Monoalkylation, hydroxylamines

IsowA, Y., and H. Kurita A New Reagent for the Syntheses of N-Monoalkylated Hydroxylamines N-Tosyl-0-2,4,6-trimethyl-benzylhydroxylamine. Bull. Chem. Soc. Japan 47, 720 (1974). 

Alkylation of hydroxylamine with primary halides and sulfonates is rarely used nowadays for preparation of A-alkylhydroxylamines due to the competing formation of N,N-dialkylhydroxylamines. A number of older procedures have been reported with low to moderate yields of Al-alkylhydroxylamines. Yet, in many cases the reported low yields can be attributed to workup losses during distillation and crystallization steps rather than to the polyalkylation. Use of excess of hydroxylamine in reactions with primary alkyl halides (e.g. 3) improves the yields of monoalkylation (equation 2). Most of the examples of alkylation of hydroxylamine in good yield involve a substitution of an activated halogen atom at benzylic positions as well as in haloacetamides 4 leading to alkylhydroxylamines such as 5 where dialkylation rates are lower (equation 3). 

Direct monoalkylation of hydroxylamine is usually not a good preparative method because of the problems with further alkylation on nitrogen. However, in a one-pot procedure hydroxylamine hydro-... 

Figure 10.25 Twenty-nine specific toxicophores for mutagenicity as identified by Kazius el al. (Kazius, J-, et al. Derivation and validation of toxicophores for mutagenicity prediction. J. Med. Chem. 2005, 48, 312-320.) (A) Specific aromatic nitro, (B) specific aromatic amine, (C) aromatic nitroso, (D) alkyl nitrite, (E) nitrosamine, (F) epoxide, (G) aziridine, (H) azide, (I) diazo, (J) triazene, (K) aromatic azo, (L) unsubstituted heteroatom-bonded heteroatom, (M) aryl hydroxylamine, (N) alkyl halide, (O) acyl halide, (P) N- or 5-mustard, (Q) polycyclic aromatics, (R) bay-region, (S) K-region, (T) sulphonate-bonded C, (U) unsaturated aldehyde, (V) alkyl A-nitro, (W) diazonium, (X) p-propiolactone, (Y) unsubstituted a,p unsaturated alkoxy, (Z) l-aryl-2-monoalkyl hydrazine, (AA) aromatic methylamine, (AB) aryl hydroxylamine ester, and (AC) polycyclic planar system.

Lam et al. synthesized isoxazolines 469 and pyrazolines 470 via monoalkylation with dimsyl anion and styrene oxide 480 and following an oxidation/ elimination strategy [292]. Oxidation of secondary alcohols 481 is performed via Jones oxidation and cyclization with cleavage from the resin follows in a separate step. Diverse elements can be introduced to the heterocycle using either hydroxylamine 483 or hydrazine derivatives 484 (Scheme 72). Corresponding six-membered heterocycles like pyridazine derivatives 471 can be obtained when the linked molecule 482 bears a benzoyl substituent instead of the phenyl substituent at the a-C-atom [293]. 

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