Water promoted, microwave-assisted oxidative novel

deamination of N-aminoquinazolinones

M. Arfan a,*, Rasool Khan a,*, Shazia Anjum b,Shabir Ahmad a, M. Iqbal Choudhary b

a Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistanb HEJRIC, International Centre for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

Received 24 September 2007

Abstract

A novel deamination of 2-alkyl/aryl 3-amino-4(3H)-quinazolinones series using aqueous KMnO4 under thermal condition and

microwave irradiation is described. Compared to thermal condition, significantly higher yields in much shorter times were observed

for reactions under microwave irradiation. A plausible mechanism has been proposed for the oxidative water-promoted

deamination.

# 2007 M. Arfan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: N-Aminoquinazolinones; Oxidative deamination; KMnO4; Water; Microwave irradiation

Quinazolinones 1 and 2 belong to an important class of fused heterocycles with a wide range of biological activities

such as anti-cancer, anti-inflammatory, anti-convulsant, anti-hypertensive, sedative-hypnotic, antitussive and

antimalarial [1–4]. In addition to its diverse biological activities, quinazolinone (2) is a synthetic precursor for a

number of naturally occurring quinazolinone alkaloids [3,5–7].

Reported literature describes the synthesis of 2-aryl/alkyl-4(3H)-quinazolinone 2 by employing Nimentowski

reaction, a condensation between anthranilic acid and alkanamide [8]. Other methods involve reaction of

arencarboximides with isotoic anhydride [9], and reacting ammonium acetate with benzoxazinone at elevated

temperature [10]. The labile nature of N–N bond has been utilized for the preparation of 2-alkyl/aryl-substituted-

4(3H)-quinazolinone via neat pyrolysis of 2-p-tolyl-3-benzylidene aminopyrido[2,3-H]quinazolin-4(3H)-one above

its melting point [11]. Procedures for N–N bond cleavage using dissolving metal reagents have been reported [12a,b].

2-Ethylquinazolin-4(3H)-one has been prepared by reduction of N-quinazolinyl aziridine using lithium or sodium in

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Chinese Chemical Letters 19 (2008) 161–165

* Corresponding authors.

E-mail addresses: m_arfan@upesh.edu.pk (M. Arfan), rasoolkhan1@hotmail.com (R. Khan).

1001-8417/$ – see front matter # 2007 M. Arfan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

doi:10.1016/j.cclet.2007.10.056

liquid ammonia [13a,b] via diazotization [14]. Reddy et al. reacted 2-aryl-3,4-dihydro-5H-1,3,4-benzotriazepin-5-

ones with KMnO4 in acetone under reflux; ring contraction resulted in formation of 2-arylquinazoliolin-4(3H)-ones

[15a,b]. The reported methods are associated with drawbacks such as expensive and sometimes hazardous solvents,

longer reaction times and formation of side products [16–18].

New green synthetic strategies are having high demand today for obvious reasons. The use of water and ionic

liquids as solvents is preferred over other volatile and toxic solvents. Moreover, domestic microwave synthetic

methods are not only environmentally friendly but are also cheap, less tedious and need much shorter reaction times

for reaction completion. The literature on microwave chemistry has tremendously increased since 1990 and large

number of conventional thermal reactions have been improved by using microwave methods. Domestic microwave

oven in organic synthesis has been used in several standard research papers [19a–e].

Herein we report KMnO4 mediated oxidative deamination of the analogs of 1, using water as solvent [20] under

conventional thermal condition. The same study has also been extended to microwave-assisted technique obtaining

some very interesting results (Scheme 1). This communication, to our knowledge documents the first facile, cheaper

and environmentally benign thermal and microwave-assisted deamination methods of an amino group attached to

nitrogen as a part of quinazolinone ring system. The methods will be equally applicable for deamination of other

N-aminoheterocyclic systems.

Under the thermal procedure, compounds 2a–j were obtained by refluxing 1a–j in aqueous KMnO4 till completion

of the reactions (Table 1). The encouraging syntheses of the aryl/alkylquinazolinone-4(3H)-ones in aqueous KMnO4

media by conventional heating procedure further prompted us to carry out the same reactions using microwave

irradiation (Scheme 1). All reactions were successfully carried out under microwave irradiation using water as solvent.

The reactions completed within 8–13 min compared to 4–5 h under thermal condition and with improved yields

(Table 1).

M. Arfan et al. / Chinese Chemical Letters 19 (2008) 161–165162

Scheme 1. Water-promoted microwave-assisted oxidative deamination.

Table 1

Deamination of aminoquinazolinones in aqueous KMnO4 using thermal (A) and microwave irradiation (B) methods

Entry (compound # ) R Method Reaction time Yield (%) M.p. (8C) Reference

1 (2a) CH3 A 4 h 73 240 [7,20]

B 10 min 81

2 (2b) C6H5 A 3 h 70 238 [15,20]

B 12 min 90

3 (2c) 4-CH3C6H4 A 4 h 73 240–242 [15]

B 10 min 81

4 (2d) 4-ClC6H4 A 4 h 72 303 [15]

B 12 min 85

5 (2e) 4-BrC6H4 A 4 h 69 170–172 [15]

B 13 min 80

6 (2f) 4-NO2C6H4 A 5 h 67 360 [15]

B 12 min 80

7 (2g) C6H4CH2 A 3 h 70 255 [18]

B 10 min 88

8 (2h) 4-HOC6H4 A 4 h 80 126 [15]

B 10 min 83

9 (2i) CH2CO2C2H5 A 4 h 65 155–157

B 10 min 83

10 (2g) C2H5 A 4 h 80 234 [15]

B 8 min 91

The mixture of substrate and aqueous solution of KMnO4 in 100 mL conical flask was irradiated in a domestic

microwave oven (1000 W) with consecutive pulses of 10–15 s for 30 s at a time. After each 30 s pulsed irradiation an

interval of 10 s was provided to the reaction content to cool down. Cooling of the reaction mixture after pulsed

microwave irradiation was found necessary as continuous irradiation resulted in spill over with complete loss of water

leading to reaction failure. The spill over also occurred when the mixture was irradiated without using a heat sink in the

form of a beaker containing water inside the microwave oven. It is proposed that the reaction mechanism involved

oxidative-hydrolytic deamination, i.e., KMnO4 mediated oxidation of the amino group to a nitroso group followed by

hydrolytic cleavage of the N-nitroso bond (Scheme 2). A research communication by Reddy et al. [15a] has reported

the formation of 2-arylquinazolin-4(3H)-ones (2b) from 2-aryl-3,4-dihydro-5H-1,3,4-benzotriazepin-5-one under

thermal condition using KMnO4 in acetone. This transformation was explained by a proposed reaction mechanism

implicating the formation of N-amino-2-arylquinazolin-4(3H)-one (1b) as one of the reaction intermediates (Scheme

3). We believe that analogous KMnO4 mediated oxidative dimerization of 1a–j as highly unlikely in aqueous medium.

Alternatively, a more plausible reaction mechanism followed in our reported method is KMnO4 mediated oxidative

transformation of the N–NH2 into N–NO followed by water promoted hydrolytic removal of the nitroso group as

shown in Scheme 2.

In conclusion, we have developed simple and environmentally friendly thermal and microwave irradiation methods

for deamination of 2-alkyl/aryl 3-aminoquinazolinone, 2-alkyl/aryl quinazolinones applicable to other analogous

systems, making use of a cheaper, readily available oxidant and medium as potassium permanganate and water,

respectively. The microwave-assisted procedure has the added advantage of very high yields and much shorter reaction

completion times over the thermal method.

1. Experimental

The chemicals and solvents used were of synthetic grade and were purified before use according to standard

methods [21]. TLC analysis was done on alumina supported pre-coated silicagel TLC plates (Merck). Melting points

were determined in open capillary using Gallen kamp melting point apparatus and are uncorrected. 1H NMR spectra

were recorded on Bruker 400 MHz in CDCl3, CD3OD or DMSO as solvent using TMS as an internal standard while

Mass spectra were recorded on JEOL MAT312 instrument.

1.1. General experimental procedure for deamination of N-aminoquinazolinone (1a–j)

1.1.1. Thermal method (A)

A mixture of an N-aminoquinazolinone (1a–j) (0.28 mmol) and KMnO4 (1.12 mmol) in 10 mL water was refluxed

for 3–5 h. After completion of reaction, as monitored by TLC, the reaction mixture was hot filtered and the filtrate was

allowed to cool. The product thus precipitated was filtered, dried and recrystallized from water–ethanol mixture to give

the corresponding deaminated quinazolinones (2a–j) in 65–80% yield (Table 1).

M. Arfan et al. / Chinese Chemical Letters 19 (2008) 161–165 163

Scheme 2. Proposed mechanism of oxidative-hydrolytic deamination.

Scheme 3. A part of the mechanism proposed by Reddy et al. [15a,b].

1.1.2. Microwave-assisted method (B)

A mixture of an N-aminoquinazolinone (1a–j) (0.28 mmol) and KMnO4 (1.12 mmol) in 10 mL water was placed in

a domestic microwave oven. A beaker containing water was placed in the oven to act as a heat sink. Microwave

radiation pulses of 10–15 s durations were provided consecutively for 30 s. Each 30 s pulsed irradiation was followed

by a 10 s interval for the reaction mixture to cool down. After completion of reaction, the water was evaporated

completely and the mixture was extracted with dichloromethane. Dichloromethane extract was dried over anhydrous

Na2SO4. After filtration, the solvent was evaporated under reduced pressure to afford the corresponding products

(2a–j) in 80–91% yields (Table 1).

1.2. Spectral data of 2a–j

2a: 1H NMR (CDCl3, 400 MHz, d ppm): 8.16 (d, 1H, J = 7.6 Hz), 7.78 (t, 1H, J = 7.1 Hz), 7.6 (d, 1H, J = 7.8 Hz),

7.48 (t, 1H, J = 7.1 Hz), 2.4 (s, 3H); FAB-MS m/z: 161 (M + 1), 159 (M � 1); EI-MS m/z: 160 (M+, 100), 145 (21), 120

(19), 92 (23), 76 (10), 64 (11).

2b: 1H NMR (CDCl3, 400 MHz, d ppm): 10.2 (s, 1H), 8.26 (d, 1H, J = 8 Hz), 7.82 (m, 4H), 7.56 (m, 4H); EI-MS m/

z: 222 (M+), 119 (100), 105 (23), 90 (30), 77 (63), 76 (18).

2c: 1H NMR (CDCl3, 400 MHz, d ppm): 10.11 (s, 1H), 7.92 (d, 1H, J = 9 Hz), 7.69 (m, 3H), 7.20 (m, 4H), 2.348 (s,

3H, CH3); EI-MS m/z: 236 (M+, 57), 119 (100), 91 (25), 90 (25), 76 (13), 63 (14).

2d: 1H NMR (CDCl3, 400 MHz, d ppm): 9.80 (s, 1H), 8.28 (d, 1H, J = 11 Hz), 8.04 (d, 2H, J = 11.07 Hz), 7.82 (d,

1H, J = 10 Hz), 7.75 (d, 1H, J = 11 Hz), 7.54 (d, 2H, J = 11 Hz), 7.42 (d, 1H, J = 11.2 Hz); EI-MS m/z: 258 (M+2, 12),

256 (M+, 52), 178 (4), 149 (13), 138 (9), 119 (100), 113 (3), 111 (12), 102 (5), 94 (14), 91 (4), 90 (13), 77 (5), 76 (8), 57

(8).

2e: 1H NMR (CDCl3, 400 MHz, d ppm): 7.95 (d, 1H, J = 11 Hz), 7.81 (d, 1H, J = 10.8 Hz), 7.76 (t, 2H, J = 8.4 Hz),

7.59 (d, 1H, J = 11.8 Hz), 7.53 (m, 2H); EI-MS m/z: 302 (M+2, 52), 301 (M+, 36), 300 (58), 299 (37), 248 (3), 185 (3.7),

183 (3.6), 157 (4), 155 (3.9), 1120 (7), 119 (100), 102 (8), 92 (12), 90 (13), 76 (17), 75 (9), 69 (19), 57 (11).

2f: 1H NMR (CDCl3, 400 MHz, d ppm): 10.3 (s, 1H), 8.34 (d, 3H, J = 9 Hz), 8 (d, 2H, J = 9 Hz), 7.9 (d, 2H,

J = 9 Hz), 7.5 (m, 1H); EI-MS m/z: 267 (M+, 12), 150 (82), 120 (44), 119 (100), 104 (65), 92 (53), 90 (20), 76 (60).

2g: 1H NMR (CDCl3, 400 MHz, d ppm): 10.2 (s, 1H), 8.2 (d, 1H, J = 7.8 Hz), 7.8 (d, 1H, J = 8 Hz), 7.2 (dd, 1H,

J = 9 Hz), 7.6 (dd, 1H, J = 8.5 Hz), 7.08 (d, 1H, J = 14 Hz), 7.06 (d, 1H, J = 16 Hz), 7.2 (dd, 2H, J = 14 Hz), 7.25 (dd,

1H, J = 16 Hz), 4.1 (s, 2H); EI-MS m/z: 236 (M+, 55), 235 (100), 207 (5), 119 (20), 92 (42), 77 (57).

2h: 1H NMR (CDCl3, 400 MHz, d ppm): 10.00 (s, 1H), 8.28 (d, 1H, J = 7.8Hz), 8.05 (d, 1H, J = 8.5 Hz), EI-MS m/

z: 252 (M+, 100), 208 (8), 132 (12), 120 (8), 119 (90), 90 (10), 77 (5).

2i: 1H NMR (CDCl3, 400 MHz, d ppm): 8.26 (d, 1H, J = 7.8 Hz), 7.76 (m, 2H), 7.49 (t, 1H, J = 7.1 Hz), 4.26 (q, 2H,

J = 7.36 Hz), 3.86 (s, 1H), 1.34 (t, 3H, J = 7.17 Hz); EI-MS m/z: 232 (M+, 62), 160 (100), 119 (37), 89 (39), 77 (28), 60

(42), 55 (21).

2j: 1H NMR (CDCl3, 400 MHz, d ppm): 10.40 (s, 1H), 8.27 (d, 1H, J = 7.8 Hz), 7.76 (t, 1H, J = 8.2 Hz), 7.65 (d,

1H, J = 8 Hz), 7.46 (t, 1H, J = 8 Hz), 2.83 (q, 2H, J = 15 Hz), 1.43 (t, 3H, J = 7.6 Hz); EI-MS m/z: 174 (M+, 92), 173

(100), 149 (14), 119 (33), 77 (7), 55 (12).

Acknowledgments

The authors (M.A. and R.K.) acknowledge International Center for Chemical and Biological Sciences, University

of Karachi, Pakistan for providing laboratory space and access to spectroscopic techniques for this work. The authors

(M.A. and R.K.) are also thankful to the University of Peshawar, Pakistan for the research grant.

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