Targeted heterocycle yields

A special class of synthesis is the utilization of retro-Diels-Alder (RDA) reactions. A double RDA sequence was used to prepare the pyrimido[l,2-A]pyridazin-3-one 118. In this versatile method both reactants of the parent compound were constructed from cyclopentadiene. The parent compound 117 contains two norbornene units and decomposes on heating in toluene in a double RDA reaction leaving two double bonds in the target heterocycle. Similarily, the parent compound 119 decomposes in a single RDA reaction to yield the benzologue, pyridazino[6,l-3]-quinazolin-10-one 120 (Scheme 13) <2000SL67>. 

Fustero has devised an intramolecular version of the iminium ion catalysed conjugate addition of nitrogen in the preparation of a series of simple pyrrolidine and piperidine derivatives [115]. The reactions proceed in chloroform to give the target heterocycles in good yield and excellent levels of stereocontrol (Scheme 32). 

As an alternative, initial S-alkylation of aminoazole 8 with appropriate alkyl-bromides (R3CH2Br) was performed. Then 3-amino-5-alkylthio-l,2,4-triazoles 11 were introduced into the MCRs with aromatic aldehydes and acetoacetamides (pathway b ). To sufficiently increase yields of target heterocycles 13, the cyclocondensations were performed under microwave irradiation in ethanol at 120°C. 

Formation of compounds like 115 seems to have occurred in the similar way as it was established for anilines and other primary amines [167]. The initial step of this reaction is treatment of aldehyde with aminozole giving Schiff base 116. Further, nucleophilic attack of imine carbon by mercapto moiety of the acid leads to the intermediate 117 and its subsequent cyclization via gem-diol 118 yields target heterocycles 115 (Scheme 55). 

To accelerate the reactions rates and to increase their yields, sometimes microwave-assisted procedures are applied. The first mention of using a solvent-free microwave procedure was in [55]. The authors described the synthesis of 1,3,5-triarylpyrazoline by the cyclization of chalcones with phenylhydrazine on a basic alumina solid support. The target heterocycles were synthesized under microwave irradiation in high yields (up to 85%) in 1-2 min instead of 3 h in the case of thermal activation. Another publication [56] deals with the rapid (2-12 min) solvent-phase cyclization of naphthyl-substituted chalcones 41 and hydrazines 42 in a microwave field yielding the appropriate pyrazolines 43 quantitatively (Scheme 2.10). 

Unlike amidines, the multicomponent reaction of a,(3-unsaturated ketones 96 (aliphatic [94] or aromatic [95, 96]) with carbonyl compounds 97 and ammonia, which are the synthetic precursors of amidines, yielded 1,2,5,6-tetrahydropyrimidines 98 instead of dihydroheterocycles. When R3 is not the same as R4 tetrahydropyrimidines 98 were mixtures of diastereomers A and B, in which the relative configurations of stereogenic centers were also established [95, 96]. In contrast to conventional mechanical shaking requiring about 48 h [95], sonicated reactions were completed within 90 min at room temperature and provided the target heterocycles in high yields and purities [96]. Ultrasonic irradiation also significantly expanded the possibilities of such three-component reactions (Scheme 3.29). 

The specific microwave effects were presumably responsible for the observed 40-fold acceleration in microwave-assisted synthesis of 1,3,5-triazines 107 compared to conventional thermal conditions. Thus, microwave heating of benzonitrile and dicyandiamide 106 in an ionic liquid ([bmim]PF6) in the presence of powdered KOH at 130 °C for just 12 min afforded 2,4-diaminotriazine 107 in 87% yield. Under otherwise identical conditions the reaction in a pre-heated oil-bath (130 °C temperature) took 8 hours to afford the target heterocycle 107 in 79% yield [140] (Scheme 57). 

Pyrimidine derivatives are synthesized from TV-substituted lactams and Viehes salt with a short reaction sequence, good yields of the targeted heterocyclic compounds, as well as their convenient isolations and purifications. Addition of dry DMF to the reaction mixture proved to be highly beneficial in increasing the yields of the targeted heterocycles. This may be attributed to the improved solubility of amidines in the toluene/DMF (2 1) solvent mixture. Pyrimidines reacted with A-methylbenzylamine in dry DMF at 140 °C in a sealed-tube to furnish products of formal nucleophilic aromatic substitution of the N-Me2 group. 

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. 

As CH-acids in the MCRs with aldehydes and aminoazoles, other classes of organic compounds were used as well. Cyanoacetic acid derivatives, acetoyl(aroyl) acetonitriles, ketosulfones, acetophenones, and other reagents were successfully introduced into these three-component heterocyclizations. For example, synthesis of pyrazolo[3,4-b]pyridine-5-carbonitriles 40 was carried out as the multicomponent treatment of 5-aminopyrazole, aldehyde, and benzoylacetonitriles solvent-free by fusion either in ammonium acetate at 120°C or in boiling ethanol with EtsN (Scheme 17) [69]. The second approach gave the worst results from the viewpoint of yields and purity of the target compounds. 

Oximes 28 are interesting precursors to / -amino acids, as well as different heterocyclic systems, so it is advantageous to develop the synthesis of the oximes 28 maximizing the side process shown in Scheme 20. This problem was solved in the earlier paper, which dealt with the double silylation of 26 with MesSiOTf/EtsN, but the yields of target derivatives were modest as a rule. ... 

Based on this precedent, Nelson et al. used an intramolecular reaction in the total synthesis of (-)-rhazinilam. In this context, trisubstituted allenes are excellent precursors for a diastereoselective heterocyclic annulation that highlights the usefulness of this reaction in target-oriented synthesis [49]. In this case, the aforementioned catalyst that yielded the best results was [AuPPh3OTf], affording a higher yield and diastereoselectivity than Pd(II). 

A secondary heterocyclic amino group is also a target for A-methylation, the reaction in this case yielding a tertiary amine. For example, normorphine (65) is bioactivated to morphine (66) in rat brain and liver (63MI10900) and the endogenous amine histamine (67) yields N - methylhistamine (68) (59MI10903). Most of the mechanistic studies on N- methylation have been carried out with endogenous compounds such as histamine and noradrenaline,... 

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