Synthesis of 2,3,4‐Trisubstituted Thiochromanes using an Organocatalytic Enantioselective Tandem Michael–Henry Reaction

Abstract

Enantioenriched 2,3,4-trisubstituted thiochromanes have been synthesized by using a cupreinecatalyzed tandem Michael addition-Henry reaction between 2-mercaptobenzaldehydes and β-nitrostyrenes. Good diastereoselectivities and enantioselectivities were obtained for the title compounds, which may be further improved through a single recrystallization (up to 98% de and> 99% ee). KeywordsHenry reaction; 2-mercaptobenzaldehyde; Michael addition; β-nitrostyrene; organocatalysis; tandem reaction Chromanes are an important class of compounds that are found in many biologically active natural products.[1] Thiochromanes, the sulfur analogues of chromanes, have also been reported to possess important biological activities. [2] There are also reports that the replacement of the oxygen atom in chromanes with a sulfur atom results in enhanced bioactivities.[2d,f] Some representative examples are collected in Figure 1. Tertatolol (1) has been shown to have affinity to 5HT A1 receptors in human and rat brains. [2a,b] Thiochromane derivative 2 also displays a mixed binding affinity to dopamine D 2 , D 3 and 5HT A1 receptors, [2d] whereas thiochromane derivative 3 shows potent anti-HIV activity. [2e] Owing to their biological activities, several asymmetric methods have been developed for the synthesis of these compounds, which include asymmetric reduction of thiochroman-4-ones, [3] enzymatic resolution of racemic 4-hydroxythiochromanes or 4-acyloxythiochromanes, [4] and enantioselective alkylation of thiochromanes via conjugate addition.[5] Last year Wang and co-workers reported an enantioselective tandem Michael-aldol reaction for the synthesis of thiochromenes catalyzed by a proline derivative.[6] Most recently, the same group also reported a quinine thiourea-catalyzed tandem Michael-aldol reaction for synthesis of [13] Moreover, the synthesis of thiochromanes by using this tandem reaction has never been studied.[14] Herein, we report an organocatalytic, enantioselective tandem Michael-Henry reaction for the direct synthesis of 2-aryl-3-nitro-4-hydroxythiochromanes.By using 2-mercaptobenzaldehyde (8) and β-nitrostyrene (9) as the model compounds, we initially studied the tandem Michael-Henry reaction using 5 mol% of DABCO as the catalyst at room temperature (entry 1, Table 1). We were pleased to find that the reaction was completed in just 5 min and only two diastereomers of the expected 2-phenyl-3-nitro-4-hydroxythiochromane (10a) were obtained in a ratio of 70:30, according to the 1 H NMR analysis of the crude product. Encouraged by this result, we further screened some readily available alkaloid catalysts 4-7 (Figure 2) in an effort to develop an enantioselective reaction, and the results are summarized in Table 1.As shown in Table 1, with 5 mol% loading of quinine (4) in diethyl ether, the reaction of 8 and 9 proceeds smoothly, and complete conversion was achieved in just 5 min (entry 2). The same two diastereomers were formed in a ratio of 75:25. However, the ee value of the major diastereomer was only 8% fo...

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

“…In the same year Zhao et al [70] reported an efficient synthesis of highly functionalized thiochromans having three chiral centers, using a tandem thio-Michael–Henry reaction of 2-mercaptobenzaldehydes 34 with β-nitrostyrenes 46 and using cupreine XXXIXa as catalyst in anhydrous diethyl ether. The protocol afforded the corresponding thiochroman 47 with excellent enantioselectivities and moderate diastereoselectivities (Scheme 24).…”

Developing Novel Organocatalyzed Aldol Reactions for the Enantioselective Synthesis of Biologically Active Molecules

“…56 For example, the reaction of 2-mercaptobenzaldehyde (87) with trans -β-nitrostyrenes ( 88 ) afforded the corresponding thiochromane in 95% yield and 86% ee (Scheme 18). A series of 2-mercaptoaldehydes and nitrostyrenes with substituents of different electronic properties reacted smoothly to furnish the desired thiochromanes in moderate diastereoselectivities and good enantioselectivities (Scheme 18).…”

Substrate‐Controlled Diastereoselectivity Switch in the Formation of Dihydrothieno[3,4‐c]coumarins via [4+1] Annulations

“…[1] As such, efficient and practical synthetic methods to establish complementary diastereoselectivity in one-pot reactions from simple materials have rarely been explored. [2] The most practical solutions to diastereodivergence from the same starting materials often rely on catalysts, especially chiral catalysts, [3][4][5][6][7] because the use of controls such as substrates, temper-ature, and solvents for complementary diastereoselectivity has been a longstanding challenge. [8] In addition, chemoselective transformations open up a new avenue for the construction of complex molecules in synthetic organic and medicinal chemistry.…”