Dimethyl sulfate Subject

The indol-3-yl-substituted indolo[2,3-()]carbazole 143 has been isolated as a product from the complex mixture generated by the decomposition of urorosein (144) (99CHE561). Interestingly, when subjected to alkylation conditions involving sodium hydride and dimethyl sulfate in THF, 143 was transformed into the N. -dimethyl derivative 145 in 36% yield (00MI2). 

Workers exposed to dimethyl sulfate have developed chromosomal aberrations in their circulating lymphocytes. Dimethy l sulfate has been subjected to a broad range of in-vitro tests for genotoxic activity, in which positive results were consistently found without the need for exogenous metabolic activation systems. It has also consistently produced positive responses in the small number of in-vivo tests to which it has been subjected. It forms a variety of alkylated bases with DNA in vitro and the same alkylated bases are formed in vivo. 

In the original analytical method developed by Freudenberg and coworkers, wood was first subjected to alkaline hydrolysis at high temperature followed by a methylation with dimethyl sulfate The free phenolic hydroxyl groups were converted by this treatment to methoxyl groups and the phenolic units were thus stabilized toward oxidative breakdown The oxidation step was carried out by addition of portions of solid potassium permanganate at a pH at or near 7 until the purple color of the solution remained (Freudenberg et al 1936)... 

In order to study this unusual dimerization in detail 49 [40] was synthesized and subjected to the same reaction conditions. The cumyl group inhibits the Grovenstein-Zimmerman rearrangement as in this case the formation of an anion at a tertiary center would be encountered, so only cleavage to the vinyllithium compound 18 is possible. Indeed, after reacting 49 with lithium metal for 4 h at room temperature and subsequent work-up with dimethyl sulfate the dimer 51 is isolated in 82 % yield, with t-butylbenzene (53) as the other product in 84 % yield (Scheme 11). 

Workers at the India Orchid company have shown that the condensation of 2-pentanone with diethyl oxalate may be catalyzed by sodium methoxide which is cheaper than sodium ethoxide. After further condensation with hydrazine hydrate, the pyrazole 18 was obtained as a mixture of methyl and ethyl esters. Methylation with dimethyl sulfate was performed neat, as in the Pfizer medicinal chemistry synthesis. The mixture of the methylated pyrazoles 19 was then nitrated and subjected to ammonolysis to give the desired pyrazole intermediate 5 (Scheme 16.8). 

To 1.17 g of (-)-7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4H-[l,4] benzoxazine was added 2.77 g of thionyl chloride in pyridine. The reaction mixture was concentrated and the concentrate was subjected to column chromatography using 40 g of silica gel and eluted with chloroform to obtain 1.18 g of the reaction product as a colorless oily product. This product was dissolved in 30 ml of dimethyl sulfoxide, and 0.41 g of sodium borohydride was added thereto, followed by heating at 80-90°C for 1 hour. The reaction mixture was dissolved in 500 ml of benzene, washed with water to remove the dimethyl sulfoxide, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography using 40 g of silica gel and eluted with benzene to obtain 0.80 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[l,4]benzoxazine as a colorless oily product [a]D25 = -9.6° (c = 2.17, CHCI3). Optical Purity >99% e.e. 

Dimethyl malonate (4.04 g, 30.6 mmol), potassium t-butoxide (3.43 g, 30.6 mmol) and anhydrous N,N-dimethylformamide (15 ml) were mixed and stirred for 10 minutes in a nitrogen atmosphere at 90°C. The mixture was then cooled to room temperature, and to the cooled mixture was added a solution of diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate (5.04 g, 15.3 mmol) prepared in the manner as described in Japanese Patent Publication No. 47-45, 746) in anhydrous N,N-dimethylformamide (15 ml). The resulting mixture was stirred at 90°C for 3 hours, and then poured into 1 N hydrochloric acid (30 ml). The mixture was subjected to extraction using two portions of diethyl ether. The ether extracts were combined, washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to give 7.97 g of yellow oil. The oil was adsorbed on silica gel (16 g) and subjected to... 

The 3-phenyl salt is treated with 10% aqueous NaOH and the resultant oil is taken up in toluene, washed with water, dried over sodium sulfate, the solvent removed by vacuum rotary evaporation (foaming ), and the residue subjected to rapid pot-to-pot distillation under nitrogen to give 75-85% recovery of 1,3-dimethyl-2-methylene-3-phenylindoline, bp 130-140°C.l-2 mm (lit.219 130°C/0.08 mm) (Note 7). 

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