A facile and highly diastereoselective synthesis of cis -2,4-diarylthiochromans

A simple methodology has been developed for diastereoselective synthesis of cis -2,4-diarylthiochromans in three steps starting from chalcones. The methodology involves reduction of the conjugate addition product of thiophenol to chalcones followed by Amberlyst-15 catalyzed cyclization of those reduction products. 79.48; H, 6.06. 136.7, Anal. Calcd for C 22 H 19 ClOS C, 72.02; H, 5.22. Found: C, 72.21; H, 5.01.


Introduction
Thiochromans (3,4-dihydro-2H-1-benzothiopyrans) (1) form a useful class of heterocyclic compounds. Derivatives of 1 have been reported to show a wide range of biological activities, the important ones of which may include their diuretic, anti-inflammatory, antipyretic, analgesic, antidepressant, antihypertensive, anti-amoebic and antimicrobial activities. 1 They are also used as agents against angina pains and as oral infertility agents. 1 Besides, they find a good number of important industrial applications, e.g., they are commonly used as fuel additives, resins, dyes, solvent clathrates and in uranium extraction. 1,2 Regarding their synthetic utilities, thiochroman derivatives are found to be useful synthons for some sesquiterpenoids, the key step in the transformation being Raney nickel induced desulfurization. 3 All the above applications of thiochromans have made them important synthetic targets for organic chemists. This has led to the development of a number of methodologies for their synthesis, which may be mainly categorized as (i) intramolecular electrophilic aromatic substitution of aryl thioethers with functional groups like carbonyl, 1,5 chlorine, 3,4 thioacetal 6 and alcohol, 7,8 (ii) thio-Claisen rearrangement of allyl phenyl sulphides, 1,8-10 (iii) reduction of the corresponding thiochromones and thiochromanones, 1,11,12 (iv) Diels-Alder cycloadition, 13,14 (v) cationic cycloadition involving a benzotriazolyl thioether derivative, 15 (vi) a thermal rearrangement, possibly involving substitution of chlorine by a thiol, 1 (vii) thermal cyclization using an oxirane ring 2 and (viii) acid and base catalysed cyclization of the corresponding alcohols. 16 In continuation of our recent studies on development of new methodologies for synthesis of thiochroman derivatives, 17,18 we report here a simple synthesis of cis-2,4-diarylthiochromans in a highly diastereoselective manner using common starting materials like chalcones and thiophenol and involving the use of the sulfonated polystyrene resin amberlyst-15 as a catalyst in the final step.

Results and Discussion
The present work began by using unsubstituted chalcone (2a) as the starting material. In the first step it was reacted with thiophenol under iodine catalyzed condition. 19 The conjugate addition product 3a was obtained in good yield. Sodium borohydride reduction of 3a gave a mixture of two diastereomeric alcohols (4a) (approximately in 1:1 ratio, as assessed by 1 H NMR) in very good yield. The mixture was directly used for the next step without separating its components. Treatment of the alcohol mixture with amberlyst-15 in dry toluene at 80 o C afforded the cis-2,4diphenylthiochroman (5a) as the only product (Scheme-1).
Scheme 1. Synthetic route to cis-2,4-diarylthiochromans (5). The cis stereochemistry has been assigned on the basis of 1 H NMR spectral features of the product. Thus, the two doublet of doublets appearing at 4.26 (J = 10.2 and 6.3 Hz) and 4.64 (J = 9.9 and 4.5 Hz) are characteristic of the pseudoaxial H-4 and axial H-2, respectively, as reported earlier. 15 Extending this study by involving eleven other chalcones, analogous results were obtained (Table 1). X-Ray crystallographic study done on 5l confirmed the cis stereochemistry (ORTEP diagram given in Figure 1) 20 .  The formation of only one diastereoisomer of 2,4-diarylthiochroman in each case clearly indicates that under the influence of amberlyst-15 a common stable carbocation 6 is formed from both the diastereoisomers of 4. Cyclization of this carbocation is highly stereoselective and the stereoselectivity is controlled by the existing chirality in it. For rationalization of the result, it may be considered that the transition state for the cyclization is formed through an approach of the thiophenoxy moiety in the way shown in Scheme-2.

Scheme 2. Plausible mechanism for diastereoselective formation of cis-2,4-diarylthiochromans (5).
There are two previous reports of cyclization of 1,3-diaryl-3-phenylsulfanylpropan-1-ols (4) leading to 2,4-diarylthiochromans. Jensen et al. 2 first performed the cyclization of 4 (prepared in a different way) by refluxing them in toluene with added TsOH and obtained only cis-2,4diarylthiochromans (5). They considered the possibility of occurrence of different mechanisms and finally concluded that the process is a case of aromatic electrophilic substitution. Few years later, Skarzewski et al. 16 reported a detailed study of cyclization of 4 with KHSO 4 in toluene as well as with MesCl/Et 3 N by using both optically active and racemic varieties of the substrates. It was their observation that both cis and trans products were formed along with products from 1,3phenyl shift (through involvement of a cyclic four membered sulfonium ion). In between these two reports, Katritzky and Button reported the synthesis of 5 and some related compounds by a Lewis acid catalyzed reaction involving α-(benzotriazolyl)methyl thioethers and styrenes 15 . It may be mentioned here that their results show that cis product was exclusively formed only in two out of seven cases studied.

Conclusions
We report here a simple method for synthesis of cis-2,4-diarylthiochromans in a highly diastereoselective manner.

Experimental Section
General. Mps were recorded on a Köfler block and are uncorrected. IR spectra were recorded on Perkin Elmer FT-IR Spectrophotometer (Spectrum BX II) as KBr pellets. 1 H and 13 C NMR spectra were obtained in CDCl 3 on Bruker AV-300 (300 MHz), Bruker AC-200 (200 MHz), Bruker DPX-300 (300 MHz) and Bruker DPX-500 (500 MHz) spectrometers using TMS as an internal standard. Mass spectrum was acquired on a Waters QTOF Micro YA263 Mass Spectrometer. Analytical samples were dried in vacuo at room temperature. Column chromatography was performed on silica gel (100-200 mesh) using petroleum ether (60-80 o C) and petroleum ether-ethyl acetate mixtures as eluents. TLC was done with silica gel G.

General method for preparation of 1,3-diaryl-3-phenylsulfanyl-1-propanones (3)
To a mixture of chalcone (2) (2 mmole) and thiophenol (2.4 mmole ) a pinch of iodine was added and the reaction mixture was kept at 6-10 °C for 1-1.5 h. Excess iodine was removed by treatment with ice cold saturated Na 2 S 2 O 3 solution and the organic material was extracted with dichloromethane (3×15 ml). The combined organic layer was dried over anhydrous Na 2 SO 4