Alcohols methylation with diazomethane

Surface oxides on graphite undergo the reactions typical of carboxylic acids, phenols and alcohols. Methylation with diazomethane or dimethylsulfate, silanization of—OH groups by reaction with halosilanes, formation of acyl chlorides by reaction with thionyl chloride, further reactions of these acyl chlorides, neutralization of acidic surface groups with different bases, ion exchange and more special reactions are used to characterize surface oxides on carbon and to modify their properties for technical applications . 

Dihydromorphinone, Cj,Hjg03N, and derivatives. Dihydromorphinone (LIII MeO HO) is formed when morphine in solution is treated with relatively large quantities of platinum or palladium catalyst under various conditions.It melts at 262-3° and yields an oxime, m.p. > 234°. The hydrochloride is the drug known as dilaudid. On 0-methyla-tion dihydromorphinone yields dihydrocodeinone (see above), and when dissolved in ether and treated with methyllithium the corresponding tertiary alcohol, 6-methyldihydromorphine, CigHggOgN, m.p. 209-211°, Wd ° 14i7° (EtOH), is formed. This on methylation with diazomethane gives 6-methyldihydrocodeine as described above (Small and Rapoport... 

GC analysis of underivatized polar fractions did not reveal any volatile sulfur compounds. However, once these fractions were methylated with diazomethane, a number of sulfur compounds were detected. (Presumably, the diazomethane methylated either carboxylic acid, phenolic, thiophenolic, sulfonic acid or even alcohol or thiol groups and thereby increased their parent molecules volatility). These additional sulfur compounds are currently under investigation in our laboratories and the results of these studies will be reported later. 

Alcohols can be O-methylated with diazomethane in the presence of a protic acid such as fluoroboric acid 210 Meerwein and Hinz211 showed that zinc chloride was an effective catalyst in 1930 and trifluoroborane later found favour 212 An alcohol adsorbed onto neutral silica gel undergoes O-methylation213 and the method can be used on a moderate scale [Scheme 4.117]214 though the perils of preparing diazomethane on a moderate scale must be the cause of some trepidation When tin(Il) chloride is used as the catalyst selective mono-0-methyla-tion of a l 2-diol can be achieved [Scheme 4 118] 215... 

Similar oxidation of nororixine, followed by borohydride reduction and methylation with diazomethane, gives the alcohol LXXII, which can also be obtained by the action of alkali on dihydrokokusagine methiodide (LXXIII) (see Section IV,B,2). 

Isotetrandrine, a crystalline base obtained from the alcoholic extract of Stephania cepharantha, is identical with 0-methylberbamine and must therefore have the structure XXX (23, 35, 126, 127, 132). A two-stage Hofmann degradation of the methiodide of isotetrandrine yielded des-V-isotetrandrine (m.p. 220°), which did not depress the melting points of des-V-berbamine methyl ether. Final proof of the relation of these two alkaloids lies in the fact that berbamine methylated with diazomethane... 

An interesting case of an alcohol reacting with diazomethane at a rate competitive with a carboxylic acid has been reported (eq 15). In this case, the tertiary structure of the molecule is thought to place the alcohol and the carboxylic acid in proximity to each other. Protonation of the diazomethane by the carboxylic acid leads to a diazonium ion in proximity to the alcohol as well as the carboxylate. These species then attack the diazonium ion at competitive rates to provide the methyl ether and ester. No reaction is observed upon treatment of the corresponding hydroxy ester with diazomethane, indicating that the acid is required to activate the diazomethane. 

The synthesis of bixin (533) requires the regiospecific introduction of a Z double bond. Attention was first focused on the total synthesis of (all- )-methylbixin (534) [35]. (3-Methylepichlorohydrin (180) was treated with sodium acetylide (68) to give the alcohol 181 which was transformed with dihydropyran and phosphorus oxychloride to the acetylenic compound 182. Condensation of two moles of 182 with oct-4-ene-2,7-dione (5) in the presence of PhLi resulted in the C2o-diol 183. Treatment with p-toluenesulphonic acid first in toluene gave the diether 184 and afterwards in ethanol led to the diol 185, which was oxidized with Mn02 to the dial 186. The Knoevenagel condensation with malonic acid (187) and methylation with diazomethane gave the diester 188, which was hydrogenated in the presence of Lindlar catalyst and isomerized with iodine to (all- )-methylbixin (534) in an overall yield of 0.04% referred to 180 (Scheme 41). 

Bisnorargemonine, C19H21O4N (mp 254°) from Argemone and Esch-scholtzia species has two phenolic hydroxyls and on methylation with diazomethane is converted to argemonine. Its hydroxyls are vicinal as indicated by its NMR-spectrum and by the intense color that it gives with alcoholic ferric chloride, and therefore its structure is known (87). 

Alkylation of A-4-thiazoline-2-one may yield O-R or N-R derivatives according to experimental conditions. With diazomethane in ethanol O-raethylation takes place (29. 36. 214). N-Methylation is reported when a basic solution of A-4-thiazoline-2-one reacts with methyl iodide or dimethylsulfate (21, 29, 215, 216), Reaction of l-chloro-2-dimethyl-aminoethane with the sodium salt of 4 R-A-4-thiazoline-2-one (91) in alcohol, first claimed to yield the aminoalkylether (217, 218), was shown after infrared investigation to give the N-substituted derivative (92) (107), even when R Ph (Scheme 45). More probably the site of reaction in... 

Thus, the acidity oi a lactam is evidently not a reliable quantity for predicting the course of the methylation. The acidity gives information only as to the reaction velocity. In this connection the reaction course of isomethylreductone (6) is illuminating, " With diazomethane in ether containing 1 mole of water, the enolraethyl ether (7) is formed. However, if water is present only in traces, then the alcoholic hydroxyl group is selectively attacked to give 8. 

The above keto-nitrile (15 grams) was methylated with a solution of diazomethane in ether. (The diazomethane solution was prepared using 20 grams of N-nitrosomethylurea.) The ether and excess diazomethane were evaporated on the steam bath and the oil dissolved in ethanol (50 ml). To this was added a solution of guanidine in ethanol (100 ml) (prepared from 8.1 grams of the hydrochloride). The solution was refluxed for 5 hours, the alcohol removed and the residue treated with 5N sodium hydroxide. The insoluble material was then filtered. After purification by precipitation from dilute acetic acid with sodium hydroxide and by recrystallization from ethanol the product formed clear colorless needles (8.0 grams), MP 218°-220°C as described in U.S. Patent 2,602,794. 

Although the biosynthetic cascade hypothesis predicts the co-occurrence of endiandric acids D (4) and A (1) in nature, the former compound was not isolated until after its total synthesis was completed in the laboratory (see Scheme 6). Our journey to endiandric acid D (4) commences with the desilylation of key intermediate 22 to give alcohol 31 in 95% yield. The endo side chain is then converted to a methyl ester by hydrolysis of the nitrile to the corresponding acid with basic hydrogen peroxide, followed by esterification with diazomethane to afford intermediate 32 in 92% overall yield. The exo side chain is then constructed by sequential bromination, cyanide displacement, ester hydrolysis (33), reduction, and olefination (4) in a straight-... 

---