Stereoselective amine-thiourea-catalysed sulfa-Michael/nitroaldol cascade approach to 3,4,5-substituted tetrahydrothiophenes bearing a quaternary stereocenter

  1. Sara Meninno,
  2. Chiara Volpe,
  3. Giorgio Della Sala,
  4. Amedeo Capobianco and
  5. Alessandra Lattanzi

Dipartimento di Chimica e Biologia “A. Zambelli”, Via Giovanni Paolo II, 84084, Fisciano, Italy

  1. Corresponding author email

This article is part of the Thematic Series "Bifunctional catalysis".

Guest Editor: D. J. Dixon
Beilstein J. Org. Chem. 2016, 12, 643–647.
Received 14 Dec 2015, Accepted 12 Mar 2016, Published 05 Apr 2016


An investigation on the stereoselective cascade sulfa-Michael/aldol reaction of nitroalkenes and commercially available 1,4-dithiane-2,5-diol to 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, is presented. A secondary amine thiourea derived from (R,R)-1,2-diphenylethylamine was found to be the most effective catalyst when using trans-β-methyl-β-nitrostyrenes affording the heterocyclic products in good yields and moderate stereoselectivities.

Keywords: cascade reaction; tetrahydrothiophenes; aymmetric synthesis; amine thioureas; organocatalysis


The interest toward the development of stereoselective methodologies to prepare tetrahydrothiophenes bearing multiple chiral centers increased over the last years [1]. Indeed, chiral non-racemic functionalized tetrahydrothiophenes are endowed with different biological activities [2-5] and they are useful ligands in asymmetric catalysis [6]. However, few asymmetric approaches are available to obtain this class of compounds and only recently organocatalytic stereoselective cascade reactions have emerged as the most successful, and straightforward approach to access them [7,8]. Aminocatalytic [9-12] and non-covalent organocatalytic cascade sulfa-Michael/Michael [13-15] and sulfa-Michael/aldol reactions [16-20] enabled the synthesis of differently functionalized tetrahydrothiophenes bearing up to three contiguous chiral centers, including quaternary ones, with good to high control of the diastereo- and enantioselectivity.

Surprisingly, to date there has been one report on a dynamic system combining a 1,1,3,3-tetramethylguanidine (TMG)/ZnI2-catalyzed diastereoselective cascade sulfa-Michael/nitroaldol reaction followed by lipases catalyzed kinetic resolution using two representative trans-β-methyl-β-nitrostyrenes and 1,4-dithiane-2,5-diol as reagents [21]. One diastereoisomer of the racemic tetrahydrothiophenes, present at the equilibrium, was preferentially acylated by the enzyme to give the product in high ee.

Different amines such as Et3N, DBU, TMG catalyze the sulfa-Michael/nitroaldol process of either trans-β-methyl-β-nitrostyrenes [21] and trans-β-nitrostyrenes [22] with 1,4-dithiane-2,5-diol. Based on all above considerations and prompted by our interest in asymmetric synthesis of functionalized tetrahydrothiophenes [14], we wondered whether we could use bifunctional organocatalysts to develop a diastereo- and enantioselective cascade sulfa-Michael/nitroaldol reaction and herein we report our preliminary results.

Results and Discussion

According to the literature data, low control of the diastereoselectivity was observed in the cascade reaction of 1,4-dithiane-2,5-diol with trans-β-nitrostyrenes, and in the case of (E)-1-aryl-2-nitropropene all four diastereoisomeric tetrahydrothiophenes were observed when using tertiary amines such Et3N, DBU or TMG [21,22].

At the outset, the sulfa-Michael/nitroaldol reaction was studied by reacting trans-β-nitrostyrene, (E)-1-phenyl-2-nitropropene and (E)-1-phenyl-2-nitrobutene in toluene at room temperature with 1,4-dithiane-2,5-diol as precursor of mercaptoacetaldehyde, using 10 mol % loading of different bifunctional organocatalysts (Scheme 1, Table 1).


Scheme 1: Organocatalysts screened in the cascade reaction.

Table 1: Asymmetric sulfa-Michael/nitroaldol reaction of nitroalkenes 13 with 1,4-dithiane-2,5-diol (4) catalyzed by catalysts IVIII.

[Graphic 1]
entry cat. 13 time (h) yield [%]a drb ee [%]c
1 I 1 5.5 75 58/42 (5/6) 9 (5)/15 (6)
2 II 1 2.5 79 60/40 (5/6) rac (5)/24 (6)
3 III 1 1.5 53 44/56 (5/6) rac (5)/12 (6)
4 IV 1 25 52 50/50 (5/6) −14 (5)/20 (6)
5 V 1 2 89 38/62 (5/6) −3 (5)/−10 (6)
6 VII 1 2 73 72/28 (5/6) −12 (5)/−24 (6)
7 I 2a 21 77 66/28/6 (7a/8a/9a) 19 (7a)
8 II 2a 17 77 66/27/7 (7a/8a/9a) 13 (7a)
9 III 2a 17 69 68/24/8 (7a/8a/9a) 4 (7a)
10 IV 2a 27 59 70/23/7 (7a/8a/9a) 2 (7a)
11 V 2a 18 72 68/24/8 (7a/8a/9a) −19 (7a)
12 VI 2a 44 16 69/25/6 (7a/8a/9a) 1 (7a)
13 VII 2a 28 90 58/30/12 (7a/8a/9a) −44 (7a)
14 VIII 2a 40 70 65/29/6 (7a/8a/9a) 19 (7a)
15 VII 3 52 80 50/27/23 (11/10/12) 42 (11)

aIsolated yield of all diastereoisomers after silica gel chromatography. bDetermined by 1H NMR analysis of the crude mixture. cDetermined by chiral HPLC analysis. Negative values indicate the prevalent formation of the opposite enantiomer.

In the case of trans-β-nitrostyrene (1), a mixture of diastereoisomers 5 and 6 were rapidly formed, irrespective of the catalyst used, with a poor level of diastereo- and enantioselectivity (Table 1, entries 1–5). Thiourea catalyst VII afforded the best result, leading to products 5/6 in a ratio of 72/28 although with low ee values (Table 1, entry 6). Reacting trisubstituted olefin 2a with compound 4, led to three isomers with modest diastereocontrol when using catalysts (I–VII). Among the catalysts tested, compound VII proved to be the most active and enantioselective, giving the major diastereoisomer 7a with 44% ee (Table 1, entry 13). Taking into account that amine thiourea VII, bearing a sterically hindered secondary amine moiety, was significantly more effective than tertiary amine-based thioureas [14,23], catalyst VIII, bearing a sterically demanding neopentyl group, was synthesized in order to check its impact on the stereoselectivity (Scheme 2).


Scheme 2: Synthesis of catalyst VIII.

Catalyst VIII was easily obtained in a two-step procedure in fair overall yield. Compound VIII proved to be less active, affording a comparable level of diastereoselectivity than compound VII, but a lower ee value for major diastereoisomer 7a was measured (Table 1, entry 14). Moreover, the opposite enantiomer of product 7a was preferentially obtained, thus suggesting that the nature of the alkyl group on the secondary amine moiety greatly affects the stereochemical outcome of the process. The relative configuration of diastereoisomers 7a/8a/9a was established by NOESY and NOE analysis on diastereoisomerically pure 7a and on a diastereoisomeric mixture of compounds 8a and 9a (see the Supporting Information File 1) [24].

Finally, catalyst VII was checked in the reaction of alkene 3 under the same conditions (Table 1, entry 15). After a longer reaction time, diastereoisomers 1012 were isolated with poor diastereomeric ratio and major isomer 11 was recoverd with 42% ee [25].

The diastereoselective ratios, determined for tetrahydrothiophenes deriving from alkenes 2a and 3, are in line with their computed thermodynamic stability in toluene (see the Supporting Information File 1). Indeed, products 8a and 9a were found to be 0.7 kcal/mol less stable compared to compound 7a. In the case of products 10–12, the predicted relative free energies for 10, 11 and 12 fall within a range of 0.1 kcal/mol.

Pleasingly, a solvent screening for the cascade reaction carried out on compound 2a with catalyst VII enabled to improve the diastereoselectivity as only 7a/8a were detected in 75:25 ratio and the enantiocontrol increased to 50% ee for diastereoisomer 7a when using chlorobenzene as the solvent at room temperature (Table 2, entry 5).

Table 2: Solvent screening in the asymmetric Michael/nitroaldol reaction of 2a with 1,4-dithiane-2,5-diol (4) catalysed by amine thiourea VII.

[Graphic 2]
entry solvent time (h) yield [%]a drb ee 7a [%]c
1 CH3CN 21 83 69/31 (7a/8a) 5
2 CH3Ot-Bu 47 93 72/24/4 (7a/8a/9a) 30
3 CHCl3 63 56 68/28/4 (7a/8a/9a) 51
4 ClCH2CH2Cl 63 55 70/30 (7a/8a) 51
5 C6H5Cl 16 69 75/25 (7a/8a) 50

aIsolated yield of all diastereoisomers after silica gel chromatography. bDetermined by 1H NMR analysis of the crude mixture. cDetermined by chiral HPLC analysis.

It is worth noting that bifunctional organocatalyst VII appears to be more effective in terms of diastereocontrol than previously employed Brønsted base/Lewis acid system TMG/ZnI2 giving four diastereoisomers instead [21].

Finally, the sulfa-Michael/nitroaldol cascade reaction was applied to other trans-β-methyl-β-nitrostyrenes under the optimized conditions (Table 3).

Table 3: Asymmetric sulfa-Michael/nitroaldol reaction of nitroalkenes 2 with 1,4-dithiane-2,5-diol (4) catalysed by amine thiourea VII.

[Graphic 3]
entry R1 time (h) yield [%]a drb ee 7 [%]c
1 Ph 16 69 75/25 (7a/8a) 50
2 4-ClC6H4 16 66 69/31 (7b/8b) 51
3 4-MeC6H4 40 76 74/26 (7c/8c) 42
4 2-naphthyl 45 90 66/26/8 (7d/8d/9d) 59

aIsolated yield of all diastereoisomers after silica gel chromatography. bDetermined by 1H NMR analysis of the crude mixture. cDetermined by chiral HPLC analysis.

Tetrahydrothiophenes, bearing three contiguous stereocenters, were isolated in good to high yield, moderate diastereoselectivity and up to 59% ee.


In conclusion, we reported a diastereo- and enantioselective cascade sulfa-Michael/nitroaldol reaction of (E)-1-aryl-2-nitropropenes with 1,4-dithiane-2,5-diol. The process was catalyzed by an easily available amine thiourea to give 3,4,5-substituted tetrahydrothiophenes, bearing a quaternary stereocenter, in good yield and moderate enantiocontrol. It has been demonstrated that a simple bifunctional amine thiourea secures a more effective control of the diastereoselectivity than Brønsted base/Lewis acid systems. Data herein illustrated suggest that fine tuning of the bifunctional organocatalyst structure and reaction conditions will be required for further improvements of the challenging cascade process.

Supporting Information

Supporting Information File 1: Experimental procedures, characterization data, NMR spectra of new compounds and HPLC traces of synthesized compounds, computational details.
Format: PDF Size: 3.7 MB Download


We thank the Italian Ministry of University and Research (MIUR) and University of Salerno for financial support.


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