Heterocycles from glycols

The synthesis of ortho esters from nitriles is usually a two-step process involving first the formation of the imino ester hydrochloride and subsequent reaction with an alcohol. Several examples are described in Table I, even a glycol such as ethylene glycol can be used to obtain heterocyclic ortho esters, as shown in Eq. (11). 

Both, esters and tertiary amino groups are tolerated, giving rise to products 6f and 6h which are useful as centers for dendrimeric structures. The pentakisalde-hyde 6g was obtained from 4-bromobenzaldehyde protected as the ethylene glycol acetal. Attempts to use heterocyclic bromides for arylation were hitherto unsuccessful. 

The reaction of perfluoro-4-methyl-2-pentene with ethylene glycol also leads to 2-fluoro-2-trifluoromethyl-3-(2,2,2-trifluoro-1 -trifluoromethylethy-lidene)-l,4-dioxane 106 (96ZOB1995). The formation of the six-membered heterocycle occurs via generation of the intermediate carbanion and fluoride ion elimination from the y-position. Subsequent intramolecular nucleophilic cyclization involving the O-nucleophilic center and the internal double bond leads to a 1,4-dioxane derivative (route e). 

Aromatic and heterocyclic aldehydes have been prepared from hydra-zides, via the arylsulfonyl derivative, in 50-65% and 20-40% yields, respectively the method fails in the aliphatic series. The hydrazide is treated with benzenesulfonyl chloride in pyridine, and the subsequent product is isolated by precipitation with water and decomf>osed by heating with sodium carbonate in ethylene glycol or glycerol at 160°. 

The aeylative cyclization of phenol with acetic anhydride was carried out over CeY type zeolites. The reaction mechanism is given in Fig. 4. At 380°C, the yield of 4-methyl coumarin was 75 % at 81% conversion of phenol. N-Methylpyrrolidine was synthesized from 1,4-butanediol and methylamine over Cr ZSM-5 and modified ZSM-5 catalysts at 300 C. The reaction mechanism is given in Fig. 5. The synthesis of a number of five- and six- membered heterocyclics have been depieted in Table 1. The reaction was carried out at 250-400°C at 30-80 hydrogen atm., under down-flow fixed bed conditions. The yield of N-methyl piperazine was 90% at 95% conversion over ZSM-5 catalysts. Similarly 2-methyl pyrazine and piperazine were synthesized from propylene glycol and ethylenediamine over HZSM-5 (Fig. 6). 

McFadyen and Stevens (cf. Bayer344h) obtained aldehydes from the corresponding carboxylic acids in yields of up to 60% by intramolecular disproportionation of aromatic and heterocyclic l-acyl-2-(benzenesulfonyl)hydrazines induced by an alkali carbonate in ethylene glycol at 160° but this method fails for aliphatic and, / -unsaturated carboxylic acids. 

An efficient method for the synthesis of dihydrothiophene ureidoformamides 149 from commercially available materials in a four-component domino process was reported by Cai et al. [82] (Scheme 12.58). The reaction efficiently assembled aromatic aldehydes 69, malodinitrile 71a, 1,3-thiazolidinedione 148, and anitines 102 with high yields by conducting the reaction in a cosolvent mixture of polyethylene glycol (PEG) 400/H2O (1 1) at 80 °C. Under optimized conditions, a wide range of aldehydes and amines were converted into the desired heterocycles with yields ranging from 27% to 90%. 

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