Open reaction with aromatic hydrazine

Scheme 9.31. Reaction of open-cage C ) derivative 51 with aromatic hydrazines.

Aluminum chloride [7446-70-0] is a useful catalyst in the reaction of aromatic amines with ethyleneknine (76). SoHd catalysts promote the reaction of ethyleneknine with ammonia in the gas phase to give ethylenediamine (77). Not only ammonia and amines, but also hydrazine [302-01-2] (78), hydrazoic acid [7782-79-8] (79—82), alkyl azidoformates (83), and acid amides, eg, sulfonamides (84) or 2,4-dioxopyrimidines (85), have been used as ring-opening reagents for ethyleneknine with nitrogen being the nucleophilic center (1). The 2-oxopiperazine skeleton has been synthesized from a-amino acid esters and ethyleneknine (86—89). 

The pyrazole ring is particularly difficult to cleave and, amongst the azoles, pyrazoles together with the 1,2,4-triazoles are the most stable and easiest to work with. This qualitative description of pyrazole stability covers the neutral, anionic and cationic aromatic species. On the other hand, the saturated or partially saturated derivatives can be considered as hydrazine derivatives their ring opening reactions usually involve cleavage of the N—C bond and seldom cleavage of the N—N bond. It should be noted, however, that upon irradiation or electron impact the N—N bond of pyrazoles can be broken. 

Fischer1-2 decided that the mode of formation, the reactions with hydrazines, aromatic diamines, and oxidizing agents, and the reduction to D-fructose could be explained by attributing to the open-chain form of D-glucosone the a-ketoaldehyde structure L. 

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. 

A noteworthy difference is observed in the condensation of thiosemicarbazide with aromatic a-halocarbonyl compounds in comparison to aliphatic a-halocarbonyl compounds. It has been found26 that the reaction of phenacyl bromide with thiosemicarbazide furnishes 5-phenyl-1,3,4-thiadiazin-2-amine together with a small amount of 5-phenylthiazolc-2-hydrazine, Similarly, the reactions of thiosemicarbazide with 2-bromo-l,2-diphenylethan-l-one,7 8,41 2-bro-mo-l-phenylpropan-l-one,10,41 and 2-bromo-l-phenylbutan-l-one 10,41 in ethanolic solution give 1,3,4-thiadizines. However, the main products are the thiazole-2-hydrazine derivatives (cf. Houben-Weyl, Vol. E8b, p 72ff). The addition of an equimolar amount of 48% hydro-bromic acid results in the exclusive formation of the 1,3,4-thiadiazines 2 a, c, and d. When the condensations of thiosemicarbazide with 2-bromo-l,2-diphenylethan-l-one, 2-bromo-1-phenylpropan-l-one or 2-bromo-l-phenylbutan-l-one are performed in ethanol at room temperature, the S-(oxoalkyl)-isothiosemicarbazide hydrobromides are formed as open-chain intermediates and also undergo cyclization in ethanol upon addition of an equimolar amount of 48% hydrobromic acid to furnish 2 a, c, and d. 

Indoloquinoxaline 693 was obtained in 83-90% yield by irradiating a mixture of isatin with o-phenylenediamine in acetic acid in an MW oven in either an open flask or closed Teflon vessel for 1-2 min. Carbethoxymethylation of isatin with ethyl chloroacetate in the presence of K2CO3 and Nal was carried out under MWI to give compound 694 in 70% yield within 4min. It could be converted into 695 by reaction with o-phenylenediamine in acetic acid in either an open flask (2 min) or closed Teflon vessel (Imin) (Scheme 134). Alternatively, carbethoxymethylation of 693 under MWI for 6 min afforded a 53% yield of 695. Reaction of 695 with hydrazine hydrate in ethanol under MWI gave the hydrazide 696 in 84% yield. MWI has been also used to condense 696 with aromatic aldehydes and monosaccharides to yield the hydrazone derivatives 697 in 58-99% yields (Scheme 134) (05JCR(S)299). 

Miscellaneous Reactions. Aromatic sulfonic acid derivatives can be nitrated using nitric acid [52583-42-3] HNO, ia H2SO4 (19). Sultones may be treated with hydrazine derivatives to give the corresponding ring-opened sulfonic acid (20). 

Oxazinium and -thiazinium cations are 67r-aromatic systems which readily react with nucleophiles at C-6. Ring opening is normally followed by recyclization so that a variety of heterocyclic systems are then formed. The behaviour of the oxygen and sulfur compounds are almost identical and so, as the latter are usually prepared from the former, it is not surprising that most attention has focussed on the reactions of 1,3-oxazinium species (72S333). These versatile synthons react with ammonia, for example, to give pyrimidines, while hydrazines afford pyrazoles and hydroxylamine produces isoxazoles (Scheme 20). 

When the nucleophile has hydrogen atoms, e.g., with ammonia, primary amines, hydroxylamine, hydrazine derivatives, phosphine, hydrogen sulfide, nitromethane (EWG = NO2), acetonitrile (EWG = CN), an ANRORC (attack by nucleophile, ring opening, ring closure) reaction results in the conversion of substituted pyrylium salts into a large variety of six-membered aromatic carbocyclic or heterocyclic compounds. 

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