Convenient synthesis of allylic thioethers from phosphorothioate esters and alcohols

Article abstract of DOI:10.1021/ol1009202

The synthesis of allylic thioethers arising from the reaction between phosphorothioate esters and alcohols is described. The synthesis is accomplished in one step by the addition of an exogenous alkoxide to the corresponding allylic phosphorothioate ester. It is demonstrated that this process is amenable to various functional groups and a wide variety of heterocycles. In contrast to conventional methods for thioether synthesis, no malodorous sulfur compounds such as thioacetic acid or thiols are required.

Full text of DOI:10.1021/ol1009202

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2668-2671
Convenient Synthesis of Allylic
Thioethers from Phosphorothioate
Esters and Alcohols
Forest Robertson and Jimmy Wu*
Department of Chemistry, Dartmouth College, HanoVer, New Hampshire 03755
jimmy.wu@dartmouth.edu
Received April 21, 2010
ABSTRACT
The synthesis of allylic thioethers arising from the reaction between phosphorothioate esters and alcohols is described. The synthesis is
accomplished in one step by the addition of an exogenous alkoxide to the corresponding allylic phosphorothioate ester. It is demonstrated
that this process is amenable to various functional groups and a wide variety of heterocycles. In contrast to conventional methods for thioether
synthesis, no malodorous sulfur compounds such as thioacetic acid or thiols are required.
The thioether linkage is present in numerous bioactive natural
and pharmaceutical agents. In fact, it has been demonstrated
in several instances that replacing a carbon or oxygen atom
with sulfur greatly enhances the bioactivity of certain
compounds with respect to their oxygenated or carbon
counterparts. For instance, structure-activity relationship
studies have shown that for diallyl sulfide, which possesses
potent anticancer properties,1 a single sulfur atom bonded
to at least one allyl side chain is required for inhibition of
carcinogenesis.2 The thioether functionality has also been
implicated in several compounds that possess antagonistic
properties against the histamine H2-receptor.3 The first of
these compounds, burimamide,4 was significantly less potent
than cimetidine (Tagamet),5 famotidine (Pepcid),6 or raniti-
dine (Zantac),7 each of which replaces a methylene group
in the burimamide skeleton with an isosteric thioether
linkage.8 Pyrimidine thionucleosides also exhibit significantly
greater inhibitory activity against human cancer cell lines
than their corresponding oxygen analogues.9 Finally, the
thioether linkage in the immunoconjugate between doxoru-
bicin and the monoclonal antibody BR96 was demonstrated
to be critical to its antitumor properties (Figure 1).10
(4) Black, J.; Duncan, W.; Durant, C.; Ganellin, C.; Parsons, E. Nature
1972, 236, 385. (b) Preiss, D.; Code, C. J. Pharmacol. Exp. Ther. 1975,
193, 614.
(5) Brimblecombe, R.; Duncan, W.; Durant, G.; Emmett, J.; Ganellin,
C.; Parsons, M. J. Int. Med. Res. 1975, 3, 86.
(6) Howard, J. M.; Chremos, A. N.; Collen, M. J.; McArthur, K. E.;
Cherner, J. A.; Maton, P. N.; Ciarleglio, C. A.; Cornelius, M. J.; Gardner,
J. D.; Jensen, R. T. Gastroenterology 1985, 88, 1026.
(7) Bradshaw, J.; Brittain, R. T.; Clitherow, J. W.; Daly, M. J.; Jack,
D.; Price, B. J.; Stables, R. Br. J. Pharmacol. 1979, 66, 464.
(8) Black, J.; Durant, G.; Emmett, J.; Ganellin, C. Nature 1974, 248,
65.
(1) (a) Arunakaran, J.; Arunkumar, A.; Vijayababu, M.; Venkataraman,
P.; Senthilkumar, K. Biol. Pharm. Bull. 2006, 29, 375. (b) Wargovich, M. J.;
Woods, C.; Eng, V. W. S.; Stephens, L.; Gray, K. Cancer Res. 1988, 48,
6872. (c) Wargovich, M. J.; Sumiyoshi, H. Cancer Res. 1990, 50, 5084.
(d) Shukla, Y.; Arora, A.; Siddiqui, I. Mol. Cancer Ther. 2004, 3, 1459.
(e) Yang, C.; Chhabra, S.; Hong, J.; Smith, T. J. Nutr. 2001, 131, 1041S.
(f) Ariga, T.; Seki, T. BioFactors 2006, 26, 93. (g) Surh, Y.; Lee, R.; Park,
K.; Mayne, S.; Liem, A.; Miller, J. Carcinogenesis 1995, 16, 2467.
(2) Wargovich, M. J. Nutr. 2006, 136, 832S–834S.
(9) Miura, S.; Yoshimura, Y.; Endo, M.; Machida, H.; Matsuda, A.;
Tanaka, M.; Sasaki, T. Cancer Lett. 1998, 129, 103.
(10) Trail, P.; Willner, D.; Lasch, S.; Henderson, A.; Hofstead, S.;
Casazza, A.; Firestone, R.; Hellstro¨m, I.; ellstro¨m, K. Science 1993, 261,
212.
(3) Ganellin, C. J. Appl. Chem. Biotechnol. 1978, 28, 183.
10.1021/ol1009202  2010 American Chemical Society
Published on Web 05/04/2010

thioethers from the corresponding phosphorothioate esters
and alcohols (Scheme 1).
Scheme 1. Two-Step Synthesis of Allylic Thioethers
We recently described a novel method for the photolytic
substitution of allylic alcohols, ethers, silyl ethers, and esters
to generate phosphorothioate esters 1.19 We were also aware
of several elegant reports from the research groups of
Skowron´ska, Krawczyk, and Tanaka in which they converted
various phosphorothioate esters to the corresponding alk-
enes.20 They proposed a mechanism that proceeds via thermal
or phosphine-promoted extrusion of sulfur from thiirane
intermediates. Because of the manner in which the requisite
phosphorothioate esters were prepared, their methodology
is restricted to the use of phosphorothioate esters directly
adjacent to carbonyl groups or nitriles.
We proposed that the addition of an exogenous alkoxide
to phosphorothioate esters 1, which are functionally distinct
from those used by Skowron´ska, Krawczyk, and Tanaka,
would initiate a series of events that would lead to the
synthesis of thioethers in a single step (Scheme 2). Attack
Figure 1. Bioactive sulfur-containing compounds.
Given the importance of sulfur-containing molecules, it
is rather surprising that, in comparison to the amount of effort
devoted to the discovery of new methods for preparing C-C,
C-O, and C-N bonds, considerably less resources have
been allocated to the development of preparing C-S bonds.
Many existing methods for synthesizing thioethers require
the use of functionalized substrates such as R-halocarbonyl
compounds,11 substrates that contain acidic C-H bonds,12
R,ꢀ-unsaturated carbonyl compounds,13 or allylic acetates/
carbonates.14 Reports utilizing the latter method for preparing
thioethers are still limited because sulfur is known to
deactivate late transition metals.15 The thiol-ene reaction16
is the anti-Markovnikov addition of thiyl radicals across
unactivated alkenes. Although this process was first described
in 1905,17 it has been a surprisingly underutilized transfor-
mation. Finally, several groups have utilized stereospecific
[3,3]-sigmatropic rearrangements to generate allylic carbam-
othioates.18 It is apparent that the development of novel
processes for preparing thioethers, and more generally, C-S
bonds, would be of great benefit to both chemists and
biologists. Herein we report an efficient synthesis of allylic
Scheme 2. Proposed Mechanism for Thioether Synthesis
(11) (a) Kato, D.-I.; Mitsuda, S.; Ohta, H. J. Org. Chem. 2003, 68, 7234.
(b) Nicolai, E.; Goyard, J.; Benchetrit, T.; Teulon, J.-M.; Caussade, F.;
Virone, A.; Delchambre, C.; Cloarec, A. J. Med. Chem. 1993, 36, 1175.
(12) (a) Freerksen, R. W.; Selikson, S. J.; Wroble, R. R. J. Org. Chem.
1983, 48, 4087. (b) Jung, M. E.; Lam, P. Y.-S.; Mansuri, M. M.; Speltz,
L. M. J. Org. Chem. 1985, 50, 1087.
on phosphorothioate ester 1 by an alkoxide would generate
thiolate 2 and phosphate 3. Nucleophilic displacement of the
phosphate would furnish the desired thioether 4.
In the event, aging a solution of 5 and the corresponding
alkoxide generated by deprotonation with NaH in methyl
tert-butyl ether (MTBE) or THF overnight furnished thio-
ethers 18a-l in good yields (Table 1). The thioether synthesis
is compatible with the presence of nitriles (vide infra), esters,
and unprotected indole nitrogens, as well as a wide range of
nitrogen-, oxygen-, and sulfur-containing heterocycles. No-
tably, the use of cinnamyl and crotyl alcohol (8 and 9)
resulted in the formation of only one of two possible
regioisomers. Bacon and co-workers reported the use of
(13) (a) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (b) Enders,
D.; Lu¨ttgen, K.; Narine, A. A. Synthesis 2007, 7, 959. (c) Kanemasa, S.;
Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675. (d) Emori,
E.; Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043.
(14) (a) Trost, B. M.; Scanlan, T. S. Tetrahedron Lett. 1986, 27, 4141.
(b) Gais, H.-J.; Jagusch, T.; Spalthoff, N.; Gerhards, F.; Frank, M.; Raabe,
G. Chem.sEur. J. 2003, 9, 4202.
(15) Kondo, T.; Mitsudo, T.-A. Chem. ReV. 2000, 100, 3205.
(16) Dondoni, A. Angew. Chem., Int. Ed. 2008, 47, 8995.
(17) Posner, T. Ber. Dtsch. Chem. Ges. 1905, 38, 646.
(18) (a) Overman, L. E.; Roberts, S. W.; Sneddon, H. F. Org. Lett. 2008,
10, 1485. (b) Crich, D.; Yang, F. J. Org. Chem. 2008, 73, 7107. (c) Minville,
J.; Girardin, M.; Spino, C. Can. J. Chem. 2007, 85, 603. (d) Spino, C.;
Boisvert, L.; Douville, J.; Roy, S.; Lauzon, S.; Minville, J.; Gagnon, D.;
Beaumier, F.; Chabot, C. J. Organomet. Chem. 2006, 5336.
(19) Han, X.; Zhang, Y.; Wu, J. J. Am. Chem. Soc. 2010, 132, 4104.
Org. Lett., Vol. 12, No. 11, 2010
2669

Table 1. Scope of the Alcohol
a Isolated yield.
phosphorodithioate esters but their scope was limited to only
four aliphatic alcohols and yields ranged from poor to
moderate.21 The scope of the phosphorothioate component
was then investigated (Table 2). Again, the range was quite
broad and was amenable to five-, six-, and seven-membered
cycloalkenes as well as symmetrically and unsymmetrically
substituted acyclic substrates.
Table 2. Scope of the Phosphorothioate Ester
Because the mechanism of C-S bond formation is likely
to proceed by an SN2 displacement, in principle, we should
be able to generate enantioenriched thioethers by utilizing
chiral secondary alcohols. To investigate this hypothesis,
thioether formation was carried out between allyl diethyl
phosphorothioate ester 30 and scalemic secondary alcohol
31 that was prepared via Corey-Bakshi-Shibata (CBS)
reduction of indanone (eq 1). We were delighted to observe
near-perfect transfer of stereochemical information from
starting material to product.
The two-step process for preparing thioethers described
above represents a significant improvement to current
methodology. Conventional methods for carrying out the
same synthesis would involve Mitsunobu displacement of
a Isolated yield.
2670
Org. Lett., Vol. 12, No. 11, 2010

the allylic alcohol with thioacetic acid followed by hydrolysis
to the thiol (Scheme 3).22 It would then be necessary to
thioacetic acid or thiols. As described in our previous report,
phosphorothioate esters are stable, odorless compounds that
can be chromatographed and stored for extended periods
without any special precautions.19
In conclusion, we have described an expedient method for
the synthesis of allylic thioethers starting from the corre-
sponding phosphorothioate esters and alcohols. This chem-
istry is compatible with a wide range of functional groups
and heterocycles. We have also demonstrated that this is a
highly stereospecific process capable of delivering enan-
tioenriched thioethers from the corresponding chiral second-
ary alcohols. Future work will focus on exploring the scope
of the stereospecific thioether synthesis and extending the
methodology to include intramolecular variants to provide
access to tetrahydrothiophene and thiane derivatives.
Scheme 3. Thioether Synthesis Utilizing Conventional Methods
activate the other alcohol for nucleophilic displacement by
conversion to a sulfonate ester. The reaction between thiol
35 and 37 would furnish thioether 38 in a four-step process,
as compared to only two steps using our chemistry. Direct
Mitsunobu reaction with thiols is unusual and limited to the
availability of the corresponding thiol. Transition-metal-
mediated allylic substitution with sulfur nucleophiles is also
possible, but because thiols can poison late transition metals,
reports of this kind are rare.15
Acknowledgment. The authors are grateful to Dartmouth
College and the Walter and Constance Burke Foundation
for their generous financial support.
Supporting Information Available: Experimental pro-
cedures and spectra for compounds 5, 18a-l, 19-29, and
32. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL1009202
Furthermore, the Mitsunobu reaction is an inherently non-
atom-economical process that produces stoichiometric amounts
of hydrazine dicarboxylate and triphenylphosphine oxide
byproduct, of which the latter can sometimes be difficult to
separate from the final product. In contrast, the byproduct
generated in our procedure is a phosphate salt that can be
readily removed upon basic aqueous workup. Our method
also avoids the handling of malodorous compounds such as
(20) (a) Maciagiewicz, I.; Dybowski, P.; Skowron´ska, A. Tetrahedron
2003, 59, 6057. (b) Maciagiewicz, I.; Dybowski, P.; Skowron´ska, A.
Tetrahedron Lett. 1999, 40, 3791. (c) Krawczyk, E. Synthesis 2006, 716.
(d) Tanaka, K.; Uneme, H.; Ono, N.; Kaji, A. Chem. Lett. 1979, 1039. (e)
Tanaka, K.; Uneme, H.; Ono, N.; Kaji, A. Synthesis 1979, 890.
(21) Bacon, W. E.; LeSuer, W. M. J. Am. Chem. Soc. 1954, 76, 670.
(22) (a) Volante, R. P. Tetrahedron Lett. 1981, 22, 3119. (b) Hughes,
D. L. The Mitsunobu Reaction. In Organic Reactions; Paquette, L. A., Ed.;
John Wiley & Sons, Inc.: New York, 1992; Vol. 42, p 335.
Org. Lett., Vol. 12, No. 11, 2010
2671