Epoxides reaction with hydrazine

The azidohydrins obtained by azide ion opening of epoxides, except for those possessing a tertiary hydroxy group, can be readily converted to azido mesylates on treatment with pyridine/methanesulfonyl chloride. Reduction and subsequent aziridine formation results upon reaction with hydrazine/ Raney nickel, lithium aluminum hydride, or sodium borohydride/cobalt(II)... 

The successful synthesis of 2-thienyl and substituted 2- and 3-thienyl-acetylenes in yields as high as 60-80% opened a wide variety of synthetic applications. Various addition reactions with carbonyl compounds or epoxides could be carried out with ease. Aliphatic as well as aromatic amine addition reactions, or condensation reactions with hydrazine or hydroxylamine could be easily performed. 

The potential of such reaction sequences for the generation of molecular diversity was also demonstrated by the synthesis of a library of heterocycles. Epoxide ring-opening with hydrazine and subsequent condensation with (3-diketones or other bifunctional electrophiles gave rise to a variety of functionalized heterocyclic structures in high purity [34]. A selection based on the substrate derived from cyclohexene oxide is shown in Scheme 12.12. 

Pyrazoles were synthesized in the authors laboratory by Le Blanc et al. from the epoxy-ketone as already stated in Sect. 3.1.1a, Scheme 35 [80]. The synthetic strategy employed by Le Blanc et al. [80] was based upon that the strategy published by Bhat et al. [81] who also described the synthesis of pyrazoles but did not report cytotoxic evaluation on the synthesized compounds. Scheme 48 shows the synthesis of the most active compound (178). Dissolution of the epoxide (179) with a xylenes followed by treatment with p-toluenesulfonic acid and hydrazine hydrate produced the pure nitro-pyrazole 180 in good yield (60%). Catalytic hydrogenation with palladium on activated carbon allowed the amino-pyrazole (178) to be obtained in a pure form. This synthesis allowed relatively large numbers of compounds to be produced as the crude product was sufficiently pure. Yield, reaction time, and purification compared to reported approaches were improved [50, 61, and 81]. Cytotoxicity of these pyrazole analogs was disappointing. The planarity of these compounds may account for this, as CA-4, 7 is a twisted molecule. 

Five-membered heterocycles have been used as substitutes for the y-lactone ring of cardenolides. Thus, the 17 -(5 -isoxazolyl)- and 17)8-(3 -pyrazolyl)-cardenolides (526) and (527) have been prepared from 20-ethoxy-21-formyl-3 -acetoxy-17)8-pregna-5,14,20-triene (528) by reaction with hydroxylamine and hydrazine hydrate, respectively. The isomeric 14a,15a- and 14) ,15/S-epoxides (529) and (530) in both series were then obtained by peracid treatment or alkaline cyclization of the respective 14,15-bromohydrin. 

Methyl urazol 225 is oxidized into iV-methyl triazoline-3,5-dione with tert-butyl hypochlorite. Without isolation it reacts with ( )-penta-2,4-diene-l-ol giving adduct ( )-226 as a racemic mixture. On treatment of ( )-226 with a lipase (R/Novozym 435) in vinyl acetate 38% of ester (5)-227 (86% ee) and 29% of alcohol R)-226 (59% ee) is isolated. Epoxidation of (S)-227 provides 13% of (—)-228 and 68% of (—)-229. The latter epoxide is hydrolyzed under acidic conditions to provide 230 that reacts with hydrazine to give enantiomerically pure (—)-l-azafagomine (O Scheme 80) [394]. This compound has a slow binding inhibitor of almond /3-glucosidase Ki = 0.33 pM). A similar sequence of reactions converts (R)-226 into (+)-l-azafagomine. The latter is not an inhibitor of 8-glucosidases [395]. 

Verbanone and its derivatives are normally made by oxidation of a-pinene [usually (+ )-116] when Takayanagi and Nishino required (— )-trans-verbanone (822), they used a synthetic procedure starting from (+ )-apoverbenone [(+ )-823] accessible from the ( —)-p-pinene series. The Wharton reaction (hydrazine hydrate) with the (trons)-epoxide of 823 yields 824, which can be oxidized to (— )-apoverbenone [( —)-823], from which 822 was obtained by reaction with lithium dimethyl cuprate. [This work was actually to prepare verbanyl acetates, the (l/ ,2/ ,5/ )-series of which notably ( + )-825 is active as pheromone mimics in the cockroach Periplaneta americana, while the (15,2S,5S)-series from 822 are inactive. 

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