M. T. Martin et al. / Tetrahedron Letters 43 (2002) 2145–2147
2147
activated sulfonyl chlorides to go to completion. How-
ever, when the temperature was increased to 85°C, the
reduction time was reduced to under an hour.
trated under reduced pressure. The compound was then
purified on silica gel by flash column chromatography
eluted with a hexanes:dichloromethane gradient (95–
65% hexane solution) to provide compound 2e.7
In conclusion we have developed a safe and efficient
one-pot synthesis of thioethers via a direct reduction/
coupling of aromatic sulfonyl chlorides to activated
alcohols with typical yields in the range of 34–87%.
Based on reaction calorimetry data, the reduction stage
is highly exothermic, however by using the two stage
addition controlled process we have described here, the
reaction can be run safely even on large scale. By
utilizing the in-situ generated thiol directly, this process
avoids problems associated with isolation and storage
of these intermediates.
Acknowledgements
We thank Dr. Jiasheng Guo for his contributions to
this project.
References
1. Guindon, Y.; Frenette, R.; Fortin, R.; Rokach, J. J. Org.
Chem. 1983, 48, 1357.
Typical experimental procedure
2. Tsay, S.; Lin, L.; Furth, P.; Shum, C.; King, D.; Yu, S.;
Chen, B.; Hwu, J. Synthesis 1993, 3, 329.
3. Ouertani, M.; Collin, J.; Kagan, H. Tetrahedron 1985, 41,
3689.
4. For a review, see: Peach, In The Chemistry of the Thiol
Group; Patai, S.. Ed.; Wiley: New York, 1974; Part 2, pp.
721–735.
Under an N2 atmosphere, zinc (1.103 g, 16.9 mmol),
followed by ethyl acetate (12 mL) was added to a
round-bottomed flask and the mixture was stirred
mechanically and heated to 40°C. Acetic acid (0.551
mL, 9.6 mmol) and water (0.174 mL, 9.6 mmol) were
then added and the temperature was increased to 60°C.
4-Methoxybenzenesulfonyl chloride (1 g, 4.8 mmol, dis-
solved in 3 mL of ethyl acetate) was then added over a
period of 5 min, and the temperature was then
increased to 85°C. Dichlorodimethylsilane (1.71g, 13.3
mmol) was then added over 10 min and the solution
was allowed to stir for 30 min. 2-Thiophenemethanol
(0.550 g, 4.8 mmol) was then added and the reaction
was stirred for an additional 30 min. The reaction was
then cooled to ambient temperature and extracted with
water (2×10 mL) followed by 50% brine (2×10 mL).
The water and brine extracts were then backwashed
with ethyl acetate (10 mL) and the combined organic
fractions were dried with MgSO4, filtered, and concen-
5. Uchiro, H.; Kobayashi, S. Tetrahedron Lett. 1999, 40,
3179.
6. For example, reduction of 1 has a predicted adiabatic
temperature rise of 124°C based upon reaction calorime-
try.
7. 1H, 13C NMR, and elemental analysis for all compounds
are in accordance with assigned structures. Spectroscopic
1
data for compound 2e is as follows: H NMR (300 MHz,
DMSO-d6) l 3.73 (s, 3H), 4.33 (s, 2H), 6.8 (m, 4H) 7.3 (m,
3H).13C NMR (75 MHz, DMSO-d6) l 159.4, 142.0, 133.5,
127.4, 127.1, 126.0, 125.9, 115.4, 55.9, 34.4. Anal calcd for
C12H12OS2: C, 60.98; H, 5.12; O, 6.77; S, 27.13. Found: C,
61.07; H, 5.33; S, 26.92.