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DOI: 10.1055/s-2006-951548
Synthesis of Chiral 3,4,5,6-Tetrahydro-1,4-thiazin-2-ones (Thiamorpholin-2-ones) - Novel Heterocycles Possessing Enhanced Carbonyl Electrophilicity over their Oxygen Counterparts
Publication History
Publication Date:
23 November 2006 (online)
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Abstract
We report herein the first synthesis of chiral derivatives possessing the 1,4-thiazinone core. As predicted, the thiolactone is more susceptible to nucleophilic attack than the equivalent lactone system.
Key words
chiral - 1,4-thiazinone - thiamorpholinone
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1a
Draffin WN.Harwood LM. Synlett 2006, 857 -
1b
Aldous DJ.Drew MGB.Draffin WN.Hamelin EM.-N.Harwood LM.Thurairatnam S. Synthesis 2005, 3271 -
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References and Notes
Representative Experimental Procedures.
Cyclization of 3a to Produce 4a and 5a.
To a solution of 2-oxo-2-phenylethyl-(S)-N-Boc-thioalanate (3a, 3.88 g, 12 mmol) in anhyd CH2Cl2 (50 mL) was added TFA (12.5 mL). The resulting solution was stirred under an atmosphere of nitrogen for 2 h. The solvent and the excess of TFA were removed in vacuo and the residue was dissolved in anhyd CH2Cl2 (50 mL) to which K2CO3 (8.28 g, 60 mmol, 5.0 equiv) was added. The resulting mixture was stirred under an atmosphere of nitrogen for 24 h. Filtration through a short pad of Celite® and removal of solvent from the filtrate in vacuo gave the crude material which was purified by flash column chromatography on silica, eluting with light PE and Et2O (4:1) to furnish the inseparable mixture of title products as a yellow oil (1.44 g, 59%).
Reduction of 4a and 5a to Produce 6a.
To a solution of (S)-3-methyl-5-phenyl-4,5-didehydro-1,4-thiazin-2-one (4a) and (S)-3-methyl-5-phenyl-5,6-didehydro-1,4-thiazin-2-one (5a, 100 mg, 0.49 mmol) in anhyd THF (5 mL) was added sodium cyanoborohydride (62 mg, 0.97 mmol 2.0 equiv) and AcOH (ca. 5 drops). The resulting solution was stirred under an atmosphere of nitrogen for 12 h. The solvent was removed in vacuo to give the crude material which was purified by flash column chromatography on silica, eluting with light PE and Et2O (8:1, then 4:1) to furnish the title product as a pale yellow oil (63 mg, 62%).
Reduction and Thiolactone Cleavage to Produce 7d.
To a solution of (S)-3-(2-methylpropyl)-5-phenyl-4,5-didehydro-1,4-thiazin-2-one (4d) and (S)-3-(2-methyl-propyl)-5-phenyl-5,6-didehydro-1,4-thiazin-2-one (5d, 92 mg, 0.38 mmol) in anhyd MeOH (8 mL) was added sodium cyanoborohydride (70 mg, 1.12 mmol, 3.0 equiv) and AcOH (ca. 5 drops). The resulting solution was stirred under an atmosphere of nitrogen for 24 h. The solvent was removed in vacuo to give the crude material which was purified by flash column chromatography on silica, eluting with light PE and Et2O (4:1) to furnish the title product as a pale yellow oil (56 mg, 61%).
Representative Analytical Data.
Compounds 4a and 5a (mixture): IR (film): νmax = 3391 (N-H), 2983 (C-H), 1683 (C=O, thiolactone) cm-1. 1H NMR (250 MHz, CDCl3) δ = 7.74-7.27 (5 H, m, Ph), 5.22 (0.35 H, s, PhC=CH), 4.22 (0.65 H, d, J = 15.3 Hz, CH2S), 4.02-3.97 (0.65 H, m, CH3CH), 3.96 (0.65 H, d, J = 15.3 Hz, CH2S), 3.66-3.61 (0.35 H, m, CH3CH), 1.59 (1.95 H, d, J = 6.3 Hz, CHCH3), 1.32 (1.05 H, d, J = 7.3 Hz, CHCH3). MS (CI): m/z (%) = 205 (44) [M+], 181 (66), 162 (100). HRMS: m/z calcd for C11H11NOS: 205.0561; found: 205.0562.
Compound 6a: IR (film): νmax = 3319 (N-H), 2929 (C-H), 1668 (C=O, thiolactone) cm-1. 1H NMR (250 MHz, CDCl3): δ = 7.45-7.32 (5 H, m, Ph), 4.30 (1 H, dd, J = 10.82 Hz, J′ = 3.31 Hz, PhCH), 3.86 (1 H, q, J = 6.67 Hz, CHCH3), 3.55 (1 H, dd, J = 11.69 Hz, J′ = 10.82 Hz, CH2S), 3.13 (1 H, dd, J = 11.69 Hz, J′ = 3.31 Hz, 1 × CH2S), 1.89 (1 H, br, NH), 1.40 (1 H, d, J = 6.67 Hz, CHCH3). 13C NMR (62.5 MHz, CDCl3): δ = 200.6, 142.3, 129.4, 128.8, 126.8, 65.2, 60.1, 38.8, 18.2. MS (CI): m/z (%) = 208 (51) [MH+], 131 (46), 121 (100). HRMS: m/z calcd for C11H14NOS: 208.0796; found: 208.0788. [α]436
20 -1.0 (c 0.70 CHCl3), [α]D
20 0.0 (c 0.70 CHCl3).
Compound 7d: IR (film): νmax = 3308 (N-H), 2956 (C-H), 1734 (C=O, ester) cm-1. 1HNMR (250 MHz, CDCl3): δ = 7.29-7.17 (5 H, m, Ph), 3.63 (3 H, s, CH3O), 3.47 (1 H, dd, J = 8.7 Hz, J′ = 4.8 Hz, PhCH), 2.95 [1 H, dd, J = 8.9 Hz, J′ = 5.5 Hz, (CH3)2CHCH2CH], 2.76 (1 H, dd, J = 13.3 Hz, J′ = 4.6 Hz, CH2S), 2.51 (1 H, m, CH2S), 1.78-1.72 [1 H, m, (CH3)2CHCH2], 1.41-1.26 [2 H, m, (CH3)2CHCH2], 0.79 [3 H, d, J = 6.6 Hz, 3 × (CH3)2CH], 0.62 [3 H, d, J = 6.6 Hz, 3 × (CH3)2CH]. 13C NMR (62.5 MHz, CDCl3): δ = 175.5, 140.8, 127.5, 126.8, 126.5, 62.6, 55.9, 50.6, 42.2, 31.8, 23.6, 22.1, 20.7. MS (CI): m/z (%) = 282 (55) [M+], 234 (100), 174 (16). HRMS: m/z calcd for C15H24NO2S: 282.1528; found: 282.1526. [α]D
20 -4.6 (c 0.77 CHCl3).
X-ray Crystal Data of 6b. C13H17NOS, M = 235.34, triclinic, space group P1, Z = 8, a =& nbsp;9.7241 (8), b = 13.4169 (12), c = 19.8594 (17), V = 2437 Å3, d = 1.283 g cm3, 12166 independent reflections were collected with MoKα radiation on a MARresearch Image Plate system. Data analysis was carried out with the XDS program, [11] the structure was solved by direct methods using Shelx86 [12] and refined on F2 using Shelx [13] to R1 = 0.1039, wR2 = 0.1641. Atomic coordinates, bond lengths and angles and thermal parameters have been deposited with the Cambridge Crystallographic Database Service. Please quote reference number CCDC 617867.