. K. Indian J. Chem.
1991, 30(B), 332; (d) Saxena, S.; Verma, M.; Saxena, A. K.; Shanker, K. Indian J.
Pharm. Sci. 1991, 53, 48.
2. (a) Alaimo, R. J.; Russel, H. E. J. Med. Chem. 1972, 15, 335; (b) Levin, J. I.; Chan, P. S.;
Bailey, T.; Katocs, A. S.; Venkatesan, A. M. Bioorg. Med. Chem. Lett. 1994, 4, 1141; (c)
Maskey, R. P.; Shaaban, M.; Grun-Wollny, I.; Laatsch, H. J. Nat. Prod. 2004, 67, 1131;
(d) Michael, J. P. Nat. Prod. Rep. 2004, 21, 650.
3. Pandey, V. K.; Tusi, S.; Tusi, Z.; Raghubir, R.; Dixit, M.; Joshi, M. N.; Bajpai, S. K.
Indian J. Chem. 2004, 43(B), 180.
4. (a) Srivastava, V. K.; Singh, S.; Gulati, A.; Shankar, K. Indian J. Chem. 1987, 26(B), 652;
(b) Pankaj, N.; Palit, P.; Srivastava, V. K.; Shanker, K. Indian J Chem. 1989, 28(B), 745.
5. Saxena, K. R.; Khan, M. A. Indian J. Chem. 1989, 26(B), 443.
6. Holla Shivarama, B.; Padmaja, M. T.; Shivananda, M. K.; Akbarali, P. M. Indian J.
Chem. 1998, 37(B), 715.
7. Gangwal, A. N.; Kothawade, U. R.; Galande, A. D.; Pharande, D. S.; Dhake, A. S. Indian
J. Heterocycl. Chem. 2001, 10, 291.
8. Singh T, Shalabh Sharma, Srivastava V K and Ashok Kumar, Indian J. Chem. 2006,
45(B), 2558.
9. Tyagi, R.; Goel, B.; Srivastava, V. K.; Kumar, A. Indian J. Pharm. Sci. 1998, 60(5), 283.
10. Raghu Ram, A. R.; Bahekar, R. H. Indian J. Chem. 1999, 38(B), 434.
11. Kumar, A.; Tyagi, M.; Srivastava, V. K. Indian J. Chem. 2003, 42(B), 2142.
12. (a) Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107, 2169; (b) Candeias, N. R.;
Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.; Trindade, A. F. Chem. Rev. 2009, 109,
2703.
13. Moseley, J. D.; Kappe, C. O. Green Chem. 2011, 13, 794.
14. (a) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659; (b) Mhaske, S. B.; Argade, N.
P. Tetrahedron 2006, 62, 9787; (c) Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773;
(d) Sadanandam, Y. S.; Reddy, K. R. M.; Rao, A. B. Eur. J. Org. Chem. 1987, 22, 169;
(e) Kalusa, A.; Chessum, N.; Jones, K. Tetrahedron Lett. 2008, 49, 5840; (f) Liu, X. W.;

Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Angew. Chem. Int. Ed. 2009, 48, 348; (g) Kshirsagar, U.
A.; Argade, N. P. Org. Lett. 2010, 12, 3716.
15. (a) Zhang, Z.-H.; Lu, H.-Y.; Yang, S.-H.; Gao, J.-W. J. Comb. Chem. 2010, 12, 643; (b)
Corbett, J. W.; Ko, S. S.; Rodgers, J. D.; Gearhart, L. A.; Magnus, N. A.; Bachheler, L.
T.; Diamond, S.; Jeffey, S.; Trainor, G. L.; Anderson, P. S.; Erickson-Vitanen, K. J. Med.
Chem. 2000, 43, 2019; (c) Liu, J. F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.; Baldino, C.
M.; McElory, E.; Brown, M. Tetrahedron Lett. 2005, 46, 1241; (d) Bowman, W. R.;
Elsegood, M. R. J.; Stein, T.; Weaver, G. W. Org. Biomol. Chem. 2007, 5, 103.
16. (a) Hour, M. J.; Huang, L. J.; Kuo, S. C.; Xia, Y.; Bastow, K.; Nakanishi, Y.; Hamel, E.;
Lee, K. H. J. Med. Chem. 2000, 43, 4479; (b) Shi, D. Q.; Rong, L. C.; Wang, J. X.;
Zhuang, Q. Y.; Wang, X. S.; Hu, H. W. Tetrahedron Lett. 2003, 44, 3199; (c) Abdel-Jalil,
R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett. 2004, 45, 3475; (d) Chen, J.; Su, W.; Wu,
H.; Liub, M.; Jin, C. Green Chem. 2007, 9, 972; (e) Chinigo, G. M.; Paige, M.; Grindrod,
S.; Hamel, E.; Dakshanamurthy, S.; Chruszcz, M.; Minor, W.; Milton, L.; Brown, M. L.
J. Med. Chem. 2008, 51, 4620; (f) Shaabani, A.; Ali Maleki, A.; Mofakham, H. Synth.
Commun. 2008, 38, 3751.
17. (a) Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008, 130, 15786;
(b) Rueping, M.; Antonchick, A. P.; Sugiono, E.; Grenader, K. Angew. Chem. Int. Ed.
2009, 48, 908.
18. (a) Zong, Y. X.; Zhao, Y.; Luo, W. C.; Yu, X. H.; Wang, J. K.; Pan, Y. Chin. Chem. Lett.
2010, 21, 778; (b) Subba Reddy, B. V.; Venkateswarlu, A.; Madan, Ch.; Vinu, A.
Tetrahedron Lett. 2011, 52, 1891; (c) Niknam, K.; Jafarpour, N.; Niknam, E. Chin. Chem.
Lett. 2011, 22, 69.
19. General experimental procedure for the synthesis of 2-(aryl)-2,3-dihydroquinazolin-
4(1H)-ones 3(a-o)
Conventional method: A mixture of 2-amino benzamide 1 (1 mmol), aldehyde 2 (1 mmol)
and 2-morpholinoethanesulfonic acid (0.1 mmol) in 50% aq. ethanol (10 mL) was stirred
at 60 C. Reaction progress was monitored by TLC (ethyl acetate:n-hexane, 1:9). After
time specified in Table 3, reaction mass was allowed to cool down to room temperature.
Thus obtained product was collected by simple filtration and washed with 50% aq.
ethanol (10 mL) This crude product 4 was purified by crystallization using Aq. ethanol
(water:ethanol, 2:8).

Microwave irradiation method: A mixture of 2-amino benzamide 1 (1 mmol), aldehyde 2
(1 mmol) and 2-morpholinoethanesulfonic acid (0.1 mmol) in 50% aq. ethanol (5 mL)
was subjected to microwave irradiations (600 W). Reaction progress was monitored by
TLC (ethyl acetate:n-hexane, 1:9). After time specified in Table 3, reaction mass was
taken out and allowed to cool down to room temperature. Thus obtained product was
collected by simple filtration and washed with 50% aq. ethanol (10 mL) This crude
product 4 was purified by crystallization using Aq. ethanol (water:ethanol, 2:8).
20. Spectral data for representative compound
1
2-phenyl-2,3-dihydroquinazolin-4(1H)-one (3a): H NMR (400 MHz, DMSO-d6) δ 5.75
(s, 1H), 6.65-6.90 (dt, 1H, J = 0.8 and 7.6 Hz, Ar-H), 6.69-6.72 (dd, 1H, J = 0.4 and 7.6
Hz, Ar-H), 7.08 (s, 1H, exchangeable with D2O), 7.22-7.26 (m, 1H, Ar-H), 7.34-7.41 (m,
3H, Ar-H), 7.48-7.50 (m, 2H, Ar-H), 7.60-7.62 (dd, 1H, J = 1.6 and 8.0 Hz, Ar-H), 8.24
(s, 1H, exchangeable with D2O); 13C NMR (100 MHz, DMSO-d6) δ 66.6, 114.4, 114.9,
117.1, 126.8, 127.3, 128.3, 128.4, 133.3, 141.6, 147.8, 163.6; Mass (ES-MS) m/z 225.1
(M+).

Graphical Abstract
A facile and rapid access towards the synthesis
of 2,3-dihydroquinazolin-4(1H)-ones
Vilas B. Labade, Pravin V. Shinde and Murlidhar S. Shingare*
Department of Chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad-431004, India.
An efficient synthetic route for 2,3-dihydroquinazolin-4(1H)-ones using 2-morpholinoethanesulfonic acid as a
potential and new organocatalyst is described. The developed synthetic protocol represents novel and very simple
route for the preparation of 2,3-dihydroquinazolin-4(1H)-one derivatives. In addition, microwave irradiation
technique is successfully implemented for carrying out the reactions in shorter reaction times.