Development of a Novel Benzyl Mercaptan as a Recyclable Odorless Substitute of Hydrogen Sulfide

Abstract

2,4,6-Trimethoxybenzyl mercaptan (4) was developed as an odorless substitute of hydrogen sulfide to afford β-mercapto ­carbonyl compounds in a Michael addition and to convert alkyl ­bromides into alkanethiols. Detrimethoxybenzylation of the ­Michael adducts prepared from 4 and α,β-unsaturated esters or ­ketones was facilely carried out by treatment with a solvent mixture of trifluoroacetic acid and toluene to give β-mercapto carbonyl compounds. Successive alkaline hydrolysis of 2,4,6-trimethoxybenzyl iso­thiouronium salt, which was obtained as a side product, regenerated 4 accompanying disulfide 8 in good yield. The disulfide 8 was also converted into 4 by reduction with LiAlH₄. A similar ­protocol was ­applicable to the synthesis of alkanethiols using the S_N2 reaction of alkyl bromides. Our method could be complementary to the classical method of using malodorous benzyl mercaptan as a nucleophile and Birch reduction for debenzylation.

odorless thiol - Michael addition - β-mercapto carbonyl compound - alkanethiol - organosulfur reagent

References and Notes

1 Node M. Kumar K. Nishide K. Ohsugi S. Miyamoto T. Tetrahedron Lett.  2001,  42:  9207 

2 Hasegawa J. Hamada M. Miyamoto T. Nishide K. Kajimoto T. Uenishi J. Node M. Carbohydr. Res.  2005,  2360 

3 Nishide K. Miyamoto T. Kumar K. Ohsugi S. Node M. Tetrahedron Lett.  2002,  43:  8569 

4 Cossar BC. Fournier JO. Fields DL. Reynolds DD. J. Org. Chem.  1962,  27:  93 

5

Each benzyl mercaptan was prepared starting with the reduction of the appropriate methoxybenzaldehyde with sodium borohydride to afford the corresponding benzyl alcohol, which was treated with thiourea under acidic conditions (for 2,6-dimethoxybenzyl alcohol: thiourea, HCl in aqueous acetone, for 3,4,5-trimethoxybenzyl alcohol: SOCl₂ in Et₂O and then thiourea in acetonitrile, for 2,4,6-trimethoxybenzyl alcohol: thiourea, p-TsOH in acetonitrile). Hydrolysis of the obtained isothiouronium salts with aq NaOH gave 2-4 in 51-76% yields.

6 Lin C.-E. Richardson SK. Garvey DS. Tetrahedron Lett.  2002,  43:  4531 

7

5c: colorless oil. ¹H NMR (200 MHz, CDCl₃): δ = 1.12 (t, J = 7.1 Hz, 3 H), 2.77 (dd, A part of AB, J _AB = 15.6 Hz, J = 10.0 Hz, 1 H), 2.96 (dd, B part of AB, J _AB = 15.6 Hz, J = 5.6 Hz, 1 H), 3.63 (s, 2 H), 3.77 (s, 6 H), 3.80 (s, 3 H), 4.00 (q, J = 7.1 Hz, 2 H), 4.30 (dd, J = 5.6, 10.0 Hz, 1 H), 6.08 (s, 2 H), 7.24 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.1, 23.8, 41.7, 45.0, 55.3, 55.7 (2 × C), 60.5, 90.4 (2 × C), 107.4, 120.7, 129.6 (2 × C), 131.1 (2 × C), 140.9, 158.5 (2 × C), 160.2, 170.5. IR (CHCl₃): 2941, 2839, 1728, 1609, 1597, 1466, 1437, 1420, 1371 cm^-1. MS (20 eV): m/z = 470 [M⁺ + 2], 468 [M⁺], 348, 256, 254, 228, 226, 211, 209, 181, 168. HRMS: m/z [M⁺] calcd for C₂₁H₂₅ ⁷⁹BrO₅S: 468.0605; found: 468.0612.

8

6a: colorless oil. ¹H NMR (200 MHz, CDCl₃): δ = 1.22 (t, J = 7.2 Hz, 3 H), 2.23 (d, J = 6.0 Hz, 1 H), 2.94 (d, J = 7.6 Hz, 2 H), 4.13 (q, J = 7.2 Hz, 2 H), 4.45 (dt, J = 6.0, 7.6 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.5 Hz, 2 H). ¹³C NMR (50 MHz, CDCl₃): δ = 14.2, 39.0, 44.4, 60.9, 121.3, 128.5 (2 × C), 131.8 (2 × C), 141.8, 170.2. IR (CHCl₃): 2985, 1730, 1489, 1406, 1373 cm^-1. MS (70 eV): m/z = 290 [M⁺ + 2], 288 [M⁺], 257, 255, 215, 213, 203, 201, 187, 185, 132, 104. HRMS: m/z [M⁺] calcd for C₁₁H₁₃ ⁷⁹BrO₂S: 287.9819; found: 287.9826.

9

7: amorphous powder. ¹H NMR (200 MHz, DMSO-d ₆): δ = 3.79 (s, 3 H), 3.81 (s, 6 H), 4.28 (s, 2 H), 6.29 (s, 2 H), 8.98 (br s, 4 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 24.9, 55.7, 56.3 (2 × C), 91.2 (2 × C), 101.1, 158.9 (2 × C), 161.7, 171.1. MS (FAB+): m/z = 257 [M⁺ - CF₃COO^-], 181, 154, 136. HRMS: m/z [M⁺ - CF₃COO^-] calcd for C₁₁H₁₇N₂O₃S: 257.0960; found: 257.0968.

10 Lynch JE. Eliel EL. J. Am. Chem. Soc.  1984,  106:  29843 

11 Eliel EL. Lynch JE. Tetrahedron Lett.  1981,  22:  2855 

12

Typical Procedure: 2,4,6-Trimethoxybenzyl mercaptan (4, 606 mg, 2.83 mmol) was added to a solution of ethyl p-bromocinnamate (601 mg, 2.36 mmol) in THF (5.0 mL) in the presence of TBAF (0.54 mmol), and the mixture was stirred for 4 h at r.t. After the reaction was complete, the reaction mixture was poured into 1 M HCl acid and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc = 4:1) to afford 5c (1.10 g, 99%).
Next, trifluoroacetic acid (0.2 mL) was added to a suspension of 5c (274 mg, 0.584 mmol) and thiourea (89 mg, 1.17 mmol) in toluene (1 mL), and the mixture was stirred for 4 h at r.t. After the reaction was finished, the solvents were removed in vacuo and the residue was washed with hexane at 60 °C. A soluble part with hexane was evaporated and purified by silica gel column chromatography (hexane-EtOAc, 4:1) to afford 6a (160 mg, 95%). Meanwhile, an insoluble part of the residue was treated with 3 M aq NaOH at r.t. for 3 h. After the reaction was complete, the mixture was poured into 1 M HCl acid and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc, 4:1 → 2:1) to afford 4 (36.3 mg, 36%) and the disulfide 8 (36.5 mg, 36%), which could be converted into 4 by reduction with LiAlH₄.