N-hydroxyindole

M. Somei (Kanazawa University, Japan) has reviewed the many significant advances in indole chemistry that have recently become possible through the application of N-hydroxyindole intermediates. Much of the fundamental chemistry of this class was accomplished in Professor Somei s laboratories. 

Alkylation of 2-cyanomethylenenitrobenzenes with allylbromides in the presence of K2CO3 and BU4NI afford allylic compounds such as 1017, which cyclizes on treatment with excess TCS 14/NEt3 in DMF at room temperature, via 1018, to the N-hydroxyindole 1019, in 91% yield, and to HMDSO 7 and EtsN HCl [93, 94] (Scheme 7.30). 

A solution of 1 mmol 1017 in 4 mL dry DMF is treated with MesSiCl 14 (0.63 mL, 5 mmol) then with triethylamine (0.7 mL, 5 mmol) at room temperature. After stirring until completion of the reaction the mixture is poured into dilute HCl, extracted with ethyl acetate, and the product isolated by column chromatography on sihca gel with hexane-ethyl acetate (3 1) as mobile phase to give, on crystallization from ethyl acetate, 91% N-hydroxyindole 1019, m.p. 218-220 °C (dec.) [93, 94] (Scheme 7.63). 

More generally, electrolytically produced nucleophilic centers (amine, hy-droxylamine, hydrazine, alcohol) react with electrophilic centers (carbonyl group, cyano group, nitroso group) as illustrated in Scheme 9 for the synthesis of N-hydroxyindoles [13]. 

The hydroxyiamino group will react with an adjacent side chain carbonyl function. Thus, 2-nitrobenzyl ketones 17 are reduced to the N-hydroxyindole [92]. Side... 

N-Hydroxyindols (11) have been prepared in two ways,65 [Eqs. (24) and (25)]. Equation (25) is a variation in which the hydroxylamino group is oxidized to a nitroso group, which then adds to a C=C bond. In acidic solution the N-hydroxy group can be reductively removed. 

Quinoline 1-oxides can be rearranged photochemically into indoles (103 — 104 — 105) or N-hydroxyindoles (106 — 107). Cinnolines are reductively ring-contracted into indoles (Section 3.2.1.6.9.ii). 

N- Hydroxyindoles can be alkylated by primary halides to give 1-alkoxyindoles which, while not extensively studied, appear to show the chemical reactions characteristic of the indole ring (78JCS(Pl)1117). 1-Acyloxyindoles can be prepared from N-hydroxyindoles and acid anhydrides or acyl halides and are fairly stable thermally. Attachment of the more electronegative sulfonyl group, however, leads to facile rupture of the N—O bond and formation of 3-sulfonyloxyindoles (equation 194) (81CPB1920). 

Bakke, J. 1970. The photocyclization of 2-(o-nitrophenyl)-ethanol to N-hydroxyindole. Acta Chem. Scand. 24, 2650-2651. 

An aromatic nitro group sometimes participates in the formation of indoles, in particular of N-hydroxy derivatives. For example, the reaction of ort/io-nitroaryl substituted acetonitriles 29 with acetaldehyde followed by treatment with K2CO3 afforded N-hydroxyindoles 30, as the major products [38] (Scheme 16). 

Polyfunctional N-hydroxyindole derivatives 32 have been synthesized by using the sequence of reactions, involving the VNS of hydrogen, alkylation, and base-catalyzed cyclization [39] (Scheme 18). 

As alluded to earlier, the reductive cyclization of nitro ketones often leads to A-hydroxyindoles when the intermediate reduction prodnct, a hydroxylamine, undergoes cyclization. This path can be made dominant if desired. Thus, as shown in Scheme 12, several researchers have developed such a methodology. Acheson may have been the first chemist to achieve this reaction. A two-phase zinc reduction of o-nitrophenylacetaldehyde yields the unstable N-hydroxyindole, which was trapped as the more stable (distillable) A-acetoxyindole (equation 1) [85]. Wong and colleagues use a lead-promoted reductive cyclization approach to Al-hydroxyindoles in excellent yields (equation 2 and 34-37) [86]. Wojciechowski s team employed a VNS synthesis of the A-hydroxyindole precursors (equation 3) [87]. 

In a program aimed at the synthesis of the A -hydroxyin-dole-containing potent antibiotic nocathiacin, Nicolaou and coworkers developed a clever synthesis of N-hydrox-yindoles (Scheme 13) [89], The key intermediate is the a,p-unsaturated nitrone 38 that undergoes nucleophilic addition to N-hydroxyindole (equation 1). Several indoles thus prepared are shown 39-42. 

To obtain biologically relevant N-hydroxyindoles, a prudent step would be to synthesize O-protected hydroxyindoles, to avoid their dimerization into kabutanes. Such were the premises of one study, presenting the annulation of nitrosoarenes with various alkylating and acylating agents, able to afford the desired compounds with excellent regioselectivity [4]. 

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