Pd(0)-Catalyzed radical aryldifluoromethylation of activated alkenes

Article abstract of DOI:10.1039/c3cc49315f

A Pd(0)-catalyzed intramolecular aryldifluoromethylation of activated alkenes under mild reaction conditions has been developed. This reaction provides a new method for construction of a variety of difluoromethylated oxindoles. Mechanistic investigations indicate that a difluoromethyl radical, which was triggered by Pd(0), initiated the cascade sequence through an addition to the alkene. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3cc49315f

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Pd(0)-Catalyzed radical aryldifluoromethylation of
activated alkenes†
Cite this: Chem. Commun., 2014,
50, 4108
Jian-Yong Wang, Yi-Ming Su, Feng Yin, Yan Bao, Xin Zhang, Yue-Ming Xu and
Xi-Sheng Wang*
Received 8th December 2013,
Accepted 27th February 2014
DOI: 10.1039/c3cc49315f
www.rsc.org/chemcomm
A Pd(0)-catalyzed intramolecular aryldifluoromethylation of acti- of iodoarenes with HCF2TMS and HCF2SnBun , respectively. Liu
3
vated alkenes under mild reaction conditions has been developed. and co-workers reported an iron-catalyzed decarboxylative difluoro-
This reaction provides a new method for construction of a variety of methylation of cinnamic acids with zinc difluoromethanesulfinate
difluoromethylated oxindoles. Mechanistic investigations indicate (DFMS).12 Recently, the Reutrakul group described a Pd-mediated
that a difluoromethyl radical, which was triggered by Pd(0), initiated Heck-type coupling of PhSO2CF2Br and styrene, in which the well-
the cascade sequence through an addition to the alkene.
known Heck reaction mechanism was proposed.13 However, this
method suffered from high Pd loading (35 mol%), narrow substrate
Organofluorine compounds are widely used in medicine and scope and low yield. Herein, we report a Pd(0)-catalyzed intra-
agriculture, as well as in life- and materials sciences because of molecular aryldifluoromethylation of activated alkenes,14,15 in
their unique metabolic stability, lipophilicity and biological which a variety of difluoromethylated oxindoles were synthesized.
properties.1 Therefore, the development of new methods for Mechanistic investigations indicate that the cascade sequence was
the introduction of fluorine or fluorinated moieties into organic initiated by an addition of a difluoromethyl radical to alkene.
molecules is of widespread importance. Since the difluoro-
Oxindoles have long been realized as one of the important
methyl group (CF2H) can act as a bio-isostere of alcohols and scaffolds used in medical and biological chemistry because of their
thiols and as a lipophilic hydrogen-bond donor,2 it has been unique bioactivities.16 Liu and co-workers reported an impressive
realized as a valuable structure motif with great potential in approach to synthesise trifluoromethylated oxindoles, in which a
pharmaceuticals, agrochemicals, and materials because of its Pd-catalyzed intramolecular oxidative aryltrifluoromethylation of
special biological properties.3
N-arylacrylamides was developed (Scheme 1).17 Recently, Sodeoka,18
In the past decades, considerable effort has been devoted to Nevado19 and Zhu20 reported copper-catalyzed or photoinduced
ꢀ
develop the practical methods to synthesize difluoromethylated CF3 radical cyclization of this kind of acrylamides to oxindoles
organic compounds.4 While transition metal mediated or catalyzed with the Togni reagent. Though the difluoromethyl moiety (CF2H)
trifluoromethylation has been demonstrated as a powerful strategy has long been realized as an important bioactive fluoroalkyl group
for incorporating the CF3 group into organic molecules,5 there are different from CF3, the synthesis of CF2H-containing oxindoles has
still few examples of transition metal-promoted difluoromethyl- never been explored. We envisioned that a difluoromethyl radical
ation. The Amii group reported a sequential cross-coupling/
hydrolysis/decarboxylation route to prepare difluoromethylarenes
catalysed by copper.6 Hu and co-workers described a copper-
mediated difluoromethylation of propargyl chlorides and alkynyl
halides to afford HCF2-containing allenes and alkynes.7 With their
own developed Togni-type I(III)-CF2SO2Ph reagent, the Hu group
reported also copper-catalyzed vinylic8 and allylic9 difluoromethyl-
ation from a,b- and b,g-carboxylic acids, respectively, through
decarboxylative fluoroalkylation. The Hartwig10 and Prakash11
groups described the direct copper-mediated difluoromethylation
Department of Chemistry, University of Technology of China, Hefei 230026, China.
E-mail: xswang77@ustc.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc49315f
Scheme 1 Radical trapping experiments.
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Table 1 Optimization of reaction conditionsa,b
Entry
Pd2(dba)3 (mol%)
Ligand (mol%)
Yield (%)
Entry
Pd2(dba)3 (mol%)
Ligand (mol%)
Yield (%)
1
2
3
4
5
6
5
5
5
5
5
5
XantPhos (20)
PPh3 (30)
X-Phos (30)
S-Phos (30)
dppe (20)
89
8
55
Trace
6
7
8
9
10
11
12c
5
5
2.5
2.5
2.5
2.5
BINAP (20)
44
82
91
90
71
Trace
DPE-Phos (20)
XantPhos (15)
XantPhos (10)
XantPhos (5)
XantPhos (10)
dppf (20)
24
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), Pd2(dba)3 (5.0 mol%), Ligand (20 mol%), KOAc (2.0 equiv.), PhSO2CF2I (1.2 equiv.) in CHCl3
b
c
(0.5 mL) at 80 1C for 24 h. Isolated yield. PhSO2CF2Br was used instead of PhSO2CF2I.
Table 2 Substrate scopea,b
could be trapped by the activated double bonds of N-arylacryl-
amides, thus giving the corresponding oxindoles after C–C bond-
forming cyclization.
Our study commenced with N-methyl-N-phenyl-methacrylamide
(1a) as the pilot substrate and PhSO2CF2I, a well established difluoro-
methylation reagent developed by Prakash and Hu,21 as the coupling
partner in the presence of catalytic Pd2(dba)3 (5 mol%) at 80 1C. To
our excitement, the desired aryldifluoromethylation product 2a was
obtained in 89% yield with XantPhos used as the ligand in chloro-
form (entry 1, Table 1). In contrast to XantPhos, most other ligands,
including diphosphine ligands (dppe, dppf and BINAP) and mono-
phosphine ligands (PPh3, S-Phos and X-Phos), showed almost no or
markedly reduced catalytic reactivity (entries 2–7). Unsurprisingly,
diphosphine ligand DPE-Phos, which has a similar structure to
XantPhos, gave the difluoromethylated product with a slightly dimini-
shed yield (entry 8). Importantly, when the Pd catalyst loading was
reduced to 5 mol% (2.5 mol% Pd2(dba)3), approximately the same
yield could be obtained (entry 9). Notably, the investigation of the
ratio of Pd/ligand showed 2 equivalents of XantPhos to Pd were
necessary to give a high yield, which indicated that the electron-rich
tetraphosphine-ligated palladium species was crucial to initiate the
transformation (entries 9–11). Lastly, control experiments confirmed
that only trace quantities of the desired product were detected
with PhSO2CF2Br13 used as the difluoromethylated reagent source
(entry 12).
With the optimized reaction conditions in hand, we next set out
to investigate the substrate scope. Initially, the examination of
different N-protecting groups revealed that methyl (2a) was still the
best choice, while the similar benzyl-protected substrate (2b) gave a
slightly reduced yield and electron-withdrawing tosyl (2c) afforded
none of the desired product at all. The substituent effects of aryl ring
(R1) were next investigated. A variety of acrylamides 1 with para-,
meta- as well as ortho-substituents were smoothly cyclized to afford
the corresponding aryldifluoromethylation oxindoles 2 with good to
excellent yields, although a mixture of two expected regioisomers was
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), Pd2(dba)3 (2.5 mol%),
XantPhos (10 mol%), KOAc (2.0 equiv.), PhSO2CF2I (1.2 equiv.) in
b
c
CHCl3 (0.5 mL) at 80 1C for 24 h. Isolated yield. Pd2(dba)3 (5.0 mol%)
and Xantphos (20 mol%) were used. 100 1C. 120 1C. PhSO2CF2I
(1.5 equiv.) were used.
d
e
f
obtained for meta-substituted substrate (2o, C2:C6 = 1.8:1). Both aryldifluoromethylated with excellent yields. To our satisfaction, the
electron-donating, such as Me and MeO, and electron-withdrawing examination of a-substituents (R3) of alkenes showed that Bn,
groups, such as F, Cl, Br, CF3 were compatible with the optimized OMe, OAc, and NPhth were also well tolerated (2t–w). Finally, a
conditions (2d–i). Notably, the bromo substituent in the aniline b-substituted (R4) internal alkene 2s was also used as viable substrate
ring (2f), as well as inactive halides including Cl and F, offered for this catalytic system, albeit with a lower yield (Table 2).
the potential for further synthetic elaboration. Importantly, acryl-
To gain insight into the mechanism of this transformation,
amides with tetrahydroquinoline (2q) and pyridine ring (2o) were a series of experiments were carried out. First, we performed
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the reaction in the presence of 1.0 equiv. TEMPO as a radical in 91% yield (Scheme 3). Furthermore, the oxindoles with
scavenger, and only trace of aryldifluoromethylated product was electron-deficient (2e) or electron-rich groups (2i) at the aniline
obtained, which was consistent with the hypothesis that the reac- ring were compatible with this method, giving the desired
tion proceeds via a radical pathway (eqn (1), Scheme 1). Kinetic difluoromethyl products 7b–c in excellent yields, respectively.
isotope experiments were next undertaken. We performed an
In conclusion, we have developed a Pd(0)-catalyzed intra-
intermolecular competition experiment between acrylamide 1a molecular aryldifluoromethylation of activated alkenes under
and its pentadeuterated analogue 1a-d5 and found no kinetic mild reaction conditions. Mechanistic investigations indicate
isotope effects (kH/kD = 1.0, see ESI†). Similarly, comparison of that a difluoromethyl radical, which was triggered via reduction
parallel independent reactions of 1a and 1a-d5 also showed a KIE of of PhSO2CF2I by Pd(0), initiated the cascade sequence through
1.0 (see ESI†). Both observations indicated that the C–H cleavage addition to alkene.
step was not rate-determining. While we failed to capture the
We gratefully acknowledge NSFC (21102138, 21372209), the
coupling product of TEMPO with PhSO2CF2I, we were able to Chinese Academy of Sciences, and the Ministry of Education
employ two kinds of radical clocks, allyl ether 3 and b-pinene 5, (SRFDP 20123402110040) for financial support. Y.-M.X. is a
ꢀ
to trap the PhSO2CF2 radical, and the cyclized product 4 and the visiting student from Anhui University.
ring-opened diene 6 were obtained in 82% yield (2.7 : 1 d.r.) and
76% yield (isolated as an isomeric mixture), respectively (eqn (2)
and (3)). Both results implicated that the difluoro(phenylsulfonyl)-
methyl radical was involved in this process.
Notes and references
1 (a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis Reactivity,
Applications, Wiley-VCH, Weinheim, 2004; (b) D. O’Hagan and
H. S. Rzepa, Chem. Commun., 1997, 645; (c) K. Mu¨ller, C. Faeh and
On the basis of these observations, a plausible mechanism
involving a radical-type catalytic cycle is depicted in Scheme 3.
Initially, reduction of PhSO2CF2I catalyzed by Pd(0) affords Pd(I) and
an electrophilic difluoro(phenylsulfonyl)methyl radical (PhSO2CF2ꢀ) A.
Addition of A to the activated double bond in acrylamide 1a results
in the formation of the carbon radical intermediate B, which is then
trapped by the aniline ring to give radical intermediate C. The
subsequent C–H cleavage step could proceed through two possible
pathways. Path I is similar to Alexanian’s hypothesis for Pd-catalyzed
radical Heck-type reactions of alkyl iodides.22 In this scenario, the
radical C is captured by Pd(I) to yield Pd(II) species D. D then
undergoes b-hydride elimination to afford the desired product 2a
and regenerate the Pd(0) catalyst. Alternatively, in Path II, radical C
is oxidized to cation E by Pd(I) followed by base-mediated deproto-
nation to give the final difluoromethylated product 2a. Notably,
this transformation avoids the use of potential hazardous radical
initiators with Pd(0) as catalyst (Scheme 2).
F. Diederich, Science, 2007, 317, 1881; (d) W. K. Hagmann, J. Med.
Chem., 2008, 51, 4359; (e) S. Purser, P. R. Moore, S. Swallow and
V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320.
2 (a) G. M. Blackburn, D. A. England and F. Kolkmann, J. Chem. Soc.,
Chem. Commun., 1981, 930; (b) J. A. Erickson and J. I. Mcloughlin,
J. Org. Chem., 1995, 60, 1626.
3 (a) M. J. Tozer and T. F. Herpin, Tetrahedron, 1996, 52, 8619;
(b) V. P. Reddy, M. Perambuduru and R. Alleti, Adv. Org. Synth.,
2006, 2, 327; (c) K. L. Kirk, Org. Process Res. Dev., 2008, 12, 305;
(d) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529.
4 For selected reviews of difluoromethylation, see: (a) G. K. S. Prakash
and J.-B. Hu, Acc. Chem. Res., 2007, 40, 921; (b) J.-B. Hu, W. Zhang
and F. Wang, Chem. Commun., 2009, 7465; (c) J.-B. Hu, J. Fluorine
Chem., 2009, 130, 1130; (d) C.-F. Ni and J.-B. Hu, Synlett, 2011, 770;
(e) W. Zhang, C.-F. Ni and J.-B. Hu, Top. Curr. Chem., 2012, 308, 25;
( f ) Z. Feng, F. Chen and X. Zhang, Org. Lett., 2012, 14, 1938.
5 For selected reviews of trifluoromethylation, see: (a) J. Zhang,
G. B. Hammond and B. Xu, Aldrichimica Acta, 2012, 45, 67; (b) B. R.
Langlois and T. Billard, Synthesis, 2003, 185; (c) M. Shimizu and
T. Hiyama, Angew. Chem., Int. Ed., 2005, 44, 214; (d) M. Schlosser,
Angew. Chem., Int. Ed., 2006, 45, 5432; (e) see also ref. 1c; ( f ) T. Furuya,
A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (g) O. A. Tomashenko
and V. V. Grushin, Chem. Rev., 2011, 111, 4475; (h) T. Besset,
C. Schneider and D. Cahard, Angew. Chem., Int. Ed., 2012, 51, 5048;
(i) A. Studer, Angew. Chem., Int. Ed., 2012, 51, 8950.
Desulfonylation of 2a mediated by Mg was found to proceed
smoothly at r.t.,23 affording the difluoromethylated oxindole 7a
6 K. Fujikawa, Y. Fujioka, A. Kobayashi and H. Amii, Org. Lett., 2011,
13, 5560.
7 J.-M. Zhu, F. Wang, W.-Z. Huang, Y.-C. Zhao, W.-C. Ye and J.-B. Hu,
Synlett, 2011, 899.
8 Z.-B. He, T. Luo, M.-Y. Hu, Y.-J. Cao and J.-B. Hu, Angew. Chem.,
Int. Ed., 2012, 51, 3944.
9 Z.-B. He, M.-Y. Hu, T. Luo, L.-C. Li and J.-B. Hu, Angew. Chem.,
Int. Ed., 2012, 51, 11545.
10 P. S. Fier and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134, 5524.
11 G. K. S. Prakash, S. K. Ganesh, J.-P. Jones, A. Kulkarni, K. Masood,
J. K. Swabeck and G. A. Olah, Angew. Chem., Int. Ed., 2012, 51, 12090.
12 Z.-J. Li, Z.-L. Cui and Z.-Q. Liu, Org. Lett., 2013, 15, 406.
13 N. Surapanich, C. Kuhakarn, M. Pohmakotr and V. Reutrakul,
Eur. J. Org. Chem., 2012, 5943.
14 For early examples on Pd(0)-mediated radical fluoroalkylations,
see: (a) Q.-Y. Chen and Z.-Y. Yang, Acta Chim. Sin., 1985, 43, 1118;
(b) Q.-Y. Chen and Z.-Y. Yang, Acta Chim. Sin., 1986, 44, 1025;
(c) Q.-Y. Chen, Z.-Y. Yang, C.-X. Zhao and Z.-M. Qiu, J. Chem. Soc.,
Perkin Trans. 1, 1988, 563; (d) Z.-Y. Yang and D. J. Burton, J. Org.
Chem., 1992, 57, 4676; (e) Z.-M. Qiu and D. J. Burton, J. Org. Chem.,
1995, 60, 5570.
Scheme 2 Possible mechanism.
15 Synthesis of oxindoles from aniline derivatives: for transition metal-
mediated syntheses see: (a) S. Jaegli, J. Dufour, H.-L. Wei, T. Piou,
X.-H. Duan, J.-P. Vors, L. Neuville and J. Zhu, Org. Lett., 2010, 12, 4498;
Scheme 3 Reductive desulfonylation.
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(b) T. Wu, X. Mu and G.-S. Liu, Angew. Chem., Int. Ed., 2011, 50, 12578;
(c) T. Wu, H. Zhang and G.-S. Liu, Tetrahedron, 2012, 68, 5229; (d) C. Dey
and E. P. Ku¨ndig, Chem. Commun., 2012, 48, 3064; (e) W.-T. Wei, M.-B.
and E. M. Carreira, Eur. J. Org. Chem., 2003, 2209; (d) C. V. Galliford
and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 8748; (e) F. Zhou,
Y.-L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381.
Zhou, J.-H. Fan, W. Liu, R.-J. Song, Y. Liu, M. Hu, P. Xie and J.-H. Li, 17 X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo and G.-S. Liu, J. Am. Chem. Soc.,
Angew. Chem., Int. Ed., 2013, 52, 3638; ( f ) X. Li, X. Xu, P. Hu, X. Xiao and 2012, 134, 878.
C. Zhou, J. Org. Chem., 2013, 78, 7343; (g) J. Xie, P. Xu, H. Li, Q. Xue, 18 H. Egami, R. Shimizu and M. Sodeoka, J. Fluorine Chem., 2013,
H. Jin, Y.-C. Cheng and C.-J. Zhu, Chem. Commun., 2013, 49, 5672; 152, 51.
(h) Y. Li, M. Sun, H. Wang, Q. Tian and S.-D. Yang, Angew. Chem., Int. 19 (a) W. Kong, M. Casimiro, E. Merino and C. Nevado, J. Am. Chem.
Ed., 2013, 52, 3972; (i) X.-H. Wei, Y.-M. Li, A.-X. Zhou, T.-T. Yang and
S.-D. Yang, Org. Lett., 2013, 15, 4158; ( j) H. Wang, L.-N. Guo and X.-H.
Duan, Adv. Synth. Catal., 2013, 355, 2222; for metal-free syntheses, see:;
Soc., 2013, 135, 14480; For a metal-free example, see: (b) W. Kong,
M. Casimiro, N. Fuentes, E. Merino and C. Nevado, Angew. Chem.,
Int. Ed., 2013, 52, 13086.
(k) H.-L. Wei, T. Piou, J. Dufour, L. Neuville and J. Zhu, Org. Lett., 2011, 20 P. Xu, J. Xie, Q.-C. Xue, C.-D. Pan, Y.-X. Cheng and C.-J. Zhu,
13, 2244; (l) D. C. Fabry, M. Stodulski, S. Hoerner and T. Gulder, Chem.–Eur. J., 2013, 19, 14039.
Chem.–Eur. J., 2012, 18, 10834; (m) K. Matcha, R. Narayan and A. P. 21 (a) G. K. S. Prakash, J.-B. Hu and G. A. Olah, Org. Lett., 2004, 6,
Antonchick, Angew. Chem., Int. Ed., 2013, 52, 7985; (n) Y. Meng, L.-N.
Guo, H. Wang and X.-H. Duan, Chem. Commun., 2013, 49, 7540;
4315–4317; (b) Y. Li, J. Liu, L.-J. Zhang, L.-G. Zhu and J.-B. Hu, J. Org.
Chem., 2007, 72, 5824.
(o) M.-B. Zhou, R.-J. Song, X.-H. Ouyang, Y. Liu, W.-T. Wei, G.-B. 22 (a) K. S. Bloome and E. J. Alexanian, J. Am. Chem. Soc., 2010, 132,
Deng and J.-H. Li, Chem. Sci., 2013, 4, 2690.
16 (a) B. S. Jensen, CNS Drugs, 2002, 8, 353; (b) H. Lin and
12823; (b) K. S. Bloome, R. L. McMahen and E. J. Alexanian, J. Am.
Chem. Soc., 2011, 133, 20146.
S. J. Danishefsky, Angew. Chem., Int. Ed., 2003, 42, 36; (c) C. Marti 23 C.-F. Ni and J.-B. Hu, Tetrahedron Lett., 2005, 46, 8273.
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