Condensations microwave assisted

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

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 pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

The one-pot synthesis of thiazolo[3,4-a]benzimidazoles has been reported using a microwave-assisted condensation-cyclization (see Scheme 17) of a substituted 1,2-diamine, substituted benzaldehyde and mercaptoacetic acid [74]. Heating the mixture at reflux for 12 min using a single-mode microwave reactor for the most part gave the fused benzimidazoles in improved yield and dramatically shorter times, when compared to classical conditions of heating at reflux in benzene for 24-48 h (Scheme 29). 

One of the first published microwave-assisted synthesis of benzothiazoles is the condensation of a dinucleophile such as 2-aminothiophenol, with an ortho-ester (neat) in the presence of KSF clay in a mono-mode microwave reactor operating at 60 W under a nitrogene atmosphere [ 12] (Scheme 12). Traditional heating (oil bath, toluene as solvent and KSF clay) gave the expected products in similar yields compared to the microwave experiments but more than 12 h were required for completion. Solvent-free microwave-assisted syntheses of benzothiazoles was also described by attack of the dinucleophiles cited above on benzaldehydes and benzaldoximines [13] (Scheme 12). This methodology was performed in a dedicated monomode microwave reactor... 

Fig. 33 Microwave-assisted fluorous Ugi condensations. Reagents and conditions a MeOH, MW 100°C, 10-20 min b TFA-THF, MW 100 °C, 10-20 min. R = Ph, furyl, 3-Me-pyridil, i-Bu, MeSC2H4, PhC2H4 R = t-Bu, cylohexyl. Bn or Bu, m-xylU...

Another series of pyrroles, structurally related to amino acids, was obtained in a microwave-assisted solvent-free condensation of a-amino acid methyl esters with chloroenones, which provided the four-carbon unit of the pyrrole. The reaction was carried out by mixing the reagents on silica gel and irradiating for 2-6 min inside a multimode microwave cavity (Scheme 7). The authors reported higher yields and cleaner products when microwaves were used instead of conventional heating [34],... 

An interesting family of polycyclic pyrroles was described in 2005 using again the synthetic sequence of a Stetter reaction for the preparation of the starting 1,4 diketones followed by a microwave-assisted Paal-Knorr condensation [35]. For example, cyclopentenone 23 (obtained in a Pauson-Khand cyclization) reacted imder Stetter reaction conditions to give the amino ketone 25 (Scheme 8). The microwave-assisted Paal-Knorr cyclization of 25 with different amines gave a small collection of tricychc pyrrole 2-carbox-amides. 

An alternative preparation of benzofurans was carried out via a microwave-assisted Mannich condensation of paraformaldehyde and a secondary amine followed by cyclization with an alkynyl phenol 185 mediated by alumina doped with Cul (Scheme 67). The reaction can be carried out in a single-step... 

Aryl substituted quinohnes 216 have also been prepared through a microwave-assisted Friedlander condensation between various acetophenones 215 and 2-aminoacetophenones 214 in the presence of a catalytic amount of diphenylphosphate (Scheme 78). These conditions are less acidic than the others reviewed here for the synthesis of quinohnes [138]. 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

The highly potent anti-HIV natural product daurichromenic acid (10-100) was synthesized by Jin and coworkers [36] using a microwave-assisted reaction of the phenol derivative 10-97 and the aldehyde 10-98 (Scheme 10.25). Normal heating gave the desired benzo[b]pyran 10-99 by a domino condensation/intramolecular SN2 -type cyclization reaction only in low yield. However, when the reaction mixture was irradiated twenty times in a microwave for 1-min intervals, 10-99 was obtained in 60% yield. This compound was then transformed into 10-100 by cleavage of the ester moiety. 

One major benefit of performing microwave-assisted reactions at atmospheric pressure is the possibility of using standard laboratory glassware (round-bottomed flasks, reflux condensers) in the microwave cavity to carry out syntheses on a larger scale. In contrast, pressurized reactions require special vessels and scale-up to more... 

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

The yields for the optimized microwave-assisted Biginelli condensations are in general comparable to or higher than those obtained using the standard reflux conditions. More importantly, however, reaction times have been brought down from several hours (4—12 h) under reflux conditions to 10-20 min employing microwave... 

Another frequently used multicomponent reaction is the Kindler thioamide synthesis (the condensation of an aldehyde, an amine, and sulfur). The Kappe group has described a microwave-assisted protocol utilizing a diverse selection of 13 aldehyde and 12 amine precursors in the construction of a representative 34-member library of substituted thioamides (Scheme 6.114) [226]. The three-component con-... 

The preparation of a-ketoamides by a microwave-assisted acyl chloride-isonitrile condensation has been described in Section 2.5.3 (see Scheme 2.5) [305],... 

Three different microwave-assisted synthetic routes to benzimidazole derivatives are summarized in Scheme 6.205, involving the condensation of 1,2-phenylenedi-amines with either carboxylic acids (Scheme 6.205 a and b) [368, 369] or two equivalents of aldehydes (Scheme 6.205 c) [370], or by cyclization of N-acylated-diamino-pyrimidines mediated by a strong base (Scheme 6.205 d and e) [371, 372],... 

The Friedlander reaction is the acid- or base-catalyzed condensation of an ortho-acylaniline with an enolizable aldehyde or ketone. Henichart and coworkers have described microwave-assisted Friedlander reactions for the synthesis of indoli-zino[l,2-b]quinolincs, which constitute the heterocyclic core of camptothecin-type antitumor agents (Scheme 6.238) [421], The process involved the condensation of ortho-aminobenzaldehydcs (or imines) with tetrahydroindolizinediones to form the quinoline structures. Employing 1.25 equivalents of the aldehyde or imine component in acetic acid as solvent provided the desired target compounds in 57-91% yield within 15 min. These transformations were carried out under open-vessel conditions at the reflux temperature of the acetic acid solvent. 

The same authors have described a related Niementowski condensation for the preparation of 3H-nitroquinazolin-4-ones. Subsequent manipulation of this structure led to 8H-thiazolo[5,4-/ quinazolin-9-ones through a series of open-vessel microwave-assisted transformations, as indicated in Scheme 6.251 [205, 438]. 

As discussed in Section 7.1.4, polymer-bound acetoacetates can be used as precursors for the solid-phase synthesis of enones [33], For these Knoevenagel condensations, the crucial step is to initiate enolization of the CH acidic component. In general, enolization can be initiated with a variety of catalysts (for example, piperidine, piperidinium acetate, ethylenediamine diacetate), but for the microwave-assisted procedure piperidinium acetate was found to be the catalyst of choice, provided that the temperature was kept below 130 °C. At higher reaction temperatures, there is significant cleavage of material from the resin. 

Microwave-assisted Knoevenagel reactions have also been utilized in the preparation of resin-bound nitroalkenes [56], The generation of various resin-bound nitroalkenes employing resin-bound nitroacetic acid has been described the latter was condensed with a variety of aldehydes under microwave conditions (Scheme 7.40). 

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