Pd-catalyzed gem-difluoroallylation of arylboronic acids with γ,γ-difluoroallylic acetates

Article abstract of DOI:10.1039/c5cc08394j

A highly regio- and stereo-selective palladium-catalyzed gem-difluoroallylation of arylboronic acids with γ,γ-difluoroallylic acetates has been described. The method allows the synthesis of a variety of gem-difluoroallylated arenes with a tosyloxy group on the CC double bond, thus providing a good opportunity for down-stream transformations.

Full text of DOI:10.1039/c5cc08394j

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DOI: 10.1039/C5CC08394J
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Pd-Catalyzed gem-Difluoroallylation of Arylboronic Acids withγ,
γ-Difluoroallylic Acetates
Received 00th January 20xx,
Accepted 00th January 20xx
Bo Zhanga and Xingang Zhang*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly regio- and stereo-selective palladium-catalyzed gem- resulted from gem-difluoroallylated products remain the
difluoroallylation of arylboronic acids with , -difluoroallylic synthetic challenges thus far.7
acetates has been described. The method allows the synthesis of a
variety of gem-difluoroallylated arenes with a tosyloxy group on difluoro-2-propen-1-ol acetate with phenylzinc chloride was
the C=C double bond, thus providing a good opportunity for the reported by Shi.6a Although a high
-substitution regioselectivity
Several years ago, a palladium catalyzed reaction of 3,3-

down-stream transformations.
was observed, an undesired defluorination of resulting gem-
difluoroallylic product occurred (Scheme 1b). In this context, a
sterically hindered 1-substituted 3-bromo-3,3-difluoropropene
(BDFP) was used as a substrate, leading to gem-difluoroallylic
product in high regioselectivity without observation of
defluorination side reaction.7 However, the reaction of BDFP
with phenylzinc chloride or tributylphenyltin still resulted in
defluorinated product. To address this crucial issue, very
As a distinct class of organic compounds in pharmaceuticals and
agrochemicals, difluoroalkylated arenes have been received
great attentions recently.1,2 This is because the introduction of
difluoromethylene (CF2) group at benzylic position can
dramatically improve the metabolic stability and change the
physiological activity of the bioactive molecules.3 Among the
numerous difluoroalkylated arenes, gem-difluoroallylic arenes
represent one of the extremely appealing compounds owning
to their important applications in medicinal chemistry4 and
versatile synthetic utility of the C=C double bond. The most
common approach to prepare such a valuable structural motif
relies on the Wittig reaction or HWE reaction from
aryldifluoromethylated aldehydes or ketones.5 Despite the
utility of this approach, multiple steps were required to prepare
the difluoroalkylated starting materials, which restricts its
widespread synthetic applications. In particular, this approach
is not suitable for the late stage synthesis of difluoroalkylated
complexes due to the requirement of difluoroalkylated
precursors. From the point of view of synthetic simplicity and
generality, a direct introduction of gem-difluoroallyl group onto
aromatic rings would be an attractive alternative (Scheme
1a).6,7 However, the regiochemical selectivity of this synthetic
strategy and suppressing undesired defluorination side reaction
recently,
a highly efficient method to prepare gem-
difluoroallylated arenes through palladium-catalyzed reaction
of organoborons with bromodifluoromethylated alkenes has
been developed by us,8 which represents a first example to
prepare such a kind of structure catalyzed by transition-metal
(Scheme 1c). Inspired by this preliminary study, we questioned
that whether ,-difluoroallylic electrophiles can also serve as a
suitable coupling partner to prepare gem-difluoroallylated
arenes (Scheme 1d). Herein, we described a Pd-catalyzed gem-
difluoroallylation of arylboronic acids with ,-difluoroallylic
acetates. The method provides a facile access to a variety of
gem-difluoroallylated arenes with high regio- and stereo-
selectivity.
a.Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: xgzhang@mail.sioc.ac.cn
Fax: +86 (21) 64166128; Tel: +86 (21)54925333
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures, and characterization data for new compounds. See
DOI: 10.1039/x0xx00000x
Scheme 1. Strategies for regio-selective synthesis of gem-difluoroallylated arenes
J. Name., 2015, 00, 1-3 | 1
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Xantphos/Pd(PPh3)4 = 1.2 benefited the reaction efficiency,
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providing 3a in 68% yield upon isolation (DeOntI:r1y01.120)3.9H/Co5wCCe0v8e3r9, 4inJ
the meanwhile, the homocoupling of 2a and defluorination of
3a were also observed. Taking into account the fact that the
addition of H2O or CuI can facilitate the transmetalation step of
the Suzuki reaction,12 H2O and CuI were employed as additives
to improve the reaction efficiency further. A best yield of 3a (84%
upon isolation) was obtained when CuI (6 mol %) was used
(entry 15). H2O also showed beneficial effect, but led to slightly
lower yield (72% upon isolation, entry 14).
We began our studies by choosing 3,3-difluoro-1-phenyl-2-
(tosyloxy) allyl acetate 1a and phenyl boronic acid 2a as model
substrates (Table 1). The use of 1a is because it can be easily
prepared from low-cost and widely available 2,2,2-
trifluoroethanol.9 In addition, the transformations of tosyloxy
group on the C=C double bond can easily lead to a variety of
difluoroalkylated arenes.10 To our delight, a 37% yield of the
desired product 3a with high stereoselectivity (Z/E > 20:1,
determined by 19F NMR) was obtained when the reaction was
carried out with 1a (1.0 equiv), 2a (1.5 equiv), Pd(PPh3)4 (10
mol %), K2CO3 (2.0 equiv) in dioxane at 80 oC (entry 1). Notably,
To demonstrate the substrate scope of this method, a variety
of arylboronic acids were examined to react with 1a (Table 2).
Table 2 Pd-catalyzed gem-difluoroalkylation of arylboronic acids 2 with 1a
no branched ,-difluoroallylic isomer and defluorinated side
product were observed in the reaction process. We reasoned
that this is probably because of the steric effect of the
substituent. Further optimization of the reaction conditions by
examining the phosphine ligands (entries 2-8) revealed that the
bidentate ligand Xantphos11 was the best ligand, providing 3a in
57% yield (entry 8). The dppf and the monodentate ligand Me-
Phos also provided moderate yields, but other ligands showed
less activity (entries 3 and 6).
Table
1 Representative results for optimization of Pd-catalyzed gem-
difluoroallylation of 2a with 1aa
entry
[Pd]
Ligand
Additive
yield (%)b
1
2
3
4
5
6
7
8
9
10
11c
12d
13e
14d
15d
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
--
PPh3
Me-Phos
S-Phos
dppe
--
--
--
--
--
--
--
--
--
--
--
--
37
42
53
45
18
50
43
57
49
ND
64
72 (68)
30
71 (72)
89 (84)
dppf
BINAP
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
--
H2O (1.25)
CuI (0.06)
aReaction conditions (unless otherwise specified): 1a (0.2 mmol, 1.0 equiv), 2a (0.3
mmol, 1.5 equiv), dioxane (1.5 mL) , K2CO3 (2.0 equiv), 5 h under N2. bDetermined
by 19F NMR using fluorobenzene as an internal standard and number in parenthesis
is isolated yield. Z/E > 20:1, determined by 19F NMR. cPd(PPh3)4 (5 mol %), Xantphos
(5 mol %). dPd(PPh3)4 (5 mol %), Xantphos (6 mol %). ePd(PPh3)4 (1 mol %), Xantphos
(1.2 mol %).
aReaction conditions (unless otherwise specified): 1a (0.4 mmol, 1.0 equiv), 2 (0.6
mmol, 1.5 equiv), , K2CO3 (2.0 equiv) and dioxane (3 mL) All reported yields are
isolated yields and the stereoselectivity of 3 is Z/E > 20:1. bCuI (6 mol%) instead of
H2O was used. cReaction ran for 15 h. dReaction run on a gram-scale.
Encouraged by these results, a survey of the reaction
parameters, such as palladium sources, bases, and solvents
were conducted (entries 8-10, for details, see the Supporting
Information). The combination of Pd(PPh3)4, dioxane, and K2CO3
remained the optimal choice (entry 8). Decreasing the loading
amount of Pd(PPh3)4 from 10 mol % to 5 mol % with a ratio of
Generally, moderate to high yields of
3 were obtained
without observation of branched isomers and electron-rich
arylboronic acids provided higher yields than that from electron
deficient ones. Most importantly, the tosyloxy group was
compatible with the reaction without formation of diarylated
byproducts, thus providing a good opportunity for downstream
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transformations. However, it should be mentioned that in most under basic condition at room temperature (VSicewheArmticele O2ndlin)e.
of the cases, H2O was proved to be an optimal additive. Unexpectedly, extension of this strategDyOtI:o10r.e10p3l9a/cCe5CtCo0s8y3lo9x4yJ
Versatile functional groups, such as vinyl, silyl, ester, group with amide group produce an unstable enamine
enonlizable ketone, and nitro, showed good tolerance (3e
3i, and 3m ). The sterically hindered substrates were also condition to afford an useful gem-difluoroproparylated arene
applicable to the reaction, providing the corresponding (Scheme 2e), thus demonstrating the versatility of the
products in moderate to good yields (3k and 3l). The reaction compounds
can also be extended to other functionalized -difluoroallylic In conclusion, we have developed an efficient and alternative
acetates , in which the substituents R did not interfere with the strategy to prepare gem-difluoroallylated arenes through
reaction efficiency. Notably, high yields of 3r and 3s were also palladium-catalyzed reaction between arylboronic acids and
obtained when R is an alkyl group, thus highlighting the -difluoroallylic acetates with high regio- and stereo-
generality of this method. It was also possible to synthesize selectivity. Application of the method led to different
compounds on a gram-scale. A good yield of 3a (76%) was difluoroalkylated arenes efficiently, which may have potential
obtained on a gram-scale synthesis, thus demonstrating the applications in medicinal chemistry. The reason for high
reliability of current reaction. regiochemical selectivity of current reaction is probably
To demonstrate the utility of this method, the because the reductive elimination of aryl(
transformations of gem-difluoroallylated arene 3a were difluoroallyl)palladium complex prefers generating of linear
,
3f,
intermediate, which subsequently eliminated under basic
-
o
9
3
.
,
1
,
3

-
performed.
product due to the steric effect of the substituents.14 However,
for the detailed reaction mechanism, it remains a point of
discussion.
This work was financially supported by the National Basic
Research Program of China (Nos. 2012CB821600 and
2015CB931900), the National Natural Science Foundation of
China (21425208, 2141002, 21172242 and 21332010), and SIOC.
Notes and references
1
For selected reviews, see: (a) B. E. Smart, J. Fluorine Chem.,
2001, 109, 3; (b) P. Maienfisch and R. G. Hall, Chimia, 2004, 58
,
93; (c) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529; (d) C.
Ni, L. Zhu and J. Hu, Acta Chim. Sinica, 2015, 73, 90; (e) M.-C.
Belhomme, T. Besset, T. Poisson and X. Pannecoucke, Chem.
Eur. J., 2015, 21, 12836.
For selected transition-metal-catalyzed difluoroalkylation, see:
(a) Z. Feng, F. Chen and X. Zhang, Org. Lett., 2012, 14, 1938;
(b) Z. Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang and X. Zhang,
Angew. Chem. Int. Ed., 2014, 53, 1669; (c) S. Ge, W. Chaladaj
and J. F. Hartwig, J. Am. Chem. Soc., 2014, 136, 4149; (d) Y.-L.
Xiao, W.-H. Guo, G.-Z. He, Q. Pan and X. Zhang, Angew. Chem.
Int. Ed., 2014, 53, 9909.
For selected examples of bioactive molecules, see: (a) K. Shen,
Y.-F. Keng, L. Wu, X.-L. Guo, D. S. Lawrence and Z.-Y. Zhang, J.
Biol. Chem., 2001, 276, 47311; (b) C. S. Burgey, K. A. Robinson,
T. A. Lyle, P. E. J. Sanderson, S. D. Lewis, B. J. Lucas, J. A.
Krueger, R. Singh, C. Miller-Stein, R. B. White, B. Wong, E. A.
Lyle, P. D. Williams, C. A. Coburn, B. D. Dorsey, J. C. Barrow, M.
T. Stranieri, M. A. Holahan, G. R. Sitko, J. J. Cook, D. R.
McMasters, C. M. McDonough, W. M. Sanders, A. A. Wallace,
F. C. Clayton, D. Bohn, Y. M. Leonard, T. J. Detwiler Jr., J. J.
Lynch Jr., Y. Yan, Z. Chen, L. Kuo, S. J. Gardell, J. A. Shafer and
J. P. Vacca, J. Med. Chem., 2003, 46, 461; (c) M. O. Anderson,
J. Zhang, Y. Liu, C. Yao, P.-W. Phuan and A. S. Verkman, J. Med.
Chem., 2012, 55, 5942; (d) J. O. Link, J. G. Taylor, L. Xu, M.
Mitchell, H. Guo, H. Liu, D. Kato, T. Kirschberg, J. Sun, N.
Squires, J. Parrish, T. Keller, Z.-Y. Yang, C. Yang, M. Matles, Y.
Wang, K. Wang, G. Cheng, Y. Tian, E. Mogalian, E. Mondou, M.
2
3
Scheme 2 Transformations of compound 3a
As shown in Scheme 2a, hydrogenation of 3a provided
difluoroalkylated arene
coupling of 3a with phenylboronic acid 2a also underwent
smoothly and provided trisubstituted in 93% yield, which was
further hydrogenated to produce compound with high
4 in excellent yield. Suzuki cross-
5
6
efficiency (Scheme 2b). This is noteworthy as difluoroalkylated
arenes have important applications in medicinal chemistry.13
Compound 3a can also be converted into difluoroalkylated
Cornpropst, J. Perry and M. C. Desai, J. Med. Chem., 2014, 57
2033.
,
ketone
7 smoothly, thus providing an alternative approach to
4
(a) Y. Gai, Y. S. Or and G. Wang, From PCT Int. Appl., WO
2010132163 A1 20101118, 2010; (b) C. W. Amdnde, B. A. Fish,
M. E. Green, D. S. Jhonson, P. B. Mullins, C. J. O'Donnell, M. Y.
Pettersson, C. M. Stiff, C. Subramanyam, T. P. Tran and T.
prepare such a kind of fluorinated compound (Scheme 2c).
Interestingly, the tosyloxy group can be easily substituted by
methoxy group when compound 3a was treated with MeOH
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Navaratnam, From PCT Int. Appl., WO 2012131539 A1
20121004, 2012.
View Article Online
DOI: 10.1039/C5CC08394J
5
(a) J. Oldendorf and G. Haufe, J. Prakt. Chem., 2000, 342, 52;
(b) S. Pikul, G. E. Mieling, K. K. Mieling, K. M. Solinsky, B. De,
N. G. Almstead and N. M. George, From U.S. Pat. Appl. Publ.,
20030139453 A1 20030724, 2003; (c) M. Bergeron, T. Johnson
and J.-F. Paquin, Angew. Chem. Int. Ed., 2011, 50, 11112.
(a) G.-q. Shi, X.-h. Huang and F.-J. Zhang, Tetrahedron Lett.,
1995, 36, 6305; (b) G.-q. Shi and W.-l. Cai, Synlett., 1996, 4,
371.
M. Kirihara, T. Takuwa, M. Okumura, T. Wakikawa, H.
Takahata, T. Momose, Y. Takeuchi and H. Nemoto, Chem.
Pharm. Bull., 2000, 48, 885 and ref 5a.
6
7
8
9
Q.-Q. Min, Z. Yin, Z. Feng, W.-H. Guo and X. Zhang, J. Am. Soc.
Chem., 2014, 136, 1230.
(a) G. H. Posner, B. T. Woodard, K. R. Crawford, S. Peleg, A. J.
Brown, P. Dolan and T. W. Kensler, Bioorg. Med. Chem., 2002,
10, 2353; (b) P. V. Ramachandran and A. Chatterjee, Org. Lett.,
2008, 10, 1195.
10 For selected examples of transition-metal-catalyzed cross-
coupling using alkenyl tosylates as a coupling partner, see: (a)
M. Fujiwara, J. Ichikawa, T. Okauchi and T. Minami,
Tetrahedron Lett., 1999, 40, 7261; (b) T. M. Gøgsig, L. S.
Søbjerg, A. T. Lindhardt, K. L. Jensen and T. Skrydstrup, J. Org.
Chem., 2008, 73, 3404; (c) J. Pschierer, N. Peschek and H.
Plenio, Green Chem., 2010, 12, 636; (d) H. Zhang, C.-B. Zhou,
Q.-Y. Chen, J.-C. Xiao and R. Hong, Org. Lett., 2011, 13, 560; (e)
J. Bucher, T. Wurm, K. S. Nalivela, M. Rudolph, F. Rominger
and A. S. K. Hashmi, Angew. Chem. Int. Ed., 2014, 53, 3854.
11 (a) V. V. Grushin and W. J. Marshall, J. Am. Soc. Chem., 2006,
128, 12644; (b) V. I. Bakhmutov, F. Bozoglian, K, Gómez, G.
González, V. V. Grushin. S. A. Macgregor, E. Martin, F. M.
Miloserdov, M. A. Novikov, J. A. Panetier and L. V. Romashov,
Organometallics, 2012, 31, 1315.
12 (a) G. B. Smith, G. C. Dezeny, D. L. Hughes, A. O. King and T. R.
Verhoeven, J. Org. Chem., 1994, 59, 8151; (b) M. B. Thathagar,
J. Beckers and G. Rothenberg, J. Am. Soc. Chem., 2002, 124
11858.
,
13 For selected examples, see: (a) H. Eto, Y. Kaneko and T.
Sakamoto, Chem. Pharm. Bull., 2000, 48, 982; (b) F. Xue, H. Li,
S. L. Delker, J. Fang, P. Martasek, L. J. Roman, T. L. Poulos and
R. B. Silverman, J. Am. Chem. Soc. 2010, 132, 14229 and ref 3c.
14 (a) T. Hayashi, A. Yamamoto and T. Hagihara, J. Org. Chem.,
1986, 51, 723; (b) B. Aakermark, S. Hansson and A. Vitagliano,
J. Am. Soc. Chem., 1990, 112, 4587; (c) A. Togni, U. Burckhardt,
V. Gramlich, P. S. Pregosin and R. Salzmann, J. Am. Soc. Chem.,
1996, 118, 1031.
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