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The Journal of Organic Chemistry
Synthesis of monocyclic sulfides
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Ethyl 4-chloropentanoate 24
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γ-Valerolactone (2.04 g, 20.35 mmol, 1 eq) was added directly to thionyl chloride (1.55 mL, 21.36 mmol,
1.05 eq) at room temperature. The mixture was stirred at 80 °C for 3 h and cooled to room temperature.
Ethanol (1.31 mL, 22.38 mmol, 1.1 eq) was added dropwise over 5 min at 0 °C. The solution was then stirred
for 16 h under reflux, cooled to room temperature, and concentrated in vacuo to give a brown oil (2.15 g).
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1H NMR analysis indicated the presence of γ-valerolactone and the product (1.6:1). The crude product was adsorbed onto
Celite® and purified by flash chromatography on silica gel using hexane/ethyl acetate (90:10) as eluent to give ethyl 4-
chloropentanoate 24 as a pale yellow oil (1.77 g, 53%); νmax(film)/cm-1 1731 (C=O), 1334 (C-O), 1187 (C-O); δH (400 MHz) 1.24
(3H, t, J 7.0, CH3), 1.51 (3H, d, J 6.1, CH3), 1.88-1.99 (1H, m, one of CH2), 2.02-2.16 (1H, m, one of CH2), 2.41-2.60 (2H, m, CH2),
4.01-4.20 (3H, m, contains 1H m of CH, and 2H q, J 7.2, of CH2 at 4.10); δC (75.5 MHz) 14.2 (CH3), 25.3 (CH3), 31.3 (CH2), 35.1
(CH2), 57.7 (CH), 60.5 (CH2), 172.9 (C=O). Spectral details in agreement with those reported in the literature.45
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Ethyl 4-chlorohexanoate 25
The title compound was prepared following the procedure described in for ethyl ester 24 using thionyl
chloride (11.01 mmol, 0.80 mL, 1.05 eq), γ-caprolactone (10.49 mmol, 1.20 g, 1 eq) and ethanol (11.54
mmol, 0.66 mL, 1.1 eq). Following work up, the crude product was isolated as a yellow oil (0.99 g). 1H NMR
analysis indicated the presence of ethyl 4-chlorohexanoate and γ-caprolactone (1:2). The crude material
was adsorbed onto Celite® and purified by flash chromatography on silica gel using hexane/ethyl acetate (95:5) as eluent to give
the ester 25 as the major component of a fraction which was a pale yellow oil (0.60 g, 33%); νmax(film)/cm-1 1736 (C=O), 1179 (C-
O); δH (400 MHz) 1.04 (3H, t, J 7.3, CH3), 1.26 (3H, t, J 7.1, CH3), 1.67-1.86 (2H, m, CH2), 1.87-1.99 (1H, m, one of CH2), 2.07-2.18
(1H, m, one of CH2), 2.44-2.61 (2H, m, CH2), 3.84-3.93 (1H, m, CH), 4.14 (2H, q, J 7.1, CH2); A signal for a minor impurity was
observed at 1.32 – 1.39 ppm as a triplet. δC (75.5 MHz) 10.9 (CH3), 14.2 (CH3), 31.3, 31.6, 33.0, (3 × CH2), 60.5 (OCH2), 64.6 (CH),
173.0 (C=O); m/z (ESI+)179 {[(C8H1535ClO2)H+], 30%, 181 {[(C8H1537ClO2)+H+], 15%}, [(M-HCl)+, 100%]. Spectral details in
agreement with those reported in the literature. 36
Methyl 4-[(2-methoxy-2-oxoethyl)thio]pentanoate 26
Methyl thioglycolate (5.82 mL, 65.15 mmol, 1 eq) in methanol (10 mL) was added to a solution of
sodium methoxide (1.50 g sodium, 65.15 mmol, 1 eq) in methanol (10 mL) at 0 °C under a nitrogen
atmosphere. The reaction mixture was stirred for 10 min and then ethyl 4-chloropentanoate 24 (9.81
g, 65.15 mmol, 1 eq) in methanol (10 mL) was added slowly. The reaction mixture was stirred for 72 h
under reflux. The filtrate was concentrated in vacuo to give a yellow oil. Water (80 mL) was added to
the oil and extracted with diethyl ether (3 × 30 mL). The combined ethereal layers were washed with
water (20 mL), brine (20 mL), dried with anhydrous MgSO4 and concentrated in vacuo to give the
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crude product as a pale yellow oil (10.32 g). H NMR analysis indicated the presence of a complex
mixture of compounds, including the product methyl 4-[(2-methoxy-2-oxoethyl)thio]pentanoate 26. The mixture was purified by
Kugelrohr distillation. The product methyl 4-[(2-methoxy-2-oxoethyl)thio]pentanoate 26 and a small quantity of remaining
disulfide, methyl bis(thioacetate) (4:1, 3.97 g, ~22%) were isolated at 175-180 °C, 15 Torr. Attempts to further purify the mixture
by distillation and base extraction were unsuccessful however the disulfide is removed during the Dieckmann condensation in
the presence of potassium t-butoxide; νmax(film)/cm-1 1733 (C=O). Methyl 4-[(2-methoxy-2-oxoethyl)thio]pentanoate 26: δH (400
MHz) 1.31 (3H, d, J 6.8, CH3), 1.87 (2H, dt appears as q, J 7.7, CH2), 2.47 (2H, m, CH2), 2.95 (1H, sextet, J 6.7, CH), 3.26 (2H, fine
ABq appears as s, CH2), 3.68 (3H, s, OCH3), 3.73 (3H, s, OCH3); δC (75.5 MHz) 20.9 (CH3), 31.1, 31.2, 32.0 (3 × CH2), 40.2 (CH), 51.6
(OCH3), 52.4 (OCH3), 171.1 (C=O), 173.6 (C=O); m/z (ESI+) HRMS (ESI+): Exact mass calculated for C9H17O4S [M+H]+, 221.0848.
Found 221.0844; m/z (ESI+) 221 [(M+H)+, 40 %)], 243 [(M+Na)+, 62%].Characteristic signals of the methyl bis(thioacetate); δH
(400 MHz) 3.60(4H, s, 2 x CH2), 3.78 (6H, s, 2 x OCH3); δC (75.5 MHz) 41.2 (2 x CH2,), 52.6 (2 x CH3), 169.8 (2 x C=O).
Methyl 4-[(2-methoxy-2-oxoethyl)thio]hexanoate 27
The title compound was prepared following the procedure described for methyl 4-[(2-methoxy-2-
oxoethyl)thio]pentanoate 26 using ethyl 4-chlorohexanoate 25 (10.25 g, 62.29 mmol, 1 eq), methyl
thioglycolate (5.57 mL, 62.29 mmol, 1 eq), sodium (1.143 g sodium, 62.29 mmol, 1 eq) and
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methanol (80 mL). Following work up, the crude product was isolated as a yellow oil (12.76 g). H
NMR analysis of the crude material indicated the presence of a mixture of a complex mixture of compounds, including the
product methyl 4-[(2-methoxy-2-oxoethyl)thio]hexanoate 27 and methyl bis(thioacetate). The crude product was purified by
Kugelrohr distillation. Methyl 4-[(2-methoxy-2-oxoethyl)thio]hexanoate 27 and remaining disulfide, methyl bis(thioacetate) were
isolated at 180-185 °C, 15 Torr (1.8:1, 4.60 g). νmax(film)/cm-1 1736 (C=O). Methyl 4-[(2-methoxy-2-oxoethyl)thio]hexanoate 27 δH
(400 MHz) 1.00 (3H, t, J 7.4, CH3), 1.52-1.69 (2H, m, CH2), 1.73-1.84 (1H, m, one of CH2), 1.90-2.01 (1H, m, one of CH2), 2.50 (2H,
t, J 7.6, CH2), 2.68-2.77 (1H, m, CH), 3.22 (2H, fine ABq appears as s, SCH2), 3.68 (3H, s, OCH3), 3.73 (3H, s, OCH3); δC (75.5 MHz)
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