Methylamine nitrosation

As an outsider in the chemistry of bicyclic aliphatic hydrocarbons, I have the feeling that these reactions are intrinsically so complex that it is too difficult to deduce from them generally applicable rules for deamination mechanisms. It would appear that concentration on reagents as simple in structure as possible would be more promising, as purity determinations by instrumental analyses of all types are easier to interpret and as the number of products would be smaller. This is clearly indicated by some of the reactions discussed in Section 7.3, particularly Brosch and Kirmse s stereochemical investigation (1991) of the [l- H]butylamine deamination and the reactions investigated by Fishbein s group, namely the first steps of the methylamine nitrosation (Hovinen and Fishbein, 1992 Hovinen et al., 1992), the decomposition... 

Use of the more expensive nitrosation reagent butylnitrite is successful when the reaction fails with the cheaper sodium nitrite reagent <2004JST23>. Introduction of a 15N label at the exocyclic nitrogen in compounds 45 where R = Me is achieved using the lsN-enriched l-phenyl-4-methyl-3-thiosemicarbazide formed from 15/V-methylamine... 

Racemic 2-aminobutan-l-ol (1) is a cheap chemical which can be easily resolved into both its enantiomers on an industrial scale. The asymmetric synthesis of chiral amines from hydrazines derived from (7 )-(—)-2-aminobutan-l-ol [(R)-(—)-l], using the general strategy disclosed in early works, is summarized here. The title hydrazine (4) is prepared as follows (eq 1). Treatment of the amino alcohol [(7 )-(—)-l] with excess ethyl formate followed by LAH reduction of the intermediate formamide gives the N-methylamine [(7 )-(—)-2]. IV-Nitrosation of the latter afforded (R)-(+)-3 which is next reduced to the hydrazine [( )-(—)-4] by means of LAH. Being unstable, the hydrazine (4) must be used immediately without purification. 

Methylating agents can be generated by chemical ni-trosation of endogenous metabolites. For example, methylamine produced by the decomposition of organic matter can condense with carbamyl phosphate, a precursor of pyrimidines, to form methylurea, which in turn can be nitrosated to yield methylnitrosourea (MNU). Such nitrosation reactions can be catalyzed by bacterial enzymes (35). 

The best known and most widely used diazoalkane is diazomethane (95 equation 39). Preparative methods for diazomethane involve, in general, the nitrosation of a methylamine derivative (93), followed by cleavage under alkaline conditions. Methylamine derivatives used have included the urethanes, ureas,carboxamides, sulfonamides, guanidines and even the methylamine adducts of unsaturated ketones and sulfones. N-nitroso-N-methyl p-toluenesulfonamide (Diazald, Aldrich) is currently the most commonly used diazomethane precursor. Diazomethane is both toxic and explosive. Although in the past it has been purified by codistillation with ether, it is now usually generated, stored and used as an ether solution without distillation. 

That diazomethane, however, cannot be obtained by straigtforward nitrosation of methylamine is due to the higher stability of the C-H bond compared with that of the C — N(a) bond in the methanediazonium ion, as already discussed in Sections 2.1 and 2.2. 

The work on methylamine — clearly the simplest aliphatic amine — also demonstrates, however, that not only the amine, but also the deamination method must be simple. We discussed the stereochemistry of the deamination in the rearrangement of a derivative of chiral methylamine (7.30) in Section 7.3, but first, we have doubts whether Gautier s result (1980, inversion) of the pyrolysis of that N-methyl-N-nitroso-toluenesulfonamide in an aprotic solvent at 95 °C is comparable with the direct nitrosation of an amine in water, and second, the result of Gautier is contrary to that of the stereochemical investigation of a somewhat more complex amide deamination, namely that of N-(l-methylpropyl)-N-nitroso-4-toluenesulfon-amide (White et al., 1981 see Sect. 7.3). ... 

The primary amine (217) underwent the Rathke reaction with the isothiourea (218) to give cimetidine (219). A better yield was obtained with dimethyl cyanodithioimido-carbonate (220) followed by methylamine. Scheme 5.51 [278, 279]. Hydrolysis of cimetidine (219) gives the guanylurea (222) slowly at room temperature but the guanidine (223) at elevated temperature [278]. A first report indicated that nitrosation gave only (224), but this was ammended when (225) was discovered as a minor product. The rate of nitrosation decreases markedly as the pH increases [280, 281]. The solution conformation of cimetidine has been investigated [278]. The MNDO calculations indicate it has a high molecular flexibility with respect... 

Scheme 10.19. A representation of a pathway to diazomethane (CH2N2) by nitrosation of methylamine (methanamine, CH3NH2) with nitrous acid (HONO). Generally, any diazomethane (CH2N2) formed under these conditions decomposes before it can be used in subsequent reactions.

CJDiazomethane is prepared by base-mediated decomposition of N-i Clmethyl-Al-nitroso-p-toluenesulfonamide with potassium hydroxide in ether-aqueous ethanol at 60-65 The resulting ethereal [ C]diazomethane solution is distilled off, trapped in a separate receiver and dried over KOH pellets. For stability reasons it should be stored at —70 °C no longer than overnight. The requisite precursor is accessible via reaction of [ C]-methylamine with p-toluenesulfonyl chloride and subsequent nitrosation of the resulting... 

Preparative Methods prepared by the reaction of p-Toluenesulfonyl Chloride with methylamine, followed by nitrosation with Sodium Nitrite in glacial acetic acid. ... 

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