A Facile Regioselective Decomposition of Tosylhydrazones: An Application towards the Synthesis of α-Lipoic Acid

Abstract

A facile regioselective decomposition of tosylhydrazones using NaOH as a base in refluxing isopropyl alcohol is described. This finding has been successfully applied towards the synthesis of (±)-α-lipoic acid (1).

tosylhydrazones - regioselectivity - olefins - α-lipoic acid

References

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Data for Selected Compounds.

25a

Methyl 4-(4-methoxycarbonyl-butyl)-2,2-dimethyl-5-oxo-(1,3)-dithiane-4-carboxylate (8c): molecular formula: C₁₄H₂₂O₅S₂; yield 70%; viscous liquid. IR (CHCl₃): 3021, 2953, 2925, 1748, 1713, 1439, 1160, 765 cm^-1. ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ = 3.76 (d, J = 18.6 Hz, 1 H), 3.75 (s, 3 H), 3.60 (s, 3 H), 3.30 (d, J = 18.6 Hz, 1 H), 2.24 (t, J = 7.3 Hz, 2 H), 1.64-1.85 (m, 5 H), 1.72 (s, 3 H), 1.64 (s, 3 H), 1.17-1.27 (m, 2 H). ¹³C NMR (125 MHz, CDCl₃ + CCl₄): δ = 197.1 (s), 173.5 (s), 170.0 (s), 61.7 (s), 53.1 (q), 51.4 (q), 50.6 (s), 36.6 (t), 33.6 (t), 32.7 (q), 32.6 (t), 32.2 (q), 25.0 (t), 24.2 (t). MS (EI): m/z (%) = 334 (26), 303 (6), 270 (15), 260 (10), 237 (2), 228 (18), 212 (14), 197 (27), 180 (36), 169 (23), 159 (27), 155 (39), 141 (32), 127 (81), 123 (68), 115 (100), 99 (94), 87 (51), 73 (76), 59 (25). HRMS (ESI⁺ mode): m/z calcd for C₁₄H₂₂O₅NaS₂ [M + Na]⁺: 357.0806; found: 357.0811.

25b

Methyl 5-[2,2-dimethyl-5-oxo-(1,3)-dithian-4-yl]pentanoate (9c): molecular formula: C₁₂H₂₀O₃S₂; yield 81%; viscous liquid. IR (CHCl₃): 3020, 1732, 1711, 772, 744 cm^-1. ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ = 3.98 (dd, J = 6.8, 5.9 Hz, 1 H), 3.64 (s, 3 H), 3.63 (d, J = 16.6 Hz, 1 H), 3.25 (d, J = 16.6 Hz, 1 H), 2.29 (t, J = 7.3 Hz, 2 H), 1.76-1.92 (m, 1 H), 1.84 (s, 3 H), 1.56-1.71 (m, 2 H), 1.66 (s, 3 H), 1.34-1.49 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃ + CCl₄): δ = 204.0 (s), 173.6 (s), 51.4 (q), 50.4 (s), 47.1 (d), 37.1 (t), 33.7 (t), 32.8 (q), 31.9 (q), 27.2 (t), 26.6 (t), 24.7 (t). MS (EI): m/z (%) = 276 (57), 262 (3), 243 (13), 225 (6), 211 (8), 202 (11), 179 (8), 170 (100), 153 (24), 142 (28), 127 (36), 111 (16), 93 (21), 73 (68), 56 (11). HRMS (ESI⁺ mode): m/z calcd for C₁₂H₂₀O₃NaS₂ [M + Na]⁺: 299.0752; found: 299.0742.

25c

5-[5-(p-Toluenesulfonyl)hydrazono-2,2-dimethyl-(1,3)-dithian-4-yl]pentanoic acid methyl ester (2c): molecular formula: C₁₉H₂₈O₄N₂S₃; yield 87%; white solid, mp 120 °C. IR (CHCl₃): 3020, 2400, 1731, 757 cm^-1. ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ = 8.53 (s, 1 H), 7.58 (d, J = 8.3 Hz, 2 H), 7.25 (d, J = 8.3 Hz, 2 H), 3.74 (dd, J = 7.8, 6.4 Hz, 1 H), 3.61 (s, 3 H), 3.56 (d, J = 15.6 Hz, 1 H), 3.21 (d, J = 15.6 Hz, 1 H), 2.37 (s, 3 H), 2.19 (t, J = 7.8 Hz, 2 H), 1.76-1.84 (m, 1 H), 1.68 (s, 3 H), 1.46 (s, 3 H), 1.20-1.61 (m, 5 H). ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ = 173.6 (s), 155.7 (s), 143.9 (s), 135.4 (s), 129.3 (d), 128.1 (d), 51.2 (q), 49.7 (s), 45.1 (d), 33.6 (t), 32.2 (q), 31.0 (q), 28.9 (t), 26.1 (t), 25.6 (t), 24.4 (t), 21.3 (q). MS (ESI, solvent: MeCN + H₂O + CH₃COONH₄): m/z = 445.04 [M + 1]. HRMS (ESI⁺ mode): m/z calcd for C₁₉H₂₉N₂O₄S₃ [M + H]⁺: 445.1289; found: 445.1271.

26

General Procedure for Decomposition of Tosylhydra-zones to Olefins.
A mixture of tosylhydrazone (1 mmol) and NaOH (2 mmol) in i-PrOH (10 mL) was refluxed for 2-3 h. The reaction was monitored by TLC, and after the completion of the reaction, i-PrOH was removed under vacuum and the residue was extracted with Et₂O. The ether layer was dried over anhyd Na₂SO₄ and filtered. Then Et₂O was removed under vacuum and the residue was purified by column chromatography.

27

Typical Procedure for Entry 3 in Table 2 (3c and 4c). The mixture of tosylhydrazone 2c (200 mg, 0.450 mmol) and NaOH (40 mg, 2 mmol) in i-PrOH (10 mL) was refluxed for 2-3 h. The reaction was monitored by TLC and after the completion of the reaction, i-PrOH was removed under vacuum and H₂O was added to the reaction mixture. Then aqueous layer was washed with Et₂O and then acidified with dilute HCl. Finally, the aqueous layer was extracted with Et₂O (3 × 15 mL). The ether layer was dried over anhyd Na₂SO₄, filtered and Et₂O was removed under vacuum. The residue was purified by column chromatography to give 93 mg (84%) of pure product (3c and 4c).
Data for 5-(2,2-dimethyl-6H-[1,3]dithiin-4-yl)pentanoic acid(3c): molecular formula: C₁₁H₁₈O₂S₂; yield 84%; viscous liquid. IR (CHCl₃): 2985, 1709, 1216, 1167 cm^-1. ¹H NMR (200 MHz, CDCl₃ + CCl₄): δ = 10.06 (br s, 1 H), 5.75 (t, J = 4.4 Hz, 1 H), 3.44 (d, J = 4.4 Hz, 2 H), 2.34 (t, J = 7.3 Hz, 2 H), 2.20 (t, J = 6.4 Hz, 2 H), 1.67 (s, 6 H), 1.42-1.74 (m, 4 H). ¹³C NMR (50 MHz, CDCl₃ + CCl₄): δ = 179.2 (s), 136.5 (s), 111.4 (d), 47.3 (s), 38.2 (t), 33.8 (t), 31.0 (q), 28.3 (t), 26.4 (t), 23.7 (t). MS (ESI, solvent: MeCN + H₂O + CH₃COONH₄): m/z = 263.05 [M + NH₃], 245.05 [M - 1].