Microwave-induced and conventional heterocyclic synthesis: An antimicrobial entites of newer quinazolinyl-Δ2-pyrazolines

Krunal G. Desai; Jiten I. Naik; Jignesh P. Raval; Kishor R. Desai

doi:10.1016/j.arabjc.2011.06.015

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ORIGINAL ARTICLE

7 (

); 597-603

doi:

10.1016/j.arabjc.2011.06.015

Microwave-induced and conventional heterocyclic synthesis: An antimicrobial entites of newer quinazolinyl-Δ²-pyrazolines

Krunal G. Desai^a,*,1, Jiten I. Naik^b, Jignesh P. Raval^c, Kishor R. Desai^d

a Process Research Laboratory-II, Active Pharmaceuticals Ingredients Division (API/Bulk Drugs), Chemical Research Department (CRD), Research and Development Centre (USFDA approved), Macleods Pharmaceuticals Limited, G-2, Mahakali Caves Road, Shantinagar, Andheri (East), Mumbai 400 093, Maharastra State, India

b Technology Transfer Department, Macleods Pharmaceuticals Limited (USFDA approved), Unit-V, Plot No. 2209, Gujarat Industrial Development Corporation (GIDC), Sarigam 396 115, Bhilad District (West), Gujarat State, India

c Department of Pharmaceutical Chemistry, Ashok & Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, New Vallabh Vidyanagar 388 121, Anand District, Gujarat State, India

d C.G. Bhakta Institute of Biotechnology, Maliba Campus, Bardoli-Mahuva Road, Surat (East) 395 007, Gujarat State, India

1st Heterocyclic Update

*Corresponding author kgdapril@yahoo.co.in (Krunal G. Desai) http://interesjournals.org/IRJPS/editors.htm (Krunal G. Desai)

Received: 2011-3-4, Accepted: 2011-6-11, Published: 2011-11-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

1 Part of Ph.D thesis.

Abstract

Heterocyclic compounds containing pyrazolines were reported to possess significant biological activity. Synthesis of 2-(ω-chloroacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-ones (2), 2-(ω-hydrazinoacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-ones (3) and 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(substituted phenyl)-Δ²-pyrazolines (4a–j) have been described. Some of the new compounds were tested against bacteria (Gram –ve and Gram +ve) and fungi.

Keywords

Quinazolinyl-Δ2-pyrazolines

Heterocyclization

Microwave effect

Potential pharmacological interest

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1 Introduction

The increasing environmental consciousness throughout the world has put a pressing need to develop an alternate synthesis approach for biologically and synthetically important compounds. The present day industrialization has led to immense environment deterioration. One of the advances in the field of green chemistry (Xie et al., 1999; Desai and Desai, 2006a,b; Desai et al., 2006a,b ) where substantial progress has been made is microwave-assisted synthesis (Verma, 1999; Desai and Desai, 2006b,c, 2007 ).

The chemistry and pharmacology of quinazolinone have been of great interest to medicinal chemistry because quinazolinone derivatives possessed various biological activities, such as antibacterial (Ghorab and Abdel-Hamide, 1995; Reddy et al., 1999), CVS (Kumar et al., 1998) and anticonvulsant (Wolf et al., 1990). Several pyrazolines are of great importance as antimicrobial agents (Kumar and Sinha, 1990; Srivastava and Srivastava, 1999).

Compounds bearing the quinazolinone moiety are endowed with various types of biological activities (Amine, 1998; Holla et al., 1998; Kumar et al., 1985 ) especially anti-inflammatory activity (Sarvanan et al., 1998; Khilil et al., 1994; Bhalla et al., 1993 ). It is also reported that substitution of halo group at 6-position in this nucleus enhances its anti-inflammatory action. A large number of pyrazolines are reported to possess potent antifungal and antibacterial activity (Kym et al., 1990; Udupi et al., 1998a,b ). This prompted us to synthesize a newer series of quinazolinone derivatives by incorporating the pyrazoline moiety at 2nd position of the quinazolinone nucleus. We report herein the synthesis of 2-(ω-chloroacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-ones (2), 2-(ω-hydrazino acetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-ones (3) and 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(substituted phenyl)-Δ²-pyrazolines (4a–j). This starting compound 2-methyl-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-ones (1) was prepared according to the reported method (Mishra et al., 1997).

2 Results and discussion

Conventional methodology sometimes has lower yields than microwave protocols. Microwave irradiation facilitates the polarization of the molecule under irradiation causing rapid reaction to occur. All the compounds synthesised were adequately characterized by their elemental analysis and spectral features.

2.1

2.1 Chemistry

2-(ω-Chloroacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-one (2) was prepared by the reaction of 2-methyl-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-one (1) with ClCH₂COCl in dry tetrahydrofuran by only conventional method. 2-(ω-Hydrazinoacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-one (3) was prepared by the reaction of 2-(ω-chloroacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-one (2) with NH₂NH₂.H₂O in absolute ethanol by both conventional and microwave method. 1′-[3H-3-p-Fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(phenyl)-Δ²-pyrazolines (4a–j) were prepared by the reaction of 2-(ω-hydrazinoacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-one (3) with 1-(o-chlorophenyl)-3-methylpyrazolideneazomethine-5-chalcones (Desai and Desai, 2007; Khalafalla and Hassan, 1986) in glacial acetic acid by conventional method and in DMF by microwave method respectively. 1-(o-Chlorophenyl)-3-methylpyrazolideneazomethine-5-chalcones was prepared by following the method reported in the literature (Desai and Desai, 2007; Khalafalla and Hassan, 1986).

Compound (1) on reaction with chloroacetylchloride yielded 2-(ω-chloroacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-one (2). Among the significant features of ¹H NMR data of (1), the disappearance of singlet at δ 2.50 (CH₃) and appearance of two singlets at δ 2.30 and δ 2.50 due to the chloroacetyl group confirmed the structure. Furthermore, compound (2) on treatment with hydrazine hydrate gave their corresponding 2-ω-hydrazinoacetonyl-3-p-fluorophenyl-6-haloquinazoline-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 δ 4.55 and δ 5.56 in ¹H NMR spectra clearly showed the presence of hydrazino group in compound (3). Further, compound (3) on refluxing with different 1-(o-chlorophenyl)-3-methylpyrazolideneazomethine-5-chalcones in the presence of glacial acetic acid yielded the corresponding 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(substituted phenyl)-Δ²-pyrazolines (4a–j). A comparative study in terms of yield and reaction period is shown in Table 1. The synthetic route of above mentioned compounds is shown in Scheme 1.

Table 1 Comparative study in terms of yield and reaction period for microwave and conventional techniques (compounds 4a–j).

Entry	Substituents R	Microwave method				Conventional method
Entry	Substituents R	Time (min)	Power (W)	Constant temperature (°C)	Yield^a (%)	Time (h)	Yield^a (%)
4a	H	10.0	400	116	88	16.0	65
4b	4″-N(CH₃)₂	9.0	500	120	82	15.5	55
4c	4″-OH	9.5	450	118	80	16.5	60
4d	4″-OCH₃	9.5	450	118	83	15.0	71
4e	3″-OC₆H₅	9.0	500	120	79	17.0	59
4f	3″,4″,5″-(OCH₃)₃	10.0	400	116	86	15.5	49
4g	3″-OCH₃-4″-OH	9.5	450	118	94	16.0	68
4h	2″-Cl	10.0	400	116	90	16.5	73
4i	4″-Cl	10.5	350	114	82	15.0	54
4j	4″-NO₂	10.0	400	118	89	15.5	63

a Yield of isolated products.

2.2

2.2 Microwave irradiation technique

All the reactions that used microwave irradiation (MWI) were completed within 9–10 min, whereas similar reactions under conventional heating (oil bath) at similar temperatures (110–120 °C) gave poor yields with comparatively longer reaction time period (Table 1), demonstrating that the effect of microwave irradiation is not purely thermal. 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). The effectiveness of microwave irradiation and conventional heating for the synthesis of compound (4a–j) has been compared (Table 1). Under microwave irradiation conditions, the yields of (4a–j) are high (94–79%). Whereas using conventional heating the yields are only 49–73%.

3 Antimicrobial activity

The compounds (4a–j) were screened for their antibacterial activity against Bacillus substilis (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 (Desai and Desai, 2005a,b, 2006d,e ). Standard antibacterial and antifungal drugs Ampicillin, Amoxicillin, Penicillin and Flucanozole were also tested under similar conditions for comparison. Results are presented in Table 2. By visualizing the antimicrobial data it could be observed that some of the compounds possess significant activity.

Table 2 Antimicrobial activity data of compounds 4a–j.

Compound	Antibacterial (mm)				Antifungal (mm)
	Gram positive (+ve)		Gram negative (−ve)		C. a ^e	C. k ^f
	S. a ^a	B. s ^b	E. c ^c	P. a ^d	C. a ^e	C. k ^f
	ATCC 6538	ATCC 6633	ATCC 8739	ATCC 1539	ATCC 10231	G03
2	–	22	9	25	10	25
3	15	0.9	8	18	18	22
4a	9	11	22	16	–	20
4b	8	0.8	9	1.1	12	0.8
4c	13	–	16	11	17	9
4d	7	10	13	13	–	12
4e	6	17	0.9	1.8	20	–
4f	11	21	–	19	0.9	20
4g	13	1.1	0.9	–	10	17
4h	15	20	12	12	17	8
4i	–	16	–	17	10	0.7
4j	9	10	12	9	7	0.8

Zone of inhibition of standard drugs (mm)
Ampicillin	30	35	30	30	–	–
Amoxicillin	25	34	38	35	–	–
Penicillin	30	38	32	38	–	–
Flucanozole	–	–	–	–	30	35

a S. a – Staphylococcus aureus.

b B. s – Bacills substilis.

c E. c – Escherchia coli.

d P. a – Pseudomonas aeruginosa.

e C. a – Candida albicans.

f C. k – Candida krusei.

3.1

3.1 Conclusion of activity

Zone of inhibition was measured in millimetre. The antifungal activities were compared to the standard drug flucanozole (30–35 mm) with DMF as solvent. Ampicillin (30–35 mm), amoxicillin (23–38 mm) and penicillin (30–38 mm) were used as standard drugs for antibacterial activity. Compounds (2), (4a), (4f), (4h) and (4i) showed significant antibacterial activity. Compounds (2), (3), (4a), (4e), (4f) and (4g) showed moderate to good antifungal activity (Table 2).

4 Experimental

4.1

4.1 General

All the melting points were determined in PMP-DM scientific melting point apparatus and were uncorrected. 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 (υ_max in cm⁻¹) were recorded on a shimadzu FT-IR 8300 spectrophotometer using KBr or Nujol technique, UV spectra (λ_max in nm) were recorded on a shimadzu UV – 160 A (200–400 nm) on using DMF as solvent, ¹H NMR spectra on a Bruker WM 400FT MHz NMR instrument using CDCl₃ or DMSO-d₆ as solvent and TMS as internal reference (chemical shifts in δ, ppm); ¹³C NMR on a Varian AMX 400 (100 MHz) spectrometer as solutions in CDCl₃ and Mass spectra on a Jeol JMS D-300 spectrometer. The elemental analysis (C, H, N) of compounds was performed on Carlo Erba-1108 elemental analyzer. The microwave assisted reactions are carried out in a “QPro-M Microwave Synthesis System” manufactured by Questron Technologies Corporation, Mississauga, Ontario L4Z 2E9 has been used (Made in Canada). In this unit, 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). There is an attachment of reflux condenser with constant stirring, avoiding the risk of high pressure development and permitting synthesis on preparative scales.

In the present work we used a new kind of QPro-M Microwave Synthesis System apparatus that is well suited for stringent reaction conditions [anhydrous atmosphere, controlled temperature (fibre optic is used as an individual sensor for temperature control) and attachment of reflux condenser with constant stirring]. This high-intensity microwave generator is equipped with magnetron. The frequency can be tuned at 2450 MHz.

4.2

4.2 Synthesis

4.2.1

4.2.1 Synthesis of 2-methyl-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-one 1

These compounds were synthesized according to the method (Mishra et al., 1997).

4.2.2

4.2.2 Conventional synthesis of 2-(ω-chloroacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-ones 2

To the solution of 2-Methyl-3-p-fluorophenyl-6-bromoquinazoline-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 °C drop wise with constant stirring for 2 h. The reaction mixtures were further stirred for 2–4 h at room temperature, and then excess of solvents distilled off. The reaction mixtures were cooled and poured onto ice-cold water. The solids that separated in each case were filtered and recrystallised from ethanol as a white solid, mp 166 °C, yield (3.14 g, 77%). IR υ_max: 173 (C⚌O), 1590 (C⚌N), 3060 (aromatic C–H), 780 (C–Br), 740 (C–Cl), 1111 (C–F), 2570 (CH₂) cm⁻¹; ¹H NMR: δ 8.75–8.30 (m, 7H, Ar-H), 2.30 (s, 2H, CH₂CO), 2.50 (s, 2H, COCH₂Cl) ppm; MS: m/z 415 [M⁺]; Anal. Calcd. For C₁₇H₁₁O₂N₂Cl Br F: C, 49.81; H, 2.68; N, 6.83. Found: C, 49.83; H, 2.70; N, 6.83%.

4.2.3

4.2.3 Conventional synthesis of 2-(ω-hydrazinoacetonyl)-3-p-fluorophenyl-6-bromo quinazoline-4(3H)-one 3

A solution of compound (2) and NH₂NH₂.H₂O (99%) in absolute ethanol (15 mL) was refluxed for 10–12 h in a 250 mL round bottom flask. The excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The products that separated were recrystallised from ethanol as a pinkish white powder, mp 196 °C, yield (2.01 g, 61%). IR υ_max: 1710 (C⚌O), 1580 (C⚌N), 3080 (aromatic C–H), 750 (C–Br), 1113 (C–F), 2570 (CH₂), 3440 (NH₂), 3380 (NH) cm⁻¹; ¹H NMR: δ 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) ppm; MS: m/z 411 [M⁺]; Anal. Calcd. For C₁₇H₁₄O₂N₄BrF: C, 50.37; H, 3.45; N, 13.82. Found: C, 50.34; H, 3.47; N, 13.84%.

4.2.4

4.2.4 Microwave mediated synthesis of 2-(ω-hydrazinoacetonyl)-3-p-fluorophenyl-6-bromo quinazoline-4(3H)-one 3

The mixture of compound (2) and NH₂NH₂·H₂O (99%) in absolute ethanol (15 mL) was taken in round bottom flask placed in a microwave oven and irradiated for about 7–8 min (300 W, 68 °C). The excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The products that separated were recrystallised from ethanol as a pinkish white crystal, yield (2.03 g, 83%).

4.2.5

4.2.5 Conventional synthesis of 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(phenyl)-Δ²-pyrazoline 4a

A solution of compound (3) (4.05 g, 0.01 mol) in glacial acetic acid (20 mL) and 1-(o-chlorophenyl)-3-methylpyrazolidene azomethine-5-chalcones (4.13 g, 0.01 mol) was refluxed for 16 h. The excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The products that separated were recrystallised from ethanol as a dark pinkish solid, mp 230 °C, yield (5.14 g, 65%).

4.2.6

4.2.6 Microwave mediated synthesis of 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(phenyl)-Δ²-pyrazoline 4a

A mixture of compound (3) (4.05 g, 0.01 mol) in glacial acetic acid (20 mL) and 1-(o-chlorophenyl)-3-methylpyrazolideneazomethine-5-chalcones (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. The excess solvent was then removed by distillation under reduced pressure and the residue was poured into ice-cold water. The products that separated were recrystallised from ethanol as a dark pinkish powder, yield (5.15 g, 88%). Likewise other compounds (4b–j) were prepared by treating (3) with various substituted chalcones.

5 Spectral data of 1′-[3H-3-p-fluoro phenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chloro phenyl-3-methyl-5-azo methine-2-pyrazolidene]-5′-(substituted phenyl)-Δ²-pyrazolines (4a–j)

5.1

5.1 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(phenyl)-Δ²-pyrazoline 4a

Dark pinkish powder, UV λ_max: 313 nm; IR υ_max: 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), 1314 (C–CH₃) cm⁻¹; ¹H NMR: δ 8.60–7.20 (m, 20H, Ar–H), 2.40 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.80 (d, 2H, 2×CH₂ of pyrazoline ring), 3.95 (t, 1H, CH of pyrazoline ring), 2.26 (s, 2H, 2×CH₂–CO) ppm; ¹³C NMR: 115–135 (aromatic >C⚌C<), 40 (CH₃), 49 (2×CH₂ of pyrazoline ring), 38 (–CH₂–), 189 (>C⚌O), 172 (aliphatic >C⚌O), 110–140 (heteroaromatics >C⚌N–) ppm; MS: m/z 800 [M⁺]; Anal. Calcd. For C₄₂H₃₂O₂N₇ClBrF: C, 62.96; H, 3.99; N, 12.24. Found: C, 62.98; H, 3.97; N, 12.26%.

5.2

5.2 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-dimethylaminophenyl)-Δ²-pyrazoline 4b

Yellowish brown solid, mp 237 °C; UV λ_max: 291 nm; IR υ_max: 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] cm⁻¹; ¹H NMR: δ 7.00–7.95 (m, 19H, Ar-H), 2.38 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.85 (d, 2H, 2×CH₂ of pyrazoline ring), 3.97 (t, 1H, CH of pyrazoline ring), 2.23 (s, 2H, 2×CH₂–CO), 2.9 (m, 6H, –N(CH₃)₂) ppm; ¹³C NMR: 113–133 (aromatic >C⚌C<), 42 (CH₃), 50 (2×CH₂ of pyrazoline ring), 40 (–CH₂–), 192 (>C⚌O), 170 (aliphatic >C⚌O), 113–143 (heteroaromatics >C⚌N–) ppm; MS (m/z): 852 [M⁺]; Anal. Calcd. for C₄₄H₃₇O₂N₈ClBrF: C, 62.00; H, 4.34; N, 13.15. Found: C, 62.03; H, 4.37; N, 13.12%.

5.3

5.3 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-hydroxyphenyl)-Δ²-pyrazoline 4c

Dark pink powder, mp 217 °C; UV λ_max: 298 nm; IR υ_max: 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) cm⁻¹; ¹H NMR: δ 6.98–7.93 (m, 19H, Ar-H), 2.42 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.78 (d, 2H, 2×CH₂ of pyrazoline ring), 3.89 (t, 1H, CH of pyrazoline ring), 2.36 (s, 2H, 2×CH₂–CO), 3.58 (s, 1H, -OH) ppm; ¹³C NMR: 114–131 (aromatic >C⚌C<), 43 (CH₃), 53 (2×CH₂ of pyrazoline ring), 37 (–CH₂–), 197 (>C⚌O), 174 (aliphatic >C⚌O), 112–141 (heteroaromatics >C⚌N–) ppm; MS (m/z): 813 [M⁺]; Anal. Calcd. for C₄₂H₃₃O₂N₇ClBrF: C, 61.70; H, 4.04; N, 12.00. Found: C, 61.72; H, 4.06; N, 12.03%.

5.4

5.4 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-methoxyphenyl)-Δ²-pyrazoline 4d

Brown powder, mp 247∼250 °C; UV λ_max: 320 nm; IR υ_max: 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–CH₃), 2831 (C–OCH₃) cm⁻¹; ¹H NMR: δ 7.20–7.90 (m, 19H, Ar-H), 2.31 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.72 (d, 2H, 2×CH₂ of pyrazoline ring), 3.99 (t, 1H, CH of pyrazoline ring), 2.28 (s, 2H, 2×CH₂–CO), 3.89 (s, 3H, –OCH₃) ppm; ¹³C NMR: 115–135 (aromatic >C⚌C<), 44 (CH₃), 51 (2×CH₂ of pyrazoline ring), 39 (–CH₂–), 199 (>C⚌O), 171 (aliphatic >C⚌O), 35.7 (OCH₃), 112–145 (heteroaromatics >C⚌N–) ppm; MS (m/z): 832 [M⁺]; Anal. Calcd. for C₄₃H₃₄O₃N₇ClBrF: C, 62.13; H, 4.09; N, 11.80. Found: C, 62.10; H, 4.11; N, 11.83%.

5.5

5.5 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(3″-phenoxyphenyl)-Δ²-pyrazoline 4e

Violet powder, mp 199 °C; UV λ_max: 300 nm; IR υ_max: 1721 (C⚌O), 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) cm⁻¹; ¹H NMR: δ 6.85–7.65 (m, 24H, Ar-H), 2.34 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.86 (d, 4H, 2×CH₂ of pyrazoline ring), 3.91 (t, 1H, CH of pyrazoline ring), 2.37 (s, 2H, 2×CH₂–CO), 6.79–7.77 (m, 5H, –OC₆H₅) ppm; ¹³C NMR: 111–132 (aromatic >C⚌C<), 42 (CH₃), 50 (2×CH₂ of pyrazoline ring), 39 (–CH₂–), 194 (>C⚌O), 170 (aliphatic >C⚌O), 115–148 (heteroaromatics >C⚌N–) ppm; MS (m/z): 890 [M⁺]; Anal. Calcd. for C₄₈H₃₆O₃N₇ClBrF: C, 64.53; H, 4.03; N, 10.98. Found: C, 64.56; H, 4.06; N, 10.95% .

5.6

5.6 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(3″,4″,5″-trimethoxyphenyl)-Δ²-pyrazoline 4f

Dark brown crystal, mp 202 °C; UV λ_max: 275 nm; IR υ_max: 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] cm⁻¹; ¹H NMR: δ 6.99–7.80 (m, 17H, Ar–H), 2.45 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.89 (d, 2H, 2×CH₂ of pyrazoline ring), 3.87 (t, 1H, CH of pyrazoline ring), 2.31 (s, 2H, 2×CH₂- CO), 3.92 (s, 3H, –OCH₃) ppm; ¹³C NMR: 110–135 (aromatic >C⚌C<), 37 (CH₃), 50 (2×CH₂ of pyrazoline ring), 38.7 (–CH₂–), 189 (>C⚌O), 171 (aliphatic >C⚌O), 37.5 (3×OCH₃), 110–140 (heteroaromatics >C⚌N–) ppm; MS (m/z): 893 [M⁺]; Anal. Calcd. for C₄₅H₄₀O₅N₇ClBrF: C, 60.64; H, 4.49; N, 11.00. Found: C, 60.66; H, 4.51; N, 11.04%.

5.7

5.7 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(3″-methoxy-4″-hydroxyphenyl)-Δ²-pyrazoline 4g

Light brown powder, mp 250∼255 °C; UV λ_max: 277 nm; IR υ_max: 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) cm⁻¹; ¹H NMR: δ 6.78–7.86 (m, 18H, Ar-H), 2.48 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.79 (d, 2H, 2×CH₂ of pyrazoline ring), 3.82 (t, 1H, CH of pyrazoline ring), 2.27 (s, 2H, 2×CH₂–CO), 3.79 (s, 3H, - OCH₃), 3.50 (s, 1H, -OH) ppm; ¹³C NMR: 112–134 (aromatic >C⚌C<), 44 (CH₃), 48 (2×CH₂ of pyrazoline ring), 35 (–CH₂–), 193 (>C⚌O), 169 (aliphatic >C⚌O), 113–148 (heteroaromatics >C⚌N–) ppm; MS (m/z): 847 [M⁺]; Anal. Calcd. for C₄₃H₃₅O₄N₇ClBrF: C, 60.95; H, 4.13; N, 11.57. Found: C, 60.93; H, 4.16; N, 11.60%.

5.8

5.8 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(2″-chlorophenyl)-Δ²-pyrazoline 4h

Yellow powder, mp 241 °C; UV λ_max: 335 nm; IR υ_max: 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) cm⁻¹; ¹H NMR: δ 6.65–7.77 (m, 17H, Ar-H), 2.42 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.88 (d, 2H, 2×CH₂ of pyrazoline ring), 3.96 (t, 1H, CH of pyrazoline ring), 2.22 (s, 2H, 2×CH₂–CO) ppm; ¹³C NMR: 114–131 (aromatic >C⚌C<), 41 (CH₃), 55 (2×CH₂ of pyrazoline ring), 38 (–CH₂–), 188 (>C⚌O), 175 (aliphatic >C⚌O), 118–150 (heteroaromatics >C⚌N–) ppm; MS (m/z): 835 [M⁺]; Anal. Calcd. for C₄₂H₃₁O₂N₇Cl₂BrF: C, 60.35; H, 3.71; N, 11.73. Found: C, 60.37; H, 3.73; N, 11.74%.

5.9

5.9 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-chlorophenyl)-Δ²-pyrazolines 4i

Pale yellow crystalline powder, mp 250 °C; UV λ_max: 298 nm; IR υ_max: 1730 (C⚌O), 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) cm⁻¹; ¹H NMR: δ 6.72–7.82 (m, 17H, Ar-H), 2.44 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.90 (d, 2H, 2×CH₂ of pyrazoline ring), 3.92 (t, 1H, CH of pyrazoline ring), 2.33 (s, 2H, 2×CH₂–CO) ppm; ¹³C NMR: 114–134 (aromatic >C⚌C<), 41 (CH₃), 49 (2×CH₂ of pyrazoline ring), 36 (–CH₂–), 196 (>C⚌O), 170 (aliphatic >C⚌O), 116–142 (heteroaromatics >C⚌N–) ppm; MS (m/z): 837 [M⁺]; Anal. Calcd. for C₄₂H₃₁O₂N₇Cl₂BrF: C, 60.35; H, 3.71; N, 11.73. Found: C, 60.33; H, 3.72; N, 3.72%.

5.10

5.10 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-nitrophenyl)-Δ²-pyrazoline 4j

Pink powder, mp 262 °C; UV λ_max: 288 nm; IR υ_max: 1728 (C⚌O), 1596 (C⚌N), 3061 (aromatic C–H), 748 (C–Cl), 771 (C–Br), 1118 (C–F), 2481 (CH₂), 2487, 2967 (aliphatic C–H), 1315 (C–CH₃), 1340 (C–NO₂) cm⁻¹; ¹H NMR: δ 7.15–7.92 (m, 19H, Ar-H), 2.36 (s, 3H, CH₃ attached to pyrazolidene nucleus), 5.76 (d, 2H, 2×CH₂ of pyrazoline ring), 3.88 (t, 1H, CH of pyrazoline ring), 2.36 (s, 2H, 2×CH₂–CO) ppm; ¹³C NMR: 113–133 (aromatic >C⚌C<), 43 (CH₃), 50 (2×CH₂ of pyrazoline ring), 37 (–CH₂–), 185 (>C⚌O), 172 (aliphatic >C⚌O), 114–146 (heteroaromatics >C⚌N–) ppm; MS (m/z): 847 [M⁺]; Anal. Calcd. for C₄₂H₃₁O₄N₈ClBrF: C, 59.60; H, 3.66; N, 13.24. Found: C, 59.61; H, 3.68; N, 13.21%.

6 Conclusion

In conclusion, this new method for the synthesis of quinazolinyl-Δ²-pyrazolines in glacial acetic acid under microwave irradiation offers significant improvements over existing procedures and thus helps facile entry into a variety of quinazolinyl-Δ²-pyrazolines of potentially high synthetic utility. Also, this simple and reproducible technique affords various quinazolinyl-Δ²-pyrazolines with short reaction times, excellent yields, and without formation of undesirable by-products.

A series of quinazolinyl-Δ²-pyrazolines derivatives were prepared and tested for their in vitro antibacterial activity against the four strains of bacteria (gram +ve, gram –ve) and antifungal activities against the two strains of human pathogenic fungi. Five compounds of the obtained series showed high in vitro antimicrobial activity. 2-(ω-chloroacetonyl)-3-p-fluorophenyl-6-bromoquinazoline-4(3H)-ones (2) showed excellent activity against B. substilis and P. aeruginosa, 1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(phenyl)-Δ²-pyrazoline (4a) showed excellent activity against E. coli indicated in vitro antibacterial activity comparable to or slightly lower than that of Ampicillin, Amoxicillin and Penicillin. Compound (2) and 2-(ω-hydrazinoacetonyl)-3-p-fluorophenyl-6-bromo quinazoline-4(3H)-one (3) showed excellent activity against C. krusei indicated in vitro antifungal activity comparable to or slightly lower than that of flucanozole. The substitution in the C₍₄₎ position of the phenyl ring by methoxy, chloro and phenoxy groups seems to be very important for antifungal effect, as well as the presence and the position of the –CH₂COCH₂– group in the connecting linker between the quinazoline and pyrazoline ring and quinazolinyl-Δ²-pyrazolines derivatives seems to be very important for anti bacterial effect.

Acknowledgements

One of the authors (Dr. Krunal G. Desai) is thankful to the Head of Chemistry and Bioscience Department of Veer Narmad South Gujarat University, Surat; Gujarat Council On Science & Technology (Grant no. GUJCOST/200389/MRP/2003-04/10689), Gandhinagar for financial assistance; SAIF, Central Instrumentation Laboratory, Punjab University, Chandigarh for spectral analysis.

References

Amine M.S., . Ind. J. Chem.. 1998;37B:303.
Bhalla M., Bhalla T., Nand S.K., . Arzneim Forsch.. 1993;43:595.
Desai K.G., Desai K.R., . Ind. J. Chem.. 2005;44B:2093.
Desai K.G., Desai K.R., . Ind. J. Chem.. 2005;44B:2097.
Desai, K.G., Desai, K.R., 2006a. Molbank (www.mdpi.org/molbank MDPI, Switzerland), M475 (MOL File: m477.mol).
Desai K.G., Desai K.R., . J. Saudi Chem. Soc.. 2006;9(3):631.
Desai K.G., Desai K.R., . J. Sulf. Chem.. 2006;27(4):315.
Desai K.G., Desai K.R., . J. Heterocycl. Chem.. 2006;43:1083;.
Desai K.G., Desai K.R., . Bioorg. Med. Chem.. 2006;14:8279.
Desai K.G., Desai K.R., . Ind. J. Chem.. 2007;46B:1186.
Desai, K.G., Desai, K.R., Padmanabhan, D., 2006a. Molbank (www.mdpi.org/molbank, MDPI, Switzerland), M475 (MOL File: m478.mol).
Desai K.G., Desai K.R., Raval J.P., . J. Iranian Chem. Soc.. 2006;3(3):233.
Ghorab M.M., Abdel-Hamide S.G., . Ind. J. Heterocycl. Chem.. 1995;5(2):115.
Holla S.B., Padmaja M.T., Akbarali P.M., . Ind. J. Chem.. 1998;37B:715.
Khalafalla A.K., Hassan M.E., . J. Ind. Chem. Soc.. 1986;LXIII:910.
Khilil M.A., Farghaly A.M., Bekhit A.A., . Arch. Pharm. (Weinhein Ger.). 1994;327:27.
Kumar A., Guru S., Sinha J.N., . Eur. J. Chem. Chim. Ther.. 1985;20:95.
Kumar A., Sinha J.N., . Ind. J. Pharm. Sci.. 1990;52(6):257.
Kumar A., Tyagi R., Verma R.S., . Ind. Drugs. 1998;35(5):261.
Kym K.H., Yvoune C., Norris B., . J. Pharm. Sci.. 1990;79:609.
Loupy A., Perreux L., Moneuse M., . Pure Appl. Chem.. 2001;11:161.
Mishra M., Srivastava S.K., Srivastava S.D., . Ind. J. Chem.. 1997;33B:826.
Reddy P.S.N., Vasantha T.V., Raju C.N., . Ind. J. Chem.. 1999;38B:40.
Sarvanan J., Mohan S., Majjunatha K.S., . Ind. J. Heterocycl. Chem.. 1998;8:55.
Srivastava S.K., Srivastava S.D., . Ind. J. Chem.. 1999;38B:183.
Udupi R.H., Rao S., Narayan B., . Ind. J. Heterocycl. Chem.. 1998;7:217.
Udupi R.H., Kushnoor A.S., Bhat A.R., . Ind. J. Heterocycl. Chem.. 1998;8:63.
Verma R.S., . Green Chem.. 1999;1:43.
Wolf J.F., Ratham T.L., Sleevi M.E., . J. Med. Chem.. 1990;33(1):16.
Xie W., Jin Y., Wang P.G., . Chemtech.. 1999;29:23.

Introduction

Results and discussion

Chemistry
Microwave irradiation technique

Antimicrobial activity

Conclusion of activity

Experimental

General
Synthesis

Spectral data of 1′-[3H-3-p-fluoro phenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chloro phenyl-3-methyl-5-azo methine-2-pyrazolidene]-5′-(substituted phenyl)-Δ2-pyrazolines (4a–j)

1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(phenyl)-Δ2-pyrazoline 4a
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-dimethylaminophenyl)-Δ2-pyrazoline 4b
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-hydroxyphenyl)-Δ2-pyrazoline 4c
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-methoxyphenyl)-Δ2-pyrazoline 4d
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(3″-phenoxyphenyl)-Δ2-pyrazoline 4e
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(3″,4″,5″-trimethoxyphenyl)-Δ2-pyrazoline 4f
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(3″-methoxy-4″-hydroxyphenyl)-Δ2-pyrazoline 4g
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(2″-chlorophenyl)-Δ2-pyrazoline 4h
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-chlorophenyl)-Δ2-pyrazolines 4i
1′-[3H-3-p-fluorophenyl-4-oxo-6-bromoquinazoline-2-acetonyl]-3′-[1-o-chlorophenyl-3-methyl-5-azomethine-2-pyrazolidene]-5′-(4″-nitrophenyl)-Δ2-pyrazoline 4j

Conclusion

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[1] Amine M.S., . Ind. J. Chem.. 1998;37B:303.

[2] Bhalla M., Bhalla T., Nand S.K., . Arzneim Forsch.. 1993;43:595.

[3] Desai K.G., Desai K.R., . Ind. J. Chem.. 2005;44B:2093.

[4] Desai K.G., Desai K.R., . Ind. J. Chem.. 2005;44B:2097.

[5] Desai, K.G., Desai, K.R., 2006a. Molbank (www.mdpi.org/molbank MDPI, Switzerland), M475 (MOL File: m477.mol).

[6] Desai K.G., Desai K.R., . J. Saudi Chem. Soc.. 2006;9(3):631.

[7] Desai K.G., Desai K.R., . J. Sulf. Chem.. 2006;27(4):315.

[8] Desai K.G., Desai K.R., . J. Heterocycl. Chem.. 2006;43:1083;.

[9] Desai K.G., Desai K.R., . Bioorg. Med. Chem.. 2006;14:8279.

[10] Desai K.G., Desai K.R., . Ind. J. Chem.. 2007;46B:1186.

[11] Desai, K.G., Desai, K.R., Padmanabhan, D., 2006a. Molbank (www.mdpi.org/molbank, MDPI, Switzerland), M475 (MOL File: m478.mol).

[12] Desai K.G., Desai K.R., Raval J.P., . J. Iranian Chem. Soc.. 2006;3(3):233.

[13] Ghorab M.M., Abdel-Hamide S.G., . Ind. J. Heterocycl. Chem.. 1995;5(2):115.

[14] Holla S.B., Padmaja M.T., Akbarali P.M., . Ind. J. Chem.. 1998;37B:715.

[15] Khalafalla A.K., Hassan M.E., . J. Ind. Chem. Soc.. 1986;LXIII:910.

[16] Khilil M.A., Farghaly A.M., Bekhit A.A., . Arch. Pharm. (Weinhein Ger.). 1994;327:27.

[17] Kumar A., Guru S., Sinha J.N., . Eur. J. Chem. Chim. Ther.. 1985;20:95.

[18] Kumar A., Sinha J.N., . Ind. J. Pharm. Sci.. 1990;52(6):257.

[19] Kumar A., Tyagi R., Verma R.S., . Ind. Drugs. 1998;35(5):261.

[20] Kym K.H., Yvoune C., Norris B., . J. Pharm. Sci.. 1990;79:609.

[21] Loupy A., Perreux L., Moneuse M., . Pure Appl. Chem.. 2001;11:161.

[22] Mishra M., Srivastava S.K., Srivastava S.D., . Ind. J. Chem.. 1997;33B:826.

[23] Reddy P.S.N., Vasantha T.V., Raju C.N., . Ind. J. Chem.. 1999;38B:40.

[24] Sarvanan J., Mohan S., Majjunatha K.S., . Ind. J. Heterocycl. Chem.. 1998;8:55.

[25] Srivastava S.K., Srivastava S.D., . Ind. J. Chem.. 1999;38B:183.

[26] Udupi R.H., Rao S., Narayan B., . Ind. J. Heterocycl. Chem.. 1998;7:217.

[27] Udupi R.H., Kushnoor A.S., Bhat A.R., . Ind. J. Heterocycl. Chem.. 1998;8:63.

[28] Verma R.S., . Green Chem.. 1999;1:43.

[29] Wolf J.F., Ratham T.L., Sleevi M.E., . J. Med. Chem.. 1990;33(1):16.

[30] Xie W., Jin Y., Wang P.G., . Chemtech.. 1999;29:23.