Domino Prins cyclisation for Stereoselective synthesis of Oxygen bridged bicyclic thioethers using Amberlyst-15

 

N. Prudhviraju¹*, R.L. Satyanarayana¹, S. Ramesh¹, J. Padmavathi¹, B. Nagamani¹, B. Jagan Mohan Reddy², B. V. Subba Reddy³

¹B.V. Raju College, Vishnupur, Bhimavaram, West Godavari District, 534202, India.

²Department of Organic Chemistry, Adikavi Nannaya University, Rajahamahendravaram, 533105, India.

³Natural Product Chemistry, CSIR-Indian Institute of Chemical Technology, Tarnaka, 500007, Hyderabad, India

 

ABSTRACT:

A domino reaction has been developed for the synthesis of Oxygen bridged bicyclic thio ethers through the coupling of 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol with aldehydes in the presence of Amberlyst-15 in dichloromethane at 25^oC. This method is a highly diastereoselective affording the corresponding bicyclic thio ethers i.e. (1R,4aR,7R,8aR)-7-methyl-1-(2,4,5-trifluorophenyl)octahydro-4a,7-epoxyisothiochromene in good yields with high selectivity. It is the first report on the synthesis of Oxygen bridged bicyclic thioethers using a domino Prins strategy.

 

 

 

INTRODUCTION:

Oxygen bridged bicyclic core (englerin) is frequently found in various natural products such as englerin, orientalol, oxyphyllol and saniculamoid A etc (Figure 1).¹

 

Figure1. Representative examples for Oxygen bridged bicycles

 

They are known to exhibit promising cytotoxicity against renal cancer cell lines.² Of various sulphur oxygenated heterocycles, tetrahydropyran ring is often present as a core structure of many biologically active natural products.³

 

Therefore, several efforts have been made to develop efficient synthetic approaches for the synthesis of these heterocycles.⁴

 

Among them, Prins cyclization is one of the most reliable strategies for the construction of tetrahydrothiopyran ring system.^5,6 In particular, Prins cascade is a highly convergent approach for the stereoselective synthesis of fused/bridged tetrahydrothiopyran derivatives.^7,8 Besides its potential use in natural products synthesis,^9-10 the scope of this cascade process has not yet been explored for the synthesis of Oxygen bridged thiobicycles from readily accessible aldehydes and 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol. However, the development of a simple and metal-free approach for the construction of Oxygen bridged bicyclic thio ethers using inexpensive and readily available reagents is well appreciated. Recently, Amberlyst-15 has received a considerable attention in organic synthesis because of its low cost and ready availability.¹¹ The mild Lewis acidity associated with Amberlyst-15 has enhanced its use in organic synthesis to perform several organic transformations using stoichiometric levels to catalytic amounts.¹²

 

 

Following our interest on the catalytic application of Amberlyst-15,¹³ we herein report a metal-free approach for the synthesis of Oxygen bridged thiobicycles from 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol.  and aldehyde through a cascade of Prins cyclization. In a preliminary experiment, 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol (1) was treated with p-fluorobenzaldehyde (2) in the presence of Amberlyst-15in dichloromethane. To our delight, the reaction proceeded smoothly at room temperature to afford the corresponding oxygen bridged bicyclic thio ether 3a in 82% yield (entry a, Table 1). 

 

Scheme 1. Cascade cyclization of 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol (1) with p-fluorobenzaldehyde (2).

 

MATERIAL AND METHODS:

General methods:  

IR spectra were recorded on FT-IR spectrometer (KBr) and reported in reciprocal centimetres (cm^-1). ¹HNMR spectra were recorded at 500 MHz and ¹³C NMR at 125 MHz. For 1H NMR, tetramethylsilane (TMS) was used as internal standard (δ = 0) and the values are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t= triplet, q =quartet, m = multiplet), and the coupling constants in Hz. For ¹³C NMR, CDCl₃ (δ = 77.27) was used as internal standard and spectra were obtained with complete proton decoupling. HRMS data were obtained using EI ionization.

 

General Procedure for Products 3(a-n):

To a stirred solution of aldehyde (1.1 mmol) and 1a or 1b (1.0mmol) in dichloromethane (5.0mL), was added Amberlyst-15 at 0^oC. The resulting mixture was stirred at 25°C for the specified time. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the mixture was quenched with water and the product was extracted with ethyl acetate. The organic layers were washed with aqueous sodium thiosulfate followed by brine solution and dried over anhydrous sodium sulfate. Removal of the solvent followed by purification on silica gel (Merck 100–200 mesh) using ethyl acetate/hexane (2:8) as eluent gave the pure tetrahydropyran.

 

Characterization data for 1a:

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃): δ 5.42 (s, 1H), 3.74-3.64 (m, 2H), 2.31-1.91 (m, 8H), 1.71 (td, J = 13.1, 7.1 Hz, 1H), 1.64-1.54 (m, 1H), 1.24 (s, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 133.5, 121.3, 68.3, 60.0, 40.5, 39.5, 35.2, 28.8, 25.6 ppm; IR(neat): ν 3353.7, 2925.4, 1648.8, 1431.0, 1044.8, 764.5 cm^-1; HRMS (m/z) calcd for C₉H₁₆OS: 172.09503, found: 172.0975.

 

Characterization data for 1b:

 

Light yellow Liquid; ¹H NMR (500 MHz, CDC_l3): δ 5.41 (s, 1H), 4.01-3.95 (m, 1H), 3.75-3.59 (m, 2H), 2.62-2.30 (m, 2H), 2.29-2.11 (m, 3H), 2.10-1.93 (m, 2H), 1.89-1.77 (m, 1H), 1.76-1.63 (m, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 133.9, 120.7, 66.2, 60.0, 40.6, 33.9, 30.4, 25.5 ppm; IR (neat): ν 3377.5, 2927.1, 1714.6, 1648.6, 1439.2, 1049.9, 758.7 cm^-1; HRMS (m/z) calcd for C₈H₁₄OS: 158.08938, found: 158.08942.

 

CHARACTERIZATION DATA OF PRODUCTS:

1-(4-fluorophenyl)-7-methyloctahydro-4a,7-epoxyisothiochromene (3a):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃): δ 7.29-7.22 (m, 1H, Ar-H), 6.93-6.85 (m, 1H, Ar-H), 4.34 (dd, J = 1.0, 10.5 Hz, 1H, H1), 4.01 (ddd, J = 1.2, 6.0, 11.5 Hz, 1H, H5), 3.83 (ddd, J = 3.0, 11.5, 12.7 Hz, 1H, H5'), 2.07 (ddd, J = 6.1, 12.8, 14.8 Hz, 1H, H4), 2.01-2.03 (m, 1H, H4'), 2.04-1.95 (m, 1H, H2), 1.74-1.54 (m, 5H, H8, H8', H9, H9', H6), 1.49 (s, 3H, Me10), 1.15-1.10 (m, 1H, H6'); ¹³C NMR (125 MHz, CDCl₃): δ 156.1, 156.0, 154.2, 154.1, 150.4, 150.3, 150.2, 148.4, 148.3, 148.2, 148.1, 148.0, 146.2, 146.1, 124.5, 124.4, 116.7, 116.7, 116.6, 116.5, 105.5, 105.3, 105.2, 105.1, 84.5, 82.1, 75.7, 65.5, 48.8, 39.3, 37.4, 37.3, 30.0, 21.2 ppm; ¹⁹F NMR (470 MHz, CDCl₃):  δ -118.98 (d, J = 15.5 Hz), -134.32 (s), -134.36 (s), -142.24 (dd, J = 21.4, 15.6 Hz); IR(neat): ν 2957.8, 2284.4, 1638.4,1514.6 1206.2, 767.9 cm^-1; HRMS (m/z) calcd for C₁₆H₁₇FOS: 278.11806, found: 278.11750.

7-methyl-1-(4-nitrophenyl)octahydro-4a,7-epoxyisothiochromene (3b):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃): δ 8.19 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 15.0 Hz, 2H), 4.19–4.00 (m, 2H), 3.97–3.77 (m, 1H), 2.22–1.85 (m, 3H), 1.75–1.56 (m, 5H), 1.52 (s, 3H), 1.20-1.12 (m, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 148.2, 147.4, 128.0, 123.5, 84.6, 82.9, 82.1, 65.3, 49.1, 40.5, 37.5, 37.1, 30.1, 21.3 ppm; IR(neat): ν 2937.9, 2267.5, 1734.8, 1527.4, 1374.3, 1074.3, 819.6, 746.1 cm^-1; HRMS (m/z) calcd for C₁₆H₁₉NO₃S: 305.11141, found: 305.11131.

 

1-(4-isopropylphenyl)-7-methyloctahydro-4a,7-epoxyisothiochromene (3c):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 7.26 (d, J = Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.09-3.99 (m, 1H), 3.99 (dd, J = 24.1, 5.7 Hz, 1H), 3.84 (ddd, J = 12.9, 11.5, 2.8 Hz, 1H), 2.98-2.78 (m, 1H), 2.14–2.05 (m, 2H), 1.98 (dd, J = 14.7, 1.9 Hz, 1H), 1.73–1.54 (m, 4H), 1.49 (s, 3H), 1.22 (d, J = 7.0 Hz, 6H), 1.17–1.11 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 148.5, 137.7, 127.4, 126.4, 84.4, 83.7, 82.3, 65.3, 48.5, 40.7, 37.6, 37.3, 33.8, 30.3, 23.9, 23.9, 21.4 ppm; IR(neat): ν 2960.4, 2864.9, 1731.8, 1457.4, 1084.8, 822.5 cm^-1; HRMS (m/z) calcd for C₁₉H₂₆OS: 302.17328, found: 302.17402.

 

1-(4-bromothiophen-2-yl)-7-methyloctahydro-4a,7-epoxyisothiochromene (3d):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 7.16 (d, J = 1.4 Hz, 1H), 6.89 (d, J = 0.8 Hz, 1H), 4.21 (d, J = 10.3 Hz, 1H), 4.03 (ddd, J = 11.5, 6.0, 1.1 Hz, 1H), 3.83 (ddd, J = 12.9, 11.5, 2.9 Hz, 1H), 2.10–2.02 (m, 2H), 1.97 (dd, J = 14.8, 1.9 Hz, 1H), 1.80 (dd, J = 12.5, 8.1 Hz, 1H), 1.75–1.56 (m, 5H), 1.50 (s, 3H), 1.17 (dt, J = 12.5, 3.1 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 145.4, 127.2, 122.3, 108.9, 84.6, 82.1, 78.7, 65.4, 49.2, 41.1, 37.3, 37.2, 30.0, 21.3 ppm; IR(neat): ν 2925.0, 1721.1, 1362.2, 1091.4,765.6  cm^-1;  HRMS (m/z) calcd for C₁₄H₁₇BrO₂S₂: 343.99326, found: 343.99320.

 

1-(3-bromophenyl)-7-methyloctahydro-4a,7-epoxyisothiochromene (3e):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 7.51 (s, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 6.3 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 4.04 (dd, J = 11.4, 5.9 Hz, 1H), 3.96 (d, J = 10.3 Hz, 1H), 3.88–3.78 (m, 1H), 2.15–1.93 (m, 3H), 1.75–1.54 (m, 5H), 1.50 (s, 3H), 1.18-1.08 (m, 1H) . ¹³C NMR (125 MHz, CDCl₃): δ 142.9, 130.9, 130.4, 129.8, 126.1, 122.5, 84.5, 83.2, 82.1, 65.3, 48.8, 40.5, 37.5, 37.2, 30.2, 21.3 ppm; IR(neat): ν 2936.7, 2861.8, 2357.3, 1717.0, 1609.4, 1371.5,1262.7, 1020.2, 958.6, 770.9 cm^-1 ;  HRMS (m/z) calcd for C₁₆H₁₉BrOS: 338.03715, found: 338.03700. 

 

4-(7-methyloctahydro-4a,7-epoxyisothiochromen-1-yl)phenol (3f):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃): δ 7.21 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.5 Hz, 2H), 4.06–3.99 (m, 1H), 3.93 (d, J = 10.4 Hz, 1H), 3.90-3.80 (m, 1H), 2.13–2.02 (m, 2H), 1.98 (dd, J = 14.8, 1.9 Hz, 1H), 1.77–1.54 (m, 5H), 1.49 (s, 3H), 1.10-1.00 (m, 1H); ¹³C NMR (125 MHz, CDCl₃); δ 155.3, 132.5, 129.0, 115.2, 84.5, 83.4, 82.4, 65.4, 48.6, 40.6, 37.5, 37.3, 30.3, 21.3 ppm; IR(neat): ν 3419.8, 2931.9, 2265.6, 1716.8, 1451.3, 1202.7, 1077.2, 764.1 cm^-1; HRMS (m/z) calcd for C₁₆H₂₀O₂S: 276.12124, found276.12023.

 

(E)-7-methyl-1-(2-nitrostyryl)octahydro-4a,7-epoxyisothiochromene (3g):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 7.93 (d, J = 8.0 Hz, 1H), 7.64–7.49 (m, 2H), 7.43–7.35 (m, 1H), 7.06 (d, J = 15.8 Hz, 1H), 6.07 (dd, J = 15.9, 6.2 Hz, 1H), 4.04-3.96 (m, 1H), 3.88–3.64 (m, 2H), 2.08–1.91 (m, 2H), 1.90–1.78 (m, 2H), 1.73–1.54 (m, 4H), 1.52 (s, 3H), 1.28–1.20 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 133.3, 133.0, 132.7, 128.7, 128.1, 126.6, 124.4, 84.5, 81.8, 81.3, 64.7, 47.3, 40.5, 37.5, 37.2, 30.2, 29.7, 21.3 ppm; IR(neat): ν 2947.8, 2862.9, 2275.5, 1738.8, 1528.4, 1372.5, 1004.7, 809.8, 745.6 cm^-1; HRMS (m/z) calcd for C₁₈H₂₁O₃N: 331.12706, found: 331.12702.

 

1-isobutyloctahydro-4a,7-epoxyisothiochromene (3h):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 4.52 (t, J = 5.3 Hz, 1H), 3.92 (ddd, J = 11.3, 5.8, 1.0 Hz, 1H), 3.60 (ddd, J = 12.7, 11.5, 2.9 Hz, 1H), 2.94 (td, J = 10.1, 1.9 Hz, 1H), 2.05–1.96 (m, 1H), 1.92 (dd, J = 14.6, 2.0 Hz, 1H), 1.87–1.73 (m, 1H), 1.63-1.57(m, 2H), 1.53–1.44 (m, 3H), 1.33–1.20 (m, 3H), 1.10-1.03(m, 1H), 0.89 (dd, J = 14.9, 6.0 Hz, 6H);  ¹³C NMR (125 MHz, CDCl₃):  δ 81.9, 79.0, 64.6, 46.6, 42.5, 35.8, 35.0, 31.4, 30.1, 29.6, 24.3, 23.9, 21.6; IR(neat): ν 2955.2, 2864.9, 1733.7, 1464.2, 1108.1,  759.3 cm ^-1 ;  HRMS (m/z) calcd for C₁₃H₂₂OS: 226.14198, found: 226.14189.

 

1-(4-methoxyphenyl)octahydro-4a,7-epoxyisothiochromene (3i):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 7.31–7.23 (m, 2H), 6.89–6.83 (m, 2H), 4.56 (t, J = 5.1 Hz, 1H), 4.07–4.01 (m, 1H), 3.90 (d, J = 10.3 Hz, 1H), 3.86-3.80 (m, 1H), 3.79 (s, 3H), 2.21–2.08 (m, 1H), 2.04–1.96 (m, 2H), 1.86–1.75 (m, 1H), 1.61–1.53 (m, 2H), 1.51–1.33 (m, 3H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 159.1, 132.4, 128.5, 113.6, 83.1, 82.0, 76.8, 65.2, 55.0, 46.9, 35.6, 34.4, 31.4, 29.8 ppm;  IR(neat): ν 2929.3, 2860.3, 1730.4, 1614.7, 1513.6, 1247.5, 1083.8, 815.5 cm^-1 ;  HRMS (m/z) calcd for C₁₆H₂₀O₂S: 276.12124, found: 276.12223.

 

1-(naphthalen-1-yl)octahydro-4a,7-epoxyisothiochromene (3j):

 

White solid;  ¹H NMR (500 MHz, CDCl₃):  δ 8.31 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H),  7.56–7.36 (m, 4H), 4.62 (d, J = 10.6 Hz, 1H), 4.57 (t, J = 5.2 Hz, 1H), 4.17–4.08 (m, 1H),  4.00 (ddd, J = 13.1, 11.5, 2.7 Hz, 1H), 2.50 – 2.40 (m, 1H), 2.33–2.22 (m, 1H),  2.11 (dd, J = 14.8, 1.9 Hz, 1H), 1.89–1.78 (m, 1H), 1.70–1.57 (m, 2H), 1.52–1.39 (m, 2H), 1.37–1.29 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 134.9, 134.2, 132.1, 128.7, 128.6, 125.9, 125.4, 125.2, 124.9, 124.6, 82.2, 81.2, 65.7, 45.2, 35.9, 35.0, 31.6, 30.1, 29.6;  IR(neat):  ν 2926.6, 2857.8,  2298.1, 1641.4, 1511.2, 1215.7,  1090.4, 771.0 cm^-1; HRMS (m/z) calcd for C₁₉H₂₆OS: 296.12633, found: 296.12630.

 

1-(4-isopropylphenyl)octahydro-4a,7-epoxyisothiochromene (3k):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 7.28-7.24 (m, 2H), 7.18 (d, J = 8.1 Hz, 2H), 4.56 (t, J = 5.0 Hz, 1H), 4.07–3.99 (m, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.82 (ddd, J = 13.1, 11.6, 2.7 Hz, 1H), 2.94–2.79 (m, 2H), 2.21–2.12 (m, 1H), 2.04–1.97 (m, 2H), 1.85–1.76 (m, 1H), 1.62–1.55 (m, 1H), 1.51-1.35 (m, 3H), 1.21 (d, J = 6.7 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃); δ 129.0, 128.4, 127.2, 126.2, 83.4, 82.0, 76.8, 65.2, 46.7, 35.6, 34.5, 33.6, 31.4, 29.8, 23.7 ppm ; IR(neat): ν 2960.4, 2863.9, 1727.6, 1638.3, 1084.7, 764.5 cm^-1; HRMS (m/z) calcd for C₁₈H₂₄OS: 288.15763, found: 288.15642.

 

(E)-1-styryloctahydro-4a,7-epoxyisothiochromene (3l):

 

White solid; ¹H NMR (500 MHz, CDCl₃):  δ 7.37 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 5.7 Hz, 2H), 7.23 (t,  J = 7.3 Hz, 1H), 6.60 (d, J = 16.0 Hz, 1H), 6.09 (dd, J = 16.0, 6.6 Hz, 1H), 4.57 (t, J = 5.2 Hz, 1H), 4.02 (dd, J = 11.4, 5.8 Hz, 1H), 3.80–3.71 (m, 1H), 3.60 (dd, J = 10.1, 6.6 Hz, 1H), 2.09 (ddd, J = 19.9, 13.8, 6.5 Hz, 1H), 1.98 (dd, J = 14.7, 2.2 Hz, 1H), 1.87–1.71 (m, 2H), 1.64–1.47 (m, 4H), 1.47-1.40 (m, 1H. ¹³C NMR (125 MHz, CDCl₃): δ 136.7, 131.5, 128.4, 127.7, 127.6, 126.4, 81.7, 81.7, 77.1, 64.7, 45.9, 35.7, 34.6, 31.6, 29.9 ppm; IR(neat): ν 2929.2, 2860.9, 2271.1, 1728.7, 1645.9, 1454.7, 1100.1, 975.1, 747.7 cm^-1; HRMS (m/z) calcd for C₁₇H₂₀OS: 272.12633, found: 272.12630.

 

1-(2-bromophenyl)octahydro-4a,7-epoxyisothiochromene (3m):

 

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃):  δ 7.55 (dd, J = 8.0, 1.1 Hz, 1H), 7.44 (dd, J = 7.8, 1.6 Hz, 1H), 7.34–7.29 (m, 1H), 7.14 (td, J = 7.9, 1.7 Hz, 1H), 4.59 (t, J = 5.2 Hz, 1H), 4.51 (d, J = 10.6 Hz, 1H), 4.07–4.00 (m, 1H), 3.88 (ddd, J = 12.9, 11.5, 2.8 Hz, 1H), 2.20–2.08 (m, 2H), 2.03 (dd, J = 14.7, 2.1 Hz, 1H), 1.88–1.78 (m, 1H), 1.64–1.55 (m, 2H), 1.54–1.44 (m, 2H), 1.44–1.36 (m, 1H) ppm; ¹³C NMR (125 MHz, CDCl₃): δ 139.4, 132.9, 129.3, 129.1, 127.6, 124.9, 82.1, 81.0, 77.1, 65.6, 46.8, 35.8, 33.5, 31.7, 29.9 ppm; IR(neat): ν 2925.5, 2860.5, 2361.9, 1708.1, 1611.9, 1465.4, 1204.5, 1076.9, 989.4, 753.4 cm^-1 ; HRMS (m/z) calcd for C₁₅H₁₇BrOS: 324.02119, found: 324.02110.

 

1-benzyloctahydro-4a,7-epoxyisothiochromene (3n):

 

Light yellow Liquid; ¹H NMR (500 MHz, CDCl₃): δ 7.31–7.25 (m, 2H), 7.24–7.17 (m, 3H), 4.52 (t, J = 5.2 Hz, 1H), 3.93–3.85 (m, 1H), 3.56 (ddd, J = 12.9, 11.5, 2.8 Hz, 1H), 3.24–3.17 (m, 1H), 2.73 (dd, J = 14.4, 3.2 Hz, 1H), 2.61 (dd, J = 14.4, 8.5 Hz, 1H), 2.06–1.96 (m, 1H), 1.90 (dd, J = 14.7, 1.8 Hz, 1H), 1.83–1.73 (m, 1H), 1.67–1.56 (m, 2H), 1.55–1.43 (m, 3H), 1.34–1.27 (m, 1H); ¹³C NMR (125 MHz, CDCl₃): δ 139.0, 129.2, 128.1, 126.0, 81.9, 81.9, 77.0, 64.7, 46.0, 39.7, 35.8, 35.3, 31.4, 30.0; IR(neat): ν 2926.1, 2864.8, 1738.5, 1474.6, 1106.3, 757.8 cm^-1;  HRMS (m/z) calcd for C₁₆H₂₀OS: 260.12633, found: 260.12629.

 

RESULTS AND DISCUSSION:

The relative stereochemistry of the compound 3a has been derived by using 1D and 2D NMR experiments. The major NOE cross peaks are depicted in Figure 2. The large scalar coupling constant between H1 and H2 (³J_H1-H2=10.5 Hz) and the presence of NOE cross peak between H1/H5' indicate H1, H2 and H5' protons are in the axial positions in chair conformation as indicated in Figure 2. The stereochemistry at C2, C3 and C7 was derived by the observation of NOE cross peaks between H1/H6', H4'/H9, H6'/H8 imply the fused "O" is in the axial position whereas C6 in the equatorial position as indicated in Figure 2.

 

Inspired by the above results, we extended this method to various aldehydes like aromatic, heterocyclic and aliphatic aldehydes.

 

Figure 2. Characteristic nOe cross peaks of 3a and ORTEP diagram of 3j.

 

Interestingly, several aromatic aldehydes such as p-nitro-,  p-isopropyl-, m-bromo-, p-hydroxy- derivatives participated well in this reaction (entries b, c, e and f, Table 1). Notably, electron-deficient substrate such as p-nitrobenzaldehyde also gave the desired product in good yield (entry b, Table 1). Furthermore, the reaction proceeded quite effectively with p-hydroxybenzaldehyde with out the protection of hydroxyl group (entry f, Table 1). In case of aromatic aldehydes, the corresponding aryl substituted oxa-thio bicycles were obtained in good yields. In addition, heteroaromatic substrate, i.e. 4-bromothiophene-2-carboxaldehyde was also effective for this conversion (entry d, Table 1). In addition, the reaction was quite successful even with α,β-unsaturated aldehydes such as 2-nitrocinnamaldehyde and cinnamaldehyde (entries g and l, Table 1). The scope of this cascade reaction was further exemplified by the coupling of 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol with different aldehydes (entries h-n, Table 1). In all cases, the corresponding products were obtained in good yields. Finally, we attempted the coupling of 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol with styrene oxide under the influence of a catalytic amount of Amberlyst-15 in dichloromethane at 25°C. Interestingly, the desired product was obtained in 72% yield (entry n, Table 1). Therefore, this method was successful not only with aldehydes but also with epoxide.    

 

The reaction was also carried out using commonly used catalysts such as Molecular Iodine, trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TSA), BF₃.OEt₂ and TMSOTf. Among them, Amberlyst-15 was found to be the best catalyst in terms of conversion. Next, we examined the effect of solvents such as dichloromethane, acetonitrile, toluene and dimethoxyethane. Among them, dichloromethane gave the best results. No improvement in the conversion was observed either by increasing the reaction time or catalyst loading.

 

 

Table 1. Synthesis of oxygen bridged thiobicycles

 

 

 

In the absence of Amberlyst-15, no cyclization was observed even after a long reaction time (24 h). The reactions proceeded smoothly at room temperature under mild and neutral conditions. No side products were detected under these conditions. No additives or stringent reaction conditions are required to facilitate the reaction. The scope and generality of this process is illustrated with respect to aldehydes and the results are presented in Table 1.

Mechanistically, the reaction was assumed to proceed via the formation of oxocarbenium ion from 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol and aldehyde after activation with Amberlyst-15. A subsequent attack of the olefin on oxo-carbenium ion led to the formation of carbocation, which is simultaneously trapped with a tertiary hydroxyl group to furnish the desired bicyclic thio ether (Scheme 2). Alternatively, Amberlyst-15 is acidic Resin and which may be responsible for the activation of aldehyde to facilitate the reaction.

 

Scheme 2. A plausible reaction pathway

 

In this cascade process, the tertiary alcohol attacks preferentially from the less hindered side to produce the oxygen bridged thio bicycle 3 with high stereoselectivity. Recently, Barbero et al. also showed the preferential equatorial attack of internal nucleophile when termination of Prins cyclization occurs intramolecularly.¹⁴

 

CONCLUSION:

We have demonstrated a novel metal-free approach for the synthesis of 1-(4-fluorophenyl)-7-methyloctahydro-4a,7-epoxyisothiochromene derivatives through a domino Prins cyclization between 4-(2-mercaptoethyl)-1-methylcyclohex-3-en-1-ol and aldehydes. The use of readily accessible precursors and inexpensive Amberlyst-15 makes it quite simple and more attractive. This method offers notable advantages such as mild/neutral conditions, good conversions and excellent selectivity.

 

ACKNOWLEDGEMENTS:

Authors are thankful to the Department of Science and Technology (DST), Govt. of India for the financial assistance (F.No.SR/FT/CS-011/2019).

 

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Received on 20.01.2021                    Modified on 05.02.2021

Accepted on 19.02.2021                   ©AJRC All right reserved