Construction of 3,5-dinitrated 1,4-dihydropyridines modifiable at 1,4-positions by a reaction of β-formyl-β-nitroenamines with aldehydes

Abstract

A novel and efficient method for the synthesis of 4--substituted 3,5--dinitro--1,4--dihydropyridines by a reaction of β--formyl--β--nitroenamines with aldehydes was developed. The reaction of nitroenamines with aldehydes leading to 1,4--dihydropyridines and the self--condensation of nitroenamines leading to pyridinium salt intermediate proceed competitively. The obtained 3,4,5--trisubstituted--1,4--dihydropyridines readily transformed into the corresponding pyridines in high yields. Introduction1,4--Dihydropyridine (DHP) derivatives have attracted great attention in the medicinal chemistry and pharmacological fields due to their wide spectrum of bioactivities. Moreover, dimeric DHPs are used as precursors for HIV--1 protease inhibitors. 4 Apart from their medicinal value, DHPs, especially 2,6--unsubstituted DHPs with electron--withdrawing groups at the 3--and 5--positions, have been employed as photoelectronic functional materials. Thus, numerous methods for the preparation of DHPs have been reported. The Hantzsch reaction, a multi--component reaction of an aldehyde, two β--keto esters, and ammonia, is the most widely used. 6 However, only a few cases of the synthesis of 2,6--unsubstituted 3,5--functionalized DHPs have been reported so far; in particular, the introduction of nitro groups at the 3--and 5--positions is quite difficult, mainly because of poor reactivity.Considering this background, we recently developed a novel method for the construction of 4--arylated 3,5--dinitro--1,4--dihydropyridines (dinitro--DHPs) (Scheme 1(a)) 7 by electrophilic substitution of electron--rich benzene derivatives with pyridinium ion X, formed by self--condensation of β--formyl--β--nitroenamine 1. The formylnitroenamine 1 is useful synthetic unit because its versatile reactivity arises from two electrophilic sites, nucleophilic amino group, and electron-- which includes a protonated α,β--unsaturated ketone and an enamine as key intermediates (Scheme 1(b)), a multi--component reaction between two molecules of β--formyl--β--nitroenamine 1 and an aldehyde 2 is designed (Scheme 1(c)). In this strategy, the nitroenamine serves as both an α,β--unsaturated iminium and an enamine, enhancing the synthetic utility of formylnitroenamine as a building block. Herein, we report a new method for the construction of various 4--substituted 3,5--dinitro--1,4--DHPs 3 and their oxidation to afford 3,5--dinitropyridines. Results and discussionAt first, we studied the reaction of N--propyl--β--formyl--β--nitroenamine 1A (0.5 mmol) with p--tolualdehyde (Tol--CHO) 2a under acidic conditions (Table 1). When the reaction was carried out in the presence of p--toluenesulfonic acid monohydrate (p--TsOH·•H 2 O, 0.25 mmol) in ethanol, the desired 4--arylated dinitro--DHP 3Aa was successfully obtained in 67% yield (entry 1, based on half of 1A), accompanied by the formation of 4--unsubstituted DHP 4A (4%). Although the yield of the desired product 3Aa slightly increased up to 78% when0.5 mmol of p--TsOH was used, the yield of the by--product 4A also...

α,β‐Unsaturated Aldehydes as C‐Building Blocks in the Synthesis of Pyridines, 1,4‐Dihydropyridines and 1,2‐Dihydropyridines

“…In 2015, a novel method for the synthesis of 3,5‐dinitro‐1,4‐dihydropyridines 76,77 from β‐formyl‐β‐nitroenamines 74 and aldehydes 75 has been disclosed (Scheme ) . The composition of the reaction mixture and the yield of reaction products 76 depend on the structure and amount of the initial aldehydes 75 .…”

Progress in Synthesis of 1,4-Dihydropyridines

“…2015 年, 他们 [109] 基于丁炔酸二酯的合成主要与醛/醌类化合物、 丙二 腈和芳类化合物为底物, 合成含有 5-腈基和 6-胺基的不 对称结构 1,4-DHPs, 其原理基于丁炔酸二酯和胺形成烯 酮胺中间体, 与丙二腈和醛形成的不饱和中间体经过 Hantzsch 反应类似历程的 Hantzsch-like 反应. 2010 年, Sun 等 [111] 在乙醇中三乙胺催化该类型反应, 高产率地得 到目标化合物(Eq.…”

Highly electron-deficient 1-propyl-3,5-dinitropyridinium: evaluation of electron-accepting ability and application as an oxidative quencher for metal complexes

“…In our previous work, we have demonstrated that 1-propyl-3,5-dinitropyridinium salt 2a·OTs is formed in situ upon treatment of N -propyl-β-formyl-β-nitroenamine 1a (R = Pr) with p -toluenesulfonic acid (TsOH), and formation of the salt 2a·OTs is confirmed by trapping as 4-arylated 1,4-dihydropyridine derivatives 3 with electron-rich benzenes. 6 On the other hand, 3,5-dinitropyridine 4 was obtained when N-tert -butylenamine 1b (R = t -Bu) was subjected to the same reaction, which is because a stable tert -butyl cation is readily eliminated ( Scheme 1 ). The easy access to 3,5-dinitropyridine 4 facilitates the N -modification to afford versatile N -alkyl-3,5-dinitropyridinium salts 2.…”