INTRODUCTION:

Substituted Tetrahydrothiopyran motifs find wide spread occurrences in a great number of biologically active natural products and therapeutic agents. Some tetrahydrothiopyrans are found in petroleum products.¹The sulfur analogues of oligosaccharides are found to be potential enzyme inhibitors.² The development of facile methods to access various six-membered cyclic thio ethers are therefore of great interest in organic synthesis.³ The intermolecular addition between a thionium and alkene provides a convenient avenue to various cyclic thio ethers. Although there are many procedures for the synthesis of Tetrahydropyrans.⁴The methods for the synthesis of Tetrahydrothiopyrans are limited. Tetrahydrothiopyrans are prepared by prins cyclization.⁵ But the existing methods are associated with major drawbacks such as lack of diasteroselectivity and use of expensive reagents. This thionium ene type cyclization can be classified into three sub types based on mikamis terminology namely (1, 5), (2, 5) and (3, 5). However the class of (3, 5) cyclization is rarely reported and its synthetic value demands in depth investigations.

Recently, molecular iodine has received considerable attention in organic synthesis because of its high tolerance to air and moisture, low cost, non toxic nature and readily availability, affording the corresponding products with high selectivity in excellent yields. The mild Lewis acidity associated with iodine has led to its use in organic synthesis using catalytic to stoichometric amounts.⁶ Thionium–ene- cyclization reactions have been intensively studied in the recent past they have been considered as powerful tools for the construction of various cyclic thioethers.⁷

In continuation of our interest in heterocyclic chemistry. Here in, we report an Iodine catalyzed (3, 5)-thionium–ene type cyclization.

MATERIAL AND METHODS:

General information:

All the chemicals were from sigma Aldrich and used without purifications. ¹H-NMR spectra were recorded in CDCl₃and CCl₄ on 400MH_Z NMR spectrometer using TMS as internal standard. The ¹³C-NMR spectra were recorded at 100MH_Z–CDCl₃and CCl₄was used as internal standard.IR spectra were recorded on FT-IR spectrometer. MASS spectra were obtained on Finnegan TSQ-70instrument.

Syntheses of 6-methylhept-5en-2thiol were synthesized as per literature procedure.⁸

General procedure for the synthesis of 2,5,5-trimethyl-3,4,4a,10b-hexahydro-2H,5Hthiopyrano[3,2-c]chromene (3a,Table 1):

To a stirred solution of 6-methylhept-5-en-2thiol (0.150g, 1.171 mmol) in dichloromethane (5 ml) was added aldehyde (0.117g,1.171 mmol) and stoichiometric amount of molecular iodine(0.148g,0.585mmol) at 25°C. The resultant mixture was stirred at the same temperature for the specified amount of time (Table 1).The progress of the reaction was monitored by TLC. After completion the reaction was quenched with water and extracted with ethyl acetate(2×5 ml).The combined organic layers were washed with aqueous sodium thio sulfate followed by brine solution and dried over anhydrous sodium sulfate. Removel of the solvent followed by purification of silica gel (merk100-200mesh) using ethyl acetate/hexane (0.5/9.5)as eluant gave the pure Tetrahydrothiopyran. All products were characterized by IR, NMR and MASS spectrometry.

¹H NMR (400 MHz, CDCl₃+CCl₄): d 7.47 (d, J = 7.5Hz, 1H), 7.18(dt, J = 8.3, 1.0 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.78(d, J = 8.3 Hz, 1H), 4.26(d, J = 10.8 Hz, 1H), 3.71 (ddq, J = 12.3, 6.3,2.4 Hz, 1H), 1.95-1.64 (m, 4H), 1.50-1.40 (m, 1H),1.40 (s, 3H), 1.33 (d, J = 6.3 Hz, 1H),1.20(s,3H); ¹³C NMR (100 MHz, CDCl₃+CCl₄): d 152.7, 128.6, 126.1, 122.5, 119.8, 116.6, 78.2, 73.7, 73.1, 44.6, 33.5, 27.7, 25.3, 21.9, 20.4; DEPT-135 (100 MHz, CDCl₃); d 152.3,128.6, 126.1, 119.8, 116.6, 73.6, 73.1, 44.5, 33.5, 27.7, 25.3, 22.1, 20.4 ; IR (neat): υ 3038, 2969, 2851, 1601, 1582,1480, 1380, 1369, 1315, 1301, 1247, 1138, 1105, 1078, 941, 931 cm^-1; HRMS calcd for C₁₅H₂₀S O[M⁺]: 248.1463, found: 248.1460.

3b: 6-Methyl-2-pentyl-3-(prop-1-en-2-yl)tetrahydro-2H-thiopyran: 1H NMR (400 MHz, CDCl3+CCl4): d4.70(s, 2H), 3.40 (ddq, J = 12.3, 6.0, 1.8 Hz, 1H), 3.20 (t, J= 9.9 Hz, 1H), 1.90 (dt, J = 10.1, 3.8 Hz, 1H), 1.70 (s,3H), 1.62-1.42 (m, 6H), 1.34-1.28 (m, 6H), 1.19 (d, J= 6.7 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H); 13C NMR (100MHz, CDCl3+CCl4):d 147.1,111.7,73.5, 49.4,33.6, 33.5, 31.9, 30.2, 25.3, 22.7, 22.0, 20.1, 14.1;DEPT-135 (100 MHz, CDCl3): d 111.7, 79.7, 73.5,49.4 ,33.6, 33.5, 31.9, 30.2, 25.3, 22.7, 22.0, 20.1,14.1; IR (neat): υ 2929, 1375, 1264, 1698, 892, 735 cm^-1; HRMS calcd for C14H26S [M+]: 226.2063, found:226.2078.

3c:6-Methyl-2-propyl-3(prop-1-en-2-yl)tetrahydro-2H-thiopyran: 1H NMR (400 MHz, CDCl3+CCl4): d 4.69(s,2H),3.38 (ddq, J = 12.2, 6.1, 2.0 Hz, 1H), 3.20 (t, J= 10.0 Hz, 1H), 1.89 (dt, J = 10.2, 3.8 Hz, 1H), 1.67(s,3H),1.68-1.56(m,6H),1.55-1.43 (m, 2H), 1.15 (d, J= 6.7 Hz, 3H), 0.85 (t, J = 6.8 Hz, 3H); 13C NMR (100MHz, CDCl3+CCl4):d 147.0,111.7,79.4,73.5, 49.4,35.7, 33.6, 30.2, 22.0, 20.1, 18.7, 14.1; DEPT-135 (100MHz, CDCl3): 111.7, 79.4, 73.5, 49.4, 35.7, 33.6, 30.2, 22.0, 20.1, 18.7, 14.1;IR(neat):υ2929, 1375, 1264, 1698, 892, 735 cm^-1; HRM Scalcd for C₁₂H₂₂S[M+]:198.2064, found:198.2060.

3d: 3-Isopropenyl-6-methyl-2-phenethyltetrahydrothiopyran:

1HNMR(400MHz,CDCl3+CCl4):d7.28-7.15(m,5H),4.69-4.71 (m, 2H), 3.42 (ddq, J = 12.5, 6.2, 2.0Hz, 1H), 3.20 (dt, J = 9.6, 2.4 Hz, 1H), 2.90 (ddd, J =13.5, 9.6, 4.7 Hz, 1H), 2.61 (ddd, J = 13.5, 9.0, 7.5 Hz,1H), 1.91 (dt, J = 9.6, 3.5 Hz, 1H), 1.81-1.52 (m, 5H),1.30 (dt, J = 12.1, 3.5 Hz, 1H), 1.21 (d, J = 6.2 Hz, 3H);13C NMR (100 MHz, CDCl3+CCl4): d 146.8, 142.6,128.5, 128.1, 125.5, 111.9, 78.4, 73.6, 49.5, 35.1, 33.4, 31.6, 30.3, 22.3, 19.5; DEPT-135 (100 MHz, CDCl3): d 128.5, 128.1, 125.5, 111.9, 78.4, 73.6, 49.5, 35.2, 33.6,31.6, 30.2, 22.5, 14.3; IR (neat): υ 3068, 3021, 2968,2925, 2862, 2845, 1083, 1071, 896, 694 cm^-1;HRM Scalcd for C₁₇H₂₄S[M+]:260.1827, found: 260.1825.

3e: 2-Furan-2-yl-3-isopropenyl-6-methyltetrahydropyran: 1HNMR(400MHz,CDCl3+CCl4): d7.357.31(m,1H),6.27(dd, J = 3.1, 2.1 Hz, 1H),6.23 (d, J = 3.1 Hz, 1H), 4.65 (brs, 2H), 4.37 (d, J =10.5 Hz, 1H), 3.59 (ddq, J = 12.3, 6.2, 2.1Hz,1H),

2.56-2.50 (m, 1H), 1.96-1.84 (m, 1H), 1.75-1.65 (m,2H), 1.55 (s, 3H), 1.48-1.26(m,1H), 1.23(d, J=6.2Hz,3H); 13CNMR (100 MHz, CDCl3+CCl4): d 153.6,145.9, 141.6, 111.8, 109.8, 107.6, 77.3, 74.3, 47.1,33.2, 30.2, 21.9, 20.4;DEPT135(100MHz, CDCl3): d 141.6, 111.8, 109.8, 107.6, 76.3, 74.3, 47.1, 33.2,30.2, 22.1, 14.2; IR (neat): υ3115,3072,2970,2932,2856,1642, 1502, 1443, 1404, 1382, 1365, 1312,1241, 1231, 1152, 1120, 1102, 1074, 1047, 1011, 905,802, 732 cm^-1; HRMS calcd for C13H18O S [M+]:222.1307, found: 222.1301.

3f:2,2-Dimethyl-6-(4-nitrophenyl)-5-(prop-1-en- 2yl)tetrahydro2Hthiopyran: 1HNMR(400MHz,CDCl3+CCl4): δ8.15 (d,J=8.8Hz,,2H), 7.50(d,J=8.8Hz,H),4.70(s,1H),4.58(s,1H),4.56(d,J=10.2Hz,1H),2.10(dt,J=10.5Hz,1H),1.961.86(m,1H),1,77-1.72(m,1H),1.69-1,65(m,2H), 1.45(s,3H), 1.35(s,3H), 1.30(s,3H); 13CNMR (100MHz,CDCl₃+CCl₄):δ 146.3, 141.4, 128.0, 127.5, 127.4,116.6, 84.3, 77.4, 74.3, 50.3, 33.6, 30.4, 22.2, 21.5; IR(neat): υ 3059, 3028, 2981, 2945, 2869, 2862, 1478,1085, 1069cm^-1; HRMS calcd for C₁₆H₂₁NO₂ S [M+]:290.2217, found: 290.2012.

3g: 6-(4-Chlorophenyl)-2-,2-dimethyl-5-(prop-1en2yl) tetrahydro2Hthiopyran: 1HNMR(400MHz,CDCl3+CCl4): δ 7.20 (m, 4H), 4.90 (s, 1H), 4.62 (s,1H), 4.49 (d, J = 9.9 Hz, 1H), 2.10 (m, 1H), 1.70 (m,2H), 1.60 (m, 2H), 1.50 (s, 6H), 1.35 (s, 3H); 13CNMR(100 MHz, CDCl₃+ CCl₄): δ 145.3,138.7,133.7, 129.6, 128.9, 128.6, 126.9, 112.6, 78.7, 74.5,49.4, 33.5, 30.3, 22.0, 21.0; IR (neat): υ 3069, 3027, 2 972, 2930,2855, 2848, 1082, 1075, 891, 699 cm^-1; HRM Scalcd for C₁₆H₂₁SCl[M+]:281.1627. found: 281.1620.

3h: 2-Methyl-6-(4-nitrophenyl)-2-phenyl-5-(prop-1en-2yl)-tetrahydro-2H-thiopyran:1HNMR(400MHz,CDCl3+CCl4): δ 8.05(d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 7.15-7,10 (m, 3H), 6.85-6.90 (m, 2H), 5.30 (s, 1H), 5.15 (s, 1H), 4.70 (d, J =

10.1 Hz, 1H), 2.65-2.55 (m, 1H), 2.02-1.92(m,2H),1.75-1.70 (m, 2H),1.55 (s, 3H), 1.40 (s, 3H ); 13C NMR (100 MHz,CDCl3+CCl4): δ148.1, 146.2, 129.0, 128.0, 125.9,124.5, 123.5, 84.1, 77.2, 74.5, 50.1, 32.5, 30.2, 22.2,21.3; IR (neat): υ 3055, 3019, 2979, 2935, 2871, 2859,1478, 1075, 1053 cm^-1;HRMS calcd for C21H23NO2 S[M+]: 353.2879, found: 353. 2856.0

3i:3-(6-Methyl-6-phenyl-3-(prop-1-en-2yl)tetrahydro-2H-thiopyran2yl)phenol:1HNMR(400Hz,CDCl3+CCl4): δ 7.547.20 (m, 7H), 6.79 (s, 2H), 5.52(s, 1H), 5.40 (s, 1H), 5.21 (d, J = 10.2 Hz, 1H), 2.90 (m,1H), 2.051.55(m,4H), 1.45 (s,3H), 1.10(s, 3H); 13CNMR (100 MHz, CDCl₃+ CCl₄): δ 151.5, 128.5, 127.9,125.9, 124.5, 127.3, 122.1, 113.6, 116.5, 96.3, 78.6, 73.5, 73.0, 44.1, 33.1, 27.6, 25.2, 21.4, 21.1; IR (neat):υ 3455, 3025, 2959, 2925, 2851, 2849, 1055, 1043 cm^-1; HRM Scalcd for C₂₁H₂₄O S [M+]: 324.4715, found:324.4709.

RESULTS AND DISCUSSION:

Initially, we attempted the coupling of 6-methyl hept-5en-2thiol (1) with salicylaldehyde in the presence of stoichometric amount of molecular iodine in dichloro methane. The reaction proceeds smoothly at 25^oC and desired 2,5,5-trimethyl-3,4,4a,10b-tetrahydro-2H,5H thiopyrano(3,2-c)chromene was obtained in 90% yield (3a,table 1).Similarly aliphatic aldehydes such as n-hexanal, n-butylaldehyde, underwent smooth coupling with thiol(1) to give the respective tetrahydro thio pyrans in good yields (entries b, c Table1). Interestingly 3-phenylpropionaldhyde and benzaldehyde, also participates well in this reaction (entries d and j Table1). Remarkably, acid sensitive aldehyde such as furfuraldehyde also afforded the desired product reasonably in good yields (entries i Table 1). Other moieties such as 6-methyl-2-phenyl hept-5-en-2-thiol and 2, 6-dimethylhept-5-en-2-thiol also participated well in this reaction to afford the isopropenyl-6-methyl-6-phenyltetrahydrothiopyran and 3-isopropenyl-6,6-dimethyltetrahydrothiopyran derivatives respectively (entries e-h, Table 1). In all cases, the desired six membered tetrahydropyrans were formed exclusively in good yields with high selectivity (Table 1). The structures of all the compounds were determined by H NMR, 13C NMR, IR, and DEPT experiments. It should be noted that aliphatic aldehydes gave higher yields than aromatic aldehydes. The reaction proceeds through a step wise manner via carbocation intermediate, but not in a concerted fashion, which is evident from the result obtained from salicylaldehyde and 6-methylhept-5-en-2thiol (1). In case of salicylaldehyde, the intermediate carbocation could be successfully trapped with ortho-hydroxyl group affording the tricyclic compound, i.e. (2,5,5-trimethyl-3,4,4a,10b-tetrahydro-2H,5H-thiopyrano(3,2-c)chromene (entry a, Table 1). This observation suggests that thionium-ene cyclization proceeds in a step wise manner via carbocation intermediate.

Mechanistically, the reaction was proposed to proceed through the formation of thiocarbenium ion from aldehyde and 6-methylhept-5en-2thiol likely after activation by iodine. The formation of (E) thiocarbenium ion via chair like transition state increases its stability relative to open thiocarbenium ion due to delocalization. The thiocarbenium ion is attacked by olefin with concominent ene-reaction resulting in the formation of trans-2, 3, 6-trisubstituted tetrahydro thio pyran.

CONCLUSION:

The successfully demonstrated a metal-free protocol for the synthesis of 2, 3, 6-trisubstituted tetrahydrothiopyrans using molecular iodine under mild conditions. The use of iodine makes this procedure simple, convenient and economically viable. This method provides a direct access to a wide range of substituted tetrahydrothiopyrans.

ACKNOWLEDGEMENTS:

Authors are thankful to the Department of Science and Technology (DST), Govt. of India for the financial assistance (F.No.SR/FT/CS-011/2009).

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Received on 15.05.2013 Modified on 10.06.2013

Asian J. Research Chem. 6(10): October 2013; Page 906-910