MCRs under Solvent-Free Conditions

The development of new MCRs under solvent-free conditions has emerged as an attractive alternative to conventional syntheses in the recent years. The main advantages of solvent-free processes are cost savings, decreased energy consumption, and reduced reaction times. The E factor is a measure of the greenness of a chemical process and is defined as the ratio of the weight of waste to the weight of product. One of the best ways to reduce the E factor of the reactions and their effect on the environment is to carry out the reactions under solvent-free conditions because the best solvent is no solvent. 

One of the limitations of this reaction is that the reaction of 1-naphthol led to a mixture of ortho- and para-addition products in 1 1.3 ratio. 

In 2010, Pitchumani and Kanagaraj reported the solvent-free multicomponent synthesis of pyranopyrazoles. The reaction of hydrazine, ethyl acetoacetate, malononitrile, and aromatic aldehydes catalyzed by per-6-amino-p-cyclodextrin at room temperature afforded the corresponding pyranopyrazoles in quantitative yields [56]. 

SCHEME 11.11 Synthesis of 3-amino-2-arylimidazo[l,2-a]pyridines 79 reported by Adib. 

Singh and coworkers reported a method for the synthesis of 2/f-indazolo[2,1 -fc]phthalazine-1,6,11 -triones and l//-pyrazolo[l,2-fc]phthalazine-5,10-diones under solvent-free 

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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. 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

A series of 4-aryl-6-(l//-indol-3-yl)-2,2-bipyridine-5-carbonitriles 9 was synthesized by Perumal and co-workers [60] via a one-pot MCR of an aromatic aldehyde, a 3-(cyanoacetyl)indole, 2-acetyl pyridine and ammonium acetate by microwave irradiation under solvent-free conditions. The compounds were obtained in high yields and in a very short period of time as compared to conventional heating. Remarkably, when 2,4-dichlorobenzaldehyde was used in this reaction, only the Hantzsch 1,4-dihydropyridine was isolated which had to be separately dehydrogenated to get the targeted pyridine (Scheme 9). 

Another interesting MW-assisted MCR for construction of the DHP ring as part of a more complex bicyclic scaffold was reported by Quiroga et al. They realized the MW-assisted synthesis of both pyrazolopyridines 7 and pyrido[2,3-d]pyrimidines 8 under solvent-free conditions (Scheme 17.8) [38]. 

In 2006, an MCR pathway to pentacyclic quinoline derivatives 439 was established by Bhuyan et al. (Scheme 13.91) [182], Novel annelated quinolines have been prepared in a three-component reaction under solvent-free conditions at high temperatures. In addition to Meldrum s acid 112 and pyrrolidine 438, a variety of other CH acids and amines have successfully been applied in this reaction. 

A convenient and clean water-mediated synthesis of a series of indolo[l,2-c] quinazoline derivatives was reported using alternative nonconventional energy sources. The products are obtained in shorter times with excellent yields (78-89 %) from the MCR of 2-arrrinobenzimidazole, malononitrile, and carbonyl compourtds [55]. In their research, 2-(2-halophenyl)-lH-indoles arrd (aryl)methanamines were adopted as raw rrraterials to generate corresponding Schiff base via the Ullrrrarm reaction. Thert, gas as oxidarrt, 3 equiv K COj as base, and 10 mol% Cu(OAc)2 as catalyst were revealed as the optimum conditions to conduct aerobic oxidative C-H amination under solvent-free conditions or water (Scheme 13.14). 

MW-assisted MCRs can also be conducted in standard organic solvents under both open and sealed vessel conditions. If solvents are heated in an open vessel, the boiling point of the solvent typically limits the reaction temperature that can be reached. The recent availability of modern monomode MW reactors [23] with on-line monitoring of both temperature and pressure has meant that MAOS in sealed vessels are increasingly commonly employed and this will be the method of choice for performing MW-assisted MCRs in the future, essentially if coupled with solvent-free procedures (cf Chapters 4 and 8). 

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