Methylation, diazomethane

Ethyl 6,7-diaryl-3-hydroxy-2-oxo-2,5-dihydro-l//-azepine-4-carboxylates, e.g. 20, with diazomethane methylate solely at the 3-hydroxy group, whereas with Meerwein s reagent the 7-ethoxy-4/7-azepines, e.g. 21, are formed.48... 

Dialkylation occurs if a stronger base (NaOH) and dimethyl sulfate is used. Entry 18 is a typical diazomethane methylation of a carboxylic acid. The toxicity of diazomethane... 

Table 10. Methoxyl Content of Diazomethane Methylated Native and Enzymatically...

The BBrs reaction with 1. l-dimethoxy-2.4.6-di-tert-butyl-4-(4 -methoxyphenyl)-X -phosphorin 200 leads to cleavage of both methoxy groups in addition to the methoxy group at the phosphorus, the 4 -methoxy group is attacked. The 2-hydro-4-(4 -hydroxyphenyl)-phosphinic acid methyl ester 201 can be methylated with methyl iodide in methanol/sodium methylate at the phenolic group, leading to 202, which can also be prepared by hydrogen peroxide oxidation of 2.6-di-tert-butyl-4-(4 -methoxy phenyl)-X -phosphorin 204 to 203, followed by diazomethane methylation (see Table 13, p. 61). 

In general, hydroxy groups on fused benzene rings undergo the expected reactions. O-Methylation is effected by diazomethane, methyl iodide or dimethyl sulfate. O-Alkylation is reversed by aluminum trichloride or tribromide in benzene or nitrobenzene. 

Attempts to alkylate the 4-hydroxy-l,2,4-triazoles 535 with Mel, Me2S04, or PhCH2Br using different bases and solvents invariantly gave difficult to separate mixtures. However, diazomethane methylated 535 to 534 together with the O-methylated isomer in a 1 2.2 ratio from which the pure N-oxide 534 could be isolated. Acylation of 535 with PhNCO gave the N-oxide 536 (1972JPR101) (Scheme 159). 

One of the several alkaloids from Gyrocarpus americanus Jacq. (Hemandiaceae) is gyroamericine (479), C37H40N206, mp 210°C (MeOH), [a]D -238° (c 1, CHC13). Diazomethane methylation furnished (—)-phaeanthine (184), the principal alkaloid of G. americanus. Placement of the lone OH group was by NMR data (tabulated for this and related alkaloids) (558). 

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. 

An alternative approach applicable both to the synthesis of racemic aspergillic acid428 and neoaspergillic acid is illustrated by the synthesis (Scheme 50) of neoaspergillic acid (8).429 The initial reaction of dl-leucine anhydride (235) with phosphoryl chloride produces, in addition to the required monochloro compound (236), some dichloro compound (237), and flavacol (4). Reaction of the latter compound with a mixture of phosphoryl chloride and phosphorus pentachloride yields further 2-chloro-3,6-diisobutylpyrazine (236). The remaining steps of the synthesis involve reactions discussed previously in this review, with the exception that the hydroxamic function is protected by diazomethane methylation and finally regenerated by ethanolic hydriodic acid treatment.429... 

Diazomethane methylates carboxylic acids because carboxylic acids readily protonate it, giving an extremely unstable diazonium cation. This compound is desperate to lose N2, the world s best leaving group, and so it does, with the N2 being substituted by the carboxylate anion. The carboxylate anion is in exactly the right position to carry out an S 2 reaction and that is what we have drawn. 

Diazomethane methylation is a good way of making methyl esters from carboxylic acids on a small scale because yields are excellent and the only by-product is nitrogen. However, there is a drawback diazomethane has a boiling point of-24°C, and it is a toxic and highly explosive gas. It therefore has to be used in solution, usually in ether the solution must be dilute, because concentrated solutions of diazomethane are also explosive. It is usually produced by reaction of N-methyl-N-nitrosourea or N-methyl-N-nitrosotoluenesulfonamide with base, and distilled out of that reaction mixture as an azeotrope with ether, straight into a solution of the carboxylic acid. 

Pyromellitic acid tetramethyl ester, mp 142-143 °C, prepared by diazomethane methylation of pyromellitic acid, is used as the internal standard and is stored as a dichloromethane solution (—1 mg/ml) in a freezer. (Any loss of solvent from the solution is conveniently verified by weighing.) From this solution, the exact volume corresponding to from 200 to 1000 pg of the internal standard is withdrawn and added to the ester mixture to be analyzed. The amount of internal standard chosen is dependent on the amount and type of sample. For samples where a high yield of esters is expected, the upper level of internal standard is used. 

Chemical methods for analysis of phenolic hydroxyl groups include determination of the increase in methoxyl content resulting from diazomethane methylation (Bjorkman and Person 1957), the increase in phenolic acetyl group content after acetylation (Lenz 1968, Mansson 1983), and low-molecular weight compounds derived from the degradation of phenolic structures (Chap. 5.2). The phenolic acetyl group of acetylated lignin may also be determined by an NMR spectroscopic technique (Lenz 1968, Robert et al. 1986) or by a selective deacetylation in pyrrolidine (aminolysis) (Mansson 1983). 

Approximately 10 mg of a dried sample is accurately weighed to the nearest 0.1 mg and placed in a 5-ml micro-reaction vial fitted with a Teflon-lined screwcap, and 0.5 ml of ethereal diazoethane (Adamson and Kenner 1937, Eistert et al. 1968) is added (Notes 5 and 6). If the orange-red color of diazoethane is discharged with evolution of nitrogen gas immediately after the addition of diazoethane, additional portions of the diazoethane solution are added to the reaction mixture until the orange-red color persists. Subsequent reaction and work-up are performed as described above for diazomethane methylation. 

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