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Organic & Biomolecular Chemistry
Page 4 of 6
ARTICLE
Based on above results, our previous findings,
the reaction is less possible a free radical process, we propose was sealed under air and then heated at 120 C for 12 h. The
three possible reaction paths for the present S‐alkylation reaction was then monitored by TLC and/or GC‐MS. Column
reactions of thiols and contaminant disulfides with alcohols or chromatography of the crude products using petroleum ether
Journal Name
10e‐f
and since mol%, corresponds to the alcohol
1
o
DOI: 10.1039/C7OB02461D
byproduct ethers. As shown in Scheme 2, alkyl halide
firstly react with thiols to give product thioethers ( ) and HX.
HX then reacts with alcohols to regenerate and afford
water as the byproduct (path a). On the other hand, alcohols
) may also generate byproduct ethers
3
may as the eluent gave the corresponding thioether 4.
2
4
Benzyl 4‐tolyl thioether (4aa). The product was obtained as a
1
3
1
colorless oil in 95% yield. H NMR (500 MHz, CDCl ): δ 7.21‐
3
7
.13 (m, 7H), 6.98 (d, J = 8.0 Hz, 2H), 3.99 (s, 2H), 2.22 (s, 3H).
(
1
6
by alkyl halide 13
3
C NMR (125.4 MHz, CDCl ): δ 138.0, 136.6, 132.9, 130.8,
1
0e
catalysis, but
under the alkyl halide catalyzed conditions (path b).
Moreover, contaminant disulfides in the commercial thiols
6 can further react with thiols to give products
1
1
29.9, 129.1, 128.7, 127.3, 39.9, 21.3. MS (EI): m/z (%) 214 (45),
23 (3), 91 (100), 65 (12). This compound was known.
4
14
5
can also be transformed into thioethers by an alkyl halide‐
catalyzed reaction with alcohols (path c). All these paths
contributed to the high efficiency of the reactions and
generally good yields of the thioethers, and the observed low
amounts of disulfides and ether byproducts in the reactions.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
Conclusions
We thank National Natural Science Foundation of China
(
21672163, 21502143), Natural Science Foundation of Zhejiang
In conclusion, we developed an efficient and practical method
for synthesis of the useful thioethers by an alkyl halide‐
catalyzed transition metal‐ and base‐free S‐alkylation reaction
of thiols with alcohols. The method tolerates a wide range of
substrates such as aryl and alkyl thiols, as well as benzylic,
allylic, secondary, tertiary, and even the less reactive aliphatic
alcohols. More interestingly, the contaminant disulfides in the
commercial thiols and byproduct ethers generated from the
alcohols could also be transformed into the thioether products
by alkyl halide catalysis, which may account for the high
efficiency of the reactions and generally good yields of the
thioethers, as well as the observed low ratios of disulfides and
ether byproducts in the reactions. Further application and
extension of the method in alcohol‐based dehydrative
heteroatom alkylation reactions are underway.
Province for Distinguished Young Scholars (LR14B020002), and
Xinmiao Talent Program of Zhejiang Province to Y.Y.
(
2017R426048) for financial support.
Notes and references
1
2
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Tavassoli, J. Chem. Soc., Perkin Trans., 1, 2000, 2529. (c) R. N.
Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron, 2001, 57, 7785.
(d) J. Otera and J. Nishikido, Esterification: Methods, Reactions, and
Applications, Wiley VCH Verlag GmbH, Weinheim, 2nd edn, 2010.
(
(a) H. Liu and X. Jiang, Chem. Asian J., 2013, 8, 2546. (b) Z. Qiao and
X. Jiang, Org. Biomol. Chem., 2017, 15, 1942. (c) G.‐P. Lu and C. Cai,
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(
(
e) J. E. Baer and R. G. Lockwood, J. Am. Chem. Soc., 1954, 76, 1162.
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2
011, 13, 4032. (g) S. Murru, B. K. Patel, J. LeBras and J. Muzart, J.
Experimental
General. The starting alcohols, thiols, alkyl halides, hydrobromic
acid (33 wt% in HOAc) and solvents were all purchased and used
without further purification. Et N∙HBr was prepared from the
Org. Chem., 2009, 74, 2217.
N. Schneider, D. M. Lowe, R. A. Sayle, M. A. Tarselli and G. A.
Landrum, J. Med. Chem., 2016, 59, 4385.
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(a) E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches and
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Mannhold, J. Med. Chem., 2005, 48, 3756.
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C.‐H. Kwon, J. Med. Chem., 2000, 43, 4160. (b) L. Llauger, H. He, J.
Kim, J. Aguirre, N. Rosen, U. Peters, P. Davies and G. Chiosis, J. Med.
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Bartels, G. Lehwark‐Yvetot, W. Hänsel, K.‐J. Schaper and J. K. Seydel,
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Clawson, B. A. Dressman, S. D. Hatch, D. A. Khalil, M. B. Kosa, P. P.
3
reaction of Et N and HBr (33 wt% in HOAc) in EtOAc according to
3
1
0f
our previous method. Most of the reactions were carried out in
sealed 10 mL Schlenk tubes and then monitored by TLC and/or GC‐
MS. All products were purified by column chromatography on silica
1
13
gel using petroleum ether (PE) as the eluent. H and C NMR
spectra were recorded on a Bruker Avance III AV500 instrument
5
6
1
13
(
500 MHz for H and 125.4 MHz for C NMR spectroscopy) by using
1
CDCl or d ‐DMSO as the solvent. Chemical shift values for H and
3
6
1
3
4
C NMR were referred to internal Me Si (0 ppm). Mass spectra
were measured on a Shimadzu GCMS‐QP2010 Plus or a Shimadzu
GCMS‐QP2010 Ultra spectrometer (EI).
General Procedure for Alkyl Halide‐Catalyzed Dehydrative S‐
Alkylation of Thiols with Alcohols for the Synthesis of
Unsymmetrical Thioethers. The neat mixture of an alcohol
1 (2.4
mmol), a thiol (2 mmol), and an alkyl halide (0.4 mmol, 20
2
3
4
| J. Name., 2012, 00, 1‐3
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