Palladium-catalyzed oxidative aryltrifluoromethylation of activated alkenes at room temperature

Article abstract of DOI:10.1021/ja210614y

A palladium-catalyzed intramolecular oxidative aryltrifluoromethylation reaction of activated alkenes has been explored. The reaction allows for an efficient synthesis of a variety of CF₃-containing oxindoles. Preliminary mechanistic study indicated that the reaction involves a Csp ³-Pd^IV(CF₃) intermediate, which undergoes reductive elimination to afford a C_sp3-CF₃ bond.

Full text of DOI:10.1021/ja210614y

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Oxidative Aryltrifluoromethylation of Activated
Alkenes at Room Temperature
Xin Mu,† Tao Wu,† Hao-yang Wang,‡ Yin-long Guo,‡ and Guosheng Liu*,†
‡
†State Key Laboratory of Organometallic Chemistry and Shanghai Mass Spectrometry Center, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
Scheme 1. Transition Metal-Catalyzed Trifluoromethylation
of Alkenes
ABSTRACT: A palladium-catalyzed intramolecular oxi-
dative aryltrifluoromethylation reaction of activated
alkenes has been explored. The reaction allows for an
efficient synthesis of a variety of CF3-containing oxindoles.
Preliminary mechanistic study indicated that the reaction
IV
3
involves a Csp −Pd (CF3) intermediate, which undergoes
3
reductive elimination to afford a Csp −CF3 bond.
he trifluoromethyl group is prevalent in pharmaceuticals,
T
agrochemicals, and functional materials.1,2 The unique
properties of trifluoromethylated molecules, such as elevated
electronegativity, hydrophobicity, metabolic stability, and bio-
availability, attract intensive attention to the development of
practical methods to synthesize such compounds.3 Among
them, transition metal-mediated or -catalyzed trifluoromethy-
lation reactions have proved to be an efficient strategy to intro-
duce a CF3 moiety into aromatic compounds.3d,4 For instance,
trifluoromethylation of aryl iodides or arylboronic acids can be
achieved by employing stoichiometric5 or catalytic amounts6 of
copper salts. For less reactive aryl chlorides, Pd-catalyzed tri-
fluoromethylation was developed by Buchwald and co-workers.
In their reaction, sterically hindered phosphine ligand Brettphos
promotes reductive elimination from LnPd(CF3)Aryl.7 Yu and
co-workers explored Pd-catalyzed trifluoromethylation of
arene C−H bonds using electrophilic Umemoto’s reagent as
CF3 source.8,9 However, these two reported trifluoromethyla-
tions were required expensive CF3 reagents at relatively high
temperature.
various CF3-substituted oxindoles, which are important in natural
products and biologically active compounds.17,18
To test our hypothesis, the initial investigation focused on
the reaction of substrate 1a with various CF3+ reagents, such as
Togni’s reagent 3 and Umemoto’s reagent 4, using Pd(OAc)2
catalyst. However, none of the desired product was observed
under these reaction conditions (Table 1, entries 1 and 2).
Inspired by our previous work on fluoroamination of alkenes,14
we tested a catalytic system combining hypervalent iodine
reagent and CF3−. Interestingly, a significant amount of aryltri-
fluoromethylation product 2a was observed with high regio-
selectivity when the reaction employed TMSCF3 and CsF to
generate CF3− in situ and PhI(OAc)2 oxidant (entry 3). Screening
of nitrogen-containing ligands L1−L5 showed that L5 gave the
best yield. A similar ligand, L6, bearing a cyclopropane group gave
worse results (entries 4−9). Exploration of oxidants revealed that
only hypervalent iodine reagents are reactive, and PhI(OAc)2
afforded the best result (entries 8, 10−12). Subsequently, a series
of Lewis acids were screened (entries 13−16). The best yield
(75%) was obtained in the presence of Yb(OTf)3 (20 mol %,
entry 15). No significant effect for the addition of radical
scavenger TEMPO indicates that a radical process is less likely
(entry 17). Finally, the highest yield was achieved in the reaction
with EtOAc as solvent (entry 18).19
Transition metal-catalyzed selective trifluoromethylation of
alkenes is quite rare. Very recently, Buchwald,10a Liu,10b and
Wang10c independently reported Cu-catalyzed allylic C−H
trifluoromethylation reactions (Scheme 1a).10 It is known that
Pd-catalyzed oxidative difunctionalization of alkenes provides
an efficient strategy to construct two vicinal chemical bonds.11
Reactions such as aminooxygenation,12 diamination,13 dioxyge-
nation,14 and fluoroamination15 have been shown to involve a
Pd(II/IV) mechanistic pathway. We hypothesize that, if a
trifluoromethylation catalytic system can be applied in the
alkene difunctionalization, a variety of CF3-containing aliphatic
compounds should be easily available (Scheme 1b, top).
Herein, we report a novel Pd-catalyzed oxidative aryltrifluoro-
methylation of activated alkenes using easily available,
inexpensive TMSCF3 as trifluoromethyl source at room
temperature (Scheme 1b, bottom).16 It is worth noting that this
method represents one of most efficient ways to synthesize
With the optimized reaction conditions, the substrate scope
was then investigated as shown in Table 2. Substrates 1a−1c
bearing alkyl, aryl, or silyl protecting groups on the nitrogen
Received: November 11, 2011
Published: December 20, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 1. Optimization of the Reaction Conditions
b
entry
ligand (15 mol %)
additive
oxidant
yield (%)
c
1
3
4
0
c
2
0
3
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OPiv)2
PhI(TFA)2
PhIO
24
25
26
34
30
55
21
38
0
4
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
L5
L5
L5
L5
5
a
6
Table 2. Pd-Catalyzed Aryltrifluoromethylation of Alkenes
7
8
9
10
11
12
0
d
13
HOTf
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
62
46
75
60
70
81 (78)
d
14
TFA
d
15
Yb(OTf)3
Sc(OTf)3
Yb(OTf)3
Yb(OTf)3
d
16
de
,
17
18
f
g
a
Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol %), CsF (0.4
mmol), TMSCF3 (4 equiv), PhI(OAc)2 (0.2 mmol) in 1.0 mL of
b
c
+
CH3CN at room temperature (30 °C) for 6 h. 19F NMR yield. CF3
d
reagent was used, without TMSCF3/CsF and oxidant. Lewis acid
(20 mol %). TEMPO (1 equiv) EtOAc as solvent. Isolated yield.
e
f
g
were good for this transformation, but tosylated substrate 1d
failed to give the desired product. A variety of anilines
substrates 2e−2r were next determined. The position of the
substituents has no significant influence on the efficiency. The
substrates bearing electron-withdrawing or electron-donating
groups always afforded the desired products 2e−2n in good to
excellent yields. Notably, halides were tolerated and furnished
the corresponding products 2k−2o in excellent yields. Sub-
strates having two substituents on the phenyl rings provided the
products 2p−2r in good yields. However, the reaction afforded
the mixture of 2r and 2r′ with moderate regioselectivity (1:3
ratio). Finally, substrates with different substituents on olefin
were examined. No reaction occurred in the case of mono-
substituent olefin (R3 = H). However, a series of α-substituted
olefins bearing different functional group, such as aryl (1s),
alcohol (1t), ester (1u), ether (1v, 1w), and phthalimide (1x),
are compatible with this catalytic system, and all reactions
produced desired products 2s−2x in moderate to good yields.
It is remarkable that only one isomer, 2w, was obtained in the
reaction of 1w with excellent diastereoselectivity.
a
All reactions were conducted at 0.2 mmol scale: Pd(OAc)2 (10 mol %),
L5 (15 mol %), Yb(OTf)3 (20 mol %), PhI(OAc)2 (2 equiv), TMSCF3
(4 equiv), and CsF (4 equiv) in EtOAc (1 mL). Isolated yield are given.
b
Only one isomer was obtained.
not confirmed at this stage. This result is consistent with a
3
mechanism of arylpalladation of alkene to give a Csp −Pd(II)
intermediate, which undergoes sequential alkene insertion and
oxidative trifluoromethylation to form product 6.
The formation of 2 indicates that a C−H bond functiona-
lization of aniline is involved in the reaction. To probe the
mechanism of C−H bond cleavage, a mixture of substrates 1a
and 1a-d5 in a 1:1 ratio was used to determine the inter-
molecular isotope effect, and substrate 1a-d1 was used for the
intramolecular isotope effect. No kinetic isotope effect (kH/
kD = 1.0, eqs 2 and 3) was observed.20 The absence of an intra-
molecular isotope effect suggests that the arylation step may
involve an electrophilic aromatic substitution process.21
Mass spectrometry experiments provided further insights
into the catalytic cycle of the trifluoromethylation. First, ESI-
MS showed a peak at m/z 435, which corresponds to the mass
of [I − OAc]+,22 in the mixture of Pd(OAc)2, L5, and 1a in
To evaluate the aryltrifluoromethylation reaction further,
diene 5 was subjected to the reaction conditions at 50 °C (eq 1).
This tandem cyclization afforded spirocyclic product 6 as a single
diastereomer in 62% yield, but its relative stereoconfiguration was
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Journal of the American Chemical Society
Communication
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
gliu@mail.sioc.ac.cn
ACKNOWLEDGMENTS
■
We are grateful for financial support from the 973 Program of
China (973-2009CB825300), the NSFC (20872155, 20972175,
and 20923005), and STCSM (11JC1415000).
Scheme 2. Proposed Mechanism for
Aryltrifluoromethylation
REFERENCES
■
(1) (a) Smart, B. E. Chem. Rev. 1996, 96, 1555. (b) Filler, R.;
Kobayashi, Y. Biomedicinal Aspects of Fluorine Chemistry; Elsevier:
Amsterdam, 1982. (c) Welch, J. T. Eswarakrishman, S., Eds. Fluorine in
Bioorganic Chemistry; Wiley: New York, 1991. (d) Banks, R. E., Smart,
B. E., Tatlow, J. C., Eds. Organofluorine Chemistry: Principles and
Commercial Applications; Plenum Press: New York, 1994.
(2) (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214.
(b) Muller, C. K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320. (d) Jeschke, P. ChemBioChem 2004, 5, 570.
(3) For reviews for trifluoromethylation, see: (a) Schlosser, M.
Angew. Chem., Int. Ed. 2006, 45, 5432. (b) Ma, J.-A.; Cahard, D.
J. Fluorine Chem. 2007, 128, 975. (c) Ma, J.-A.; Cahard, D. Chem. Rev.
2008, 108, PR1. (d) Tomashenko, O. A.; Grushin, V. V. Chem. Rev.
2011, 111, 4475.
(4) For early examples of transition metal-catalyzed perfluoroalky-
lation of aromatic compounds, see: (a) Kitazume, T.; Ishikawa, N.
Chem. Lett. 1982, 137. (b) Zhou, Q.-L.; Huang, Y.-Z. J. Fluorine Chem.
1988, 39, 87. (c) Zhou, Q.-L.; Huang, Y.-Z. J. Fluorine Chem. 1989, 43,
385. (d) Chen, Q.; Wu, S. J. Chem. Soc., Chem. Commun. 1989, 705.
(5) For recent Cu-mediated trifluoromethylation of aryl iodide, see:
(a) Chu, L.-L.; Qing, F.-L. Org. Lett. 2010, 12, 5060. (b) Senecal,
T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174.
(c) Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu, Y.-C.;
Xiao, J.-C. Angew. Chem., Int. Ed. 2011, 50, 1896. (d) Dubinina, G. G.;
Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600.
(e) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2011, 50, 3793. (f) Tomashenko, O. A.; Escudero-
Adan, E. C.; Belmonte, M. M.; Grushin, V. V. Angew. Chem., Int. Ed.
2011, 50, 7655. (g) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002,
327. (h) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc.
2008, 130, 8600. (i) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A.
Organometallics 2008, 27, 6233.
(6) For Cu-catalyzed trifluoromethylation of aryl iodide, see:
(a) Popov, I.; Lindeman, S.; Daugulis, O. J. Am. Chem. Soc. 2011,
133, 9286. (b) Weng, Z.-Q.; Lee, R.; Jia, W.-G.; Yuan, Y.-F.; Wang,
W.-F.; Feng, X.; Huang, K.-W. Organometallics 2011, 30, 3229. (c) Liu,
T.; Shen, Q.-L. Org. Lett. 2011, 13, 2342. (d) Xu, J.; Luo, D.-F.; Xiao,
B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem. Commun. 2011, 47,
4300. (e) Kondo, H.; Oishi, M.; Fujikawa, K.; Amii, H. Adv. Synth.
Catal. 2011, 353, 1247. (f) Knauber, T.; Arikan, T.; Roschenthaler, G.-V.;
Goosen, L. J. Chem. Eur. J. 2011, 17, 2697. (g) Oishi, M.; Kondo, H.;
Amii, H. Chem. Commun. 2009, 1909.
CH3CN. The intermediate I is generated from the (L5)Pd(OAc)2
complex by loss of HOAc.23 In the standard catalytic reaction,
we are delighted that two signals at m/z 668 and 678, which are
related to the masses of [IV − CF3]+ and [IV − OAc]+, were
observed (Scheme 2).24 In addition, stoichiometric reaction gave a
19F NMR signal at −27.1 ppm, which is consistent with the data of
aryl−PdIVCF3 species reported by Sanford.9c,d The above obser-
vations provide support that this aryltrifluoromethylation may
IV
3
involve a Csp −Pd CF3 intermediate, IV.
Based on the above analysis, a possible catalytic cycle is shown
in Scheme 2. The reaction is initiated by coordination of the
olefin to Pd(II) complex I. Nucleophilic attack of the tethered
arene affords Pd complex III. This species undergoes oxidation
IV
3
by PhI(OAc)2/TMSCF3 to form a Csp −Pd (CF3) intermediate
3
IV, which generates a Csp −CF3 bond via reductive elimination
and releases Pd catalyst I.25
In summary, we have developed a novel Pd-catalyzed oxidative
aryltrifluoromethylation of activated alkenes using TMSCF3/
CsF as trifluoromethyl group source and PhI(OAc)2 as oxidant.
Preliminary mechanistic studies indicate that the reaction pro-
ceeds through initial arylpalladation of alkene, followed by
IV
3
(7) (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson,
D. A.; Buchwald, S. L. Science 2010, 328, 1679. For Pd-catalyzed
trifluoromethylation of aryl bromide, see: (b) Samant, B. S.; Kabalka,
G. W. Chem. Commun. 2011, 47, 7236. For the stoichiometric
reaction, see: (c) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc.
2006, 128, 12644.
sequential oxidation and reductive elimination of Csp −Pd CF3
species to provide the products in good yields. This reaction
creates an opportunity to construct a variety of bioactive mole-
cules containing trifluoromethylated oxindole moieties. Further
investigation of this transformation is in progress.
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Journal of the American Chemical Society
Communication
(8) For Pd-catalyzed oxidative trifluoromethylation, see: (a) Wang,
X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3648. (b) Mu,
X.; Chen, S.; Zheng, X.; Liu, G. Chem.Eur. J. 2011, 17, 6039.
(9) For the stoichiometric reaction and mechanistic studies of the
oxidative trifluoromethylation, see: (a) Ball, N. D.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878. (b) Ye, Y.; Ball,
N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132,
14682. (c) Ball, N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S. J. Am. Chem.
Soc. 2011, 133, 7577. (d) Racowski, J. M.; Ball, N. D.; Sanford, M. S.
J. Am. Chem. Soc. 2011, 133, 18022.
Racowski, J. M.; Dick, A. R.; Sanford, M. S. J. Am. Chem. Soc. 2009,
131, 10974.
(23) Compared to noneffective bis-nitrogen ligands L1−L4 and L6,
ligand L5, which contains an acid proton, is easy to transform into a
monoionic ligand.
(24) For detailed analysis, see the Supporting Information.
(25) Other mechanistic pathways cannot be excluded at this point.
Further investigations are ongoing.
(10) For Cu-catalyzed allylic C−H bond trifluoromethylation, see:
(a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50,
9120. (b) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.;
Gong, T.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300. (c) Wang, X.;
Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc.
2011, 133, 16410. For Cu-catalyzed trifluoromethylation of terminal
alkyne, see: Chu, L.-L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262.
(11) For some recent reviews on the oxidative difunctionalization of
alkenes, see: (a) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008,
6, 4083. (b) Kotov, V.; Scarborough, C. C.; Stahl, S. S. Inorg. Chem.
2007, 46, 1910. (c) Jacques, B.; Muniz, K. In Catalyzed Carbon−
̃
Heteroatom Bond Formation; Yudin, A. K., Ed.; Wiley-VCH:
Weinheim, 2010; p 119. (d) Chemler, S. R. Org. Biomol. Chem.
2009, 7, 3009. (e) Muniz, K. Angew. Chem., Int. Ed. 2009, 48, 9412.
̃
(12) (a) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc.
2005, 127, 7690. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128,
7179. (c) Desai, L. V.; Sanford, M. S. Angew. Chem., Int. Ed. 2007, 46,
5737.
́
(13) (a) Iglesias, A.; Per
́
ez, E. G.; Muniz, K. Angew. Chem., Int. Ed.
̃
2010, 49, 8109. (b) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz,
K. J. Am. Chem. Soc. 2005, 127, 14586. (c) Muniz, K. J. Am. Chem. Soc.
2007, 129, 14542. (d) Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11,
1147.
̈
̃
̃
(14) (a) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009, 131,
3846. (b) Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130,
2962.
(15) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354.
(16) TMSCF3 is available from Green Chemical Co. in China for
U.S. $60/100 g.
(17) For some reviews on biologically active compounds containing
oxindole moieties, see: (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Catal.
Synth. 2010, 352, 1381. (b) Galliford, C. V.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 8748. (c) Marti, C.; Carreira, E. M. Eur. J.
Org. Chem. 2003, 2209. (d) Lin, H.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2003, 42, 36. (e) Jensen, B. S. CNS Drug Rev. 2002, 8, 353.
(18) For synthesis of oxindoles by using Pd catalyst, see: (a) Jaegli,
S.; Dufour, J.; Wei, H.-L.; Piou, T.; Duan, X.-H.; Vors, J.-P.; Neuville,
L.; Zhu, J. Org. Lett. 2010, 12, 4498. (b) Wei, H.-L.; Piou, T.; Dufour,
J.; Neuville, L.; Zhu, J. Org. Lett. 2011, 13, 2244. (c) Pinto, A.; Jia, Y.;
Neuville, L.; Zhu, J. Chem. Eur. J. 2007, 13, 961.
(19) In the absence of Pd catalyst, the reaction affords
aryltrifluoromethylation product in 31% yield (24 h), and 27% yield
with 1 equiv of TEMPO. It is possible that this transformation is
promoted by PhI(OAc)2. For some selective examples of hypervalent
iodine-promoted olefin functionalization, see: (a) Roben, C.; Souto,
̈
́
J. A.; Gonzalez, Y.; Lishchynskyi, A.; Muniz, K. Angew. Chem., Int. Ed.
̃
2011, 50, 9478. (b) Kang, Y.-B.; Gade, L. H. J. Am. Chem. Soc. 2011,
133, 3658. (c) Lovick, H. M.; Michael, F. E. J. Am. Chem. Soc. 2010,
132, 1249.
(20) For the reaction in eq 1, no H/D scrambling was observed in
the recovered starting material 1a and 1a-d5. For details, see the
Supporting Information.
(21) For the corresponding KIE value of the electrophilic aromatic
substitution process, see: (a) Tunge, J. A.; Foresee, L. N. Organo-
metallics 2005, 24, 6440−6444. (b) Taylor, R. Electrophilic Aromatic
Substitution; John Wiley & Sons Inc.: New York, 1990; pp 25−57.
(22) Electrosprayionization commonly results in loss of one X-type
ligand from Pd complexes.For details, see ref 9d and the following:
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