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Synlett 2003(11): 1673-1677
DOI: 10.1055/s-2003-41016
LETTER
© Georg ThiemeVerlag Stuttgart ˙ New York

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

Jacek G. Sośnicki*
Technical University of Szczecin, Institute of Chemistry and Environmental Protection, Al. Piastów 42, 71065 Szczecin, Poland
Fax: +48(91)4494639; e-Mail: sosnicki@ps.pl.;
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Publication History

Received 10 June 2003
Publication Date:
11 August 2003 (online)

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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.

Key words

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

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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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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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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-5ax), 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-5eq), 1.65 (3 H, s, COCH3), 2.30-2.40(1 H, m, H-4ax), 2.49 (1 H, dd, J = 18.1Hz, 11.1 Hz, H-3ax), 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-3eq), 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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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-CH3 α), 0.75 (3 H, s, 5-CH3 β),0.80 (3 H, d, J = 7.2 Hz, 6-CH3 β),0.86 (3 H, t, J = 7.3 Hz, CH3), 1.00-1.38(7 H, m, CH2-4, CH2, 2 × CHH, H-7β), 1.40-1.55 (4H, m, 2 × CHH, H-7aα,H-6α), 1.71 (3 H, s, COCH3), 2.06 (1H, td, J = 12.5 Hz,6.9 Hz, H-4aβ), 2.39-2.49 (2 H, m,H-7α, 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-3α), 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-CH3 β), 22.88(CH2-4), 23.58 (5-CH3 α),25.02 (5-CH3 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-7aα),46.50 (CH-4aβ), 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.