C-Aminomethylation

Fig. 26. C-Aminomethyl derivative of pyrrole starting trom the eorresponding N-hydroxymethyl compound and amine.

The manner of attack on the substrate by the reactive species appears to be strictly related to the nature of the aminomethylating reagent. In an acidic medium, or when a consistent amount of methyleneimmonium ion is present, the electrophilic reaction by the reagent on the substrate takes place (53, Fig. 29). - °° For instance, in C-aminomethylation of the Me group of methyl-nitrooxazoles, kinetically investigated in hydroalcoholic solution, an Sis attack by the methyleneimmonium cation upon the substrate has been postulated. ... 

Heterocyclic substrates, such as pyrrole and imidazole derivatives 68, may undergo selective Mannich reactions. C-Aminomethylation is favored by acidic conditions, whereas N-Mannich bases are produced when free amine and formaldehyde, or N,0-acetals in anhydrous solvents, are employed. Heterocyclic N-Mannich bases, however, are not particularly stable and may therefore behave as aminomethylation agents (see,... 

Uracil derivatives 92 are usually aminomethylated at position 3, although the reaction with formaldehyde alone shows an equilibrium constant for hydroxymethylation in position 1, which is about twice the value obtained for the reaction at position 3. The C-aminomethylation reaction takes place at position 5, when unsubstituted, as these substrates resemble the structure of push-pull olefines (67, Table 8). ... 

C-Aminomethylation Reactions on Acetylenic Substrates and on 218 Hydrogen Cyanide... 

Aminomcthyl derivatives are usually described as unstable intermediates affording more stable C-aminomethyl products by deaminomethylation (sec above). However, the synthesis of ebumane alkaloids involves as a key step the formation of a mcthylol derivative of the a-dicarboxyester 455 (Fig. 173), which then leads to the tcu-ahydro-pyranc ring 456 by intramolecular 0-aminoalkylation reaction with the immonium ion present in the molecule. 

Aminomcthylation of hctcroatoms (X-aminomcthylation in Table 6) is generally the easiest, whereas C-aminomethylation requires a great variety of experimental conditions. Indeed, the C—H moiety bound to a carboxyl group is among the less reactive systems, so that alkyl ketones require conditions A alkyl esters, which would be unstable under such conditions, have to be allowed to react with methyleneimmonium salts. Alkenes, as well as ferrocenyl derivatives, are also barely reactive. By contrast, the nitro group of nitroalkanes behaves as a very good activator of aminomcthylation, and phenols are readily aminomethylated. 

C-Branched thymidines bearing 5 -(S)-C-aminomethyl, 5 -(S)-C-azido-methyl, and 5 -(S)-cyanomethyl have been prepared from the key intermediate 5 -... 

A soln. of methyl 2-C-(aminomethyl)-4,6-0-benzylidene-2,3-dideoxy-2-[(/ -tolyl-sulfonyl)amino]-a-D-ribohexopyranoside in 90% acetic acid treated dropwise with aq. NaN02, and after stirring for 1 h the mixture poured into satd. NaHC03 spiro[methyl 4,6-0-benzylidene-2,3-dideoxy-a-D-ribo-hexopyranoside-2,2 -N-(/ -tolyl-sulfonyl)aziridine]. Y 89%. The products are valuable intermediates in the preparation of branched-chain aminosugars. F.e. and prepn. of the startg. m. s. R.J. Alves et al., J. Org. Chem. 53, 4616-8 (1988). 

The value of the 1,3-dithian route to branched-chain sugar derivatives has been illustrated further by stereospecific syntheses of 3-C-formyl, 3-C-hydroxymethyl, and 3-C-methyl derivatives of D-psicose from the ketone (373) via the dithianyl adduct (374). Addition of nitromethane to (373) gave both 3-C-nitromethyl-o-psicose and -fructose derivatives, which, after separation by chromatography, were reduced to the corresponding 3-C-aminomethyl derivatives. The use of dithianyl derivatives in the synthesis of streptomycin components is dealt with in Chapter 18. 

B (517) has also been synthesized from ribostamydn by introducing the 3 -deoxy and N -[(S)-4-amino-2-hydroxybutyryl] groups. Neomydn and paromomycin have been converted into their 5"-amino-5"-deoxy analogues, via the corresponding 5"-bromides, and 3 -deoxyparomamine (available by hydrolysis of lividomycin) has been transformed, by way of the action of nitromethane on its 6 -aldehyde derivative, into isomeric 6 -C-aminomethyl-3 -deoxyparomamines (519). The use of the Tipson-Cohen procedure to prepare 3, 4 -unsaturated derivatives of butirosin and kanamycin is mentioned in Chapter 12. 

Branched-chain Sugars. - 5-C-Methyl-a L-idopyranose, 6-deoxy-7-C-(2-furyl)-l,2 3,4-di-0-isopropylidene-L-gtycero-a-D-galacto-htptopyranose, tert-butyl 4-C-aminomethyl 3-C-carboxymethyl-2,3,4-trideoxy-a-D-fyxo-hexopyranoside-5-lactam, the 3-C-substituted 3-deoxy-a-D-altroside (20), methyl 4,6-0-benzylidene-2-0-(4-bromobenzoyl)-3-C-(3-methyl-... 

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