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Synlett 2010(5): 725-728  
DOI: 10.1055/s-0029-1219382
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Thioimidate N-Oxides: From Nature to Synthetic Pathways

Julie Schleissa, Deimante Cerniauskaitea, David Gueyrarda, Renato Iorib, Patrick Rollina, Arnaud Tatibouët*a
a Institut de Chimie Organique et Analytique, UMR 6005, Associé au CNRS, Université d’Orléans, B.P. 6759, 45067 Orléans, France
Fax: +33(2)38417281; e-Mail: arnaud.tatibouet@univ-orleans.fr;
b Consiglio per la Ricerca e la Sperimentazione in Agricoltura (C.R.A.-C.I.N.), Via di Corticella 133, 40129 Bologna, Italy
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Publication History

Received 23 October 2009
Publication Date:
10 February 2010 (online)

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Abstract

Inspired by the unexpected reactivity of desulfated naturally occurring glucoraphenin, methods to synthesize thioimidate N-oxides (TIO) have been devised on simple or carbohydrate templates. Either through halocyclization or under Mitsunobu conditions, the starting thiohydroximates cyclized to generate efficiently the corresponding TIO.

Key words

carbohydrates - cyclization - heterocycles - azasugars - thio function

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15

Preparation of the Thiohydroximate 19
NCS (0.88 g, 6.6 mmol) was added to a solution of aldoxime 18 (1.75 g, 6 mmol) in DMF (5 mL), and the mixture was left at r.t. for 4 h. After cooling to -78 °C, ethanethiol (1.33 mL, 18 mmol) then Et3N (2.5 mL, 18 mmol) were added dropwise. The reaction mixture was slowly allowed to reach r.t. and stirred for a further 12 h. After hydrolysis (H2O, 100 mL) and extraction with CH2Cl2 (3 ¥ 100 mL), the combined organic phases were washed with brine (3 ¥ 50 mL), dried over MgSO4, filtered, and then evaporated. Purification of the residue over silica gel (PE-EtOAc, 7:3) afforded the 4-O-silylated derivative of 24 as an oil. This intermediate was dissolved in THF (20 mL) and reacted with TBAT (1.2 equiv) at r.t. for 14 h. H2O (20 mL) was then added and the mixture was extracted with CH2Cl2 (3 ¥ 30 mL). The combined organic phases were washed with brine, dried over MgSO4, then evaporated under reduced pressure. S-Ethyl 2,3-O-isopropylidene-l-erythronimidothioate (19) was isolated as a colorless solid (1.2 g, 84% yield) by silica gel flash chromatography (PE-EtOAc, 1:1). Mp 40-41 °C; R f  = 0.18 (PE-EtOAc, 1:1); [a]D ²0 -54 (c 1.0, CHCl3). IR (KBr): 3356, 2992, 1688, 1451, 1375, 1269, 1223, 1208, 1056, 998, 895, 859, 806, 740 cm-¹. ¹H NMR (400 MHz, CDCl3): d = 1.33 (t, 3 H, J = 7.6 Hz, CH3CH2), 1.40 and 1.53 [2 s, 6 H, C(CH3)2], 3.11 (m, 2 H, CH3CH2), 3.68 (m, 1 H, H-4b), 3.79 (m, 1 H, H-4a), 4.40 (dd, 1 H, J 2,3 = 6.0 Hz, J 3,4 = 4.4 Hz, H-3), 4.89 (d, 1 H, J 2,3 = 6.0 Hz, H-2), 9.40 (s, 1 H, NOH). ¹³C NMR (100 MHz, CDCl3) : d = 15.1 (CH3CH2), 25.6 (CH3CH2), 25.4, 27.3 [C(CH3)2], 61.7 (C-4), 76.9 (C-2), 78.6 (C-3), 109.5 (C(CH3)2), 150.8 (C=N). MS (IS): m/z = 236.0 [M + H]+. ESI-HRMS: m/z [M + H]+ calcd for C9H18NO4S: 236.0957; found: 236.0968.

16

Preparation of the Thioimidate N -Oxide 21
Ph3P (55 mg, 0.21 mmol) was added to a solution of DEAD (40% in toluene, 95 mL, 0.21 mmol) in THF (10 mL). After 10 min of stirring, the thiohydroximate 19 (50 mg, 0.21 mmol) was added, and the reaction mixture was kept at reflux overnight. After hydrolysis (H2O, 20 mL) and extraction with CH2Cl2 (3 ¥ 30 mL), the combined organic phases were dried over MgSO4, filtered, and then evaporated. (3S,4S)-2-Ethylsulfanyl-3,4-isopropylidene-dioxy-3,4-dihydro-5H-pyrrole-1-oxide (21) was isolated as a colorless solid (45 mg, 98% yield) after silica gel flash chromatography (EtOAc). Mp 145-150 °C; R f  = 0.5 (EtOAc); [a]D ²0 -136.5 (c 1.0, MeOH). IR (neat): 1570, 1422, 1383, 1261, 1234, 1204, 1154, 1076, 1021, 864, 836, 706, 663 cm-¹. ¹H NMR (400 MHz, CDCl3): d = 1.37 (t, 3 H, J = 7.6 Hz, CH3CH2), 1.39 and 1.44 [2 s, 6 H, C(CH3)2], 3.13 (q, 2 H, J = 7.6 Hz, CH3CH2), 4.06 (dt, 1 H, ² J 5b,5a = 14.7 Hz, J 5b,4 = 5 J 5b,3 = 1.2 Hz, H-5b), 4.13 (dd, 1 H, ² J 5b,5a = 14.7 Hz, J 5a,4 = 5.3 Hz, H-5a), 4.90 (ddd, 1 H, J 4,3 = 6.5 Hz, J 4,5a = 5.3 Hz, J 4,5b = 1.4 Hz, H-4), 5.34 (d, 1 H, J 4,3 = 6.5 Hz, H-3). ¹³C NMR (100 MHz, CDCl3): d = 15.6 (CH3CH2), 23.4 (CH3CH2), 26.0, 27.2 [C(CH3)2], 66.4 (C-5), 73,1 (C-4), 81.7 (C-3); 112.8 [C(CH3)2], 144.0 (C-2). MS (IS): m/z = 218.0 [M + H]+. ESI-HRMS: m/z [M + H]+ calcd for C9H16NO3S: 218.0851; found: 218.0841.