New Stereoselective Synthesisof 2-Allyl-4-nitroalkylpiperidine-2-thiones and their Transformationto Annulated Piperidinones

Abstract

Highly stereocontrolled access to trans-3-allyl-4nitro-alkyl-1,6-disubstituted δ-thiolactamswas achieved starting from piperidine-2-thione or commercially available2-mercaptopyridine via Michael-addition of nitroalkanes to 5,6-dihydropyridin-2-thiones,S-allylation and thio-Claisen rearrangement. The corresponding lactamsobtained by desulfurisation, were found to be suitable precursorsfor the construction of trans-fused bicyclic2-piperidinone derivatives (octahydro[2]pyrindinones)in a regio- and stereoselective radical 5-exo-trig annulationprocess.

thiolactams - lactams - nitro compounds - thio-Claisen rearrangement - radical 5-exo-trig annulation

References

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<A NAME="RG13103ST-10">10</A>

Preparation of 3b from2-mercaptopyridine: To a cooled and stirred solution of 2-mercaptopyridine(6.6 g, 0.059 mol) in dry THF (100 mL) at 0 °C 100 mL of1.6 M BuLi solution in hexane (1.6 mol) was added via syringe over5 min under argon. The mixture was stirred at 0 °C for2 h. After quenching with aqueous saturated NH₄Cl (20mL), the water layer was extracted with ethyl acetate (2 × 150mL) and the combined organic layers were dried over MgSO₄.Filtration, concentration in vacuo and purification by flash column chromatography(silica gel, n-hexane/ethylacetate, 7:3) yielded 1 in 72% (7.2g, 0.043 mol) as yellow solid, which was recrystallized from n-hexane. To a stirred mixture of 1 (362 mg, 2.14 mmol) and DBU (98 mg, 0.64mmol) in acetonitrile (4 mL) a portion of 0.27 mL of 3-buten-2-one (3.24mmol) was added over 10 min. The mixture was stirred for further1.5 h. After addition of diluted HCl (0.5 M, 10 mL) the solutionwas extracted with ethyl acetate (2 × 80 mL) and the combinedorganic layers were dried over MgSO₄. Filtration, concentrationin vacuo and purification by column chromatography (silica gel, n-hexane/ethyl acetate, 8:2)afforded 3b in 68% yield (348mg, 1.45 mmol) as yellow oil. IR(film): 2932, 2872, 1714, 1660,1622, 1492, 1346, 1150 cm^-1. MS (EI,70 eV): m/z = 239 (M⁺,56), 197 (14), 196 (98), 182 (13), 113 (16), 112 (100), 111 (53),97 (11), 78 (15), 71 (23), 67 (11), 55 (10%). ¹HNMR (400.1 MHz CDCl₃): δ = 0.90 (3H, t, J = 7.1 Hz, CH₃),1.17-1.38 (4 H, m, 2 × CH₂), 1.52-1.75(2 H, m, CH₂), 2.17 (3 H, s, COCH₃), 2.28(1 H, dd, J = 18.4 Hz, 6.6 Hz,CHH-5), 2.52 (1 H, ddt, J =18.4Hz, 14.0 Hz, 2.7 Hz, CHH-5), 2.95 (1H, dt, J =18.3 Hz, 5.4 Hz, COCHH), 3.23 (1 H, ddd, J =18.3Hz, 8.0 Hz, 6.3 Hz, COCHH), 3.51 (1 H,ddd, J =13.2 Hz, 8.0 Hz, 5.9Hz, NCHH), 3.90 (1 H, pseudo q, J = 7.2 Hz, CH-6), 4.62 (1 H,ddd, J = 13.2 Hz, 6.0 Hz, 5.2Hz, NCHH), 6.06 (1 H, br t, J = ca 8.4 Hz, CH-4), 6.43 (1H, dd, J = 9.5 Hz, 2.9 Hz, CH-3). ¹³CNMR (100.6 MHz CDCl₃): δ = 13.95 (CH₃), 22.60(CH₂), 27.30 (CH₂-5), 28.60 (CH₂),30.23 (COCH₃), 30.36 (CH₂), 41.06 (COCH₂),48.85 (NCH₂), 59.33 (CH-6), 128.25 (CH-4), 132.35 (CH-3),188.49 (C-1), 207.36 (CO); Anal. Calcd for C₁₃H₂₁NOS:C, 65.23; H, 8.84; N, 5.85; S, 13.40. Found: C, 65.10; H, 8.79;N, 5.80; S, 13.24.

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<A NAME="RG13103ST-13">13</A>

Preparation of 3c:To a solution of 1-methylpiperidine-2-thione (1)(0.97 g, 7.5 mmol) in dry THF (130 mL) a portion of 4 g of 55-56% moistenedwith oil NaH (Fluka) and methyl phenylsulfinate (1.87 g, 12.0 mmol)was added. The mixture was heated under reflux for 1 h and the solventwas evaporated in vacuo. To a cooled (0 °C) and vigorously stirredresidue, a mixture of 150 mL of water and 3 mL of H₃PO₄ wasadded carefully. The solution was extracted with CH₂Cl₂ (3 × 150mL) and combined organic layers were dried over Na₂SO₄.The solvent was evaporated and the residue was taken up in toluene(130 mL) and Na₂CO₃ (4 g) and the mixturewas heated under reflux for 1 h. After concentration in vacuo, purificationby column chromatography (silica gel, n-hexane/ethylacetate, 7:3 then 6:4 then 1:1) afforded 3c in50% yield (0.48 g, 3.77 mmol) as yellow solid, which wasrecrystallized from n-hexane. Mp 76-79 °C(n-hexane). IR (KBr) 3064, 2964, 2900,1622, 1520, 1392, 1344, 1272, 1242, 1130, 1108 cm^-1.MS (EI, 70 eV): m/z = 127(100, M⁺), 112(3), 97(12), 94(9), 84 (23%). ¹HNMR (400.1 MHz CDCl₃): δ = 2.39-2.45(2 H, m, CH₂-5), 3.50 (3 H, s, N-CH₃), 3.57(2 H, t, J = 7.6 Hz, CH₂-6), 6.23(1 H, dt, J = 9.5 Hz, 4.4 Hz,H-4), 6.50 (1 H, dt, J = 9.5 Hz,1.7 Hz, H-3). ¹³C NMR (100.6 MHz CDCl₃): δ = 23.64 (CH₂-5),42.77 (N-CH₃), 49.63 (CH₂-6), 130.12 (CH-4), 132.43(CH-3), 190.00 (C-1). Anal. Calcd for C₆H₉NS:C, 56.65; H, 7.13; N, 11.01; S, 25.21. Found: C, 56.46; H, 7.11; N,10.99; S, 25.11.

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<A NAME="RG13103ST-15">15</A>

Preparation of 4a-c. General procedure. α,β-Unsaturated thiolactam 1 or 3 (11.8 mmol)was dissolved in a solution of 2-nitropropane (5.15 mL, 59.1 mmol)and DBU (1.08 g, 7.09 mmol) in acetonitrile (10 mL). The mixturewas kept in refrigerator at -22 °C for 24 h (for 3b the reaction time was prolonged for3 days at r.t.) and the reaction mixture was subjected to columnchromatography (silica gel, n-hexane/ethylacetate, 8:2 then 7:3) to afford 4. Selecteddata:(4b). Yield 47%. White solid.Mp 102-103 °C (n-hexane:ethyl acetate).IR (KBr): 2956, 2932, 2872, 1710, 1534, 1512, 1376, 1348, 1176,1160 cm^-1; MS (EI, 70 eV): m/z = 327 (M⁺ - 1,2), 295 (3), 285 (80), 282 (47), 281 (79), 238 (100), 212 (50),196 (19), 170 (32), 154 (24), 138 (25), 112 (25), 97 (16), 69 (33),55 (27), 43 (11%). ¹H NMR (400.1 MHz C₆H₆): δ = 0.81(3 H, t, J = 7.1 Hz CH₃),0.79-0.90 (1 H, m, CHH), 0.90-0.98(1 H, m, CHH), 0.93 (3 H, s, CH₃),0.94 (3 H, s, CH₃), 1.04 (1 H, td, J = 13.5Hz, 5.2 Hz, H-5_ax), 1.06-1.18 (3 H, m, CH₂,CHH), 1.25-1.31 (1 H, m CHH), 1.31 (1 H, dq, J = 13.5Hz, ca 2.6 Hz, H-5_eq), 1.65 (3 H, s, COCH₃), 2.30-2.40(1 H, m, H-4_ax), 2.49 (1 H, dd, J = 18.1Hz, 11.1 Hz, H-3_ax), 2.57 (1 H, ddd, J = 18.2Hz, 6.5 Hz, 5.2 Hz, COCHH), 3.02 (1 H,dt, J = 18.2 Hz, 7.1 Hz, COCHH), 3.07 (1 H, ddd, J = 18.1Hz, 5.8 Hz, 2.0 Hz, H-3_eq), 3.39-3.46 (1 H,m, H-6), 3.46 (1 H, dt, J = 13.2Hz, 7.0 Hz, NCHH), 4.50 (1 H, ddd, J = ca 12.7 Hz, 6.8 Hz, 5.2Hz, NCHH). ¹³CNMR (100.6 MHz C₆H₆): δ = 14.03(CH₃), 19.77 (CH₃), 22.66 (CH₂),24.31 (CH₃), 26.74 (CH₂-5), 28.46 (CH₂),29.49 (COCH₃), 31.56 (CH₂), 36.27 (CH₂),40.37 (COCH₂), 42.88 (CH₂-3), 48.69 (NCH₂),61.12 (CH-6), 90.19 (CNO₂), 196.41 (C-1), 205,78 (CO).Anal. Calcd for C₁₆H₂₈N₂O₃S:C, 58.50; H, 8.59; N, 8.53; S, 9.76. Found: C, 58.44; H, 8.56; N,8.45; S, 9.58.

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<A NAME="RG13103ST-19">19</A>

Preparation of 8 from 4. General procedure: Thiolactam 4 (3.9 mmol) was dissolved in allylbromide(2.86 g, 23.6 mmol) and the mixture was kept at r.t. for 5 h (4b) or 2 days (4c).Excess of allylbromide was removed in vacuo and the resulting saltwas drying under reduced pressure at r.t. (1 h, 2 mmHg). The crudesalt was dissolved in CHCl₃ (40 mL) and Et₃N(4.6 mmol) was added. The mixture was stirred at 48-50 °Cfor 2 h. After concentration in vacuo, purification by column chromatography(silica gel, n-hexane/ethyl acetate,7:3 then 6:4 then 1:1) afforded 6. To astirred solution of 6 (1.1 mmol) in CH₂Cl₂ (15mL), MCPBA (57-80%, 620 mg) was added in a fewportions at 0 °C. After stirring for 0.5 h the solutionwas shaken with 15 mL of saturated NaHCO₃. The layerswere separated and the aqueous phase was extracted with CH₂Cl₂ (2 × 50mL). The combined organic layers were dried over MgSO₄.Filtration, concentration in vacuo and purification by flash column chromatography(silica gel, ethyl acetate) yielded 7.A solution of 7 (0.254 mmol), Bu₃SnH(0.2 mL, 7.6 mmol) and AIBN (17 mg, 0.1 mmol) in toluene (1 mL)was heated at 100 °C under Ar for 30 h with periodic additionsof Bu₃SnH (3 × 0.10 mL) and AIBN (3 × 15mg). After cooling to the room temperature the reaction mixturewas subjected to column chromatography (silica gel, CHCl₃/MeOH,9:1 then silica gel, diethyl ether/petroleum ether, 7:3)to give the mixture of 8 and 9. The subsequent separation by column chromatography(silica gel, diethyl ether/petroleum ether, 1:1 then 7:3)allowed to obtain pure analytical sample of 8. Selecteddata: Yield 43% (the mixture of 8b and 9b). 8b (majordiastereoisomer). Colorless oil. IR (film): 2960, 2872, 1716, 1642,1468, 1374, 1160 cm^-1. MS (EI, 70eV): m/z = 307 (M⁺,5), 251 (18), 250 (100), 192 (44), 180 (23), 164 (11), 137 (52),67 (17), 55 (17%). ¹H NMR (400.1 MHz C₆H₆): δ = 0.61(3 H, s, 5-CH_{3 α}), 0.75 (3 H, s, 5-CH_{3 β}),0.80 (3 H, d, J = 7.2 Hz, 6-CH_{3 β}),0.86 (3 H, t, J = 7.3 Hz, CH₃), 1.00-1.38(7 H, m, CH₂-4, CH₂, 2 × CHH, H-7_β), 1.40-1.55 (4H, m, 2 × CHH, H-7a_α,H-6_α), 1.71 (3 H, s, COCH₃), 2.06 (1H, td, J = 12.5 Hz,6.9 Hz, H-4a_β), 2.39-2.49 (2 H, m,H-7_α, COCHH), 2.83(1 H, dt, J = 17.5 Hz, 7.1 Hz,COCHH), 3.19 (1 H, dt, J = 13.5Hz, 7.0 Hz, NCHH), 3.37-3.42(1 H, m, H-3_α), 3.94 (1 H, ddd, J =13.5 Hz, 6.7 Hz, 5.5 Hz,NCHH). ¹³C NMR(100.6 MHz C₆H₆): δ = 14.18(CH₃), 17.77 (6-CH_{3 β}), 22.88(CH₂-4), 23.58 (5-CH_{3 α}),25.02 (5-CH_{3 β}), 27.08 (CH₂),29.18 (CH₂), 29.59 (COCH₃), 33.23 (CH₂),35.64 (CH₂-7), 39.71 (C-5), 41.10 (NCH₂),42.23 (COCH₂), 43.41 (CH-6), 45.38 (CH-7a_α),46.50 (CH-4a_β), 59.45 (CH-3), 172.39 (C-1),206.22 (C=O). Anal. Calcd for C₁₉H₃₃NO₂:C, 74.22; H, 10.82; N, 4.56. Found: C, 74.12; H, 10.85; N, 4.66.

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