CC BY-NC-ND
0Journal of Saudi Chemical Society (2012) 16, 387-393
ORIGINAL ARTICLE
Microwave synthesis, characterization and antimicrobial study of new pyrazolyl-oxopropyl-quinazolin-4(3H)-one derivatives
Jignesh P. Raval a *, Krunal G. Desai b, Kishor R. Desaic
a Department of Pharmaceutical Chemistry, Ashok & Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, New Vallabh Vidyanagar 388121, Anand, Gujarat, India
b Department of Chemistry, Veer Narmad South Gujarat University, Udhna-Magdalla Road, Surat 395001, Gujarat, India c Director, C.G. Bhakta Institute of Biotechnology, Bardoli-Mahuva Road, Surat (East) 395007, Gujarat, India
Received 9 November 2010; accepted 12 February 2011 Available online 16 February 2011
KEYWORDS
Quinazoline; Pyrazolyl-quinazoline; Pyrazolyl-oxopropyl-quinaz-olin-4(3H)-one; Microwave effect; Antimicrobial activity
Abstract Heterocyclic compounds containing pyrazolyl-oxopropyl-quinazolin-4(3H)-one are reported to possess significant biological activity. Syntheses of 6-bromo-2-(3-chloro-2-oxopropyl)-3-(4-fluoro-phenyl)quinazolin-4(3H)-one 2 6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxopropyl)qui nazolin-4(3H)-one 3 and 6-bromo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino) phenyl)-5-(substituted phenyl)-4,5-dihydro-1 H-pyrazol-1 -yl)-2-oxopropyl)-3-(4-fluorophenyl)quinazo-lin-4(3H)-one 5a-j using microwave irradiation have been described. These compounds have been characterized on the basis of the UV, IR, 1HNMR, 13C NMR, Mass and elemental analysis. Compounds have been evaluated for their antimicrobial activity.
© 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Tel.: +91 2692 231894; fax: +91 2692 229189.
E-mail addresses: drjpraval@yahoo.co.in (J.P. Raval), kgdapril@ yahoo.co.in (K.G. Desai), k_r_desai@rediffmail.com (K.R. Desai).
1319-6103 © 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
Peer review under responsibility of King Saud University. doi:10.1016/j.jscs.2011.02.003
1. Introduction
Recent developments in the chemistry of quinazoline derivatives have given rise to more than ten thousand publications or patents, and yielded more than one thousand derivatives. It was stimulated by the pharmaceutical utilization of some alkaloids possessing the quinazoline skeleton, which are freely found in nature. Such a natural alkaloid is Febrifugine (known as Chans-San's alkaloid), which was used as an antimalarial agent in 200 years B.C. (Wiseloge, 1963). Most of these compounds have been tested for their pharmacological, herbicidal, biocidal and other properties. At present, quinazoline derivatives are used in the pharmaceutical industry, in medicine and in agriculture because of wide variety of activities such as, antimicrobial (Desai and Desai, 2005), potent anticancer
Scheme-1
(a) Conventional method: ClCH2COCl / THF, reflux, 2-4 hours i(b) Conventional method: NH2NH2.H2O / C2H5OH, reflux, 10-12 hours i(c) Microwave method: NH2NH2.H2O / C2H5OH, |iw, t = 7.0-8.0 mins at p = 300W. i(d) Conventional method: Glacial CH3COOH, reflux, 15-17 hours i(e) Microwave method:Glacial CH3COOH, |iw, t = 9.0-10.0 mins atp 1 = 350W.
i(d) i(e)
H (4a, 5a), 4-N(CH3)2(4b, 5b), 4-OH (4c, 5c), 4-OCH3 (4d, 5d), 3-OC6H5(4e, 5e),
3,4,5-trimethoxy (4f, 5f),
3-OCH3-4-OH(4g, 5g), 2-Cl (4h, 5h),
4-Cl(4i, 5i), 4-NO2 (4j, 5j).
Scheme 1
(Mani Chandrika et al., 2008), antihistaminic (Alagarsamy et al., 2008), and CNS activities like analgesic and antiinflammatory (Alagarsamy et al., 2003, 2007; Tyagi et al., 1998; Rather et al., 2010), sedative-hypnotic and anticonvulsant (Varsha et al., 2008). Furthermore pyrazolyl-quinazoline system possesses diverse biological activities such as antimicrobial (Patel and Barat, 2010), phosphodiesterase inhibitors (Asproni et al., 2010), antidepressant and anticonvulsant (Sinha and Sritastava, 1994) activities. This prompted us to synthesize, using microwave irradiation, a new series of pyrazolyl-oxopro-pyl-quinazolin-4(3H)-one derivatives, by incorporating the pyrazolyl moiety at 2nd position of the quinazolinone nucleus.
In continuation with our ongoing research programme on microwave assisted synthesis of heterocyclic compounds (Raval and Desai, 2009; Raval et al., 2006, 2008, 2009, 2010), we now report on the microwave assisted synthesis of 6-bromo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneami no) phenyl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 5a-j (Scheme 1).
2. Experimental section
General procedure. All the melting points were determined in PMP-DM scientific melting point apparatus and are uncor-rected. The purity of compounds was checked routinely by TLC (0.5 mm thickness) using silica gel-G coated Al plates (Merck) and spots were visualized by exposing the dry plates
in iodine vapours. The IR spectra (vmax in cm-1) were recorded on a Shimadzu FT-IR 8300 spectrophotometer using KBr or Nujol technique, UV spectra (kmax in nm) were recorded on a Shimadzu UV-160 A (200-400 nm) using DMF as solvent, 1H NMR spectra on a Bruker WM 400FT MHz NMR instrument using DMSO-d6 as solvent and TMS as internal reference (chemical shifts in d, ppm); 13C NMR were recorded on Varian AMX 400 (100 MHz) spectrometer as solutions in DMSO-d6 and Mass spectra were recorded on a Jeol JMS D-300 spectrometer. The elemental analysis (C, H and N) of compounds was performed on Carlo Erba-1108 elemental analyzer. The microwave assisted reactions were carried out in a ''QPro-M Microwave Synthesis System'' manufactured by Questron Technologies Corporation, Ontario L4Z 2E9 (Made in Canada), where microwaves are generated by magnetron at a frequency of 2450 MHz having an output energy range of 100-500 W and individual sensor for temperature control (fibre optic is used as a individual sensor for temperature control) with attachment of reflux condenser with constant stirring and synthesis on preparative scales (avoids the risk of high pressure development).
2.1. Chemistry
6-Bromo-2-(3-chloro-2-oxopropyl)-3-(4-fluorophenyl)quinazo-lin-4(3H)-one 2 was prepared by the reaction of 6-bromo-3-(4-fluorophenyl)-2-methylquinazolin-4(3H)-one 1 with ClCH2 COCl in dry THF by only conventional method. 6-Bromo-3-
(4-fluorophenyl)-2-(3-hydrazinyl-2-oxopropyl)quinazolin-4(3 H)-one 3 was prepared by the reaction of 6-bromo-2-(3-chloro-
2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 2 with NH2NH2-H2O in absolute ethanol by both conventional and microwave method. 6-Bromo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-5-(substituted phenyl)-4,5-dihydro-1 H-pyrazol-1-yl)-2-oxopropyl)-3-(4-fluo-rophenyl)quinazolin-4(3H)-ones 5a-jwere prepared by the reaction of 6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxo-pro pyl)quinazolin-4(3H)-one 3 with 1-(4-(1-(2-chlorophenyl)-
3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-3-(substi-tuted phenyl)-prop-2-en-1-ones 4a-jin glacial acetic acid by conventional method and in DMF by microwave method, respectively. Starting compound 6-bromo-3-(4-fluorophenyl)-2-methylquinazolin-4(3H)-one 1 was prepared according to the reported method (Mishra et al., 1997) and compounds 4a-j were prepared according to the reported procedure (Desai and Desai, 2007).
2.2. Synthesis of 6-bromo-3-(4-fluorophenyl)-2-methylquinaz-olin-4(3H)-one 1
Title compound was synthesized according to reported method (Mishra et al, 1997).
2.3. Conventional synthesis of 6-bromo-2-(3-chloro-2-oxopro-pyl)-3-(4-fluorophenyl) quinazolin-4(3H)-one 2
To the solution of 6-bromo-3-(4-fluorophenyl)-2-methylqui-nazolin-4(3H)-one 1 (3.33 g, 0.01 mol) in dry THF (20 mL), a solution of ClCH2COCl (2.26 mL, 0.02 mol) in dry THF (10 mL) was added at 0 0C dropwise with constant stirring for 2 h. The reaction mixture was further stirred for 2-4 h at room temperature and then excess of solvents was distilled off. The reaction mixture was cooled and poured onto ice-cold water. The solid that separated in each case was filtered and recrystallised from ethanol. Yield (3.14 g, 77%) as a white solid, mp 166 oc. UV (kmax CH3OH): 238 nm; IR (vmax cm"1): 173 (C=O), 1590 (C=N), 3060 (ArH), 780 (c-Br), 740 (C-Cl), 1111 (C-F), 2570 (CH2); *H NMR (400 MHz, DMSO-d6) d ppm: 8.75-8.30 (m, 7H, Ar-H), 2.30 (s, 2H, CH2CO), 2.50 (s, 2H, COCH2Cl); MS: m/z 408 [M + ]; Anal. Calcd for C17HuO2N2ClBrF: C, 49.81; H, 2.68; N, 6.83. Found: C, 49.83; H, 2.70; N, 6.83%.
2.4. Conventional synthesis of6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxopropyl) quinazolin-4(3H)-one 3
The solution of compound 2 (4.09 g, 0.01 mol) and NH2NH2-H2O (0.01 mol, 0.9 mL, 99%) in absolute ethanol (15 mL) was refluxed for 10-12 h in a 250 mL round bottom flask. After the completion of reaction (monitored using TLC), the excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The product that separated was recrystallised from ethanol. Yield (2.01 g, 61%) as a pinkish white powder, mp 196 0C. UV (kmax CH3OH): 234 nm; IR (vmax cm"1): 1710 (C=O), 1580 (C=N), 3080 (aromatic C-H), 750 (C-Br), 1113 (C-F), 2570 (CH2), 3440 (NH2), 3380 (NH); 1H NMR (400 MHz, DMSO-d6) d ppm: 8.70-8.20 (m, 7H, Ar-H), 2.35 (s, 2H, CH2CO), 5.56 (br, 1H, NH, exchangeable), 4.55 (hump, 2H, NH2, exchangeable), 2.45 (d, 2H, CH2NH); MS: m/z 405 [M + ]; Anal. Calcd for C17H14O2N4BrF: C, 50.37; H, 3.45; N, 13.82. Found: C, 50.34; H, 3.47; N, 13.84%.
2.5. Microwave mediated synthesis of 6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxopropyl) quinazolin-4(3H)-one 3
The mixture of compound 2 (4.09 g, 0.01 mol) and NH2NH2-H2O(0.01 mol, 0.9 mL, 99%) in absolute ethanol (15 mL) was taken in round bottom flask placed in a microwave oven and irradiated for about 7-8 min (350 W). After the completion of reaction (monitored using TLC), the excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The product that separated was recrystallised from ethanol. Yield (2.03 g, 83%) as a pinkish white crystal.
2.6. Conventional synthesis of 6-bromo-2-[3-{3-[4-{1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino}phenyl]-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl}-2-oxopropyl]-3-(4-fluorophenyl)quinazolin-4(3H)-one
Compound 5a. The solution of compound 3 (4.05 g, 0.01 mol) in glacial acetic acid (20 mL) and 1-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-3-phenyl-prop-2-en-1-one 4a (4.13 g, 0.01 mol) was refluxed for 16 h. After
Table 1 Physical and analytical characterization data of compounds (5a-j).
Entry Substituents R Molecular formula Colour M.p. (°C) kmax in nm Elemental analysis (%)
CH3OH Calcd (found)
5a H C42H32O2N7ClBrF Dark pinkish powder 192 313 62.96 (62.98) 4.03 (3.97) 12.24 (12.26)
5b 4-N(CH3)2 C44H37O2N8ClBrF Yellowish brown solid 237 291 62.60 (62.03) 4.42 (4.37) 13.27 (13.12)
5c 4-OH C42H32O3N7ClBrF Dark pink powder 217 298 61.74 (61.72) 3.95 (4.06) 12.00 (12.03)
5d 4-OCH3 C43H34O3N7ClBrF Brown powder 247 320 62.14 (62.1o) 4.12 (4.11) 11.80 (11.83)
5e 3-OC6H5 C48H36O3N7ClBrF Violet powder 199 300 64.54 (64.56) 4.06 (4.06) 10.98 (10.95)
5f 3,4,5-(OCH3)3 C45H38O5N7ClBrF Dark brown crystal 202 275 60.65 (60.66) 4.30 (4.51) 11.00 (11.04)
5g 3-OCH3-4-OH C43H34O4N7ClBrF Light brown powder 250 277 60.97 (60.93) 4.05 (4.16) 11.57 (11.60)
5h 2-Cl C42H31O2N7Cl2BrF Yellow powder 241 335 60.37 (60.37) 3.74 (3.73) 11.73 (11.74)
5i 4-Cl C42H31O2N7CI2BrF Pale yellow crystalline powder 255 298 60.37 (60.33) 3.74 (3.72) 11.73 (11.52)
5j 4-NO2 C42H31O4N8ClBrF Pink powder 262 288 59.62 (59.61) 3.69 (3.68) 13.24 (13.21)
Table 2 Spectral data of compounds (5a-j).
Entry IR
'H NMR d ppm (400 MHz, DMSO-d6)
13C NMR d ppm (100 MHz, DMSO-d6)
MS (m/z) [M+]
5a 1725 (C=O), 1590 (C=N), 3060 (aromatic C-H), 745 (C-Cl), 770 (C-Br), 1118 (C-F), 2480 (CH2), 2480, 2960 (aliphatic C-H)
5b 1728 (C=O), 1598 (C=N), 3052
(aromatic C-H), 748 (C-Cl), 767 (C-Br), 1115 (C-F), 2479 (CH2), 2485, 2957 (aliphatic C-H), 1318 (C-CH3), 1315 [C-N(CH3)2]
5c 1721 (C=O), 1589 (C=N), 3065 (aromatic C-H), 741 (C-Cl), 772 (C-Br), 1111 (C-F), 2484 (CH2), 2478, 2964 (aliphatic C-H), 1315 (C-CH3), 3572 (C-OH)
5d 1730 (C=O), 1578 (C=N), 3050 (aromatic C-H), 744 (C-Cl), 780 (C-Br), 1128 (C-F), 2475 (CH2), 2485, 2965 (aliphatic C-H), 1317 (C-CH), 2831 (C-OCH3)
5e 1721 (CO), 1593 (C=N), 3061 (aromatic C-H), 748 (C-Cl), 771 (C-Br), 1113 (C-F), 2473 (CH2), 2467, 2964 (aliphatic C-H), 1310 (C-CH3)
5f 1725 (C=O), 1591 (C=N), 3062
(aromatic C-H), 743 (C-Cl), 771 (C-Br), 1112 (C-F), 2483 (CH2), 2481, 2962 (aliphatic C-H) 1313 (C-CH3), 2828
[C-(OCH3)3]
5g 1728 (C=O), 1590 (C=N), 3060
(aromatic C-H), 745 (C-Cl), 770 (C-Br), 1118 (C-F), 2480 (CH2), 2480, 2960 (aliphatic C-H), 1312 (C-CH3), 3566 (C-OH), 2825 (C-OCH3)
5h 1726 (C=O), 1592 (C=N), 3063 (aromatic C-H), 749 (C-Cl), 775 (C-Br), 1120 (C-F), 2482 (CH2), 2488, 2966 (aliphatic C-H), 1315 (C-CH3)
8.60-7.20 (m, 20H, Ar-H), 2.40 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.80 (d, 2H, 2 x CH2 of pyrazoline ring), 3.95 (t, 1H, CH of pyrazoline ring), 2.26 (s, 2H, 2 x CH2-CO)
7.00-7.95 (m, 19H, Ar-H), 2.38 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.85 (d, 2H, 2 x CH2 of pyrazoline ring), 3.97 (d, 1H, CH of pyrazoline ring), 2.23 (s, 2H, 2 x CH2-CO), 2.9 [m, 6H, -N(CH3)2)] 6.98-7.93 (m, 19H, Ar-H), 2.42 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.78 (d, 2H, 2 x CH2 of pyrazoline ring), 3.89 (t, 1H, CH of pyrazoline ring), 2.36 (s, 2H, 2 x CH2-CO), 3.58 (s, 1H, -OH)
7.20-7.90 (m, 19H, Ar-H), 2.31 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.72 (d, 2H, 2 x CH2 of pyrazoline ring), 3.99 (t, 1H, CH of pyrazoline ring), 2.28 (s, 2H, 2 x CH2-CO), 3.89 (s, 3H, -OCH3)
6.85-7.65 (m, 19H, Ar-H), 2.34 (s, 3H, CH3 attached to pyrazolidene nucleus),
5.86 (d, 2H, CH2 of pyrazoline ring), 3.91 (1, 1H, 2 x CH of pyrazoline ring), 2.37 (s, 2H, 2 x CH2-CO), 6.79-7.77 (m, 5H, -OC6H5)
6.99-7.80 (m, 17H, Ar-H), 2.45 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.89 (d, 2H, 2 x CH2 of pyrazoline ring),
3.87 (t, 1H, CH of pyrazoline ring), 2.31 (s, 2H, 2 x CH2-CO), 3.92 (s, 3H, -OCH3)
6.78-7.86 (m, 18H, Ar-H), 2.48 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.79 (d, 2H, 2 x CH2 of pyrazoline ring), 3.82 (t, 1H, CH of pyrazoline ring), 2.27 (s, 2H, 2 x CH2-CO), 3.79 (s, 3H, -OCH3), 3.50 (s, 1H, -OH)
6.65-7.77 (m, 17H, Ar-H), 2.42 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.88 (d, 2H, 2 x CH2 of pyrazoline ring), 3.96 (t, 1H, CH of pyrazoline ring), 2.22 (s, 2H, 2 x CH2-CO)
5i 1730 (CO), 1588 (C=N), 3058 (aromatic C-H), 735 (C-Cl), 773 (C-Br), 1120 (C-F), 2481 (CH2),
2482, 2961 (aliphatic C-H), 1314 (C-CH3)
6.72-7.82 (m, 17H, Ar-H), 2.44 (s, 3H, CH3 attached to pyrazolidene nucleus), 5.90 (d, 2H, 2 x CH2 of pyrazoline ring), 3.92 (t, 1H, CH of pyrazoline ring), 2.33 (s, 2H, 2 x CH2-CO)
115-135 (aromatic > 800
C=C<), 40 (CH3), 49
(2 x CH2 of pyrazoline
ring), 38 (-CH2-), 189
(>C=O), 172 (aliphatic
>C=O), 110-140
(heteroaromatics >
113-133 (aromatic > 842 C=C<), 42 (CH3),
50 (2 x CH2 of pyrazoline ring), 40 (-CH2-), 192 (>CO), 170 (aliphatic >C=O), 113-143 (heteroaromatics >C=N-)
114-131 (aromatic >C 815 =C<), 43 (CH3), 53
(2 x CH2 of pyrazoline ring), 37 (-CH2-), 197 (>CO), 171 (aliphatic >C=O), 112-141 (heteroaromatics >C=N-)
115-135 (aromatic > 830 C=C<), 44 (CH3),
51 (2 x CH2 of pyrazoline ring), 39 (-CH2-), 199 (>C=O), 171 (aliphatic >C=O), 35.7 (OCH3), 112-145 (heteroaromatics >C=N-)
111-132 (aromatic >C= 890 C<), 42 (CH3), 50 (2 x
CH2 of pyrazoline ring), 39 (-CH2-), 194 (>C=O), 170 (aliphatic >C=O), 115-148 (heteroaromatics >C=N-)
110-135 (aromatic >C=C<), 888
37 (CH3), 50 (2 x CH2 of pyrazoline ring), 38.7 (-CH2-), 189 (>C=O). 171 (aliphatic >C=O), 37.5 (3 x OCH3), 110-140 (heteroaromatics > C=N-)
112-134 (aromatic >C= 843 C<), 44 (CH3), 48 (2 x
CH2 of pyrazoline ring), 35 (-CH2-), 193 (>C=O),
169 (aliphatic >C=O),
113-141 (heteroaromatics >C=N-)
114-131 (aromatic >C= 833 C<), 41 (CH3), 55 (2 x
CH2 of pyrazoline ring),
38 (-CH2-), 188 (>C=O), 175 (aliphatic >C=O), 118-150 (heteroaromatics >C=N-)
114-134 (aromatic >C=C<), 833 41(CH3), 49(2 x CH2 of pyrazoline ring), 36 (-CH2-), 196 (>C=O),
170 (aliphatic >C=O), 116-142 (heteroaromatics >C=N-)
Table 2 (continued)
Entry IR 'H NMR S ppm 13C NMR S ppm MS (m/z)
cm-1 (KBr) (400 MHz, DMSO-d6) (100 MHz, DMSO-d6) [M+]
5j 1728 (C=O), 1596 (C=N), 3061 (aromatic 7.15-7.92 (m, 17H, Ar-H), 2.36 (s, 3H, 113-133 (aromatic >C=C<), 844
C-H), 749 (C-Cl), 771 (C-Br), 1118 (C-F), CH3 attached to pyrazolidene nucleus), 43 (CH3), 50 (2 x CH2 of
2481 (CH2), 2487, 2967 (aliphatic C-H), 5.76 (d, 2H, 2 x CH2 of pyrazoline ring), pyrazoline ring), 37 (-CH2-), 185
1315 (C-CH3), 1340 (C-NO2) 3.88 (t, 1H, CH of pyrazoline ring), 2.36 (>C=O), 172 (aliphatic >C=O),
(s, 2H, 2 x CH2-CO) 114-141 (heteroaromatics >C=N-)
the completion of reaction (monitored using TLC), the excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The product that separated was recrystallised from ethanol. Yield (5.14 g, 65%) as a dark pinkish solid, mp 230 0C.
2.7. Microwave mediated synthesis of 6-bromo-2-[3-{3-[4-{1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino}phenyl]-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl}-2-oxopropyl]-3-(4-fluorophenyl)quinazolin-4(3H)-one
Compound 5a. A mixture of compound 3 (4.05 g, 0.01 mol) in glacial acetic acid (20 mL) and 1-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-3-phenyl-prop-2-en-1-one 4a (4.13 g, 0.01 mol) was taken in 250 mL round bottom flask placed in a microwave oven and irradiated for about 8-10 min (350 W). After the completion of reaction (monitored using TLC), the excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The product that separated was recrystallised from ethanol. Yield (5.15 g, 88%) as a dark pinkish powder. Likewise other compounds 5b-jwere prepared by treating 3 with various substituted chalcones.
The Physical, analytical characterization and spectral data of 5a-jare presented in Tables 1 and 2.
2.8. Antimicrobial activity
The compounds 2, 3 and 5a-jwere screened for their antibacterial activity against Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 6538), Escherichia coli (ATCC 8739) and Pseudomonas aeruginosa (ATCC 1539) and antifungal activity against Candida albicans (ATCC 10231) and Candida krusei (G03) by filter paper disc technique (GCLMD, 1970; NCCLS, 1997). Standard antibacterial and antifungal drugs Ampicillin, Amoxicillin, Penicillin and Flucanozole were also tested under similar conditions for comparison. Results are presented in Table 4. By visualizing the antimicrobial data it could be observed that some of the compounds possess significant activity.
3. Results and discussion
3.1. Characterization
Compound 1 on reaction with chloroacetylchloride yielded 6-bromo-2-(3-chloro-2-oxopropyl)-3-(4-fluorophenyl)quinazo-lin-4(3H)-one 2. Among the significant feature of *H NMR data of 1, the disappearance of singlet at S 2.50 (CH3) and appearance of two singlets at S 2.30 and S 2.50 due to the
chloroacetyl group confirmed the structure. Furthermore, compound 2 on treatment with hydrazine hydrate gave corresponding 6-bromo-3-(4-fluorophenyl)-2-(3-hydrazinyl-2-oxo-propyl)quinazolin-4(3H)-one 3. The appearance of bands at 3380 and 3440 cm-1 for NH and NH2, respectively in the IR spectra, and two broad signals at S 4.55 and S 5.56 in *H NMR spectra clearly showed the presence of hydrazino group in compound 3. Further, compound 3 on refluxing with 1-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino) phenyl)-3-(substituted phenyl)-prop-2-en-1-ones 4a-jin the presence of glacial acetic acid yielded the corresponding 6-bro-mo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1 H-pyrazol-5(4H)-ylideneamino)phenyl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxopropyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 5a-j(Scheme 1). The structures of compounds 5a-jwere confirmed on the basis of UV, IR, NMR, 13C NMR and MS spectral data (Table 1 and 2).
The same compounds have been also synthesized using conventional approach and comparative study in terms of yield and reaction period is shown in Table 3. All the reactions under microwave irradiation were completed within 9.0-10.5 min with yield (79-94%), whereas similar reactions in boiling eth-anol under conventional heating (steam bath) gave poor yields (49-73%) with remarkably longer reaction time periods (15.017.0 h) (Table 3), demonstrating that the effect of microwave irradiation is not purely thermal. Actually, microwave irradiation facilitates the polarization of the molecules under irradiation causing rapid reaction to occur. This is consistent with the reaction mechanism, which involves a polar transition state (Loupy et al, 2001).
Table 3 Comparative study in terms of yield and reaction period for microwave and conventional techniques for compounds (5a-j).
Entry Microwave methoda Conventional method
Time (min) Temp Yield (%) Time (h) Yield (%)
5a 10.0 116 88 16.0 65
5b 9.0 120 82 15.5 55
5c 9.5 118 80 16.5 60
5d 9.5 118 83 15.0 71
5e 9.0 120 79 17.0 59
5f 10.0 116 86 15.5 49
5g 9.5 118 94 16.0 68
5h 10.0 116 90 16.5 73
5i 10.5 114 82 15.0 54
5j 10.0 118 89 15.5 63
a Power: 350 W.
Table 4 Antimicrobial activity of compounds (5a-j).
Entry Antibacterial in (ig/mL) Antifungal in (ig/mL)
Gram positive Gram negative
S.a.a ATCC 6538 B.sb ATCC 6633 E.c.c ATCC 8739 P.a.d ATCC 1539 C.a.e ATCC 10231 C.kf G03
2 - 22 9 25 10 25
3 15 0.9 8 18 18 22
5a 9 11 22 16 - 20
8 6 0.8 9 1.1 12 0.8
5c 13 - 16 11 17 9
5d 7 10 13 13 - 12
5e 6 17 0.9 1.8 20 -
5f 11 21 - 19 0.9 20
5g 13 1.1 0.9 - 10 17
5h 15 20 12 12 17 8
5i - 16 - 17 10 0.7
5j9 10 12 9 7 0.8
Ampicillin 40 45 40 50 - -
Amoxicillin 35 40 38 45 - -
Penicillin 40 38 42 48 - -
Flucanuzole - - - - 40 35
a S.a. - Staphylococcus aureus.
b B.s. - Bacillus subtilis.
c E.c. - Escherichia coli.
d P.a. - Pseudomonas aeruginosa.
e C.a. - Candida albicans.
f C.k. - Candida krusei.
3.2. Antimicrobial activity
Antimicrobial results are presented in Table 4. By visualizing the antimicrobial data it could be observed that some of the compounds possess significant activity. Zone of inhibition was measured in millimetres. The antifungal activities were compared to the standard drug Flucanozole (35-40 min), while Ampicillin (40-50 mm), Amoxicillin (35-45 mm) and Penicillin (38-48 mm) were used as standard drugs for antibacterial activity. Compounds 2, 5a, 5f, 5h and 5i showed significant antibacterial activity. Compounds2, 3, 5a, 5e, 5f and 5g showed moderate to good antifungal activity.
4. Conclusion
A new method for the synthesis of 6-bromo-2-(3-(3-(4-(1-(2-chlorophenyl)-3-methyl-1H-pyrazol-5(4H)-ylideneamino)phenyl)-5-(substituted phenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxopro-pyl)-3-(4-fluorophenyl)quinazolin-4(3H)-one 5a-jusing microwave irradiation offers significant improvement over existing procedures and thus helps facile entry into a synthesis of variety of pyrazolylquinazolinone derivatives. Also, this simple and reproducible technique affords various pyrazolyl-oxopropyl-quinazolin-4(3H)-one derivatives with short reaction times, excellent yields, and without formation of undesirable side products.
Acknowledgements
Authors are thankful to Gujarat Council Science and Technology (Grant no. GUJCOST/200389/MRP/2003-04/ 10689), Gandhinagar for financial assistance and Mr. Priyakant
R. Raval (Cyanamid India Ltd., Atul) for providing assistance
in spectral analysis.
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