Synthesis of Nitro Alcohols by Riboflavin Promoted Tandem Nef‐Henry Reactions on Nitroalkanes

Abstract

We disclose a unprecedented riboflavin promoted Nef reaction of primary nitroalkanes coupled with a nitroaldol reaction. This tandem process allows the synthesis of functionalized nitro alcohols under mild reaction conditions. Secondary nitroalkanes fail to give the expected nitroaldol products although they are consumed under the reaction conditions.magnified image

Catalytic artificial nitroalkane oxidases – a way towards organocatalytic umpolung

“…The reaction of different primary nitroalkanes 3d and 3f together under the optimal conditions provided a mixture of four products (Table 3, entry 8 and ESI S2.4†). The use of (nitromethyl)benzene ( 3g ) produced a different product than the expected one, as the primarily formed β-nitroalcohol 4g probably underwent elimination of water and subsequent Michael addition with a third nitroalkanide anion to give a five-membered ring product 7 , as described in the literature 11 (Table 3, entry 9, Scheme 3).…”

“…Inspired by a protocol for the reaction with a stoichiometric amount of riboflavin, 11 we used 0.55 equiv. of base relative to the substrate and 1 mL of water as a solvent for 0.6 mmol of 3a .…”

“…9 Later, Foss and others utilised nitrite, produced from nitromethane in a catalytic process using ethylene-bridged flavinium salt 2 , as a nontoxic source of nitrogen dioxide for the stoichiometric agent in the oxidation of alcohols and ethers catalysed by TEMPO. 10 Recently, Lupidi, Palmieri and Petrini 11 reported a tandem process where a nitroalkane was converted to an aldehyde using riboflavin ( 1a ), which was followed by a Henry reaction 12 with another nitroalkane anion (Scheme 2C) to form β-nitroalcohol. There, two equivalents of riboflavin 1a relative to the substrate were used.…”

Interrupted Nef and Meyer Reactions: A Growing Point for Diversity-Oriented Synthesis Based on Nitro Compounds

“…The conversion of nitroalkane salts into aldehydes and ketones through acid hydrolysis (known as the Nef reaction) was discovered independently by M. I. Konovalov in 1893 [ 2 ] and J. Nef in 1894 [ 3 ]. In the following decades, these reactions received much development both in terms of methodology and application in the synthesis of complex natural molecules [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. Of the most important examples where the nitro to carbonyl group conversion is used, the method of chain elongation in carbohydrates (the Fischer–Sowden method) can be mentioned [ 6 , 17 ].…”