Microwave irradiation, condensation

Keywords barbituric acid, aromatic aldehyde, montmorillonite KSF, microwave irradiation, condensation... 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

Like oxalic acid, oxalic esters and o-phenyldiamines give 2,3(l//,477)-quinox-alinediones that bear substituents according to those on the substrate such condensations appear to be assisted substantially by microwave irradiation. 

Microwave and fluorous technologies have been combined in the solution phase parallel synthesis of 3-aminoimidazo[l,2-a]pyridines and -pyrazines [63]. The three-component condensation of a perfluorooctane-sulfonyl (Rfs = CgFiy) substituted benzaldehyde by microwave irradiation in a single-mode instrument at 150 °C for 10 min in CH2CI2 - MeOH in the presence of Sc(OTf)3 gave the imidazo-annulated heterocycles that could be purified by fluorous solid phase extraction (Scheme 9). Subsequent Pd-catalyzed cross-coupling reactions of the fluorous sulfonates with arylboronic acids or thiols gave biaryls or aryl sulfides, respectively, albeit it in relatively low yields. 

Linking the ketone and carboxylic acid components together in an Ugi reaction facilitates the synthesis of pyrrolidinones amenable to library design. The three-component condensation of levulinic acid 30, an amine and isocyanide proceeds under microwave irradiation to give lactams 31 [65]. The optimum conditions were established by a design of experiments approach, varying the equivalents of amine, concentration, imine pre-formation time, microwave reaction time and reaction temperature, yielding lactams 31 at 100 °C in poor to excellent yield, after only 30 min compared to 48 h under ambient conditions (Scheme 11). 

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. 

Thiazolines (2,3-dihydrothiazoles) were also prepared under microwave irradiation. Hamelin and coworkers have described the alumina-supported solvent-free synthesis of various 4-iminothiazolines by condensation of disymmetric thioureas and a-chloro ketone (Scheme 10). The experiments... 

Oxetanes are present in several biologically active natural compounds as, for example, the taxol ring skeleton. An interesting method used to obtain this particular ring is the thermal [2 -i- 2] cycloaddition reaction. Longchar and co-workers reported a novel [2-1-2] cycloaddition of /1-formil enamides 5, often used in other cycloaddition and condensation processes, with acetylenic dienophiles 6 under microwave irradiation (in a domestic oven) to afford ox-etenes 7 in 80% yields [29]. This reaction was directed towards the synthesis of D-ring annelated heterosteroids (Scheme 2). 

Considering the formation of saturated five-membered heterocycles with two heteroatoms, it is worth to note the possibility to prepare 1,3-dioxolanes, dithiane, oxathianes 148 [93] and dioxolanones 149 [94] by condensation of the corresponding carbonyl compounds under microwave irradiation in acid medium (Scheme 52). The reaction, which is very useful for the protection of carbonyl compounds or for the preparation of useful synthetic intermediates, has also been carried out under batch conditions over Montmorillonite KIO clay in more than 150 g scale, using a 1 L quartz reactor [95]. 

Cyclic ureas can be obtained by reaction of simple urea with 1,2-diamino derivatives in DMF in the presence of ZnO and under microwave irradiation (Scheme 53). In this unusual condensation, two molecules of ammonia are eliminated. The reaction is very sensitive to the presence of ZnO. Without this catalyst, a yield of 20% is reported together with the formation of several by-products. The reaction was also carried out under reduced pressure... 

Pyridines are traditionally prepared using the Hantzsch reaction, a condensation between 2 mol of a 6-ketoester, 1 mol of an aldehyde and 1 mol of ammonia. The product of this reaction is a 1,4-dihydropyridine which can be further oxidized to the corresponding pyridine compound (as 155 in Scheme 54). A first report described the Hantzsch reaction carried out under microwave irradiation on Bentonite clay and ammonium nitrate as ammonia... 

Benzimidazoles have been prepared by direct condensation of o-phenylene-diamine 190 with a carboxyhc acid at 110 °C in water and under microwave irradiation (Scheme 69) [124]. Differently functionahzed benzimidazoles 192 were obtained with this method especially regarding the nature of the substituent on the imidazole ring. 

Benzannulated NHPs are straightforwardly accessible from AUV-disubsti luted o-phenylenediamines either via base-induced condensation with substituted dichlorophosphines [25] or PC13 [26], or via transamination with tris(dialkylamino) phosphines [13, 14, 27], respectively. An analogous NH-substituted derivative was obtained in low yield via transamination of o-phcnylcncdiaminc with ethoxy-bis(diethylamino)phosphine [28], and condensation of o-phenylenediamine with excess tris(diethylamino)phosphine furnished a l,3-bis(phosphino)-substituted heterocycle [29], Intermediates with one or two NH functions were detectable by spectroscopy but could not be isolated in pure form under these conditions. However, 2-chloro-benzo-l,3,2-diazaphospholene and the corresponding 1-phenyl derivative were prepared in acceptable yield via condensation of PC13 with o-phenylenediamine under microwave irradiation [30], or with A-phenyl-o-phenylenediamine under reflux [27], respectively, in the absence of additional base. The formation of tetrameric benzo-NHPs during transamination of A-alkyl-o-phenylenediamines with P(NMe2)3 has already been mentioned (cf. the section entitled 1,3,2-Diazaphospholes and 1,3,2-Diazaphospholides ). 

Acyl hydrazides are useful precursors for the synthesis of 1,2,4-triazoles. Reaction of acyl hydrazides 149 with imidoylbenzotriazoles 148 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 150 <06JOC9051>. Treatment of A-substituted acetamides with oxalyl chloride generated imidoyl chlorides, which reacted readily with aryl hydrazides to give 3-aryl-5-methyl-4-substituted[ 1,2,4]triazoles <06SC2217>. 5-Methyl triazoles could be further functionalized through a-lithiation and subsequent reaction with electrophiles. ( )-A -(Ethoxymethylene)hydrazinecarboxylic acid methyl ester 152 was applied to the one-pot synthesis of 4-substituted-2,4-dihydro-3//-1,2,4-triazolin-3-ones 153 from readily available primary alkyl and aryl amines 151 <06TL6743>. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoylhydrazides with thioamides under microwave irradiation <06JCR293>. 

Several 3-mercapto-l,2,4-trizines have been synthesized through the condensation of thiosemicarbazide with diketones under microwave irradiation in a solventless system <06PS87>. The synthesis and cyclocondensation reactions of 3-substituted-5-(2-aminobenzyl)-l//-[l,2,4]triazin-6-ones have been reported <06JHC613>. 

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