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

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.

chiral - 1,4-thiazinone - thiamorpholinone

References and Notes

For recent communications, see:

<A NAME="RG27506ST-1A">1a</A> Draffin WN. Harwood LM. Synlett  2006,  857 

<A NAME="RG27506ST-1B">1b</A> Aldous DJ. Drew MGB. Draffin WN. Hamelin EM.-N. Harwood LM. Thurairatnam S. Synthesis  2005,  3271 

<A NAME="RG27506ST-1C">1c</A> Aldous DJ. Hamelin EM.-N. Harwood LM. Thurairatnam S. Synlett  2001,  1841 

<A NAME="RG27506ST-1D">1d</A> Aldous DJ. Drew MGB. Hamelin EM.-N. Harwood LM. Jahans AB. Thurairatnam S. Synlett  2001,  1836 ; see also references cited therein

<A NAME="RG27506ST-2A">2a</A> Harwood LM. Robertson SM. J. Chem. Soc., Chem. Commun.  1998,  2641 

<A NAME="RG27506ST-2B">2b</A> Alker D. Hamblett G. Harwood LM. Robertson SM. Watkin DJ. Williams CE. Tetrahedron  1998,  54:  6089 

A few reports of thiamorpholinones embedded within β-lactam structures have appeared:

<A NAME="RG27506ST-3A">3a</A> Costerousse G. Cagniant A. Didierlaurent S. Bull. Soc. Chim. Fr.  1989,  830 

<A NAME="RG27506ST-3B">3b</A> Hakimelahi GH. Tsay S.-C. Ramezani Z. Hwu JR. Helv. Chim. Acta  1996,  79:  813 

<A NAME="RG27506ST-4">4</A> Gottstein WJ. Babel RB. Crast LB. J. Med. Chem.  794,  8:  1965 

<A NAME="RG27506ST-5">5</A> Caplar V. Lisini A. Kajfez F. Sunjic V. J. Org. Chem.  1978,  43:  1355 

<A NAME="RG27506ST-6">6</A>

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%).

<A NAME="RG27506ST-7">7</A>

Representative Analytical Data.
Compounds 4a and 5a (mixture): IR (film): ν_max = 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): ν_max = 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): ν_max = 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).

<A NAME="RG27506ST-8">8</A> Bhabani K. Barua NC. Tetrahedron  1991,  47:  8587 

<A NAME="RG27506ST-9">9</A>

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 ų, d = 1.283 g cm³, 12166 independent reflections were collected with MoK_α 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.

For example, see:

<A NAME="RG27506ST-10A">10a</A> Drew MGB. Harwood LM. Price DW. Park G. Tetrahedron Lett.  2000,  5077 

<A NAME="RG27506ST-10B">10b</A> Drew MGB. Harwood LM. Park G. Price DW. Tyler SNG. Park CR. Gho SG. Tetrahedron  2001,  57:  5641 

<A NAME="RG27506ST-11">11</A> Kabsch W. J. Appl. Cryst.  1988,  21:  916 

<A NAME="RG27506ST-12">12</A> Sheldrick GM. Acta Crystallogr., Sect. A: Fundam. Crystallogr.  1990,  46:  467 

<A NAME="RG27506ST-13">13</A> Sheldrick GM. Program for Crystal Structure Refinement   University of Göttingen; Germany: 1993.