Palladium-catalyzed intramolecular C-H difluoroalkylation: Synthesis of substituted 3,3-difluoro-2-oxindoles

Article abstract of DOI:10.1002/anie.201410471

The synthesis of 3, 3-difluoro-2-oxindoles through a robust and efficient palladium-catalyzed C-H difluoroalkylation is described. This process generates a broad range of difluorooxindoles from readily prepared starting materials. The use of BrettPhos as the ligand was crucial for high efficiency. Preliminary mechanistic studies suggest that oxidative addition is the rate-determining step for this process.

Full text of DOI:10.1002/anie.201410471

Angewandte
Chemie
DOI: 10.1002/anie.201410471
À
C H Activation
À
Palladium-Catalyzed Intramolecular C H Difluoroalkylation:
Synthesis of Substituted 3,3-Difluoro-2-oxindoles**
Shi-Liang Shi and Stephen L. Buchwald*
Abstract: The synthesis of 3,3-difluoro-2-oxindoles through
À
a robust and efficient palladium-catalyzed C H difluoroalky-
lation is described. This process generates a broad range of
difluorooxindoles from readily prepared starting materials.
The use of BrettPhos as the ligand was crucial for high
efficiency. Preliminary mechanistic studies suggest that oxida-
tive addition is the rate-determining step for this process.
T
he incorporation of fluorinated functional groups into
organic molecules has been widely recognized as a general
strategy in pharmaceutical research and drug development.
Fluorinated analogues of pharmaceutically relevant com-
pounds often possess properties conducive to drug develop-
ment, such as improved lipophilicity, metabolic stability, and
bioavailability relative to their nonfluorinated counterparts.[1]
For these reasons, substantial effort has been devoted to the
development of synthetic methods for the assembly of
fluorinated small molecules.[2] The fluorination[3] and trifluor-
omethylation[4] of arenes have been the most prominent
targets of these efforts, and as a result, increasingly general
and practical methods are now available for these trans-
formations.[2] In contrast, methods for the synthesis of
difluoroalkylated arenes remain limited.[5] In particular, the
synthesis of fluorinated heterocyclic compounds by the
difluoroalkylation of arenes is a promising but underutilized
strategy.
Figure 1. Bioactive oxindoles and isatins (top), 3,3-difluoro-2-oxindoles
Derivatives of oxindole and isatin appear in a variety of
naturally occurring and synthetic bioactive compounds
(Figure 1).[6] As bioisoteric analogues[7] of both classes of
heterocycles, compounds containing the 3,3-difluoro-2-oxin-
dole ring system have demonstrated considerable promise as
potential medicinal agents.[8] There are, however, only
a limited number of approaches for their preparation, each
of which suffers from serious drawbacks.[9] Difluorooxindoles
have been prepared by the treatment of isatin derivatives with
diethylaminosulfur trifluoride (DAST) or by electrophilic
fluorination of indoles.[9a–c] However, the limited stability of
as bioisosteric analogues of oxindoles and isatins and their proposed
synthesis from chlorodifluoroacetanilides (bottom).
the requisite reagents and modest functional-group tolerance
diminish the utility and practicality of these procedures.[10]
Moreover, both approaches depend on the availability of the
pre-existing bicyclic ring system, whose construction may be
nontrivial. The synthesis of the difluorooxindole ring system
under free-radical conditions[9d] or in the presence of a stoi-
chiometric amount of copper[9e] has also been reported.
However, these methods are limited by their scope, synthetic
efficiency, or the accessibility of the required starting
materials. A synthesis of difluorooxindoles through a palla-
[*] Dr. S.-L. Shi, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
[11]
À
dium-catalyzed C H difluoroalkylation process
would
constitute a general and practical alternative to these
previously reported methods.
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health for financial support
(GM46059). The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National
Institutes of Health. S.-L.S. thanks JSPS for a fellowship. We thank
Dr. Yiming Wang, Dr. Michael Pirnot, and Dr. Daniel T. Cohen for
assistance with the preparation of this manuscript.
In 2003, we disclosed the palladium-catalyzed synthesis of
oxindoles from a-chloroacetanilides.[12] The application of
this method to the kilogram-scale synthesis of two drug
candidates, a serine palmitoyl transferase inhibitor (3;
Figure 1)[13] and a long-term oxazolidinone antibacterial
(4)[14] illustrate the practicality and atom- and step-econom-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410471.
À
ical advantages of this C H functionalization protocol. An
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analogous process wherein chlorodifluoroacetanilides are
transformed into difluorooxindoles would similarly enable
the rapid construction of these compounds from readily
available starting materials. Chlorodifluoroacetanilides can
be prepared in one step by acylation of the corresponding
(hetero)arylamines with inexpensive chlorodifluoroacetic
anhydride. Although the oxidative addition[15] of palladium(0)
product (entries 7–12). No conversion of the starting material
was observed in the absence of either a phosphine ligand or
palladium source (entries 13 and 14). Lastly, exposure of 1a to
Friedel–Crafts cyclization conditions (1.2 equiv AlCl3) led to
the decomposition of the starting material without formation
of the desired product.
Under optimized reaction conditions (Table 2), we
explored the substrate scope of this transformation. A series
of chlorodifluoroacetanilides with electron-rich, electron-
neutral, and electron-deficient substituents on the aryl
À
to the analogous C Cl bond of chlorodifluoroacetanilides, as
À
well as the subsequent C C bond-forming reductive elimi-
nation[4a,16] are expected to be challenging processes, we
posited that the use of bulky biarylphosphine ligands would
facilitate these elementary steps. We disclose herein the
successful development of an efficient palladium-catalyzed
[a]
À
Table 2: Palladium-catalyzed C H difluoroalkylation of arenes.
À
C H difluoroalkylation reaction for the synthesis of 3,3-
difluoro-2-oxindoles.
We began our investigation of the proposed transforma-
tion by exposing the chlorodifluoroacetanilide 1a to base
(K2CO3) and palladium catalysts generated from premixing[17]
1 mol% of [Pd2dba3] and 4 mol% of a variety of phosphine
ligands (Table 1). The use of JohnPhos (L1), the optimal
ligand for the previous oxindole synthesis, provided 2a in low
yield (entry 1). Catalysts derived from CyJohnPhos (L2),
RuPhos (L3), XPhos (L4), and tBuXPhos (L5) were more
effective, but still only provided the desired oxindole in low to
moderate yields (entries 2–5). However, when BrettPhos (L6)
was employed as the ligand, the difluorinated oxindole 2a was
isolated in high yield (78%; entry 6). The use of other
monophosphine ligands, as well as bidentate phosphine
ligands, such as PPh3, PCy3, P(tBu)3, dppe, binap, and
Xantphos, resulted in low to no conversion to the desired
À
Table 1: Palladium-catalyzed C H difluoroalkylation: Ligand identifica-
tion.[a]
[a] Yields of isolated product are an average of two runs on a 1.0 mmol
scale. [b] Reaction conditions: [Pd2dba3] (1 mol%), L6 (4 mol%), 10 h.
group were found to undergo the desired transformation to
afford the corresponding difluorooxindoles in good yield.
This process was found to be compatible with ketone (2h),
ester (2g), amide (2i), acetal (2i), hemiaminal (2b), amino
(2d, 2e), and trifluoromethoxy (2 f) functional groups.
Entry
Ligand
Yield [%][b]
Entry
Ligand
Yield [%][b]
Given the prevalence of heterocycles in medicinal
chemistry, we also investigated the scope of heterocyclic
substrates (Table 3).[18] A broad array of heterocycle sub-
strates featuring monocyclic, bicyclic, and tricyclic rings were
compatible with the optimized reaction conditions. The scope
included heterocycles such as pyridine (2k), tetrahydroquino-
line (2m, 2o), 1,4-benzoxazine (2n), dihydrophenanthridine
(2q), dihydroquinolinone (2p), tetrahydrobenzazepine (2r),
dihydrodibenzoazepine (2s), tetrahydrobenzooxazepine (2t),
tetrahydrobenzothioazepine (2x), and tetrahydrobenzodia-
zepine (2y) ring systems. Unsymmetrical indole and carba-
zole substrates provided products 2j and 2l as chromato-
graphically separable regioisomers with moderate selectivity.
Interestingly, the cyclization occurred preferentially at the
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L6
PPh3
7
17
13
38
8
9
10
11
PCy3
PtBu3
dppe
binap
Xantphos
L6
16
16
13
4
0
0
53
12
85 (78)[c]
6
13[d]
14[e]
–
0
[a] Reactions were run in 0.2 mmol scale. [b] Determined by 19F NMR
analysis of the crude reaction mixture using PhCF3 as an internal
standard. [c] Yield of isolated product. [d] Without [Pd2dba3]. [e] Without
ligand. binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl, CPME=cy-
clopentyl methyl ether, dba=dibenzylidene acetone, dppe=1,2-bis(di-
phenylphosphino)ethane, Xantphos=4,5-bis(diphenylphosphino)-9,9-
dimethylxanthene.
2
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[a]
À
Table 3: Palladium-catalyzed C H difluoroalkylation of heteroarenes.
Scheme 1. Observed kinetic isotope effects.
[a] Yields of isolated product are an average of two runs in 1.0 mmol
scale. [b] Reaction was conducted in 5.0 mmol scale. r.r.=regioisomeric
ratio. MOM=methoxymethyl.
more sterically hindered position of these substrates, in
contrast to our previous palladium-catalyzed oxindole syn-
thesis.[12] To demonstrate the robustness of our reaction
conditions, the synthesis of 2t was also conducted on a 5 mmol
scale to afford the desired product in undiminished isolated
yield.
To probe the mechanism of this transformation, we
synthesized the isotopically labeled substrates [D1]-1a and
[D5]-1a (Scheme 1) for the determination of the intra- and
intermolecular kinetic isotope effects, respectively. An
inverse kinetic isotope effect was observed when [D1]-1a
was subjected to standard reaction conditions (kH/kD = 0.79;
Scheme 1a). On the other hand, no kinetic isotope effect was
observed upon exposure of a 1:1 mixture of 1a and [D5]-1a to
the standard reaction conditions (kH/kD = 1.01; Scheme 1b).
Based on these data, a plausible mechanism for this
transformation is shown in Scheme 2. The initial step of this
process is likely the oxidative addition of the chlorodifluoro
amide to Pd0 to generate a PdII enolate. The absence an
intermolecular isotope effect indicates that the rate-deter-
Scheme 2. Proposed catalytic cycle (the ligand was omitted for clarity).
inverse kinetic isotope effect observed in the intramolecular
experiment is likely a secondary isotope effect resulting from
the sp2 to sp3 rehybridization of the arene carbon atom to
which the proton or deuteron is attached.[20] The observation
of an inverse isotope effect implies that palladation is slow
À
relative to C H bond cleavage in the electrophilic aromatic
substitution process, and is in contrast to our previously
reported palladium-catalyzed oxindole synthesis from a-
chloroacetanilides.[12] Alternative mechanisms in which palla-
dation occurs through concerted either a metalation/depro-
tonation or s-bond metathesis pathway are excluded on the
basis of the observed inverse intramolecular isotope effect.[21]
In summary, we have developed a practical palladium-
À
catalyzed aromatic C H difluoroalkylation reaction using
readily available chlorodifluoroacetanilides. The bulky biar-
ylphosphine ligand, BrettPhos, was found to be the only
phosphine ligand capable of efficiently providing the desired
difluorooxindole product. This method allows the straightfor-
ward and efficient preparation of a wide range of substituted
3,3-difluoro-2-oxindoles. The high level of functional-group
tolerance and ready availability of starting materials should
make this protocol broadly useful and attractive in academic
and industrial settings.
À
mining step occurs prior to a C H bond cleavage or
rehybridization event, thus suggesting that oxidative addition
is rate-determining.[19] Subsequently, electrophilic aromatic
substitution of the arene furnishes a six-membered pallada-
cycle, which then undergoes reductive elimination to provide
the observed product and regenerate the Pd0 species. The
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Matheis, K. Jouvin, L. J. Goossen, Org. Lett. 2014, 16, 5984 –
5987; n) Y. Gu, X. Leng, Q. Shen, Nat. Commun. 2014, 5:5405
DOI: 10.1038/ncomms6405.
Received: October 26, 2014
Revised: November 14, 2014
Published online: && &&, &&&&
[6] a) Y.-J. Wu in Heterocyclic Scaffolds II, Topics in Heterocyclic
Chemistry, Vol. 26. (Ed.: G. W. Gribble), Springer, Berlin, 2010,
p. 1 – 30; b) J. J. Badillo, N. V. Hanhan, A. K. Franz, Curr. Opin.
Drug Discovery Dev. 2010, 13, 758 – 776.
[7] For a discussion on bioisosteres, see: N. A. Meanwell, J. Med.
Chem. 2011, 54, 2529 – 2591.
À
Keywords: C H activation · cross-coupling · fluorine ·
heterocycles · palladium
.
[1] a) K. Mꢀller, C. Faeh, F. Diederich, Science 2007, 317, 1881 –
1886; b) T. Hiyama, Fluorine Compounds: Chemistry and
Applications, Springer, Berlin, 2000; c) T. Yamazaki, T. Taguchi,
I. Ojima in Fluorine in Medicinal Chemistry and Chemical
Biology (Ed.: I. Ojima), Wiley-Blackwell, Chichester, 2009,
pp. 3 – 46; d) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur,
Chem. Soc. Rev. 2008, 37, 320 – 330; e) J. Wang, M. Sꢁnchez-
Rosellꢂ, J. L. AceÇa, C. del Pozo, A. E. Sorochinsky, S. Fustero,
V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432 – 2506.
[2] For selected reviews, see: a) T. Liang, C. N. Neumann, T. Ritter,
Angew. Chem. Int. Ed. 2013, 52, 8214 – 8264; Angew. Chem.
2013, 125, 8372 – 8423; b) O. A. Tomashenko, V. V. Grushin,
Chem. Rev. 2011, 111, 4475 – 4521; c) T. Besset, C. Schneider, D.
Cahard, Angew. Chem. Int. Ed. 2012, 51, 5048 – 5050; Angew.
Chem. 2012, 124, 5134 – 5136; d) X.-F. Wu, H. Neumann, M.
Beller, Chem. Asian J. 2012, 7, 1744 – 1754; e) R. J. Lundgren, M.
Stradiotto, Angew. Chem. Int. Ed. 2010, 49, 9322 – 9324; Angew.
Chem. 2010, 122, 9510 – 9512; for selected examples of arene
fluorination and trifluoromethylation, see: f) D. A. Nagib,
D. W. C. MacMillan, Nature 2011, 480, 224 – 228; g) Y. Ji, T.
Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su, D. G.
Blackmond, P. S. Baran, Proc. Natl. Acad. Sci. USA 2011, 108,
14411 – 14415; h) P. Tang, T. Furuya, T. Ritter, J. Am. Chem. Soc.
2010, 132, 12150 – 12154; i) X. Wang, L. Truesdale, J.-Q. Yu, J.
Am. Chem. Soc. 2010, 132, 3648 – 3649; j) N. D. Ball, J. W.
Kampf, M. S. Sanford, J. Am. Chem. Soc. 2010, 132, 2878 – 2879;
k) L. Chu, F.-L. Qing, J. Am. Chem. Soc. 2012, 134, 1298 – 1304.
[3] a) D. A. Watson, M. Su, G. Teverovskiy, Y. Zhang, J. Garcꢃa-
Fortanet, T. Kinzel, S. L. Buchwald, Science 2009, 325, 1661 –
1664; b) H. G. Lee, P. J. Milner, S. L. Buchwald, Org. Lett. 2013,
15, 5602 – 5605; c) H. G. Lee, P. J. Milner, S. L. Buchwald, J. Am.
Chem. Soc. 2014, 136, 3792 – 3795.
[4] a) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson,
S. L. Buchwald, Science 2010, 328, 1679 – 1681; b) T. D. Senecal,
A. T. Parsons, S. L. Buchwald, J. Org. Chem. 2011, 76, 1174 –
1176; c) E. J. Cho, S. L. Buchwald, Org. Lett. 2011, 13, 6552 –
6555; d) M. Chen, S. L. Buchwald, Angew. Chem. Int. Ed. 2013,
52, 11628 – 11631; Angew. Chem. 2013, 125, 11842 – 11845.
[5] a) Y. Guo, J. M. Shreeve, Chem. Commun. 2007, 3583 – 3585;
b) K. Fujikawa, Y. Fujioka, A. Kobayashi, H. Amii, Org. Lett.
2011, 13, 5560 – 5563; c) P. S. Fier, J. F. Hartwig, J. Am. Chem.
Soc. 2012, 134, 5524 – 5527; d) G. K. S. Prakash, S. K. Ganesh, J.-
P. Jones, A. Kulkarni, K. Masood, J. K. Swabeck, G. A. Olah,
Angew. Chem. Int. Ed. 2012, 51, 12090 – 12094; Angew. Chem.
2012, 124, 12256 – 12260; e) K. Araki, M. Inoue, Tetrahedron
2013, 69, 3913 – 3918; f) Q. Qi, Q. Shen, L. Lu, J. Am. Chem. Soc.
2012, 134, 6548 – 6551; during the preparation of this manuscript,
the following metal-catalyzed difluoroalkylation reactions were
reported: g) Q.-Q. Min, Z. Yin, Z. Feng, W.-H. Guo, X. Zhang, J.
Am. Chem. Soc. 2014, 136, 1230 – 1233; h) S. Ge, W. Chaładaj,
J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 4149 – 4152; i) Z.
Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang, X. Zhang, Angew. Chem.
Int. Ed. 2014, 53, 1669 – 1673; Angew. Chem. 2014, 126, 1695 –
1699; j) Y.-L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan, X. Zhang,
Angew. Chem. Int. Ed. 2014, 53, 9909 – 9913; Angew. Chem.
2014, 126, 10067 – 10071; k) Y.-B. Yu, G.-Z. He, X. Zhang,
Angew. Chem. Int. Ed. 2014, 53, 10457 – 10461; Angew. Chem.
2014, 126, 10625 – 10629; l) S. Ge, S. I. Arlow, M. G. Mormino,
J. F. Hartwig, J. Am. Chem. Soc. 2014, 136, 14401 – 14404; m) C.
[8] For examples of 3,3-difluoro-2-oxindole analogues in biological
studies, see: a) N. Zhou, A. M. Polozov, M. O’Connell, J.
Burgeson, P. Yu, W. Zeller, J. Zhang, E. Onua, J. Ramirez,
G. A. Palsdottir, G. V. Halldorsdottir, T. Andresson, A. S.
Kiselyov, M. Gurney, J. Singh, Bioorg. Med. Chem. Lett. 2010,
20, 2658 – 2664; b) G. D. Zhu, V. B. Gandhi, J. C. Gong, Y. Luo,
X. S. Liu, Y. Shi, R. Guan, S. R. Magnone, V. Klinghofer, E. F.
Johnson, J. Bouska, A. Shoemaker, A. Oleksijew, K. Jarvis, C.
Park, R. De Jong, T. Oltersdorf, Q. Li, S. H. Rosenberg, V. L.
Giranda, Bioorg. Med. Chem. Lett. 2006, 16, 3424 – 3429;
c) A. K. Podichetty, A. Faust, K. Kopka, S. Wagner, O. Schober,
M. Schꢄfers, G. Haufe, Bioorg. Med. Chem. 2009, 17, 2680 – 2688.
[9] a) W. J. Middleton, E. M. Bingham, J. Org. Chem. 1980, 45,
2883 – 2887; b) R. P. Singh, U. Majumder, J. M. Shreeve, J. Org.
Chem. 2001, 66, 6263 – 6267; c) Y. H. Lim, Q. Ong, H. A. Duong,
T. M. Nguyen, C. W. Johannes, Org. Lett. 2012, 14, 5676 – 5679;
d) Y. Ohtsuka, T. Yamakawa, Tetrahedron 2011, 67, 2323 – 2331;
e) J. Zhu, W. Zhang, L. Zhang, J. Liu, J. Zheng, J. Hu, J. Org.
Chem. 2010, 75, 5505 – 5512.
[10] a) L. N. Markovskij, V. E. Pahinnik, A. V. Kirsanov, Synthesis
1973, 787 – 789; b) W. J. Middleton, J. Org. Chem. 1975, 40, 574 –
578; c) P. A. Messina, K. C. Mange, W. J. Middleton, J. Fluorine
Chem. 1989, 42, 137 – 143.
[11] a) Y. Fujiwara, J. A. Dixon, R. A. Rodriguez, R. D. Baxter, D. D.
Dixon, M. R. Collins, D. G. Blackmond, P. S. Baran, J. Am.
Chem. Soc. 2012, 134, 1494 – 1497; b) Q. Zhou, A. Ruffoni, R.
Gianatassio, Y. Fujiwara, E. Sella, D. Shabat, P. S. Baran, Angew.
Chem. Int. Ed. 2013, 52, 3949 – 3952; Angew. Chem. 2013, 125,
4041 – 4044; c) Y. Fujiwara, J. A. Dixon, F. O’Hara, E. D. Funder,
D. D. Dixon, R. A. Rodriguez, R. D. Baxter, B. Herle, N. Sach,
M. R. Collins, Y. Ishihara, P. S. Baran, Nature 2012, 492, 95 – 99;
d) Y.-M. Su, Y. Hou, F. Yin, Y.-M. Xu, Y. Li, X. Zheng, X.-S.
Wang, Org. Lett. 2014, 16, 2958 – 2961; e) J. Jung, E. Kim, Y. You,
E. J. Cho, Adv. Synth. Catal. 2014, 356, 2741 – 2748; f) L. Wang,
X.-J. Wei, W.-L. Jia, J.-J. Zhong, L.-Z. Zhong, L.-Z. Wu, Q. Liu,
À
Org. Lett. 2014, 16, 5842 – 5845. For recent examples of C H
trifluoroethylation, see: g) W. Song, S. Lackner, L. Ackermann,
Angew. Chem. Int. Ed. 2014, 53, 2477 – 2480; Angew. Chem.
2014, 126, 2510 – 2513; h) H. Zhang, P. Chen, G. Liu, Angew.
Chem. Int. Ed. 2014, 53, 10174 – 10178; Angew. Chem. 2014, 126,
10338 – 10342.
[12] E. J. Hennessy, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
12084 – 12085.
[13] E. J. Kiser, J. Magano, R. J. Shine, M. H. Chen, Org. Process Res.
Dev. 2012, 16, 255 – 259.
[14] A. Choy, N. Colbry, C. Huber, M. Pamment, J. V. Duine, Org.
Process Res. Dev. 2008, 12, 884 – 887.
[15] To the best of our knowledge, the oxidative addition of
À
palladium to a C Cl bond of a difluoroalkyl chloride has not
been described in the literature. The palladium-catalyzed
difluoroalkylation reactions using difluoroalkyl bromides have
been reported. See Ref. [5g,i,k].
[16] a) V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc. 2006, 128,
4632 – 4641; b) V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc.
2006, 128, 12644 – 12645.
[17] The beneficial effects of catalyst premixing have been reported
previously. See: a) J. P. Wolfe, S. L. Buchwald, J. Org. Chem.
2000, 65, 1144 – 1157; b) S. Ueda, M. Su, S. L. Buchwald, Angew.
4
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Chem. Int. Ed. 2011, 50, 8944 – 8947; Angew. Chem. 2011, 123,
9106 – 9109; c) S. Ueda, M. Su, S. L. Buchwald, J. Am. Chem.
Soc. 2012, 134, 700 – 706.
[20] An inverse secondary intramolecular KIE of similar magnitude
has been reported for a hydroarylation reaction and was
attributed to sp2- to sp3-carbon atom rehybridization in an
arene dearomatization step: J. A. Tunge, L. N. Foresee, Organo-
metallics 2005, 24, 6440 – 6444.
[18] a) J. A. Joule, K. Mills in Heterocyclic Chemistry, 5th ed., Wiley,
Chichester, 2010; b) R. Leurs, R. A. Bakker, H. Timmerman,
I. J. P. de Esch, Nat. Rev. Drug Discovery 2005, 4, 107 – 120.
[19] For a useful discussion on analyzing KIE, see: E. M. Simmons,
J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066 – 3072;
Angew. Chem. 2012, 124, 3120 – 3126.
À
[21] An alternative mechanism in which C C bond formation
proceeds by carbopalladation of the aromatic ring followed by
b-hydride elimination cannot be excluded. See Ref. [12].
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Communications
À
C H Activation
S.-L. Shi, S. L. Buchwald*
&&&& — &&&&
À
Palladium-Catalyzed Intramolecular C H
Difluoroalkylation: Synthesis of
Substituted 3,3-Difluoro-2-oxindoles
Scoped out: An efficient synthesis of the
title compounds by a palladium-catalyzed
available starting materials. BrettPhos
was found to facilitate this transforma-
tion with unique efficiency. CPME=
cyclopentyl methyl ether, dba=dibenzyli-
dene acetone.
À
C H difluoroalkylation is described. This
method features a broad substrate scope,
operational simplicity, and utilizes readily
6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!