Zhu et al.
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compounds.1 Fluoroalkylation reactions are commonly
divided into nucleophilic, electrophilic, and free radical
fluoroalkylations, and a variety of fluoroalkylating reagents
have been developed over the past three decades.1-7 However,
most fluoroalkylation methods are limited in the construction
of sp3 C-Rf bonds and not capable to facilitate the efficient
formation of sp2 C-Rf bonds. Although the transition metal-
catalyzed C-C cross-coupling reaction between organometal-
lic reagents and aryl (or alkenyl) halides are well-developed,8
the similar type of fluoroalkyl cross-coupling (sp2 C-Rf bond
formation) reactions are much less explored.9-13 Currently, the
most widely used synthetic method for the construction of sp2
C-Rf bonds is the cross-coupling reaction between fluoroalkyl
iodides (RfI) and aryl (or alkenyl) halides in the presence of a
SCHEME 1. Three Types of Reactions Involving Iododifluoro-
acetamides 1
(3) For reviews on electrophilic fluoroalkylations, see: (a) Umemoto, T.
Chem. Rev. 1996, 96, 1757–1777. (b) Umemoto, T. Recent Advances in Perfluor-
oalkylation Methodology. In Fluorine-Containing Synthons; Soloshonok, V. A.,
Ed.; American Chemical Society: Washington, DC, 2005. (c) Kieltsch, I.;
Eisenberger, P.; Stanek, K.; Togni, A. Chimia 2008, 62, 260–263.
stoichiometric amount of copper powder, which was discov-
ered in the late 1960s.14-16 This copper-mediated fluoroalkyl
cross-coupling reaction was believed to be involving a
“Rf-Cu” species,17 and several modified Cu-mediated sp2
C-Rf bond formation reactions have been developed.16,18
It should be noted that, although Cu-mediated trifluo-
romethylation and other perfluoroalkylations of aryl (or
alkenyl) halides are well documented,16 the corresponding
difluoromethylation involving a “RCF2-Cu” intermediate
was less studied, with the only two examples being alkoxy-
carbonyldifluoromethylation19 and (diethoxyphosphinyl)-
difluoromethylation with XCF2COOR and XCF2P(O)(OR)2
reagents (X= I andBr).20 Recently, as our continuing effort in
developing selective difluoromethylation methodologies,2a,7
we embarked on the previously unknown Cu-mediated cross-
coupling reaction between iododifluoroacetamides 1 and aryl
(and alkenyl) halides. It was found that, unlike previously
known alkoxycarbonyldifluoromethylation19 and (diethoxy-
phosphinyl)difluoromethylation,20 the reaction with an iodo-
difluoroacetamide 1 could give three types of products: cross-
coupling product 2, intramolecular cyclization product 3, and
homocoupling product 4 (Scheme 1). More importantly, the
selectivity among these three products could be controlled by
tuning the substituents on the nitrogen atom of compound 1,
which makes the reaction practically useful for the synthesis
of gem-difluorinated compounds 2-4.
(4) For review on chemistry of fluoroalkyl radicals, see: Dolbier, W. R.,
Jr. Chem. Rev. 1996, 66, 1557–1584.
(5) For recent examples of radical fluoroalkylations, see: (a) Kino, T.;
Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.;
Yamakawa, T. J. Fluorine Chem. 2010, 131, 98–105. (b) Nagib, D. A.; Scott,
M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875–10877. (c)
Shustova, N. B.; Popov, A. A.; Mackey, M. A.; Coumbe, C. E.; Phillips, J. P.;
Stevenson, S.; Strauss, S. H.; Boltalina, O. V. J. Am. Chem. Soc. 2007, 129,
11676–11677. (d) Antonietti, F.; Gambarotti, C.; Mele, A.; Minisci, F.;
Paganelli, R.; Punta, C.; Recupero, F. Eur. J. Org. Chem. 2005, 4434–4440.
(e) Antonietti, F.; Mele, A.; Minisci, F.; Punta, C.; Recupero, F.; Fontana, F.
J. Fluorine Chem. 2004, 125, 205–211. (f ) Li, Y.; Hu, J. Angew. Chem., Int.
Ed. 2007, 46, 2489–2492. (g) Li, Y.; Liu, J.; Zhang, L.; Zhu, L.; Hu, J. J. Org.
Chem. 2007, 72, 5824–5877. (h) Jin, L.-M.; Chen, L.; Yin, J.-J.; Guo, C.-C.;
Chen, Q.-Y. J. Fluorine Chem. 2005, 126, 1321–1326. (i) Jin, L.-M.; Chen, L.;
Guo, C.-C.; Chen, Q.-Y. J. Porphyrins Phthalocyanines 2005, 9, 109–120.
(6) (a) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry 2008,
19, 2633–2644. (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–
996. (c) Prakash, G. K. S.; Hu, J. Trihalomethyl Compounds. In Science of
Synthesis; Charette, A. B., Ed.; Thieme: New York, 2005; Vol. 22. (d) Ma,
J.-A.; Cahard, D. Chem. Rev. 2004, 104, 6119–6146.
(7) For reviews on difluoromethylation and monofluoromethylation, see:
(a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465–7478. (b) Hu, J.
J. Fluorine Chem. 2009, 130, 1130–1139.
(8) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(9) Copper-catalyzed Aryl-Rf coupling reaction: Oishi, M.; Kondo, H.;
Amii, H. Chem. Commun. 2009, 1909–1911.
(10) Palladium-catalyzed Aryl-Rf coupling reaction: (a) Kitazume, T.;
Ishikawa, N. Chem. Lett. 1982, 137–140. (b) Guo, Y.; Shreeve, J. M. Chem.
Commun. 2007, 3583–3585. (c) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang,
Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679–1681.
(11) (a) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc.
2008, 130, 8600–8601. (b) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A.
Organometallics 2008, 27, 6233–6235. (c) Dubnina, G. G.; Brennessel,
W. W.; Miller, J. L.; Vicic, D. A. Organometallics 2008, 27, 3933–3938.
(12) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,
12644–12645. (b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006,
128, 4632–4641. (c) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23,
3398–3416. (d) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc.
2010, 132, 2878–2879.
Results and Discussion
1. Cross-Coupling Reaction between Iododifluoroaceta-
mides (1) and Aryl/Alkenyl Halides. Iododifluoroacetamides
1 were prepared according to Huang’s procedure.21 First, we
examined the Cu-mediated cross-coupling reaction under
different conditions, using N,N-diethyl iododifluoroacetamide
(1a) and 1-iodo-4-nitrobenzene (5a) as model substrates
(Table 1). It turned out that the product yield was sensitive
(13) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160–171.
(14) (a) McLoughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921–5940.
(b) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969, 10, 4095–4096.
(15) Burton, D. J.; Lu, L. Fluorinated Organofluorine Compounds. In
Organofluorine Chemistry, Techniques and Synthons; Chambers, R. D., Ed.;
Springer: New York, 1997.
(16) For a review on fluoroalkyl organometallic compounds, see: Burton,
D. J.; Yang, Z.-Y. Tetrahedron 1992, 48, 189–275.
(17) (a) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108, 832–
834. (b) Willert-Porada, M. A.; Burton, D. J.; Baenziger, N. C. J. Chem. Soc.,
Chem. Commun. 1989, 1633–1634.
(18) (a) Burton, D. J.; Wiemers, D. M. J. Am. Chem. Soc. 1985, 107, 5014–
5015. (b) Chen, Q.-Y.; Wu, S.-W. J. Chem. Soc., Chem. Commun. 1989,
705–706. (c) Chen, Q.-Y.; Wu, S.-W. J. Chem. Soc., Perkin Trans. 1 1989,
2385–2387. (d) MacNeil, J. G., Jr.; Burton, D. J. J. Fluorine Chem. 1991, 55,
225–227. (e) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91–94.
(f ) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002, 327–330. (g) References
9, 11, and 17.
(19) (a) Taguchi, T.; Kitagawa, O.; Morikawa., T.; Nishiwaki, T.;
Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103–
6106. (b) Sato, K.; Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem.
2004, 125, 509–515.
(20) (a) Yokomatsu, T.; Suemune, K.; Murano, T.; Shibuya, S. J. Org.
Chem. 1996, 61, 7207–7211. (b) Yokomatsu, T.; Murano, T.; Suemune, K.;
Shibuya, S. Tetrahedron 1997, 53, 815–822.
(21) (a) Zhang, Y. F.; Lu, L.; Huang, W. Y. Youji Huaxue 1989, 9, 441–
444. (b) Huang, W.-Y.; Lu, L.; Zhang, Y.-F. Chin. J. Chem. 1990, 68–74. (c)
Hung, M.-H.; Lu, L.; Yang, Z.-Y. J. Org. Chem. 2004, 69, 198–201.
5506 J. Org. Chem. Vol. 75, No. 16, 2010