trans-2-Phenyl-4-thiophenoxy-3,4-dihydro-2H-1-benzothiopyran

Abstract

Iodine-catalyzed cyclocondensation of cinnamaldehyde and thiophenol yields rapidly trans-2-phenyl-4-thiophenoxy-3,4-dihydro-2H-1-benzothiopyran in excellent yield with very high diastereoselectivity.

Introduction

3,4-Dihydro-2H-1-benzothiopyran derivatives (thiochromans) exhibit a wide range of biological activities, which include anti-bacterial, anti-inflammatory, anti-psychotic, anti-hyperplasia and anti-cancer activities [1]. Therefore, development of new and facile synthetic routes leading to such heterocycles for assessment of their biological potential is of considerable interest. A survey of the literature shows that there are a variety of methods available for the synthesis of these compounds, among which the reaction of thiophenols with α,β-unsaturated aldehydes [2,3] or allyl alcohols [4] in presence of various acidic catalysts are particularly important. Iodine is known to show Lewis acid properties [5,6,7] and in recent years these are being nicely exploited for achieving varieties of addition, elimination and condensation reactions. Thus, the conjugate addition of thiophenol to α,β-unsaturated ketones has been reported to be catalyzed by iodine [5]. Our endeavor to synthesize 3,4-dihydro-2H-1-benzothiopyrans started by taking two readily available fragments, viz., thiophenol and cinnamaldehyde and using iodine as catalyst, the interesting results of which are presented herein.

Results and Discussion

In the present study, when a mixture of thiophenol and cinnamaldehyde in CH₂Cl₂ was stirred at room temperature for 16 hours, only one product was obtained in excellent yield (90%). Characterization of the product from its spectral (IR, ¹H and ¹³C NMR including HMBC and HMQC, and MS) data showed it to be trans-2-phenyl-4-thiophenoxy-3,4-dihydro-2H-1-benzothiopyran (1). The trans configuration was ascertained from a comparison of the J-values of the four aliphatic protons of the product with the reported J-values for the aliphatic protons of cis and trans isomers of 4-acetoxy-2-alkylchromans [8] and 4-methoxyflavans [9] and those for cis-1,3-diarylthiochromans [10]. Confirmation of the said structure was finally obtained from X-ray crystallographic studies (ORTEP diagram shown in Figure 1) [11].

Scheme 1. Synthetic route to the title compound 1.

Scheme 1. Synthetic route to the title compound 1.

Our attempt to reduce the reaction time by carrying out the reaction at the boiling temperature of CH₂Cl₂ was not very successful, because the product was not at all clean, possibly due to some polymerization reactions.

In a report of synthesis of 2-aryl-4-thioaryloxy-3,4-dihydro-2H-1-benzothiopyrans and 2-alkyl-4-thioaryloxy-3,4-dihydro-2H-1-benzothiopyrans, Ishino et al. [2] reported that they obtained both the cis and trans isomers of these compounds (2a/2b and 3a/3b) and they could not separate the diastereomers. Without isolating the pure diastereomers, they determined the composition of the mixtures from the ¹H NMR spectral data of the product mixtures. Subsequently, Jafarzadeh et al. [3] have reported the synthesis of such compounds without mentioning any stereochemistry (i.e., the products having the structure 4) by tungstophosphoric acid catalyzed cyclocondensation of α,β-unsaturated aldehydes and thiophenols, but the ¹H NMR spectral data reported by them corresponded neither with the data reported by Ishino et al. [2] nor with the data recorded by us. Moreover, the ¹H NMR spectral data for the aliphatic protons of two compounds (4a and 4b) of the same series reported by them differed significantly [4a: δ 3.54 (1H, d, J = 7.3 Hz), 5.19 (1H, d, J = 9.3 Hz), 6.22 (1H, dd, J = 1.8 and 8.7 Hz), 6.39 (1H, dd, J = 1.9 and 8.9 Hz); 4b: δ 4.98 (1H, d, J = 7.0 Hz), 6.18 (1H, d, J = 9.2 Hz ), 6.41 (1H, dd, J = 1.7 and 8.5 Hz ), 6.89 (1H, dd, J = 1.6 and 8.5 Hz)]. It was very difficult to understand why the data for these two closely related compounds differed so widely. This left some doubt about the identity of the compounds isolated by Jafarzadeh et al. [3]. The very high diastereoselectivity of the iodine-catalyzed reaction described here may be accounted for by considering that the stable cation 5 generated by initial combination of the two reactants followed by a cyclization is attacked very selectively from the side opposite of the existing phenyl (Scheme 2)

Experimental Section

To a mixture of cinnamaldehyde (1 mmol) and thiophenol (2 mmol) in dry dichloromethane (30 mL), iodine (64 mg, 0.25 mmol) was added and the reaction mixture was stirred in N₂ atmosphere at room temperature (30 °C). When the reaction was complete after 16 h, the reaction mixture was diluted with dichloromethane (25 mL) and the resulting solution was washed with sodium thiosulphate solution (2 × 25 mL) and water (2 × 25 mL), successively. The solid material obtained after removal of the solvent showed one TLC spot and it was purified further by passing through a silica gel (100–200 mesh) column followed by crystallization from chloroform-petroleum ether, yield: 90%; mp. 102 °C, colorless cubes.

IR (KBr) cm⁻¹: 3028, 2903, 1585, 1562, 1470, 1453, 1436, 1297, 1249, 1152, 1058, 960, 745. ¹H NMR (300 MHz, CDCl₃): δ 2.43–2.51 (2H, m, H₂-3), 4.74 (1H, t, J = 3.1 Hz, H-4), 5.15 (1H, dd, J = 9.2 and 5.6 Hz, H-2), 7.00–7.06 (1H, m, H-6), 7.10–7.17 (2H, m), 7.28–7.38 (7H, m), 7.41–7.45 (2H, m), 7.49–7.52 (2H, m). ¹³C NMR (75 MHz, CDCl₃): δ 34.69, 40.50, 49.15, 123.91, 125.89, 127.84, 127.90, 128.72, 129.16, 130.73, 131.55, 133.10, 134.25, 134.74, 140.72. MS (TOF MS ES⁺): Calcd. for C₂₁H₁₈S₂ (M+K)⁺: 373.0487; found 373.0115. Elemental analysis: Calcd. for C₂₁H₁₈S₂: C, 75.40; H, 5.42. Found: C, 75.12; H, 5.59%.

Conclusions

Thus, we report here a very simple and highly diastereoselective synthesis of trans-2-phenyl-4-thiophenoxy-3,4-dihydro-2H-1-benzothiopyran which itself and its analogues are expected to find important applications.