Dihydrobenzenes in organicsynthesis

Abstract

The thesis entitled “Dihydrobenzenes in Organic Synthesis” consists of three chapters.

Chapter I Chapter I deals with a brief introduction to the addition of electrons to unsaturated systems, in particular monobenzenoid compounds, ?,??unsaturated ketones and styrenes, using metal–ammonia solutions. The mechanism of reduction and the stereochemical factors involved in such reduction processes have been discussed. The dihydrobenzenes, obtained by the reduction of aromatic substrates by metals in liquid ammonia, have been extensively used in the stereospecific synthesis of natural products, and some of these synthetic applications of dihydrobenzenes have been reviewed.

Chapter II Chapter II deals with the synthesis of a variety of substrates, including some natural products, using dihydrobenzenes, and is divided into four parts. Part 1 Part 1 contains the results of investigations on the alkylations of mesomeric anions obtained from dihydrobenzenes with potassium amide in liquid ammonia, resulting in a simple and efficient synthesis of 2?alkyl?, 2,3?dialkyl?, and 2,4?dialkylcyclohex?2?en?1?ones. Thus, alkylation of 1?methoxycyclohexa?1,4?diene with alkyl halides in the presence of potassium amide in liquid ammonia afforded the 6?alkyl?1?methoxycyclohexa?1,4?dienes, which are readily hydrolysed to the corresponding 2?alkylcyclohex?2?en?1?ones. Similar alkylations of

1,5?dimethoxycyclohexa?1,4?diene, 1?methoxy?5?methylcyclohexa?1,4?diene, and 1?methoxy?4?methylcyclohexa?1,4?diene

with potassium amide in liquid ammonia afforded the 6?alkylated cyclohexadienes, which were hydrolysed to the corresponding 2?alkyl?, 2,3?dialkyl?, and 2,4?dialkylcyclohex?2?en?1?ones in good yield.

Part 2 Part 2 describes an alternative total synthesis of stemphol (1) and isostemphol (2). Stemphol, 2?n?butyl?5?n?pentylresorcinol, has been isolated from the mould Stemphylium majusculum. Its structure was deduced from mass spectral data and confirmed by synthesis. A simple synthesis of stemphol has been achieved using a cycloaddition reaction involving the diene (3) and the dienophile (4). The diene (3) was obtained by alkylation of 1,5?dimethoxycyclohexa?1,4?diene with n-butyl bromide and potassium amide in liquid ammonia. Reaction of this diene with dienophile (4), prepared from n-propargyl alcohol, afforded an adduct which spontaneously aromatised to the aldehyde (5). Decarbonylation of (5) with tris(triphenylphosphine)rhodium chloride, followed by demethylation, afforded stemphol, identical with the authentic sample. Similarly, isostemphol (2) was obtained from cycloaddition of diene (6)—prepared by n-pentyl alkylation of 1,5?dimethoxycyclohexadiene—with dienophile (7). The adduct aromatised and, after decarbonylation and demethylation, furnished isostemphol (2), confirming its structural difference from stemphol.

Part 3 Part 3 deals with the synthesis of a sex pheromone, (Z)?heneicos?6?ene?11?one (8), a C?? ketone isolated from the Douglas fir tussock moth Orgyia pseudotsugata. 2?n-Pentylcyclohex?2?en?1?one (9), prepared by n-pentyl alkylation of 1?methoxycyclohexa?1,4?diene followed by acid hydrolysis, was converted to the acetylenic aldehyde (10) via its epoxide and tosyl hydrazone. Addition of n-decylmagnesium bromide to aldehyde (10), followed by further transformations, afforded the sex pheromone. In an alternative method, 2?n-pentyl?3?n-decyclohex?2?en?1?one (11) was converted to the acetylenic ketone (12).

Part 4 Part 4 describes the total synthesis of the methyl ester of acoric acid, an antiepileptic compound isolated from Acorus calamus. Although acoric acid (13) has been synthesised earlier, this method differs in that it involves the Michael addition of anions generated by metal–ammonia reduction of benzoic acids. The conditions for addition of methyl acrylate and methyl crotonate to mesomeric anions generated from lithium–ammonia reductions of benzoic acid, 4?methoxybenzoic acid, and 3?methoxybenzoic acid have been investigated. Reduction of 4?methyl?3?methoxybenzoic acid with lithium in liquid ammonia, followed by addition of methyl crotonate, afforded compound (16), which was transformed into methyl acorate (14).

Chapter III Chapter III describes investigations toward the total synthesis of 11?desoxyprostaglandins. Two routes were examined based on the aromatic precursors 5?methoxyindan?1?one and 6?methoxy?2?acetylnaphthalene. The preparation of an important intermediate (17) for the synthesis of desoxyprostanic acids is described.