Markovnikov-selective hydrothiolation of styrenes: Application to the synthesis of stereodefined trisubstituted olefins

Article abstract of DOI:10.1021/ol4015909

BT-sulfones react with aromatic aldehydes to furnish trisubstituted alkenes with excellent Z stereoselectivity. These sulfones are synthesized by hydrothiolation of styrene and styrenyl derivatives (followed by oxidation). This method provides a conceptually novel way to prepare these important sulfur compounds.

Full text of DOI:10.1021/ol4015909

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3802–3804
Markovnikov-Selective Hydrothiolation
of Styrenes: Application to the Synthesis
of Stereodefined Trisubstituted Olefins
Markku A. Savolainen and Jimmy Wu*
Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755,
United States
jimmy.wu@dartmouth.edu
Received June 5, 2013
ABSTRACT
BT-sulfones react with aromatic aldehydes to furnish trisubstituted alkenes with excellent Z stereoselectivity. These sulfones are synthesized by
hydrothiolation of styrene and styrenyl derivatives (followed by oxidation). This method provides a conceptually novel way to prepare these
important sulfur compounds.
The Julia olefination reaction (and its numerous modifi-
cations) is a convenient tool for the synthesis of stereo-
defined(E)- and (Z)-1,2-disubstituted alkenes(Scheme 1).1
As such, it is therefore an important transformation in the
repertoire of synthetic chemists.
amounts of phosphine oxides and hydrazine dicarboxy-
lates. These side products often complicate the purification
of the desired thioethers and render the reaction less
desirable from an industrial point of view. Alternatively,
these intermediates can also be prepared by alkylation with
alkyl halides.2
Our group has been involved in developing new methods
for the construction of carbonÀsulfur bonds.3 Recently,
we reported an improved method for preparing the requi-
site thioethers for Julia olefination reactions through the
Ga(OTf)3-catalyzed direct displacement of alcohols.4 The
only byproduct is water.
Scheme 1. Alkene Synthesis by Julia Olefination
In theory, the thioether precursors required for the
Julia olefination may also be prepared by hydrothiola-
tion5 between an alkene and the appropriate thiol. Anti-
Markovnikov additions of thiols across alkenes (thiolÀene
reaction) have been known since 1905.6 This is a radical-
mediated reaction that satisfies many of the criteria of click
One particular drawback of the Julia olefination reac-
tion lies in the preparation of the requisite sulfone starting
materials. These are accessed by oxidation of the corre-
sponding thioether which, in turn, is typically obtained by
the Mitsunobu reaction between an alcohol and the appro-
priate thiol. While the Mitsunobu reaction has been vali-
dated in numerous complex total syntheses, it is decidedly
not atom economical since it produces stoichiometric
(2) For lead references, see: (a) Williams, D. R.; Cortez, G. S.; Bogen,
S. L.; Rojas, C. M. Angew. Chem., Int. Ed. 2000, 39, 4612. (b) Crimmins,
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M. W.; Holub, N.; Jørgensen, K. A. J. Am. Chem. Soc. 2009, 131, 10581.
(3) (a) Han, X.; Zhang, Y.; Wu, J. J. Am. Chem. Soc. 2010, 132, 4104.
(b) Robertson, F. J.; Wu, J. J. Am. Chem. Soc. 2012, 134, 2775.
(c) Robertson, F. J.; Wu, J. Org. Lett. 2010, 12, 2668.
(4) Han, X.; Wu, J. Org. Lett. 2010, 12, 5780.
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(5) Castarlenas, R.; Di Giuseppe, A.; Perez-Torrente, J. J.; Oro, L. A.
Angew. Chem., Int. Ed. 2013, 52, 211.
(1) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(6) Posner, T. Ber. Deut. Chem. Ges. 1905, 38, 646.
r
10.1021/ol4015909
Published on Web 07/03/2013
2013 American Chemical Society

chemistry. It has recently emerged as a powerful tool for
bioconjugation and in supramolecular chemistry.7 In con-
trast, Markovnikov-selective hydrothiolation is unusual
and is an active area of research.8À11
Table 1. Scope of Markovnikov-Selective Hydrothiolation
In this study, we report the synthesis of Julia-type
thioethers by Brønsted acid catalyzed, Markovnikov-
selective hydrothiolation of styrene and its derivatives 1 with
2-mercaptobenzothiazole (2) to furnish 3. This is a concep-
tually novel and, in principle, perfectly atom economical
approach for preparing these important intermediates.
We also demonstrate that the subsequently derived
sulfones participate in stereoselective olefination reactions
to generate trisubstituted Z alkenes 4. This is significant in
that there are exceedingly few examples of highly stereo-
selective syntheses of trisubstituted alkenes by way of Julia
olefination. These compounds are most commonly pre-
pared via transition metal-catalyzed cross-coupling reac-
tions with alkenyl halides or vinylmetal species derived
from the corresponding alkynes.12,13
In order to identify optimal conditions for the hydro-
thiolation, we surveyed the reaction between styrene (1a)
and 2-mercaptobenzothiazole (2) catalyzed by various
Lewis and Brønsted acids. After extensive optimization,
wediscoveredthat10equivoftrifluoroaceticacid(TFA) in
dichloromethane at room temperature afforded the de-
sired hydrothiolation product 3a with the highest isolated
yield and selectivity (98% yield and >20:1 Markovnikov
(7) Dondoni, A. Angew. Chem., Int. Ed. 2008, 47, 8995.
(8) For examples of Brønsted acid catalyzed hydrothiolations of
alkyl-substituted alkenes, see: (a) Ipatieff, V. N.; Pines, H.; Friedman,
B. S. J. Am. Chem. Soc. 1938, 60, 2731. (b) Screttas, C. G.; Micha-Screttas,
M. J. Org. Chem. 1979, 44, 713.
regioselectivity). Omission of TFA did not provide any of
the desired hydrothiolation product. Instead, it generated
a compound of which mass spectrometry and NMR data
are consistent with hydroxythiolation across the alkene.
The precise structural assignment remains tobeconfirmed.
With these optimized conditions in hand, we proceeded
to explore the scope of the hydrothiolation. As is evident in
Table 1, this method is compatible with both electron-rich,
electron-deficient, and cyclic styrenyl substrates. It should
be noted that Brønsted acids often promote unwanted
polymerization of styrene and its derivatives. These by-
products are not formed in any appreciable amounts. It is
likely that attack of a putative benzylic carbocation inter-
mediate by the highly nucleophilic 2 is faster than the rate
of polymerization.
(9) For lead references of Lewis acid catalyzed hydrothiolations of
ꢀ
~
alkenes, see: (a) Weıwer, M.; Chaminade, X.; Bayon, J. C.; Dunach, E.
~
Eur. J. Org. Chem. 2007, 2464. (b) Weıwer, M.; Coulombel, L.; Dunach,
~
E. Chem. Commun. 2006, 332. (c) Weıwer, M.; Dunach, E. Tetrahedron
Lett. 2006, 47, 287.
(10) For an example of Montmorillonite K 10-catalyzed hydrothio-
lation of alkenes, see: Kanagasabapathy, S.; Sudalai, A.; Benicewicz,
B. C. Tetrahedron Lett. 2001, 42, 3791.
(11) For lead references of metal-catalyzed hydrothiolation of
alkynes, see: (a) Weiss, C. J.; Marks, T. J. J. Am. Chem. Soc. 2010,
132, 10533. (b) Weiss, C. J.; Wobser, S. D.; Marks, T. J. J. Am. Chem.
Soc. 2009, 131, 2062. (c) Cao, C.; Fraser, L. R.; Love, J. A. J. Am. Chem.
Soc. 2005, 127, 17614. (d) Yang, J.; Sabarre, A.; Fraser, L. R.; Patrick,
B. O.; Love, J. A. J. Org. Chem. 2009, 74, 182. (e) Ogawa, A.; Ikeda, T.;
Kimura, K.; Hirao, T. J. Am. Chem. Soc. 1999, 121, 5108. (f) Kondoh,
A.; Takami, K.; Yorimitsu, H.; Oshima, K. J. Org. Chem. 2005, 70, 6468.
(g) Ananikov, V. P.; Malyshev, D. A.; Beletskaya, I. P.; Aleksandrov,
G. G.; Eremenko, I. L. Adv. Synth. Catal. 2005, 347, 1993. (h) Sarma, R.;
Rajesh, N.; Prajapati, D. Chem. Commun. 2012, 48, 4014.
(12) (a) Normant, J. F.; Alexakis, A. Synthesis 1981, 841. (b)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c) Casson, S.;
Kocienski, P. Contemp. Org. Synth. 1995, 2, 19. (d) Fallis, A. G.;
Forgione, P. Tetrahedron 2001, 57, 5899. (e) Tan, Z.; Negishi, E. Angew.
Chem., Int. Ed. 2006, 45, 762. (f) Shimizu, M.; Nakamaki, C.; Shimono,
K.; Schelper, M.; Kurahashi, T.; Hiyama, T. J. Am. Chem. Soc. 2005,
127, 12506.
To explore the synthesis of configurationally enriched
trisubstituted alkenes, we carried out olefination reactions
between sulfone5 (preparedby mcpba oxidation of 3e) and
several aldehydes (Table 2). The reactions were carried out
in the presence of lithium diisopropyl amide (LDA) under
Barbier-type conditions which was required to minimize
homocoupling of the BT-sulfone.1 The reaction is compa-
tible with a wide array of functionalized aromatic and
(13) For some examples of trisubstituted olefin synthesis using olefin
cross metathesis, see: (a) Chatterjee, A. K.; Grubbs, R. H. Org. Lett.
€
2000, 2, 3153. (b) Furstner, A.; Thiel, O. R.; Ackermann, L. Org. Lett.
2001, 3, 449.
Org. Lett., Vol. 15, No. 14, 2013
3803

Table 2. Stereodefined Trisubstituted Olefin Synthesis
Figure 1. X-ray crystal structure of 9l and 9m.
three chemical steps were needed to access the requisite
tetrazone thione starting materials. In comparison, our
method provides analogous structures in a single step via
formal hydroamination. Finally, Vicario and co-workers
showed that treatment of tetrazole thiones with H2 and
Raney-Ni generated the corresponding isoureas and
formamidines.15 Further work related to this unusual reac-
tion (e.g., mechanistic studies and the conversion of 9jÀm to
the corresponding amines) is ongoing in our laboratories.
In this communcation, we have described the Markov-
nikov-selectivehydrothiolation of styrenylderivativeswith
2- mercaptobenzothiazole (2) to furnish thioethers 3. This
method represents a more atom economical alternative to
a classical means for preparing these important intermedi-
ates (usually by the Mitsunobu reaction). Oxidation to the
sulfone followed by reaction with various aldehydes using
the modified Julia olefination protocol furnishes stereo-
defined trisubstituted alkenes. This method provides a
high stereochemical bias for Z-olefins.
heteroaromaticaldehydes. The desired alkenes4aÀk could
be isolated in good yields with high Z-selectivities. These
are among the best selectivities obtained for the prepara-
tion of trisubstituted alkenes utilizing the Julia olefination
reaction.14
Other Julia-type thiols were also explored for their utility
in the Markovnikov-selective hydrothiolation of styrenes.
However, these experiments yielded mixed results. In the
case of 1-phenyl-1H-tetrazole-5-thiol (7), catalytic Ga(OTf)3
was required to furnish the Markovnikov-selective hydro-
thiolation. The use of 2-mercaptopyridine (8) generated
hydrothiolation products as 1:1 mixtures of regioisomers.
At elevated temperatures, the reaction between 7 and
1jÀm unexpectedly yielded formal hydroamination pro-
ducts (eqs 1À2).15 The X-ray crystal structures of two
representative compounds are shown in Figure 1.16 Inter-
estingly, related tetrazole thiones have been converted to the
carbodiimides by photochemical irradiation.17 In that work,
Acknowledgment. J.W. acknowledges financial support
provided by Dartmouth College and an NSF CAREER
Award (CHE-1052824). We thank Dr. Richard Staples
(Michigan State University) for assistance with X-ray
crystallography.
(14) (a) Mi, B.; Maleczka, R. E., Jr. Org. Lett. 2001, 3, 1491. (b)
Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681. (c) Blakemore, P. R.;
Kocienski, P. J.; Marzcak, S.; Wicha, J. Synthesis 1999, 64, 1209.
(15) For another example in which phenyl-1H-tetrazole-5-thiol (6) is
alkylated at nitrogen, see: Uria, U.; Reyes, E.; Vicario, J. L.; Badıa, D.;
Carrillo, L. Org. Lett. 2011, 13, 336.
Supporting Information Available. Experimental pro-
cedures and spectra for all previously unreported com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) CCDC 940539, 940540.
(17) Alawode, O. E.;Robinson, C.;Rayat, S. J. Org. Chem. 2010, 76, 216.
The authors declare no competing financial interest.
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