Alkylation diazomethane

Barbituric acid derivatives resemble uracils in their preference for A-alkylation with most reagents (76AJC1769, 78AJC2517>. Large alkyl groups may favor 0-alkylation. Diazomethane converts barbituric acid into 6-methoxy-l-methyluracil (72CJC880). Information is also available on the alkylation of perimidinones (81RCR816>. 

Na2Mo02 2H2O) and sodium methylamino- or ethylamino-dithiocarbamate. In THF, the Mo compound is treated with various simple diazoalkanes, e.g., phenyl-, diphenyl-, methylphenyl-, and secondary alkyl-diazomethanes. In this reaction (10-21), metalloazines of type 10.54 are formed as yellow crystals in a broad spectrum of yields up to 99%. The ratio of (Z)- to ( )-isomers was determined based on NMR spectroscopy. These metalloazines behave as active carbonyl equivalents in a Wittig-type reaction with phosphoranes (10-22) and form the corresponding ethene derivatives. 

Recourse to an alcohol cosolvent was the premier means of accelerating diazoalkane-based ring expansion reactions for more than half a century. Alkyl diazomethanes were prepared by base-catalyzed decomposition (for further... 

The most recent example of pyrrolidine synthesis by C-H functionalization was illustrated in 2014, when Che and coworkers demonstrated the synthesis of pseu-doheliotridane, a simple pyrrolidine alkaloid, by employing a ruthenium-catalyzed C-H insertion reaction (Scheme 16.44) [89]. Although diazocarbonyl compounds are generally required as the precursor of the metal carbenoid intermediate, they utilized an alkyl diazomethane as the carbene source. To this end, tosylhydrazone 192 was reacted with [Ru(TTP)(CO)] (TTP tetra(p-tolyl)porphyrin) (1 mol%) and KjCOj, which generated ruthenium carbene 193 in situ, followed by C-H insertion to produce pseudohehotridane in 95% yield with high diastereoselectivity. 

Nitraminothiazoles are sufficiently acidic to be alkylated by diazomethane the methyl substituent is introduced on the exocyclic nitrogen (194). When sulfathiazole is methylated with diazomethane in ether, a mixture of ring-methylated and amino-methylated products is obtained, the ratio being 30 70 (85). With anion 31 (R = p-NO CsH4SO -) the ratio becomes 15 85 (195). 

The nitro group increases the acidity of the hydrogen born by the exocyclic nitrogen, and alkylation of 2-nitraminothiazole with diazomethane is possible (87), The formed 2-(A"-methylnitramino)-thiazole also may be obtained from the reaction of 2-nitraminothiazole with dimethylsulfate in basic medium (194). 

The reactivity of sulfathiazoles has been reviewed (65). Methylation in alkaline solution with dimethyl sulfate gives only the ring methylated derivative (85). Mixtures of products are obtained with diazomethane as alkylating agent (see p. 37). Other alkyl halides in aqueous alkali lead also to ring-alkylated products (85. 251, 650. 669-671). 

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... 

Diazomethane alkylation of A-4-thiazoline-2-ones (36, 214) or the Williamson reaction of 2-halogenothiazoles (6. 287-300) provide good yields of 2-alkoxythiazole otherwise obtained by reaction between O-esters of monothiocarbamic acid with a-halocarbonyl compounds (see Chapter II). 

Heating the adduct of ethylene oxide and sulfur dioxide with primary alcohols in the presence of alkaH hydhdes or a transition-metal haHde yields dialkyl sulfites (107). Another method for the preparation of methyl alkyl sulfites consists of the reaction of diazomethane with alcohoHc solutions of sulfur dioxide (108). 

Trimethyl isocyanurate [827-16-7] can be synthesized in 60% yield by the reaction of CA with dimethyl sulfate in alkaline medium (13) or with diazomethane (63) and in essentially quantitative yield by thermal rearrangement of trimethyl cyanurate [877-89-4]. Isomerization of alkyl cyanurates to the corresponding isocyanurates is frequendy observed (11,64). 

N-Unsubstituted 1,2,3-triazoles are methylated mainly in the 1-position with methyl iodide and silver or thallium salts, but mainly in the 2-position by diazomethane. There is also some steric control. For example, 4-phenyl-l,2,3-triazole with dimethyl sulfate gives the 2-methyl-4-phenyl (38%) and l-methyl-4-phenyl isomers (62%), but none of the more hindered 1-methyl-5-phenyltriazole (74AHC(16)33). JV-Unsubstituted 1,2,4-triazoles are generally alkylated at N-1. 

Azolinones are protonated on oxygen in strongly acidic media. O-Alkylation of 2-azolinones can be effected with diazomethane thiazolinone (486) forms (487). Frequently O- and iV-alkylation occur together, especially in basic media where proton loss gives an ambident anion. 

These compounds generally exist in carbonyl forms. The oxygen function can be converted into halogen by phosphorus halides. Reactions with electrophiles are quite complex. Thus urazole (511) reacts with diazomethane quickly to yield (512), which is more slowly converted into (513). 1-Phenylurazole gives (514) however, 4-phenylurazole yields (515). Oxadiazolinones of type (516) can be alkylated at both O- and N-atoms. 

Monoesterification of a symmetrical dihydroxy aromatic compound can be effected by reaction with polymer-bound benzoyl chloride (Pyr, benzene, reflux, 15 h) to give a polymer-bound benzoate, which can be alkylated with diazomethane to form, after basic hydrolysis (0.5 M NaOH, dioxane, H2O, 25°, 20 h, or 60°, 3 h), a monomethyl ether. ... 

On the other hand, alkyl substitution on the 1,1-difluoroallene does not affect the regiospecificity of diazomethane addition [24] (equation 17)... 

Another method of replacing hydrogen by methyl, in addition to the use of alkyl halide and alkyl sulphate, is by the action of dIazomethane on the phenol... 

It is not known whether the amine assists the elimination of the nitrogen, but that the iminium salt retains its stereochemistry has been demonstrated (709). When a mixture of 68 and 69of 1 5 ratio is treated with diazomethane, the ratio of 70 71 obtained in 75% yield and determined spectroscopically was still 1 5. The traw-N-isopropyl-N-methylisobutylidinium perchlorate (69) was prepared by alkylation of an aldimine salt with diazomethanc and... 

CH2N2, HBF4, CH2CI2, Et3N, 25°, 1 h, 95% yield. Hydroxyl amines will O-alkylate without the acid catalyst. TMSCHN2 serves as a safe and stable alternative to diazomethane (74-93% yield). ... 

Final structure determination of the monomethyl derivatives was made possible only on performing straightforward syntheses of the compounds, analogous to syntheses of allantoxaidine. The 1-methyl (19) and 3-methyl (20) derivatives were prepared by cyclization of 1- and 3-methyl biuret,respectively. The 3-methyl derivative was also obtained by cyclization of A ,A -bis(methylcarbamyl)formami-dxne. The 1-methyl derivative was the same as the product obtained by Biltz on methylation of silver salt of allantoxaidine with methyl iodide. The same product is formed primarily during methylation of dioxotriazine with diazomethane. An excess of this agent produces the expected 1,3-dimethyl derivative (21). These results of alkyl-... 

The pyrimidine compounds are known to undergo a rearrangement of the 0-alkyl derivatives to the iV-alkyl ones. The methoxy derivatives of 1,3,5-triazine display a similar behavior. On applying methyl iodide to 2,4-dimethoxy-l,3,5-triazine one of the methyl groups is shifted giving rise to l-methyl-4-methoxy-derivative (22). This compound was also obtained by methylation of 4-methoxy-2-oxo-1,2-dihydro-1,3,5-triazine (18) with diazomethane. At higher temperature (100°C) in presence of methyl iodide a shift of both methyl groups takes place and methiodide is formed simultaneously (23). Similarly,... 

The hexahydro derivatives are weakly basic substances, some of them forming hydrochlorides. Dioxohexahydrotriazine yields a 1,5-diacetyl derivative (35), in which the positions of the acetyl groups were determined by acetylation of the A-alkyl derivatives and methylation with diazomethane according to Scheme 4. ... 

Early investigators adduced various kinds of chemical evidence in support of a monohydroxy-dioxo structure for barbituric acid (112) (a) reaction with diazomethane afforded a mono-O-methyl deriva- iye,i59,i6o barbituric acid and its 5-alkyl derivatives are much stronger acids than the 5,5-dialkyl derivatives, and (c) the 5-bromo and 5,5-dibromo derivatives have different chemical properties. - The early physical evidence also appeared to substantiate the monoenol structure, this formulation having been suggested for barbituric acid in 1926 on the basis of its ultraviolet spectrum and again in 1934, In the 1940 s, ultraviolet spectroscopic studies led to the suggestion of other monohydroxy and dihydroxy structures for barbituric acid, whereas its monoanion was assigned structure 113 (a clear distinction between ionization and tautomerism was not made in these papers). 

The alkylation of 2-nitramidopyridine (285 286) with dimethyl sulfate yields only the 1-methyl derivatives however, both possible derivatives were obtained for some substituted compounds, this behavior was thought to be associated with their tautomerism. Diazomethane also gave a mixture of alkylated products. Infrared... 

Cyclic hydroxamic acids and V-hydroxyimides are sufficiently acidic to be (9-methylated with diazomethane, although caution is necessary because complex secondary reactions may occur. N-Hydroxyisatin (105) reacted with diazomethane in acetone to give the products of ring expansion and further methylation (131, R = H or CH3). The benzalphthalimidine system (132) could not be methylated satisfactorily with diazomethane, but the V-methoxy compound was readil3 obtained by alkylation with methyl iodide and potassium carbonate in acetone. In the pyridine series, 1-benzyl-oxy and l-allyloxy-2-pyridones were formed by thermal isomeriza-tion of the corresponding 2-alkyloxypyridine V-oxides at 100°. 

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