A-Methoxylation

Generation of an anion at the 3-position of certain 2-methoxyisoxazolidines leads to loss of the A-methoxyl group (Scheme 92) (79T213). 

Floripavidine, CjjHjgOjN. This occurs in the crude mixture of non-phenolic bases, and is separated from fioribundine by repeated crystallisation of the mixed hydrochlorides from water. The base crystallises from alcohol in prisms, has m.p. 241-2°, and [a]n — 156-25° (MeOH) the hydrochloride, m.p. 209-10°, hydriodide, and methiodide, m.p. 228-30°, were prepared. The alkaloid contains no hydroxyl group (Zerewitinoff), but a methoxyl, a dioxymethylene, and a methylimino group are present. 

These results indicate that quinine and quinidine differ in structure from cinchonine and cinehonidine in containing a methoxyl group in position 6 in a quinoline nucleus. The identity of the other oxidation products, meroquinenine, cincboloiponic and loiponic acids, in all foiu" cases indicates that the second half of the molecule has the same structure in all four alkaloids. Further, this second half must be joined to the quinoline nucleus at position 4 by a group capable of conversion into carboxyl. 

Each contains a methoxyl and a methylimino group and gives a dihydroderivative. The chief difference between them seems to be that although each ca,n be demethylated by heating with hydrobromic acid, (I) yields... 

The location of a methoxyl group at position 4 in ring A was proved indirectly by Windaus, whence it follows that the three vicinal methoxy groups in that ring must occupy positions 2-, 3- and 4-. The positions of all four methoxyl groups in colchicine were later clearly settled by Barton, Cook and Loudon (p. 653). 

Cevadine contains neither a methoxyl nor a methylimino group it yields crystalline benzoyl and o-nitrobenzoyl derivatives, m.p. 255° and 236° respectively, and a methiodide, which decomposes at 210-2°, and is converted by silver oxide into eevadinemethylhydroxide.i When warmed with alcoholic soda, cevadine undergoes hydrolysis into eevine and angelic and tiglic acids. When hydrogen chloride is passed into cevadine in alcohol, ethyl tiglate and eevine are formed. ... 

The most interesting product arising from more drastic degradation experiments is a base, C Hi ONa, m.p. 115-120°, obtained by distilling mitragynine with zinc dust. It contains a methoxyl and a methylimino group, and has a reactive methylene group, since it forms a p-nitrobenzyl-idene derivative, m.p. 255°. This base closely resembles both ind- and jM/r-iV-methylharmine, but is not identical with either. 

Both alkaloids contain a hydroxyk group and a tertiary nitrogen but neither a methoxyl nor a methylimino group. Each contains one ethylenic linkage and hydrogenates to an oily dihydro-derivative dihydro-a-nupharidine gives a hydrochloride, m.p. 240-2°, and a picrate, m.p. 190-2° dihydro- -nupharidine hydriodide melts at 279-280°. 

On distillation with zinc dust the alkaloid gives an easily hydrogenated pyrrole base, and on dehydrogenation by platinised asbestos at 260-290 it yields (1) an amorphous dehydro-base, which forms an oxime and a methiodide, C17H23O4N. Mel, decomp. 227-8 , and contains a lactone and a methoxyl group, (2) a neutral pyrrole derivative, and (3) an acid giving a dark green colour with ferric chloride (1939). 

No molecular-ion peak is observed from either isomer. The loss of a methoxyl group to give m/e 131 is shown in Equation 16 to be from the C—1 position, on the basis of analogy to reported studies using per-O-methylated sugars with a methoxyl-d3 substituent on C-l (24). 

Boron tribromide cleaved a methoxyl group (e.g., 79 - 80) (Scheme 19) (65) as well as a methylenedioxy group (66). Tetrahydroberberine (26) was converted to tetrahydrocoptisine (82) by treatment with boron tribromide and subsequent methylenation (67). 

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