ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Catalytic Oxidative 1,2-Shift in
1,10-Disubstituted Olefins Using
Arene(iodo)sulfonic Acid as the
Precatalyst and Oxone as the Oxidant
Vikram C. Purohit,* Shawn P. Allwein, and Roger P. Bakale
Chemical Process Research and Development, Teva Pharmaceuticals,
383 Phoenixville Pike, Malvern, Pennsylvania 19355, United States
Received February 14, 2013
ABSTRACT
An efficient, catalytic hypervalent iodine-mediated oxidative 1,2-shift of 1,10-disubstituted olefins is described. This methodology provides
concise access to homobenzylic ketones with electron-donating substituents. In the case of cyclic systems, this transformation results in ring-
expanded β-benzocycloalkanones, which are useful for further elaboration.
Catalytic application of hypervalent iodine reagents1
has become an engaging area of research in the field
of organocatalysis.2 The seminal work by Koser et al.3
toward the application of stoichiometric hydroxytosyloxy
iodobenzene (HTIB) in promoting oxidative 1,2-shifts of
1,1-disubstituted olefins for the preparation of homobenzylic
ketones stands as a benchmark for seeking environmentally
benign conditions (Scheme 1). Historically, this transfor-
mation employed stoichiometric Tl(NO3)3.4 Although the
efficiency for a thallium-mediated transformation is typi-
cally high, the cost,5 toxic nature, and resulting byproducts
limit its use in the pharmaceutical industry.6 In the case
of cyclic systems and depending on the desired ring size,
the homo-β-benzocycloalkanone motif provides a useful
functionality for further elaboration to pharmacologically
significant intermediates. Herein we report a catalytic reaction
design that provides a practical synthesis of homobenzylic
ketones while circumventing the use of stoichiometric oxida-
tive reagents.
1-Methoxy-5,7,8,9-tetrahydrobenzocyclohepten-6-one
(1c) is an intermediate in the synthesis of a preclinical
candidate (Scheme 1). Initially, this intermediate was pre-
pared through a two-step procedure that utilized a Wittig
olefination of corresponding tetralone 1a, followed by an
oxidative ring expansion of 1b using stoichiometric thallium
(1) (a) Uyanik, M.; Yasui, T.; Ishihara, K. Bioorg. Med. Chem. Lett.
2009, 19, 3848. (b) Yakura, T.; Omoto, M. Chem. Pharm. Bull. 2009, 57,
643. (c) Zhou, Z-S; He, X.-H. Tetrahedron. Lett. 2010, 51, 2480. (d)
Uyanik, M.; Yasui, T.; Ishihara, K. Tetrahedron 2010, 66, 5841. (e)
Yusubov, M. S.; Zhdankin, V. V. Mendeleev Commun. 2010, 20, 185. (f)
Dohi, T.; Takenaga, N.; Fukushima, K.; Uchiyama, T.; Kato, D.;
Motoo, S.; Fujioka, H.; Kita, Y. Chem. Commun. 2010, 46, 7697. (g)
Uyanik, M.; Ishihara, K. Aldrichimica Acta 2010, 43, 83. (h) Zhou, Z.;
He, X. Synthesis 2011, 2, 207. (i) Rodriguez, A.; Moran, W. J. Org. Lett.
2011, 13, 2220. (j) Xu, Y.; Hu, J.; Yan, J. T. Chin. Chem. Lett. 2012, 23,
891. (k) Uyanik, M.; Mutsuga, T.; Ishihara, K. Molecules 2012, 17, 8604.
(l) Hamamoto, H. Chem. Pharm. Bull. 2012, 60, 799. (m) List, B. Topics
in Current Chemistry: Asymmetric Organocatalysis; Springer: Heidelberg,
2010: Vol. 290. (n) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed.
2006, 45, 4402. (o) For asymmetric application, see: Uyanik, M.;
Okamoto, H.; Yasui, T.; Ishihara, K. Science 2010, 328, 1376. (p)
Uyanik, M.; Yasui, T.; Ishihara, K. Angew. Chem., Int. Ed. 2010, 49,
2175.
(4) (a) Taylor, E. C.; Conley, R.. A.; Katz, A. H.; McKillop, A. J.
J. Org. Chem. 1984, 49, 3840. (b) McKillop, A.; Swann, B. P.; Taylor,
E. C. . J. Am. Chem. Soc. 1973, 95, 3340. (c) Taylor, E.; McKillop, A. J.;
Swann, B. P. J. Am. Chem. Soc. 1971, 93, 4919. (d) Yamauchi, T.;
Nakao, K.; Fuji, K. J. Chem. Soc., Perkin Trans. 1 1987, 6, 1255.
(5) Tl(NO3)3 is commercially available from Sigma-Aldrich: $4/g.
(6) Green Chemistry: Theory and Practice; Anastas, P. T., Warner, J. C.,
Eds.; Oxford University Press: New York, 2000; pp 1ꢀ129.
(2) For reviews, see: (a) Kita, Y.; Dohi, T. Chem. Commun. 2009,
2073. (b) Varvoglis, A. Tetrahedron 2010, 66, 5739. (c) Dohi, T. Chem.
Pharm. Bull. 2010, 58, 135. (d) Merritt, E. A.; Olofsson, B. Synthesis
2011, 4, 517. (e) Yusubov, M. S.; Zhdankin, V. V. Curr. Org. Syn. 2012,
9, 247. (f) Zhdankin, V. V. J. Org. Chem. 2011, 76, 1185.
(3) Justik, M. W.; Koser, G. Tetrahedron. Lett. 2004, 45, 6159.
r
10.1021/ol400432x
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