Methyl enol ethers

As expected, heterocyclic enols and potential enols (i.e, compounds existing mainly in the CH form) behave toward diazomethane similarly to the open chain and isocyclic enols, i.e. they form enol methyl ethers by reactions of the SnI type (cf. footnote 29). Examples of this behavior are barbituric acid, picrolonic acid, dchydroacetic acid (64), 3-methyl-l-phenylpyrazolin-5-one, 1-phenylpyrazoli-dine-3,5-dione, 1,2-diphenylpyrazolidine-3,5-dionc, 3-hydroxy-... 

As discussed in Section III J, in general, catalytic asymmetric aldol reactions have been studied using enol silyl ethers, enol methyl ethers, or ketene silyl acetals as a starting material. So far several types of chiral catalysis have been reported.75-85 The chiral lanthanoid complex prepared from Ln(OTf)3 and a chiral sulfonamide ligand was effective in promoting an asymmetric Mukaiyama aldol reaction with a ketene silyl acetal.86 The preparation of the catalyst and a representative reaction are shown in Figure 45. 

Recent success was achieved in carrying out direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones [22]. No preconversion of the ketone moiety to a more reactive species such as an enol silyl ether or enol methyl ether is necessary. 

One-carbon homologation. The products 3) obtained by reaction of 2 with alkyl halides can be converted under mild conditions lo one-carbon homologated aldehydes, carboxylic acids, or enol methyl ethers. 

Methylation. Phenols are converted into methyl ethers by reaction with this reagent and ethyldiisopropylamine in CHjOH/CH.CN. Under the same conditions, readily enolizable ketones are converted into enol methyl ethers. 

Having developed an efficient catalytic asymmetric nitroaldol reaction, we next applied our attention to a direct catalytic asymmetric aldol reaction. The aldol reaction is generally regarded as one of the most powerful carbon-carbon bond-forming reactions. The development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis. In all these catalytic asymmetric aldol-type reactions, however, preconversion of the ketone moiety to a more reactive speeies such as an enol silyl ether, enol methyl ether or ketene silyl... 

Codeine [i] on heating in alcohol with [319-23] or without [324] acid, with [319-21] or without [322-4] hydrogen, in the presence of noble metal catalysts, undergoes rearrangement to dihydrocodeinone [xiv]. The yields claimed for the transformation are up to 95 per cent. [323], but Rapoport [304] was unable to obtain yields in excess of 50 per cent. Thebadnone-A [xxxvn] is a by-product in this reaction, and can be made the main product by modifying the conditions [325] (cf. the conversion of codeine methyl ether to thebainone-A enol methyl ether by sodium ethoxide). 

Catalytic or sodium and alcohol reduction of thebainone-A enol methyl ether [vi] affords a substance initially allotted the structure [ix] as it is different from an isomeric substance obtained by the catalytic reduction of dihydrotbebaine- >, at that time believed to be [n] [3]. It is now clear that this base is in fact dihydrothebainone A°-enol methyl ether [x] and is formed from [vi] by 1 4-addition of hydrogen to the conjugated system. The product of catalytic reduction of dihydrothebaine- must therefore be the isomeric AB-enol methyl ether [ix] produced by saturation of the 8 14-double bond of [iv]. Bentley, Robinson, and Wain [5] have in this way obtained a base different from that obtained by Small and Browning [3], but believe their product is the true dihydrothebainone-A5-enol methyl ether [ix] as it can also be prepared in 98 per cent, yield by the sodium and liquid ammonia reduction of dihydrothebaine [xi] [5]. 

Dihydrothebainone [xn] or its A6-enol methyl ether [x] is produced in considerable quantity in all reductions of thebaine even under mild conditions, and cannot arise from further reduction of dihydrothebaine. It undoubtedly arises from 1 6-reduction of the conjugated system to give thebainone-A enol methyl ether [vi], which then suffers further 1 4-reduction to dihydrothebainone A6-enol methyl ether [x], the latter boing hydrolysed in acid solution to dihydrothebainone [xn]. This mechanism was suggested by SchOpf and Winterhalder [14], but Small... 

Hydrolysis of dihydrothebaine methine [ix] affords dihydrocodeinone methine [xxi], which can be reduced catalytically to the dihydromethine [xix] or with aluminium amalgam to dihydrothebainone methine [xxn]. The nitrogen-free product of degradation of dihydrocodeinone methine [xxi] has not been isolated [3]. It was hoped to prepare the AB-enol methyl ether [xxm] of dihydrothebainone dihydromethine by the sodium and liquid ammonia reduction of dihydrothebaine methiodide, but only a complex mixture of products was obtained in this way. Sodium ammonia reduction of the methiodide of [vn] yielded only the original base, but [xxm] was finally obtained by the catalytic reduction of dihydrothebaine- dihydromethine [xxiv] [18]. 

When thebaine [i] is reduced by sodium and boiling alcohol [1-3], or best by sodium in liquid ammonia [4-5], scission of the 4 5-oxygen bridge occurs with the addition of two atoms of hydrogen and production of a phenolic dihydrothebaine, for which the name dihydrothe-baine-< has now been adopted [5]. The sodium-ammonia reduction is rapid, simple, and results in excellent yields of product. Reduction of thebaine with lithium aluminium hydride also yields a phenolic base, /3-dihydrothebaine, which is isomeric with dihydrothebaine- [6], Dihydrothebaine- was first allotted the structure [n] on the basis of its reactions [3], and 3-dihydrothebaine the structure [m] with the abnormal configuration at C-14 on the basis of its hydrolysis to ]S-thebainone-A [iv] [6] thebainone-A enol methyl ether [m] with the normal configuration at C-14, which results from the isomerization of codeine methyl ether [v] under the influence of hot sodium ethoxide, is known to give thebainone-A [rv, C-14 epimer] on hydrolysis [3]. 

Dihydro thebaine-< absorbs only one mole of hydrogen on catalytic reduction, yielding dihydrothebainone AB-enol methyl ether [ix], which is identical with the product of sodium and liquid ammonia reduction of the non-phenolic dihydrothebaine [x] [5]. (A compound of different melting-point and specific rotation was prepared by Small and Brown-ing [3] by the catalytic reduction of dihydrothebaine-< and allotted the structure [xi] owing to a misconception of the structure of the latter. It is probably a mixture [5].) Dihydrothebainone [xn] is produced by the hydrolysis of [ix] showing that no rearrangement of the thebaine skeleton occurs during sodium and alcohol reduction [5]. 

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]. 

Thebainone-A enol methyl ether [m] can be reduced catalytically or with sodium and alcohol to dihydrothebainone A6-enol methyl ether [xi] [3, 12] (erroneously given the A5 structure [rx] at first [3]) and from the catalytic reduction dihydrothebainol-6-methyl ether, identical with the compound obtained from /3-dihydrothebaine, is also obtained [12]. The fact that tliebainono-A onol methyl other and /3-dihydrothebaine... 

Thebainone-A enol methyl ether gives thebainone-A on hydrolysis so readily that no salts of the enol ether can be prepared even in anhydrous media [3]. 

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],... 

Thebainone-A can also be prepared by the catalytic rearrangement of codeine [vi] under the influence of palladized charcoal at 80° C. [2] by the hydrolysis of thebainone-A enol methyl ether [vn] (prepared by the rearrangement of codeine methyl ether on heating with sodium ethoxide) [3] by the hydrolysis of /j-ethylthiocodide [vm] (obtained by the action of sodium ethoxide on bromo- or /3-chlorocodide) [4-8] (see Chap. XVII) and, in small amount, by the hydrolysis of dihydrothe-baine- [iv] [3]. 

No enol ether of /3-thebainone-A epimeric with thebainone-A enol methyl ether [vn] has been prepared /3-dihydrothebaine was first thought to be such a compound [16] but subsequently was shown to have the structure [hi] [17]. 

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