Methylation of nitrogen

Methylation of nitrogen at the 2 position also proves to be consistent with diuretic activity. Condensation of 160 with urea affords the heterocycle, 193. Treatment of this compound with methyl iodide and base effects alkylation on the more acidic ring nitrogen (194). Basic hydrolysis then gives the N-methylated aminosulfonamide (195). Condensation of this with chloroacetalde-... 

The second way differs from the first in that the methylation of nitrogen is accomphshed before the cyclocondensation reaction. In order to do this, the initial 2-amino-5-chlorobenzo-phenone is first tosylated by p-toluenesulfonylchloride and the obtained tosylate (5.1.3) transformed into the N-sodium salt, which is then alkylated by dimethylsulfate. The resulting 2-A -tosyl-A -methyl-5-chlorobenzophenone (5.1.4) is hydrolyzed in an acidic medium, giving 2-methylamino-5-chlorobenzophenone (5.1.5), which undergoes cyclocondensation by reaction with ethyl ester of glycine hydrochloride, forming the desired diazepam (5.1.2) [1-5]. 

Methylation of nitrogen. N-Methylmethyleneaziridine (1) is not methylated by methyl fluorosulfonate in CHCI, at —60° but rather is converted into a water-soluble polymer. Methylation is achieved by the dimethylchloronium salt in SO2 at -78°. The product (2) shows remarkable thermal stability. 

Dimethyl carbonate can be used for methylation of nitrogen in amine compounds at a temperature of 180°C under continuous-flow gas-liquid phase-transfer catalysis conditions (which involve transfer of organic ionic reactant species between water and an organic phase) as shown below for the methylation of aniline ... 

Method 1. Place 20 g. of crude benzoin (preceding Section) and 100 ml. of concentrated nitric acid in a 250 ml. round-bottomed flask. Heat on a boiling water bath (in the fume cupboard) with occasional shaking until the evolution of oxides of nitrogen has ceased (about 1 -5 hours). Pour the reaction mixture into 300-400 ml. of cold water contained in a beaker, stir well until the oil crystallises completely as a yellow solid. Filter the crude benzil at the pump, and wash it thoroughly with water to remove the nitric acid. RecrystaUise from alcohol or methylated spirit (about 2-5 ml. per gram). The yield of pure benzil, m.p. 94-96°, is 19 g. 

The diazonium ion from 2 2 dimethylpropylamine rearranges via a methyl shift on loss of nitrogen to give 1 1 dimethylpropyl cation... 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

Alkylation of pyrimidin-2(or 4)-amine on a ring-nitrogen gives an imine, e.g. (8), of quite high basic strength (pjSTa 10.7) because its cation, e.g. (13 R = Me), has typical and effective resonance stabilization indeed, methylation of pyrimidine-2,4-diamine gives a still stronger base (pjSTa> 13) due to an even more resonance-stabilized cation (14). 

Table 4 H NMR Spectral Data for Ring Hydrogens of Nitrogenous Azoles (b) fV(l)-Methyl Derivatives...

A 600-mL, three-necked, round-bottomed flask 1s equipped with a mechanical stirrer, a short gas inlet tube, and an efficient reflux condenser fitted with a potassium hydroxide drying tube. The flask is charged with 13.4 g (0.05 mol) of 3-ben2y1-5-(2-hydroxyethyl)-4-methyl-l,3-th1azol1um chloride (Note 11, 72.1 g (1.0 mol) of butyraldehyde (Note 2). 30.3 g (0.3 mol) of triethylamine (Note 2), and 300 raL of absolute ethanol. A slow stream of nitrogen (Note 3) is begun, and the mixture is stirred and heated In an oil bath at 80°C. After 1.5 hr the reaction mixture is cooled to room temperature and concentrated by rotary evaporation. The residual yellow liquid Is poured Into 500 mL of water contained 1n a separatory funnel, and the flask is rinsed with 150 mL of dichloromethane which is then used to extract the aqueous mixture. The aqueous layer is extracted with a second 150-mL portion of... 

On hydrogenation at 80°, or on electrolytic reduction, aphyllidine is converted into d-sparteine (p. 133). On exhaustive methylation one nitrogen atom is eliminated in three stages, leaving a product, b.p. 235-255°/ll mm., as a viscous, yellow, alkaline oil of uncertain composition. Aphylline, on similar treatment, yields hemiaphylline, CjgH jON, b.p. 217-220°, as a viscous, yellow oil, not markedly basic. 

Preparation—Cortexolone 1,21-Methyl Orthoacetate. A mixture of cortexolone (10 g), methyl orthoacetate (10 ml) dimetliylformamide (10 ml) and /)-toluenesulfonic acid (40 mg) is heated at 110-120° for 4 hr, the alcohol produced during the reaction being removed by a stream of nitrogen. Addition of a few drops of pyridine and evaporation under vacuum affords a residue which yields 7.8 g of product (67%), mp 174-176°, after trituration with methanol [a]o 92° (Diox). 

Pyrolysis at 190° of the resulting diastereomeric A -pyrazolines (8) and (11) leads to elimination of nitrogen and formation of the cis- and tmns-cydo-propanecarboxylates (9) and (12), respectively. Thermal decomposition of the A -pyrazoline (13) affords methyl tiglate (14) in addition to the cyclopropane derivative (15) in a ratio 2 1, while A -pyrazolines such as (3) give only 0L,[i- or, y-unsaturated esters, and no cyclopropane derivatives. 

Expulsion of nitrogen with formation of the A -l-methyl compound (9) occurs by heating (8) at ca. 220° or at room temperature by contact with acidic adsorbents. ° However, in this case perchloric acid or boron trifluoride etherate catalyzed fragmentation is not possible, although high yields (80 %) of (9) are obtained by heating (8) with quinoline or aniline. The la,2a-methylene compound (10) is always obtained as a by-product in 5% yield. 

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