[E015]
Multi-component synthesis of 3,2-substituted quinazolin-4(3H)-ones under solvent-free conditions
Anshu Dandia*, Ruby Singh and Pritima Sarawgi
Department of Chemistry, University of Rajasthan, Jaipur-302004 (INDIA)
Abstract : Rapid one-pot solvent-free procedure has been developed for the synthesis of 2,3-disubstituted quinazolin-4 (3H)-ones by neat three component cyclocondensation of anthranilic acid, phenyl acetyl chloride / benzoly chloride and substituted anilines under microwave irradiation. The experimental methodology and microwave conditions described here are well established, allowing significant rate enhancement and good yields compared to multisteps conventional reaction conditions. The reaction is generalized for o, m & p substituted anilines with electron donating and withdrawing groups to give quinazolin-4(3H)-ones. Ortho substituted anilines fail to undergo ring closure quinazolines under conventional conditions. The detailed reaction mechanism of title reaction has also been discussed.
Introduction:
Quinazoline compounds are reported to be physiologically and pharmacologically active and find application in the treatment of several diseases like leprosy and mental disorder and also exhibit a wide range of activities1. Methaquolone2, a sedative and hypnotic drug has been reported to possess anticonvulsant activity. Significance is that this compound possesses the potent pharmacodynamic nucleus i.e. quinazoline.
Recently, several scientists elucidated that quinazoline system possess variable sites at positions 2 and 3 which can be suitably modified by the introduction of different heterocyclic moieties to yield the potential anticonvulsant agents3.
Incorporation of fluorine atom or CF3 group to heterocycles is known to influence the biological activity4. Fluorinated quinazoline has been focused the attraction of pharmacologist and chemists during last several years due to wide variety of activity possessed by them5. Number of patent mentions the utility of fluorinated quinazoline as important antifungal6, herbicidal7, pesticidal8, CNS depressant9 and AMPA inhibitors10 etc. Thus, their synthesis has been of great interest in the elaboration of biologically active heterocyclic compounds.
Microwave induced rate enhancement of various reaction becoming popular with organic chemists11. However recently more interest has been focussed on "dry media" synthesis and particularly on solvent-free procedure using various mineral oxides12 and solventless reaction with neat reactants in the absence of a catalyst or solid support13.
Conventional synthesis of quinazolin-4(3H)-ones involves two steps14 i.e. (i) cyclodehydration of 2-benzamidobenzoic acid 1 with excess of acetic anhydride under anhydrous conditions and removal of excess of acetic anhydride under reduced pressure gave benzoxazin-4-one 2 (ii) refluxing the 2 with amines in glacial acetic acid /pyridine15 . The products were obtained in moderate yield and require 10-12 hrs refluxing.
For the aforementioned reasons and in view of our general interest in the development of environmentally friendlier synthetic alternatives using microwaves16, we studied extensively the synthesis of fluorine containing quinazolin-4(3H)-ones under microwave irradiation by various methods i.e., (A) using inorganic solid support montmorillonite KSF / acidic alumina (scheme-1); (B) neat one-pot synthesis without using any dehydrating agent, solvent or support (scheme-2). The best results obtained from neat synthesis (method B) have been reported.
In method-A the intermediate benzoxazin-4-one 2 was synthesized "in situ" by the cyclodehydration of 1 with acetic anhydride using inorganic solid supports. The method is environmentally friendly, as acetic anhydride remains adsorbed over the solid support and there is no evaporation into the atmosphere.
The condensation reaction of 2 with wide variety of amine derivatives e.g. para/meta/ortho substituted anilines and phenylhydrazine has been studied. Meta / para substituted anilines and phenyl hydrazine gave cyclized product quinazoline 4. While the ortho substituted anilines gave, an intermediate o-acylaminobenzanilide 3, which in contrast to earlier report of Mishra et al.14 where they reported the formation of cyclized quinazolones in case of ortho substituted anilines also. However synthesis of same compound (R = o-nitrophenyl) was repeated conventionally under identical conditions as mentioned by Mishra et al., and identified as o-acylaminobenzanilide 3 not as quinazolones. 3 were cyclized by the catalytic amount of PTSA and few drops of DMF in 3-4 min. under microwave irradiation.
Although, the solvent-free procedure using inorganic support under microwaves is
an attractive ecofriendly methodology, it requires appreciable amount of solvent
for adsorption of reactants and elution of products.
Further in view of our aim to synthesise a series of quinazolones with pharmacophoric groups and to establish structure activity relationship in quinazolones, we have developed a 'green chemistry procedure' using neat reaction conditions, which aims at complete elimination of the solvent as well as solid support from the reaction. These no solvent reactions, when coupled with microwave irradiation prove to be advantageous for environmental reasons as well, due to their uniform heating effect and shorter reaction time.
Experimentally, anthranilic acid, phenyl acetyl chloride / benzoyl chloride and corresponding amines are mixed and irradiated inside the microwave oven. The formation of final product quinazolone 4 can proceed via two pathways I & II (Scheme-2)
Path I involves first N-phenylacetylation of anthranilic acid and condensation of resultant 2-benzamidobenzoic acid 1 with the amines and then intramolecular amidation of the intermediate amidine 5 afforded the desired final product 4. While path II involves N-phenylacetylation of amines instead of anthranilic acid. The possibility of all routes are confirmed by isolation of intermediates in some cases e.g., 5 and phenyl acetyl anilide 6. Thus, N-phenylacetylation step occurs very quickly and during the short reaction time. Attempts to use PhCH2COOH instead of PhCH2COCl were not successful.
In conclusion, we have introduced a simple one-pot three component cyclocondensation reaction for the synthesis of quinazolin-4(3H)-ones without using any dehydrating agent, solvent or support. Reaction occurred in shorter time with easy work-up process and this method is applicable even when o-substituted anilines are used.
The formation of o-acyl aminobenzanilide 3 and quinazoline 4(3H)- ones 4 have been confirmed on the basis of spectral studies. The IR spectra of 3a-d showed characteristic absorption bands at 3360-3410 (NH), 1700, 1680 (both C=O). The 1H NMR spectra of 3a-d showed broad peaks at d 8.80 & 8.95 due to two NHCO protons (exchangeable with D2O) and a singlet at d 4.20-4.26 ppm due to COCH2Ph protons. 13C NMR spectrum of 3a also showed the presence of two carbonyl signals at d169.9 and 169.2 ppm. The remaining signals were obtained at d 140.8 - 115.5 (aromatic carbons) 45.0 (CO-CH2)ppm.
IR spectra of quinazolones 4a-j showed the only one carbonyl absorption band at 1695-1700 and 1605-1610 (C=N) cm-1 confirms the ring closure in all compounds, It was further confirmed on the basis of 13C NMR spectrum of 4g which showed only one signal at d 169.7(C=O) ppm along with other peaks at 155.4 (C=N), 139.5-116.9 (aromatic carbons) and 24.1 (CH2Ph) ppm. Further, the disappearance of NH in 4g-j peaks at this region (d 8.80 & 8.95ppm) showed the formation of quinazolones 4 . The presence of fluorine atom attached to phenyl ring has been confirmed by 19F NMR . The detailed spectral data of compound 3a-d & 4a-j are given in table-4. In the mass spectrum of representative compound 4b the molecular ion peak at m/z 326 (100%) corresponding to the molecular weight of compound. Other peaks were observed at 311 (2.5), 235 (39.7), 207 (3.6), 180 (4.2), 91 (80), 65 (50) etc.
Experimental section:
Melting points were determined in open glass capillary and were uncorrected. IR spectra were recorded on a perkin Elmer (model-577) in KBr pellets. 1H NMR and 13C NMR were recorded on Jeol model FX 90Q and Bruker-DRX-300 using CDCl3 as solvent and TMS as internal reference at 300.13 and 75.47 MHz, respectively. 19F NMR was recorded on Jeol model FX 90Q at 84.25 MHz, using CDCl3 as solvent and or hexafluorobezene as external reference. Mass spectrum of representative compound was recorded on Kratos 50 mass spectrometer at 70 eV. Purity of all compounds were checked by TLC using silica gel 'G' coated glass plates and benzene-ethylacetate (8 ; 2) as eluent. The microwave induced reactions were carried out in BMO-700T domestic oven manufactured by BPL multimode Sanyo utilities and appliances Ltd. operating at 700W generating 2450 MHz frequency. Montmorillonite KSF and acidic alumina were Aldrich product and used as received.
2-Phenylmethyl-3-(3-trifluoromethylphenyl)-quinazolin-4(3H)-one 4a was prepared by three different procedures under microwave irradiation.
Method A ; Using inorganic solid supports
A mixture of 2-benzamidobenzoic acid 1 (2 mmol) and acetic anhydride (2.5 mmol) was adsorbed on acidic alumina / montmorillonite KSF, mixed thoroughly and irradiated inside the microwave oven at 640 watt until the completion of reaction (TLC). After completion of reaction the 3-trifluromethylaniline (2 mmol) was added to the reaction mixture and irradiated for appropriate time (table 1). The product was extracted into ethanol and the excess solvent was evaporated on a roto-evaporator to give compound, which was purified by methanol and identified as 4a.
From the comparative results, it has been observed that the montmorillonite KSF is the best solid support as comparison to acidic alumina (table-1). The remaining compounds 4b-f (in case of meta / para substituted anilines / phenyl hydrazine) and 3a-d (in case of ortho substituted anilines) were similarly prepared by using montmorillonite KSF.
Method-B ; Neat- three component cyclocondensation
An equimolar mixture of anthranilic acid (2 mmol), phenyl acetyl chloride / benzoyl chloride (2 mmol) and 3-trifluromethylaniline (2 mmol) contained in a tall beaker was placed in the microwave oven and irradiated for 5 min (TLC) at 640 Watts. The reaction mixture was cooled at room temperature and a solid mass was obtained which was crystallized from ethanol. All compounds 4b-j listed in table-3 were similarly synthesized by this mehod comparatively in high yield and reduce time.
Method-C ; Alternative procedure for preparation of 4a
A mixture of 2-benzamidobenzioc acid17 (2 mmol) and 3-trifluromethyl aniline (2 mmol) was irradiated for 4 min (TLC) at 640 Watts. After cooling, the resultant residue was crystallized from methanol yielding 91 % of 4a (path I). In order to verify the viability of path II under the above conditions, a mixture of phenyl acetyl anilide 6 (2 mmol) and anthranilic acid (2 mmole) was irradiated (5 min, TLC). The resultant residue was crystallized from ethanol yield = 90%.
The identity of compounds synthesized by various method was established by their mixed m.p., IR and 1H NMR spectral studies.
Synthesis of 4g-j from 3a-d ;
A mixture of compound 3a-d (2 mmol), catalytic amount of toluene-p sulfonic acid (PTSA) and few drops of DMF was irradiated under microwaves until the completion of reaction (monitored by TLC, table-3). The resultant residues were crystallized from ethanol.
Acknowledgements:
Financial assistance from CSIR & UGC, New Delhi is gratefully acknowledged. We are also thankful to RSIC, CDRI, Lucknow, for the elemental and spectral analyses.
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