Cobalt ( II ) Chloride Catalyzed one Pot Synthesis of 2-substituted and 3-substituted-4 ( 3 H )-Quinazolinones

Cobalt(II) chloride (10mol%) was found to be an efficient catalyst for one pot synthesis of variety of 2-substituted-4(3H)quinazolinones by condensation of anthranilamide and aldehydes and synthesis of 3-substituted-4(3H)quinazolinones by condensation of anthranilic acid, orthoester, primary amines at reflux giving good to excellent yields (75-95%).


INTRODUCTION
The quinazolinone core and its derivatives form an important class of compounds, as they are present in a large family of products with broad biological activities.4(3H)-quinazolinones are versatile nitrogen heterocyclic compounds, displaying a broad spectrum of biological and pharmacological activities such as anti-fungal, 1 antitumour, 2 hypotensive, 3 anti-cancer, 4,5 anti-HIV, 6 antiinflammatory, 7 anti-bacterial, 8 etc.Furthermore, 4(3H)-quinazolinones substituted at 2,3-position derivatives play a pivotal role in the hypertensive activity. 9,10everal bioactive natural products such as febrifugine and isofebrifugine contain quinazolinone moieties with potential anti-malarial activity 11 Similarly quinazolinone containing moieties have been known as tyrosine kinase inhibitors, 12 dihydrofolate reductase inhibitors, 13 and tubulin polymerization inhibitors. 14Due to their wide range of applications these compounds have received a great deal of attention in connection with their synthesis.

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In continuation of our work to develop new organic transformations, [27][28][29] we report here in that cobalt(II) chloride which acts as a mild lewis acid might be useful and inexpensive catalyst for the synthesis of 2-substituted-4(3H)quinazolinones and 3-substituted-4(3H)quinazolinones.Although cobalt(II) chloride has been extensively used as a mild catalyst for a variety of organic transformations, [30][31][32] there are no examples of the use of cobalt chloride as catalyst for the synthesis of 2-substituted-4(3H)-quinazolinones and 3substituted-4(3H)quinazolinones.

MATERIAL AND METHODS
Chemicals were purchased from Merck and Fluka and directly used for the synthesis.Thin layer chromatography (TLC): precoated silica gel plates (60 F254, 0.2mm layer; E. Merck). 1 H NMR (Avance 300 MHz) spectra were recorded in DMSO using TMS as internal standard.Chemical shifts (´) are reported in ppm, Melting points (M.P.) were determined on a Fischer-Johns melting point apparatus.IR and MS were recorded on a Thermo Nicolet Nexus 670 FT-IR Spectrometer and Finnegan MAT 1020 Mass spectrometer operating at 70 ev.Elemental analyses were performed on a Perkin Elmer 2400series II Elemental CHN analyzer.

General procedure for the synthesis of 2substituted-4(3H)quinazolinones
To a mixture of anthranilamide (1mmol) in acetonitrile (5mL), CoCl 2 (10mol%) was added to the appropriate aldehyde (1.3mmol) was refluxed at 70 o C for the time specified in (Table -3) for each substrate, after completion of the reaction as indicated by TLC the reaction mixture was allowed to cool and quenched with NaHCO 3 followed by brine solution and extracted with ethyl acetate dried over Na 2 SO 4 , concentrated under vacuum, and the crude mixture was purified by column chromatography (hexane:ethylacetate 7:3) to afford the corresponding pure 2-substituted-4(3H)quinazolinones 3a-3m (Table -3).All the products are well characterized by spectral analysis (IR, 1 HNMR, MS) and were found to be identical those reported in the literature. 20,25

-( 4 -H y d r o x y p h e n y l -3 -m e t h o x y ) -4 ( 3 H )quinazolinone (3c)
mp( o C) 25

RESULTS AND DISCUSSION
In an effort to develop more widely applicable methodology, in order to optimize the reaction conditions initially we have studied the efficacy of cobalt(II) chloride by taking catalytic amount of 10 mol% and anthranilamide (1mmol) and benzaldehyde (1.3mmol) in acetonitrile (5mL) as model reaction(3a) refluxed at 70 o C for 5h, the reaction gave corresponding 2-Phenyl-4(3H)quinazolinone 93% yield.(Table 3, entry 1).In the absence of cobalt(II) chloride even up to 15h no reaction was observed.The model reaction (3a) was performed in various solvents using cobalt(II) chloride as catalyst to identify the best medium for the reaction.A range of solvents such as CHCl 3 ,    Encouraged by the results obtained for benzaldehyde (3a) we generalized the reaction scope for a number of other structurally divergent aromatic aldehydes, aliphatic aldehydes such as (propanaldehyde, butyraldehyde, and acetaldehyde, Table 3, entry 1j, 1k, 1l) heterocyclic aldehydes (furan-2 aldehyde, thiophene-2 aldehyde Table 3, entry 1f, 1m).In general electron rich counter parts such as hydroxy, methoxy, methyl groups require less reaction time than those of electron withdrawing groups such as (nitro group, halide group) were employed and reacted well to give the corresponding 2-substituted 4(3H)quinazolinones.
In a similar fashion we studied the efficacy of different catalyst chosen (10mol%) as standard on the model reaction (4a) by taking anthranilic acid, triethyl orthoformate, aniline, acetonitrile, (5mL), heating at 70 o C for 6 hours results in the formation of 3-phenyl-4(3H)quinazolinone in 95% yield (Table-2, (4a) entry 7).The results shown that cobalt(II) chloride is emerged as best catalyst both in terms of reaction time and yields.Model reaction (4a) is screened for the best solvent by taking various solvents and acetonitrile is emerged as the best solvent (Table-1 4a, entry 7).Various 3substituted 4(3H)quinazolinone were prepared by using structurally varied anilines including pyridine-2-amine (Table-4 entry 2k).All the 2-substituted-4(3H)quinazolinones and 3-substituted-4(3H)quinazolinones are well characterized by spectral analysis and with authentic samples.

CONCLUSION
In conclusion we have developed clean and efficient alternative protocols for the synthesis of 2-substituted-4(3H)quinazolinones from anthranilamide, aldehydes and synthesis of 3substituted-4(3H)quinazolinones from three component reaction of anthranilic acid, triethyl orthoformate, primary amines.The notable feature of these methodologies are by using a mild, inexpensive, easily available, cobalt (II) chloride as catalyst.We believe that this methodology will be a valuable addition for the synthesis of 2substituted-4(3H)quinazolinones and 3substituted-4(3H)quinazolinones which are important synthetic interest because of their pharmacological and therapeutic properties such as anti-inflammatory, antiviral, anticancer activities etc…..

a
All the products are characterized by spectral analysis b Isolated yields c heating at 70 0 C mp( o C)