Iodomethane with ammonia

Synthesis.—3,5-Diaryl- and 3,5-dialkyl-1,2-dithiolium salts (121 R = Ar or Bu ) can be prepared in good yield by the sulphurization of diketones (Scheme 9). Treatment of these salts (121) with pyridine affords the corresponding 4-olates (122), which can be O-alkylated with iodomethane and similar compounds. With ammonia, ring scission and re-cyclization occurs, and the corresponding iso-thiazolium-4-olates are formed. An unusual synthesis of 1,2-dithiolium salts (124) is by the photolysis of l,2-dithiole-3-thiones (123) in benzene or acetonitrile, in the presence of aryl or alkenyl bromides or iodides. 

Alkylation of the enolate of a carboxylic acid, formed as an intermediate in the Birch reduction of an aromatic acid, has been successfully exploited in synthesis, e.g., in the synthesis of gibberellic acid. A model compound 24 was reduced with sodium in diethyl ether-liquid ammonia and the resulting carbanion was alkylated with iodomethane to give 25 in ca. 80% yield87. 

Fischer and Bergmann 75 adapted the method of Hinsberg 76 for the N-methylation of benzenesulfonamides in the synthesis of Sar, 5-aminopentanoic acid, and racemic Orn. Two years later Fischer and Lipschitz 73 succeeded in the synthesis of optically active, N-methylated derivatives of Ala, Leu, Phe, and Tyr. TV-Tosyl amino acids were N-methylated with two equivalents of iodomethane at 65-68 °C in a sealed pressure tube. The tosyl group was then deprotected either with sodium in liquid ammonia or with hot hydrochloric acid, but partially racemic products were obtained that were purified by crystallization with optically active bases. 77 Cheung and Benoiton did not observe racemization during deprotection with sodium in liquid ammonia. 78 ... 

The imine groups in benzodiazepines could increase the acidity of the hydrogen atoms attached to C-3 or to methyl substitutents at C-2 and C-4, and thus these sites might be susceptible in basic conditions to attack by alkyl halides. 2,4-Dimethylbenzodiazepine reacted with iodomethane and sodium amide in liquid ammonia to give 2,3,4-trimethylbenzodiazepine (59JCS1132). The site of reaction was confirmed by the reaction of the product with phenylhydrazine, which gave 3,4,5-trimethyl-l-phenylpyra-zole. 

Methyl l-Methoxyltellurobenzoate)1 A solution of 0.171 g (1 mmol) 2-methoxybenzoyl chloride in 8 ml tetrahydrofuran is added to 0.174 g (1 mmol) of freshly prepared sodium telluride (liquid ammonia method). The mixture is stirred at 0° for 1 h and then filtered. The solvent is evaporated from the filtrate under reduced pressure. The red, oily residue is cooled to — 63° under nitrogen and mixed with 2 ml (32 mmol) iodomethane. The mixture is warmed to — 30° and stirred at this temperature for 2 h. The excess iodomethane is evaporated under reduced pressure below 0°. The residue is treated with 5 ml dichloromethane, the black mixture is filtered, and the filtrate evaporated under reduced pressure below 0° to give yellow crystals yield 84% m.p. 25°. 

The intermediate anions may be trapped by other electrophiles besides a proton. For instance, treatment of methyl benzoate with sodium-ammonia gives the enolate 8, which is alkylated by iodomethane to give the reduced compound 9 (Scheme 11.5). The methyl group is located a to the electron-withdrawing ester group as predicted above. 

N-a-Amino acids (10 mg) were typically dissolved in 200 mM, pH 10 sodium metaborate buffer (1 ml), and methylated directly by the addition of a 1 1 v/v solution (20 gl) of [ C]iodomethane in acetonitrile, with rapid mixing of the sealed biphasic mixture at 37°C for 24 h. Cystine dimethyl ester, in particular, was first converted to the diamide at pH 9.5 using ammonia. Histidine amide was first acetylated prior to reaction with iodomethane. 

Use SpartanView to compare electrostatic potential maps of the reactants and the transition state for the Sfj2 reaction of ammonia with iodomethane. Which is more polar How would the reaction rate change if a polar aprotic solvent such as DMSO were replaced with a polar protic solvent such as water ... 

Dithiazolium bromides 1 react with an excess of anhydrous ammonia at room temperature to give the amidinothioureas 2a, b (cf. Houben-Weyl, Vol. E8d, p 45ff), which undergo cyclization with thiophosgene in dichloromethane to afford the 2/f-1,3,5-thiadiazine-2-thiones 3a, b.105 Compounds 3a and b then react with iodomethane to yield the 1,3,5-thiadiazinium iodides 4 a and b.105 The methylsulfanyl groups of 4 a and b can be substituted by treatment with secondary amines to yield products 4c and d.105... 

The preparation of ethylenebis(dimethylphosphine) has been described by metallation of phosphine with sodium, followed by methylation of the resulting sodium phosphide with iodomethane. Two further metallation-methylation sequences using sodamide and iodomethane produce sodium dimethylphosphide, which is treated with 1,2-dichloroethane in liquid ammonia, to give the diphosphine.2 Other procedures involve heating tetramethyldiphosphane with ethylene,3 or tetramethyldiphosphane disulfide with ethylene, both... 

In the presence of acids (e.g. ethanol) sufficiently strong to protonate the enolate anion, however, the ketone is generated in the reducing medium and is reduced further to the saturated alcohol. The formation of enolate anions such as 63 during metal-ammonia reduction of a,p-unsaturated ketones is shown by their ready trapping with electrophiles such as iodomethane. 

Triethylarsine, (CH CH ljAs, reacts with iodomethane only four times faster than dimethyl selenide, (CH Se. However, ammonia reacts with iodomethane 3x10 times faster than water. Compare the difference in rate. 

Although ammonia and amines react readily with alkyl halides to give alkylation, the reaction is not always useful synthetically. Consider the reaction of methylamine with iodomethane (Figure 9.47). The product is dimethylamine. Because alkyl groups donate electron density, dimethylamine is more nucleophilic than methylamine, so that, as soon as it is formed, it will compete with methyl-amine for the available iodomethane. So if we restrict the amount of iodomethane, we will get a mixture of products, and if we add an excess of iodomethane, we will have a runaway reaction, to give the quaternary salt tetramethylammonium iodide. 

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