Microwave-assisted Condensation Reactions

Microwave-assisted Knoevenagel reactions have also been used for preparation of resin-bound nitroalkenes [56]. A variety of resin-bound nitroalkenes has been generated by use of resin-bound nitroacetic acid, which was condensed with a variety of aldehydes under microwave conditions. To demonstrate the potential of these resin-bound products in combinatorial applications, the readily prepared nitroalkenes were subsequently employed in Diels-Alder reactions with 2,3-dimethylbutadiene [56]. 

A more recent report discussed a microwave-assisted tetronate synthesis entailing domino addition/Wittig olefinations of polymer-bound a-hydroxy esters with the cumulated phosphorus ylide Ph3P=C=C=0 [59]. The desired immobilized a-hydroxy esters can be obtained by microwave-mediated ring opening of the corresponding glycidyl esters by OH-, NH-, or SH-terminal polystyrenes of the Merri- 

---

In an attempt to couple halobenzaldehydes with amines, A1203 was pre-absorbed with the substituted benzaldehydes and imidazole or piperidine as a base and irradiated with microwaves. However, the corresponding benzylic alcohols and benzoic acids were unexpectedly obtained by the Cannizzaro route (Scheme 4.20). The products of Cannizzaro reactions were also obtained as the main products, when microwave-assisted condensation reactions of benzaldehydes with vinyl acetate using barium hydroxide as the catalyst were attempted40. 

A range of microwave-assisted condensation reactions was used in the synthesis of indole alkaloids with pharmaceutical applications. An example is shown in Scheme 5.2-108 [251]. A one-pot synthesis of a pharmaceutically active compound was synthesized by a series of three condensation reactions in a range of [BF4] and [PFe] ionic liquids. This is shown in Scheme 5.2-109 [252]. 

A one pot synthesis of series of some y-spiroiminolactone derivatives has been reported by Azizian et al. (2004) via a microwave-assisted condensation reaction of isocyanides, dialkyl acetylenedicarboxylates and indenoquinoxilin-ll-ones in DMF or in a solvent less operation on montmorillonite KIO support. 

Kidwai and Rastogi (2005) have reported a solvent-free synthetic route for the synthesis of tetrahydroacridinones through microwave-assisted condensation reaction of an aldehyde, dimedone and a primary aromatic amine. The best microwave method was found to be the neat reaction technology without the use of any solvent or inorganic solid supports. The reactions were completed within 5 min with 82-87% yields, when compared to the conventional solution phase method with longer reaction times (hours) and comparatively lower yields. 

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. 

Developing their work on the use of microwave-assisted Niementowski reactions, the same group published the synthesis of novel triaza- and tetraaza-benzo a -indeno[l,2-c]anthracen-5ones by the condensation of anthranilic acid with 2-(2-aminophenyl)indole or benzimidazole (Scheme 3.49)78,79. 

The DHPMs should be synthesized in solution using standard Biginelli three-component condensation reaction mixtures. Although microwave-assisted Biginelli reactions have been published under solvent-free conditions,46 50 we felt that such methods would... 

The time consuming chromatographical purification of heterocycles 28 and 29 slowed down the rate of library production. A phase separation using fluorous chemistry was employed by Zhang and Lu to address the workup and purification of fused 3-aminoimidazo[ l,2-a]pyridines (such as 30) [54]. Thus, attachment of a perfluorooctanesulfonyl tag to aldehydes and subsequent Ugi three-component microwave-assisted condensations with 2-aminopyridines and isocyanides furnished the desired heterocycles 30, which were conveniently isolated by fluorous solid-phase extraction. The fluorous tag could be subsequently used as an activating group in the post-condensation modifications, such as Suzuki-Miyaura cross-coupling reactions. 

Various thiazolo-heterocyclic compounds (xi) as novel MCH IR antagonist (MCH-1 receptor) have also been effectively synthesized by Guo et al. [12]. The reaction involved the microwave assisted condensation of a-heteroarylamines (ix) with 3-dimethylamino-2-aryl-propenoates (x). 

Resin-bound nitroalkenes were synthesized via a Knoevenagel condensation of resin-bound nitro acetic acid with aryl and alkyl substituted aldehyde (Scheme 9.29). In this way an extra site of diversity can be introduced into the cycloaddition products of these nitroalkenes. Furthermore, the resin-bound nitroalkenes can serve as activated alkenes in other cycloaddition reactions (Diels-Alder, 1,3-dipolar cycloaddition, [2 + 2] cycloaddition) and therefore lead to the solid phase synthesis of other interesting compoimd classes (see also Scheme 9.3, Sect. 9.2). Formation of the resin-bound nitroalkenes 73a-e was realized in one step via a microwave-assisted condensation of aldehyde 72a-e (10 equiv.) with the resin-bound nitro acetic acid 71, followed by dehydration of the intermediate y -nitroalcohol [6] (Scheme 9.29). THF was used as the solvent in order to obtain optimal diffusion of the aldehyde in the polystyrene resin. 

As discussed in Section 16.1.4, polymer-bound acetoacetates can be used as precursors for the solid-phase synthesis of enones [30]. For these Knoevenagel condensations, the crucial step is to initiate enolization of the CH acidic component. For the microtvave-assisted enolization procedure, however, piperidinium acetate was found to be the catalyst of choice, if temperatures were kept below 130 °C. A 21-member library, of polymer-bound enones was generated (Scheme 16.33) by using a multi-vessel rotor system for parallel microwave-assisted synthesis. Reaction... 

Real-time in situ Raman analysis of microwave-assisted organic reactions has also been reported [40, 41]. Raman spectroscopy provides a combination of high selectivity along with the ability to conduct analysis directly through the wall of glass reaction vessels and in monitoring the Knoevenegel condensation reaction of salicylaldehyde and benzyl acetoacetate to form 3-acetylcoumarin, observations were made inside the microwave compartment of the synthesizer. 

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],... 

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]... 

---