Heterocyclic systems, substitutions with

Since diazaquinones are among the most powerful dienophiles, they undergo [4+2] cycloaddition (Diels-Alder) reactions with a great variety of dienes to give various heterocyclic systems accessible with difficulty by other methods. Diazaquinone reacts with butadiene and substituted butadienes, carbocyclic and heterocyclic dienes, 1-vinylcycloalkenes, polyaromatic compounds and vinylaromatic compounds to afford bicyclic and polycyclic bridgehead diaza systems, including diazasteroids (Scheme 56). 

The investigation of a series of model meat systems has demonstrated the important role of volatile sulfur-containing heterocyclic components substituted with sulfur in the 3-position. One of these 3-substituted sulfur compounds, 2-methy1-3-methy1thio-furan was identified recently in the volatiles from cooked beef aroma (5J and from a heated yeast extract composition (6J and is considered a meaty character impact compound. 

The decision was taken to explore and optimize this random lead by the synthesis of analogs. The only published work on similar 6-membered-aromatic-N-heterocyclic compotmds as ftmgicides was the triarimol project of Eli Lilly. But although most of the Eli Lilly patents include compounds with a two-carbon bridge between a halogen substituted phenyl ring and the N-heterocyclic system, compotmds with an one-carbon bridge seem always preferred (. ... 

In the second, which belongs to a systematic study of the transmission of substituent effects in heterocyclic systems, Noyce and Forsyth (384-386) showed that for thiazole, as for other simple heterocyclic systems, the rate of solvolysis of substituted hetero-arylethyl chlorides in 80% ethanol could be correlated with a constants of the substituent X only when there is mutual conjugation between X and the reaction center. In the case of thiazole this situation corresponds to l-(2-X-5-thiazolyl)ethyl chlorides (262) and l-(5-X-2-thiazolyl)ethyl chlorides (263). 

Benzisoxazoles undergo electrophilic substitution in the benzo ring, but with nucleophiles the reaction occurs in the isoxazole moiety, often leading to salicylonitriles with 3-unsubstituted systems. The isomeric 2,1-benzisoxazoles are characterized by the ease with which they may be converted into other heterocyclic systems. 

Semicarbazide hydrochloride [705] and amidrazones [106] react with trifluo-ropyruvates to give six-membered heterocycles A variety of trifliioromethyl substituted heterocyclic systems is available, starting from the hydrate of trifluoropy-ruvicacid, a versatile 1,2-bielectrophihc building block (reaction type 2, equation 10) [107] (equation 24). 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

Reaction of the substituted 3-amino-2-methylaminopyrimidin-4-one 200 with acetic anhydride gives rise to the tricyclic heterocyclic system 201 in good yield (Equation 52) <1995MI445>. 

Many versatile approaches to the construction of fused heterocyclic systems (6 5 6) with ring junction heteroatoms have been reported. More general reactions which can be used for synthesis of derivatives of several tricyclic systems, and transformations which have potential for use in the preparation of a series of substituted compounds, are discussed in this section. Formation of the five-membered ring is presented first because it is a conceptually simple approach. It should be noted, however, that the addition of a fused six-membered ring to a bicyclic component offers much more versatility in the construction of a (6 5 6) system. Each subsection below starts with intramolecular cyclization of an isolated intermediate product. Reactions which follow are one-pot intermolecular cyclizations. 

Electron-rich heterocyclic systems such as indolizines react readily with DEAZD (and PTAD) to give substitution products (Eq. 16).141 None of the formal [8 + 2] cycloaddition products (e.g., 89) are observed. This is in direct contrast to the reaction of indolizines with electrophilic acetylenes which gives high yields of cycloaddition products, presumably via a stepwise mechanism, in the presence of palladium on charcoal.142 This example of... 

When thioxo (or thiol) derivatives (as part of a thiourea function incorporated into the heterocyclic system) are present, effective. Y-alkylation is observed. Thus, the 3-heteroaryl-substituted [l,2,4]triazolo[3,4-/)][l,3,4]thiadiazole-6(5//)-thiones 37 dissolved in sodium hydroxide solution react with alkyl halides to afford the corresponding 6-alkylthio derivatives 38 (Equation 4) <1992IJB167>. The mesoionic compounds 39, inner salts of anhydro-7-aryl-l-methyl-3-methylthio-6-sulfonyl-[l,2,4]triazolo[4,3-A [l,2,4]triazolium hydroxides, are methylated with methyl iodide to give the corresponding quaternary salts 40 (Equation 5) <1984TL5427, 1986T2121>. 

The synthetic interest in direct substitution of protonated heteroaromatic bases by carbamoyl and a-amidoalkyl radicals arises because the reaction is applicable to a variety of heteroaromatic bases having highly reactive nucleophilic positions and because a variety of amides can be used. The selectivity of attack is complete at the a- and y-positions of the heterocyclic system owing to the nucleophilic character of both carbamoyl and a-amidoalkyl radicals, The results with formamide are shown in Table VI. Quinoline with dimethylformamide gave a variety... 

In summary (Scheme 15), 2-lithiopiperidines and 2-lithiopyrrolidines appear to be very versatile nucleophiles for the elaboration of these heterocyclic systems, affording a variety of 2-substituted heterocycles in excellent yields. The stereoselectivity of the reaction is near 100% in the piperidine series with most carbonyl electrophiles (retention of configuration) and alkyl halides (inversion of configuration). In the pyrrolidine series, the selectivity is also near 100% with carbonyl electrophiles (retention), but less selective (inversion predominates) with alkyl halides (less problematic with Af-aUylpyrrolidines). 

One of the earliest uses for rhodium(II)-catalyzed dipoles was demonstrated in Davies furan synthesis [22]. Isomiinchnones were also shown to produce substituted furans [115]. Additional furan syntheses have been described using silylacetates [116], unsaturated esters [117], and fluoroalkyl diazo acetates [118]. The synthesis of furofuranones and indenofuranones 35 from a-diazo ketones having pendant alkynes has also been reported (Eq. 6) [119]. Other fused heterocyclic systems include furo[3,4-c]furans [120, 121] furo[2,3-b]furans [122] as well as thiobenzofurans [123], and benzoxazoles[124] have also been synthesized with this methodology. 

Only two examples of the synthesis pyrimidoazocines have been described. In Ref. 82JHC1257, a three-stage synthesis of a new heterocycle system, pyrimido[5,4-c]benz[l]azocine, has been proposed. Condensation of 4-methyl-2-phenyl-5-pyrimidincarboxylate (112) with 3,4-dimethoxy-6-nitrobenzaldehyde (113) led to the substituted alkene 114, which, after catalytic hydrogenation of the nitro group on Raney nickel and subsequent intramolecular cyclization of product 115, was converted into pyrimidobenz[l]azocine 116 (Scheme 32). 

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