Heterocycles synthesis under solvent-free conditions

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

The synthesis of biologically significant fluorinated heterocyclic compounds has been accomplished by 1,3-dipolar cycloaddition of nitrones to fluorinated dipolarophiles [51], This reaction was noticeably improved under solvent-free conditions and using microwave irradiation (Eq. (8) and Tab. 3.5). 

A new approach for the synthesis of functionalized 4-alkylquinolines was developed utilizing electrogenerated carbanions <07SL1031>. The desired 4-alkylquinolines 83 were synthesized through a sequential alkylation/heterocyclization of p-(2-aminophenyl)-a,p-ynones 84 and the electrogenerated carbanions of nitroalkanes 85. This novel approach avoided metal and base catalysts and is performed under solvent free conditions. 

Significant improvements in the synthesis of pyrido-fused heterocycles were achieved when the reaction was performed under solvent-free conditions and applying the tert-amino effect as the key ring-closure method [183]. It was shown, as depicted in Eq. (91), that MW can improve the reaction yield under similar sets of conditions compared with A heating. When extending the reaction time, as often quoted, nearly quantitative yields were obtained, irrespective of the mode of activation. The specific MW effect observed here is consistent with the proposed polar mechanism for the cyclization [184],... 

Isoxazolidines is another class of heterocycles that are very useful in medicinal chemistry. DABCO has been used for the synthesis of these compounds by using activated nitrocompounds in the presence of dipolar-ophiles. Pyrazolines could also be obtained by means of DABCO in the [3 + 2] cycloaddition reaction of ethyl diazoacetate with various activated olefins, under solvent-free conditions. ... 

These include the SSA-catalyzed synthesis of heterocyclic compounds such as xanthenes, coumarins, oxazoles, and so on. Xanthenes are of great therapeutic and biological interest on account of their many biological activities such as anti-inflanunatory, antiviral, antibacterial properties, and so on. Seyyed Hamzeh et al. (2008) carried out the SSA-catalyzed synthesis of aryl-14 f-dibenzo[fl,y]xanthenes from aldehydes and P-naphthol and 1,8-dioxo-octahydro-xanthenes from aldehydes and 1,3-dicarbonyl componnd such as dimedone under solvent-free conditions (Schemes 5.25, 5.26). Reactions were carried out at 80°C. Nazeruddin et al. (2011) documented an effective method for 9,10-dihydro-12-aryl-8 f-benzo[a]xanthenes-ll(12 f)-one derivatives in excellent yield and short reaction time using SSA under solvent-free conditions (Scheme 5.27). 

Siddiqui, Z.N. and Farooq, F. 2012. Silica supported sodium hydrogen sulfate (NaHS04-Si02) A novel, green catalyst for synthesis of pyrazole and pyranyl pyridine derivatives under solvent-free condition via heterocyclic P-enaminones. J. Mol. Catal. A Chem. 363-364 451 59. 

Kumar, B. S. Reddy, Y. T. Reddy, P. N. Kumar, P. S. Rajitha, B. Selectfluor a simple and efficient catalyst for the synthesis of substituted coumarins under solvent-free conditions. J. Heterocycl. Chem. 2006, 43, 477 79. 

Bose DS, Kumar RK (2006) High-yielding microwave assisted synthesis of quinoline and dihydroquinoline derivatives under solvent-free conditions. Heterocycles 68 549-559... 

Bose DS, Chary MV, Mereyala HB (2006) Water-tolerant and reusable catalyst for the one-pot synthesis of dihydropyrimidin-2(lH)-ones under solvent-free conditions. Heterocycles 68 1217-1224... 

Li J, Jiang D-N, Chen J-X, Liu MC, Ding JC, Wu HY (2011) Eco-friendly synthesis of quinoxaline derivatives by grinding under solvent-free conditions. J Heterocyclic Chem 48 (2) 403 06. doi 10.1002/jhet.597... 

Soleimani, E. Khodaei, M. M. Batooie, N. Samadi, S. Tetrakis(acetonitrile)copper(I) hexafluorophosphate catalyzed coumarin synthesis via Pechmann condensation under solvent-free condition. J. Heterocycl. Chem. 2012, 49, 409-412. 

A survey of microwave activation in the chemistry of Hantzsch 1,4-dihydropyridines (1,4-DHP) was reported in 2003 [195]. The experimental method proposed more than a century ago remains the most widely used for synthesis of these heterocycles. Since 1992 the process has been adapted to microwave irradiation under a variety of conditions to reduce the reaction time and enhance the yield. Among these experiments, Zhang reported a solvent-free process starting from 3-aminocrotonate (20 mmol), methyl acetoacetate (20 mmol), and aromatic aldehydes (20 mmol) in a domestic oven [196]. Yields from 59 to 77% were reported for 10-min reaction. A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP. Only procedures involving solvent-free conditions under the action of microwave irradiation led to the aromatized pyridine derivatives. 

Domino [3+3] heterocyclization reactions have been established for the synthesis of anti-tetrahydropyrimidone derivatives 64 in 70-86% yields (Scheme 12.23) [44]. These reactions were conducted by reacting +aryhdene-2-phenyloxazol-5(4H)-ones 52 with aryl amidines 63 under solvent-free and microwave irradiation conditions within 17-28min. The selective constmction of the anti-tetrahydropyrimidinone skeleton with one amide function was readily achieved under TEA (triethylamine) catalyzed condition by ring-opening of the oxazoles in a one-pot operation. 

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