THE REDUCTION OF THEBAINE

The first reduction of thebaine [i] was achieved by sodium and boiling alcohol and resulted in the production of a phenolic dihydrothebaine in only moderate yield [1-3]. The same compound, now called dihydro-thebaine-, is more conveniently prepared in yields of up to 95 per cent, by the reduction of thebaine with sodium in liquid ammonia without the addition of alcohol [4-5]. 

Dihydrothebaine- was originally given the structure [n], which was in accord with most of its chemical properties [3-4] except its failure to condense with benzoquinone or maleic anhydride and its failure to yield a derivative of 14-bromothebainone [iii] on treatment with bromine [5], However, the production of a conjugated diene as final product in a sodium-alcohol or sodium-ammonia reduction is contrary to general experience and examination of the infra-red and ultra-violet absorption spectra of dihydrothebaine-, thebaine, /3-dihydrothebaine, several 1 4-dihydroanisole derivatives, and 1-alkoxy-l 3-dienes led to modification of the structure of dihydrothebaine- to [iv] [6], which structure is more in accord with its properties than is [n], and in particular explains why the hydrogenation of this base proceeds with absorption of only one mole of hydrogen (see Chap. XIV). 

Dihydrothebaine- must arise from thebaine by addition of two electrons to the system —0—CH—CH=C— to give the transient ion [v], which immediately adds a proton from the ammonia to give the anion of [rv]. 

An isomer of dihydrothebaine- is obtained by the reduction of thebaine with lithium aluminium hydride [7] and was called by its discoverers /3-dihydrothebaine, although it bears no relationship to the truo, non-phenolic, dihydrothebaine (see below). It was originally thought to bo a diasterooisomor, differing only at C-14, of thebainone-A onol methyl other [vx] (prepared by the isomerization of oodoine methyl 

Examination of the infra-red and ultra-violet absorption spectrum of /3-dihydrothebaine indicated that it has in fact the structure [n] initially allotted to dihydrothebaine- [6]. Such a conjugated diene would be expected to imdergo 1 4-addition of hydrogen with final production of [vm], a reduction parallel to the production of tetrahydrothebaine from thebaine (see below). 

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Thebainone (Schopf), CigHjjOgN. This substance, which must be distinguished from Pschorr s thebainone (metothebainone of Schopf (see p. 248) ), is formed, along with the latter in the reduction of thebaine by stannous chloride in hydrochloric acid, and was isolated by Schopf and Hirsch. Its prior isolation by Pschorr, as confirmed by Morris and Small, has been referred to already. It crystallises with 0-5 HjO, has m.p. 151-2°, yields a hydriodide, m.p. 258-9°, methiodide, m.p. 223°, and an oxime, m.p. 185-6°. On catalytic hydrogenation it yields dihydrothebainone (LI), and can be degraded to 3 4 6-triacetoxyphenanthrene, m.p. 165-7°. On this basis formula (XLIX) is assigned to it. The mechanism of the formation of codeinone, thebainone and mefathebainone from thebaine is discussed by Schopf and Hirsch. ... 

Further work by Schopf and Borkowsky [86] indicated the need for modification of the structure with attachment of the side-chain at C-14 in metathebainone [lvih], which is formed by the reduction of thebaine with stannous chloride in concentrated hydrochloric acid [27], The true thebainono [lix] was later isolated from the stannous chloride reduction under difforont conditions. Metathebainone arises as a result of rearrangement of thebaine in concentrated hydrochloric acid, now believed to involve the intermediate [i.x], which is also believed to be common to the morphothobaino and thobouino transformations [88-80J. (Hoc Chap. XXV,)... 

Dihydro-electrolytic reduction of desoxycodeine-C [xv] to dihydro-desoxycodeine-B [lxxiv], and dihydro-i/r-codeine-C the structure [lxxhi] by analogy with the sodium and alcohol reduction of desoxycodeine-C to dihydrodesoxycodeine-C [lxxv] sodium and alcohol reductions have a known tendency to effect 1 4 addition of hydrogen to an allylic ether [248, 281, 423]. (Cf. the reduction of thebaine [lxxvii] to dihydrothebaine-< [lxxvih] [265, 405, 424].)... 

The reduction of thebaine and the chemistry of its reduction products are dealt with in Chapters XII, XIII, XIV, XV, and XVI. 

S-Dihydrothebaine [n] absorbs two moles of hydrogen on reduction over platinum oxide, the product being dihydrothebainol-6-methyl ether [xm] [6], identical with the compound obtained in the reduction of thebaine in neutral solution [3]. The configuration at C-14 in [xm] is not known. A dihydro-derivative, dihydrothebainone A6-enol methyl ether [xi], can also be isolated from the products of reduction [12]. 

The reduction of thebaine methiodide with sodium in liquid ammonia leads to dihydrothebaine- dihydromethine [xxx], also accessible by the reduction of dihydrothebaine- methiodide the methyl ether can be prepared in the same way from dihydrothebaine methyl ether methiodide. [xxx] can be hydrolysed by mineral acids to the-bainone-B dihydromethine [xxxi], and reduced with difficulty to dihydrothebainone dihydromethine AB-enol methyl ether. Its methiodide on reduction with sodium and ammonia yields 4-hydroxy-3 6-dimethoxy-13-ethyl-7 13 9 10-tetrahydrophenanthrene [Xxxii] and on alkaline degradation gives A6,8-6-methoxythebendiene [xxxm] [11],... 

This enol ether [xxxi] is the product of catalytic or sodium amalgam reduction of thebainone-A enol methyl ether [vn] [3], from which it arises by 1 4-addition of hydrogen to the conjugated system, and it can also be prepared by the hydrogenation of thebaine in neutral solution [3]. It is very readily hydrolysed to dihydrothebainone, which doubtless arises from this during the reduction of thebaine in acid solution. (Dihydrothebainone was prepared by Speyer and Ereunds [10] by the reduction of thebaine in neutral solution and no doubt arose from the enol ether by hydrolysis during the isolation of the product.)... 

The reduction of thebaine with lithium aluminium hydride has been reexamined, and in the presence of aluminium chloride conditions have been found to give either thebainone-A enol methyl ether or neodihydrothebaine as the main product. Also obtained was a new base, isometathebainone enol methyl ether (86), identified by hydrolysis to isometathebainone (87), which gives... 

Further work on the reduction of thebaine by chemical means has been published since Chapter 8 of Volume II was written. This supports the conclusions outlined previously (Vol. II, pp. 199-203), (402, 403). A careful search of the mother liquors from the commercial hydrogenation of thebaine has led to the isolation of about 1 % of neopine methyl ether (CCCLIII) (404). It is, of course, possible that more of this substance is formed than can be isolated since most of it might well be reduced further to tetrahydrothebaine which is also produced in the reduction. 

Patent details have been published, covering the preparation of neopinone from thebaine by a route previously reported (Volume 8, p. 113). Mercuric acetate reacts with thebaine in methanol to give 7-hydroxymercurineopinone dimethyl ketal (145 R = Me, M = Hg, X = OH), which can be converted into neopinone by treatment with acetic acid. The patent also covers the preparation ofothercompoundsof general structure (145), where R = alkyl, M = Hg,Pd,or Pt, and X = OAc, OCOPh, Br, or Cl. Conditions for the reduction of thebaine to /3-dihydrothebaine (146) in good yield by potassium and liquid ammonia have... 

The reduction of thebaine to mixtures of /3-dihydrothebaine and dihydrothe-baine-< with potassium, calcium, and lithium in liquid ammonia has been studied. 

The intimate details of the conversion of thebaine to codeine has also been worked out . Thebaine (II) is demethylated to a postulated tautomeric mixture of neopinone (III) and codei-none (IV) followed by reduction to codeine (V). Although the opium poppy is capable of demethylating codeine methyl ether, the plant apparently does not use this route and the reported isolation of this compound is attributed to the reduction of thebaine in the isolation and purification processes. ... 

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