Rapid access to β-trifluoromethyl-substituted ketones: Harnessing inductive effects in wacker-type oxidations of internal alkenes

Article abstract of DOI:10.1002/anie.201404712

We present a practical trifluoromethyl-directed Wacker-type oxidation of internal alkenes that enables rapid access to β-trifluoromethyl-substituted ketones. Allylic trifluoromethyl-substituted alkenes bearing a wide range of functional groups can be oxidized in high yield and regioselectivity. The distance dependence of the regioselectivity was established by systematic variation of the number of methylene units between the double bond and the trifluoromethyl group. The regioselectivity enforced by traditional directing groups could even be reversed by introduction of a competing trifluoromethyl group. Besides being a new powerful synthetic method to prepare fluorinated molecules, this work directly probes the role of inductive effects on nucleopalladation events.

Full text of DOI:10.1002/anie.201404712

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Angewandte
Communications
DOI: 10.1002/anie.201404712
Synthetic Methods
Rapid Access to b-Trifluoromethyl-Substituted Ketones: Harnessing
Inductive Effects in Wacker-Type Oxidations of Internal Alkenes**
Michael M. Lerch, Bill Morandi, Zachary K. Wickens, and Robert H. Grubbs*
Dedicated to the MPI fꢀr Kohlenforschung on the occasion of its centenary
Abstract: We present a practical trifluoromethyl-directed
Wacker-type oxidation of internal alkenes that enables rapid
access to b-trifluoromethyl-substituted ketones. Allylic tri-
fluoromethyl-substituted alkenes bearing a wide range of
functional groups can be oxidized in high yield and regiose-
lectivity. The distance dependence of the regioselectivity was
established by systematic variation of the number of methylene
units between the double bond and the trifluoromethyl group.
The regioselectivity enforced by traditional directing groups
could even be reversed by introduction of a competing
trifluoromethyl group. Besides being a new powerful synthetic
method to prepare fluorinated molecules, this work directly
probes the role of inductive effects on nucleopalladation events.
regioselectivity of the Wacker reaction. In contrast, trifluoro-
methyl groups are relatively noncoordinating and their
influence on regioselectivity remains to be established.
Recent progress has enabled the Wacker-type oxidation of
internal alkenes,[9] and as we explored the regioselectivity in
one such system, we discovered that more electron deficient
directing groups provide higher regioselectivity.[9g] Thus, we
hypothesized that strongly electron-withdrawing substituents
could enable the highly regioselective oxidation of internal
alkenes at the distal position without having to rely upon
chelation assistance (Scheme 1).[9b–g,10a]
O
rganofluorine compounds are important for the pharma-
ceutical, agrochemical, and materials industries.[1–4] The
incorporation of fluorine into organic molecules can signifi-
cantly alter their chemical, physical, and biological properties,
such as molecular conformation, basicity, lipophilicity, and
metabolic stability. An estimated 25% of the marketed drugs
contain fluorine.[2b–d] However, the synthesis of fluorine-
containing compounds remains a challenge for target-ori-
ented synthesis because of the low abundance of organo-
fluorine compounds from traditional chemical feedstocks.[2-
b,5a,b] Hence, significant efforts have been directed towards the
development of efficient methods for the synthesis of this
important class of compounds.[5,6] Unfortunately, b-trifluoro-
methyl-substituted ketones remain challenging to prepare,
despite their potential as versatile fluorinated building
blocks.[7]
Scheme 1. Regiocontrol in Wacker oxidations of internal alkenes.
BQ=p-benzoquinone.
In contrast to Tsuji–Wacker conditions, which proved
unreactive towards these electron-deficient internal
alkenes,[10] our recently reported procedure for the Wacker-
type oxidation of internal alkenes resulted in good conver-
sions and excellent regioselectivities.[9c,g] The optimum reac-
tion conditions were found to be 7.5 mol% Pd(OAc)2 and
a stoichiometric amount of p-benzoquinone in MeCN/H2O
(7:1) for 24 h at 408C.[11] Under these conditions, a variety of
alkenes bearing allylic trifluoromethyl groups could be
oxidized in 70–91% yield. As predicted by the inductive
hypothesis, each example exhibited excellent (ꢀ 20:1) regio-
selectivity for the distal oxidation product (Table 1).[12] The
newly developed procedure tolerates a variety of synthetically
useful, orthogonal alcohol protecting groups (entries 1–4) and
amine precursors (entries 5 and 6). Even alkenes containing
unprotected alcohols (entry 7) could be oxidized chemo-
selectively. The excellent functional-group tolerance of this
reaction was further demonstrated by its compatibility with
nitriles (entry 8), tosylates (entry 9), and primary alkyl halides
(entry 10). In all cases, selectivities of ꢀ 20:1 (distal oxidation
In principle, a Wacker oxidation[8] of readily available[6a–d]
alkenes bearing an allylic trifluoromethyl group could provide
practical and rapid access to b-trifluoromethyl-substituted
ketones. Traditionally, directing groups capable of coordinat-
ing to the palladium center have been exploited to control the
[*] M. M. Lerch, Dr. B. Morandi, Z. K. Wickens, Prof. Dr. R. H. Grubbs
Division of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, CA 91125 (USA)
E-mail: rhg@caltech.edu
[**] We gratefully acknowledge financial support from the King Abdullah
University of Science and Technology Centre in Development, King
Fahd University of Petroleum and Minerals, and the NSF. Further-
more, we thank the Gordon and Betty Moore Foundation, the SNSF
for a fellowship to B.M., and the Swiss Study Foundation for
a fellowship to M.M.L.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404712.
8654
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Table 1: Substrate scope of the CF3-directed Wacker oxidation of internal
alkenes.[a,b]
Next, we sought to probe the directing power of the
Entry
1[e]
Product
Yield[c]
72
Sel.[d]
trifluoromethyl group relative to classical Wacker directing
groups. To this end, a series of intramolecular competition
experiments was designed and executed to directly compare
the influence of functional groups proximal to the double
bond (Scheme 2).[14] To more precisely evaluate the influence
of the trifluoromethyl group on the observed selectivities, we
additionally probed substrates bearing a nondirecting alkyl
group in place of the trifluoromethyl group. In each of the
investigated cases, the replacement of an alkyl substituent
with a trifluoromethyl group led to an inversion of selectivity,
thereby demonstrating that the predominantly inductive
trifluoromethyl group can override the regiocontrol provided
ꢀ20:1
2
3
91
70
ꢀ20:1
ꢀ20:1
4
5
75
85
ꢀ20:1
ꢀ20:1
6
7
8
77
84
75
ꢀ20:1
ꢀ20:1
ꢀ20:1
9
82
74
ꢀ20:1
ꢀ20:1
10[f]
[a] 0.25 mmol alkene. [b] E/Z ratio between 5:1 and 10:1. [c] Yield of
isolated products. [d] Sel.=distal oxidation/proximal oxidation, as
determined by 19F and 1H NMR analysis of the crude reaction mixture.
[e] 0.5 mmol alkene. [f] 0.21 mmol alkene.
over proximal oxidation) were obtained and further establish
the previously unprecedented[13] powerful directing effect of
the trifluoromethyl group in Wacker-type oxidations of
internal alkenes.
We then probed the efficiency of the procedure on
a preparatively useful scale. The reaction of 1,1,1-trifluoro-
12-methoxydodec-3-ene (Table 1, entry 2) on a gram scale
(4 mmol) proceeded in 70% yield and in ꢀ 20:1 selectivity for
the distal oxidation product. This scalability combined with
the reliance upon only commercially available (and compa-
ratively inexpensive) reagents bodes well for the immediate
application of this reaction in target-oriented synthesis.
Scheme 2. Intramolecular competition experiments to probe the effect
of the trifluoromethyl group: Pd(OAc)2 (7.5 mol%), BQ (1.0 equiv),
MeCN/H2O (7:1), HBF4 (0.27m), 408C, 24 h. Bn=benzyl; Bz=ben-
zoyl; Fur=2-furoyl, PhtN=phthalimide. [a] Results reproduced from
Ref. [9g].
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by traditional coordinating groups. For example, a homoallylic
2-furoyl ester results in selective oxidation to product b (a/
b 1:8). However, upon introduction of the trifluoromethyl
group, the observed regioselectivity is reversed and the
alkene is selectively oxidized to product a (a/b 12:1). Fur-
thermore, the introduction of the trifluoromethyl group is
strong enough to override the selectivity determined by the
benzoate group, a group known for its powerful directing
ability (a/b 1:10 versus 15:1). These competition experiments
thus further illustrate the powerful directing ability of the
trifluoromethyl group for the synthesis of valuable fluori-
nated products. Moreover, these observations offer a platform
to predict the regioselectivity of Wacker-type oxidations of
internal alkenes bearing potentially competing directing
groups, which is critical for the adoption of this oxidation
method in target-oriented synthesis.
internal alkenes, we hypothesized that inductive effects could
lead to formal anti-Markovnikov regioselectivity. Thus, 4,4,4-
trifluoro-1-butene was subjected to both our standard reac-
tion conditions as well as the classical Tsuji–Wacker con-
ditions (Scheme 3). The alkene was oxidized with full
conversion and 3:1 selectivity for the terminal position of
the alkene under both procedures.[16] This finding demon-
strates the important and general role of inductive effects on
nucleopalladation regioselectivity, as, to our knowledge, these
results comprise the first examples of achieving a formally
anti-Markovnikov Wacker oxidation using inductive effects
to reverse the Markovnikov selectivity.[17]
To probe the distance dependence of the observed
directing effects, a series of alkenes bearing trifluoromethyl
groups in varied proximity to the alkene were subjected to the
catalytic conditions (Table 2). When the distance from the site
Scheme 3. Influence of inductive effects on the regioselectivity of the
Wacker oxidation of terminal alkenes. Quantitative conversion relative
to BQ was observed. DMF=N,N-dimethylformamide. Conditions A
(Tsuji–Wacker): [Pd(PhCN)2Cl2] (5 mol%), BQ (1.0 equiv), DMF/H2O
(7:1), 408C, 16 h; conditions B (dicationic Pd): Pd(OAc)2 (7.5 mol%),
BQ (1.0 equiv), MeCN/H2O (7:1), HBF4 (0.27m), 408C, 16 h.
Table 2: Distance dependence of the CF3-directed Wacker oxidation of
internal alkenes.[a]
In conclusion, trifluoromethyl groups were shown to be
highly efficient directing groups for Wacker-type oxidations,
thereby enabling facile access to b-trifluoromethyl-substi-
tuted ketones. The broad functional-group tolerance of the
oxidation, combined with the readily accessible starting
materials, bodes well for the immediate application of the
method. Furthermore, we have presented important insight
into the selectivity-controlling factors in Wacker-type oxida-
tions of internal alkenes. The inductive influence appears to
be a general phenomenon in Wacker-type oxidations, as
illustrated by the (3:1) aldehyde selectivity obtained in the
Wacker oxidation of 4,4,4-trifluoro-1-butene. Overall, the
results described herein provide a foundation for the devel-
opment of an in-depth understanding of the regioselectivity of
nucleopalladation events that will ultimately lead to an
improved predictability of Wacker oxidation regioselectivity
in target-oriented synthesis.
Entry
1[d,e]
2[f]
Substrate
Yield[b]
74
Sel.[c]
ꢀ20:1
5.5:1
1.9:1
86
3[g]
74
[a] 0.1 mmol alkene. [b] Yield of isolated products. [c] Sel. =distal
oxidation/proximal oxidation, as determined by 19F and 1H NMR analysis
of the crude reaction mixture. [d] 0.21 mmol alkene, see Table 1, entry 10.
[e] E/Z 5:1. [f] E/Z 1:6. [g] E/Z 1:16.
of unsaturation was increased, the selectivity for the distal
oxidation decreased steadily (n = 1: ꢀ 20:1; n = 2: 5.5:1; n = 3:
1.9:1),[15] in accordance with an inductive model. The
synthetically useful selectivity (5.5:1) obtained with a homo-
allylic trifluoromethyl-substituted substrate (Table 2, entry 2)
illustrates the applicability of this strategy to prepare
d-trifluoromethyl-substituted ketones. Even a trifluoromethyl
group four bonds away from the alkene (entry 3) exerts an
appreciable influence on the regioselectivity (1.9:1).
Having established the powerful directing effect of the
trifluoromethyl group on the regioselectivity of Wacker
oxidations of internal alkenes, we reasoned that the inductive
influence of the trifluoromethyl group could potentially have
an impact on the regioselectivity exhibited by terminal
alkenes. Under Wacker conditions, terminal alkenes are
oxidized with high selectivity to methyl ketones, in accord-
ance with Markovnikovꢀs rule.[8] Based upon our results with
Received: April 25, 2014
Published online: July 18, 2014
Keywords: alkenes · ketones · palladium · regioselectivity ·
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trifluoromethyl group
[1] For selected books on fluorine-containing molecules and their
chemistry, see a) P. Kirsch in Modern Fluoroorganic Chemistry:
Synthesis Reactivity, Applications, Wiley-VCH, Weinheim, 2013;
b) T. Hiyama in Organofluorine Compounds: Chemistry and
Applications, Springer, Berlin, 2000; c) K. Uneyama in Organo-
fluorine Chemistry, Blackwell, Oxford, 2006.
[2] For a selection of books and reviews of fluorine in medicinal
chemistry and pharmacology, see a) I. Ojima in Fluorine in
8656 www.angewandte.org
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Angewandte
Chemie
Medicinal Chemistry and Chemical Biology (Ed.: I. Ojima),
Wiley-Blackwell, Chichester, 2009; b) J. Wang, M. Sꢁnchez-
Rosellꢂ, J. L. AceÇa, C. del Pozo, A. E. Sorochinsky, S. Fustero,
V. A. Soloshonok, H. Liu, Chem. Rev. 2013, 113, 2432 – 2506;
c) K. Mꢃller, C. Faeh, F. Diederich, Science 2007, 317, 1881 –
1886; d) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320 – 330; e) D. OꢀHagan, Chem. Soc.
Rev. 2008, 37, 308 – 319.
Struchkova, P. A. Belyakov, V. A. Tartakovsky, Tetrahedron Lett.
2009, 50, 2998 – 3000.
[8] For the initial development of the Wacker process, see a) J.
Smidt, W. Hafner, R. Jira, J. Sedlmeier, R. Sieber, R. Rꢃttinger,
H. Kojer, Angew. Chem. 1959, 71, 176 – 182; b) J. Smidt, W.
Hafner, R. Jira, R. Sieber, J. Sedlmeier, A. Sabel, Angew. Chem.
1962, 74, 93 – 102; Angew. Chem. Int. Ed. 1962, 1, 80 – 88; for the
development of the Tsuji – Wacker procedure, see c) J. Tsuji in
Palladium Reagents and Catalysts: New Perspectives for the 21st
Century, 2nd ed., Wiley, 2004; d) J. Tsuji, Synthesis 1984, 369 –
384, and references therein; for a mechanistic discussion, see
e) J. A. Keith, P. M. Henry, Angew. Chem. 2009, 121, 9200 – 9212;
Angew. Chem. Int. Ed. 2009, 48, 9038 – 9049; f) J.-E. Bꢅckvall, B.
Akermark, S. O. Ljunggren, J. Am. Chem. Soc. 1979, 101, 2411 –
2416; g) R. I. McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011,
111, 2981 – 3019; h) M. J. Gaunt, J. Yu, J. B. Spencer, Chem.
Commun. 2001, 1844 – 1845; for the usage of O2 as terminal
oxidant, see i) A. N. Campbell, S. S. Stahl, Acc. Chem. Res. 2012,
45, 851 – 863; j) C. N. Cornell, M. S. Sigman, Inorg. Chem. 2007,
46, 1903 – 1909; k) K. M. Gligorich, M. S. Sigman, Chem.
Commun. 2009, 3854 – 3867.
[9] For the oxidation of internal alkenes under Wacker-type
conditions, see a) D. G. Miller, D. D. M. Wayner, J. Org. Chem.
1990, 55, 2924 – 2927; b) T. Mitsudome, K. Mizumoto, T.
Mizugaki, K. Jitsukawa, K. Kaneda, Angew. Chem. 2010, 122,
1260 – 1262; Angew. Chem. Int. Ed. 2010, 49, 1238 – 1240; c) B.
Morandi, Z. K. Wickens, R. H. Grubbs, Angew. Chem. 2013, 125,
3016 – 3020; Angew. Chem. Int. Ed. 2013, 52, 2944 – 2948; d) R. J.
DeLuca, J. L. Edwards, L. D. Steffens, B. W. Michel, X. Qiao, C.
Zhu, S. P. Cook, M. S. Sigman, J. Org. Chem. 2013, 78, 1682 –
1686; e) T. Mitsudome, S. Yoshida, T. Mizugaki, K. Jitsukawa, K.
Kaneda, Angew. Chem. 2013, 125, 6077 – 6080; Angew. Chem.
Int. Ed. 2013, 52, 5961 – 5964; f) T. Mitsudome, S. Yoshida, Y.
Tsubomoto, T. Mizugaki, K. Jitsukawa, K. Kaneda, Tetrahedron
Lett. 2013, 54, 1596 – 1598; g) B. Morandi, Z. K. Wickens, R. H.
Grubbs, Angew. Chem. 2013, 125, 9933 – 9936; Angew. Chem.
Int. Ed. 2013, 52, 9751 – 9754.
[10] In some cases, the introduction of suitable coordinating groups
proximal to internal alkenes promoted Wacker oxidation (very
substrate dependent), see a) J. Tsuji, H. Nagashima, K. Hori,
Tetrahedron Lett. 1982, 23, 2679 – 2682; b) E. Keinan, K. K. Seth,
R. Lamed, J. Am. Chem. Soc. 1986, 108, 3474 – 3480; c) S.-K.
Kang, K.-Y. Jung, J.-U. Chung, E.-Y. Namkoong, T.-H. Kim, J.
Org. Chem. 1995, 60, 4678 – 4679; d) B. M. Trost, T. L. Calkins,
Tetrahedron Lett. 1995, 36, 6021 – 6024; e) Y. Sato, N. Saito, M.
Mori, J. Org. Chem. 2002, 67, 9310 – 9317; f) P. R. Skaanderup, R.
Madsen, J. Org. Chem. 2003, 68, 2115 – 2122; g) S. B. Narute,
N. C. Kiran, C. V. Ramana, Org. Biomol. Chem. 2011, 9, 5469 –
5475.
[11] Early reports indicated that the use of Pd(OAc)2 in chloride-free
conditions resulted in precipitation of Pd0. This limitation,
however, could be overcome by the addition of strong acid (e.g.
HClO4 or HBF4), see a) J. E. Bꢅckvall, R. B. Hopkins, Tetrahe-
dron Lett. 1988, 29, 2885 – 2888; b) J.-E. Bꢅckvall, R. B. Hopkins,
H. Grennberg, M. Mader, A. K. Awasthi, J. Am. Chem. Soc.
1990, 112, 5160 – 5166.
[3] For an introduction to fluorine in agrochemistry, see P. Jeschke
in Modern Methods in Crop Protection Research, Wiley-VCH,
Weinheim, 2012, pp. 73 – 128.
[4] For a selective introduction to fluorineꢀs role in materials
chemistry, see a) R. Berger, G. Resnati, P. Metrangolo, E. Weber,
J. Hulliger, Chem. Soc. Rev. 2011, 40, 3496 – 3508; b) F. Babudri,
G. M. Farinola, F. Naso, R. Ragni, Chem. Commun. 2007, 1003 –
1022.
[5] For recent reviews on methods to access trifluoromethylated
compounds in general, see a) M. Shimizu, T. Hiyama, Angew.
Chem. 2005, 117, 218 – 234; Angew. Chem. Int. Ed. 2005, 44, 214 –
231; b) M. Schlosser, Angew. Chem. 2006, 118, 5558 – 5572;
Angew. Chem. Int. Ed. 2006, 45, 5432 – 5446; c) T. Furuya, A. S.
Kamlet, T. Ritter, Nature 2011, 473, 470 – 477; d) T. Liang, C. N.
Neumann, T. Ritter, Angew. Chem. 2013, 125, 8372 – 8423;
Angew. Chem. Int. Ed. 2013, 52, 8214 – 8264; e) O. A. Toma-
shenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475 – 4521;
f) M. C. Pacheco, S. Purser, V. Gouverneur, Chem. Rev. 2008,
108, 1943 – 1981; g) N. Shibata, S. Mizuta, H. Kawai, Tetrahe-
dron: Asymmetry 2008, 19, 2633 – 2644; h) A. Studer, Angew.
Chem. 2012, 124, 9082 – 9090; Angew. Chem. Int. Ed. 2012, 51,
8950 – 8958; i) J. Nie, H.-C. Guo, D. Cahard, J.-A. Ma, Chem.
Rev. 2010, 110, 455 – 529.
[6] For copper-catalyzed trifluoromethylation reactions of terminal
alkenes, see a) A. T. Parsons, S. L. Buchwald, Angew. Chem.
2011, 123, 9286 – 9289; Angew. Chem. Int. Ed. 2011, 50, 9120 –
9123; b) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J.
Wang, J. Am. Chem. Soc. 2011, 133, 16410 – 16413; c) J. Xu, Y.
Fu, D.-F. Luo, Y.-Y. Jiang, B. Xiao, Z.-J. Liu, T.-J. Gong, L. Liu, J.
Am. Chem. Soc. 2011, 133, 15300 – 15303; d) L. Chu, F.-L. Qing,
Org. Lett. 2012, 14, 2106 – 2109; for a selection of further recent
reports, see e) A. E. Allen, D. W. C. MacMillan, J. Am. Chem.
Soc. 2010, 132, 4986 – 4987; f) P. Novꢁk, A. Lishchynskyi, V. V.
Grushin, J. Am. Chem. Soc. 2012, 134, 16167 – 16170; g) S.
Mizuta, S. Verhoog, K. M. Engle, T. Khotavivattana, M. OꢀDuill,
K. Wheelhouse, G. Rassias, M. Mꢄdebielle, V. Gouverneur, J.
Am. Chem. Soc. 2013, 135, 2505 – 2508; h) H. Morimoto, T.
Tsubogo, N. D. Litvinas, J. F. Hartwig, Angew. Chem. 2011, 123,
3877 – 3882; Angew. Chem. Int. Ed. 2011, 50, 3793 – 3798; i) L.
Chu, F.-L. Qing, Org. Lett. 2010, 12, 5060 – 5063; j) X. Wang, L.
Truesdale, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 3648 – 3649.
[7] For alternative methods to access b-trifluoromethylated carbon-
yl compounds, see (by Friedel—Crafts alkylations) a) G. Blay, I.
Fernꢁndez, M. C. MuÇoz, J. R. Pedro, C. Vila, Chem. Eur. J.
2010, 16, 9117 – 9122; b) Y. Huang, E. Tokunaga, S. Suzuki, M.
Shiro, N. Shibata, Org. Lett. 2010, 12, 1136 – 1138; c) L. Wen, Q.
Shen, X. Wan, L. Lu, J. Org. Chem. 2011, 76, 2282 – 2285; by
Michael additions to b-trifluoromethyl enones, see d) M.
Yasuda, K. Chiba, N. Ohigashi, Y. Katoh, A. Baba, J. Am.
Chem. Soc. 2003, 125, 7291 – 7300; e) T. Konno, T. Tanaka, T.
Miyabe, A. Morigaki, T. Ishihara, Tetrahedron Lett. 2008, 49,
2106 – 2110; f) O. Marrec, J. Borrini, T. Billard, B. R. Langlois,
Synlett 2009, 1241 – 1244; g) O. Marrec, C. Christophe, T. Billard,
B. Langlois, J.-P. Vors, S. Pazenok, Adv. Synth. Catal. 2010, 352,
2825 – 2830; h) H. Kawai, S. Okusu, E. Tokunaga, H. Sato, M.
Shiro, N. Shibata, Angew. Chem. 2012, 124, 5043 – 5046; Angew.
Chem. Int. Ed. 2012, 51, 4959 – 4962; by trifluoromethylation of
enones, see i) A. A. Zemtsov, V. V. Levin, A. D. Dilman, M. I.
[12] The lower reactivity of these substrates compared to unfunc-
tionalized internal alkenes is likely due to the decreased electron
density of the double bond bearing a neighboring, electron-
withdrawing trifluoromethyl group, which slows down the rate of
oxidation.
[13] For a selection of references about using the trifluoromethyl
group to control reactions and selectivity, see a) S. Fioravanti, D.
Colantoni, L. Pellacani, P. A. Tardella, J. Org. Chem. 2005, 70,
3296 – 3298; b) A. Fu, W. Meng, H. Li, J. Nie, J.-A. Ma, Org.
Biomol. Chem. 2014, 12, 1908 – 1918; c) G. Hornyꢁk, J. Fetter, G.
Nꢄmeth, L. Poszꢁvꢁcz, G. Simig, J. Fluorine Chem. 1997, 84, 49 –
Angew. Chem. Int. Ed. 2014, 53, 8654 –8658
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8657

.
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Communications
51; d) J. Liu, K. J. Boarman, Chem. Commun. 2005, 340 – 341;
e) J. Liu, N. L. Wendt, K. J. Boarman, Org. Lett. 2005, 7, 1007 –
1010; f) J. Nie, G.-W. Zhang, L. Wang, A. Fu, Y. Zheng, J.-A. Ma,
Chem. Commun. 2009, 2356 – 2358; g) A. Vargas, F. Hoxha, N.
Bonalumi, T. Mallat, A. Baiker, J. Catal. 2006, 240, 203 – 212;
h) I. Ojima, K. Kato, M. Okabe, T. Fuchikami, J. Am. Chem. Soc.
1987, 109, 7714 – 7720; i) I. Ojima, M. Okabe, K. Kato, H. B.
Kwon, I. T. Horvath, J. Am. Chem. Soc. 1988, 110, 150 – 157; j) T.
Katagiri, S. Yamaji, M. Handa, M. Irie, K. Uneyama, Chem.
Commun. 2001, 2054 – 2055; k) V. A. Soloshonok, T. Hayashi, K.
Ishikawa, N. Nagashima, Tetrahedron Lett. 1994, 35, 1055 – 1058;
l) V. A. Soloshonok, D. V. Avilov, V. P. Kukhar, Tetrahedron
1996, 52, 12433 – 12442; m) X. Lin, F.-L. Qing, Org. Lett. 2013,
15, 4478 – 4481.
transition state at the distal position and the stabilization of
negative charge build up at the proximal position effected by the
trifluoromethyl group.
[17] For reports that achieved anti-Markovnikov selectivity in
Wacker oxidation, see a) J. Muzart, Tetrahedron 2007, 63,
7505; b) B. W. Michel, A. M. Camelio, C. N. Cornell, M. S.
Sigman, J. Am. Chem. Soc. 2009, 131, 6076 – 6077; c) B. Weiner,
A. Baeza, T. Jerphagnon, B. L. Feringa, J. Am. Chem. Soc. 2009,
131, 9473 – 9474; d) B. W. Michel, J. R. McCombs, A. Winkler,
M. S. Sigman, Angew. Chem. 2010, 122, 7470 – 7473; Angew.
Chem. Int. Ed. 2010, 49, 7312 – 7315; e) M. S. Sigman, E. W.
Werner, Acc. Chem. Res. 2011, 44, 874 – 884; f) G. Dong, P. Teo,
Z. K. Wickens, R. H. Grubbs, Science 2011, 333, 1609 – 1612;
g) P. Teo, Z. K. Wickens, G. Dong, R. H. Grubbs, Org. Lett. 2012,
14, 3237 – 3239; h) J. J. Dong, M. FaÇanꢁs-Mastral, P. L. Alsters,
W. R. Browne, B. L. Feringa, Angew. Chem. 2013, 125, 5671 –
5675; Angew. Chem. Int. Ed. 2013, 52, 5561 – 5565; i) Z. K.
Wickens, B. Morandi, R. H. Grubbs, Angew. Chem. 2013, 125,
11467 – 11470; Angew. Chem. Int. Ed. 2013, 52, 11257 – 11260;
j) Z. K. Wickens, K. Skakuj, B. Morandi, R. H. Grubbs, J. Am.
Chem. Soc. 2014, 136, 890 – 893.
[14] For direct comparison, substrates with an allylic trifluoromethyl
group and an allylic directing group (-OBn, -OBz, -OFur) were
designed and tested. However, these substrates were oxidized in
very low conversion.
[15] Compounds containing a vinylic trifluoromethyl group were
found to not react under the optimized conditions.
[16] We hypothesize that this selectivity is derived from a combina-
tion of the higher stability of the positive charge build up in the
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