CuI-mediated trifluoromethylations with stannanes. preliminary communication

Article abstract of DOI:10.1002/hlca.201200450

(Trifluoromethyl)stannane reagents such as Bu₃SnCF₃ are effective in CuI-mediated trifluoromethylation reactions of aryl iodides. The reactions proceed via the intermediacy of [CuCF₃] species.

Full text of DOI:10.1002/hlca.201200450

Helvetica Chimica Acta – Vol. 95 (2012)
2231
CuI-Mediated Trifluoromethylations with Stannanes
Preliminary Communication
by Italo A. Sanhueza, Mads C. Nielsen, Marcel Ottiger, and Franziska Schoenebeck*
Laboratory for Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zꢀrich,
Wolfgang-Pauli-Strasse 10, CH-8093 Zꢀrich
(e-mail: schoenebeck@org.chem.ethz.ch; homepage: http://www.schoenebeck.ethz.ch/)
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
(Trifluoromethyl)stannane reagents such as Bu3SnCF3 are effective in CuI-mediated trifluorome-
thylation reactions of aryl iodides. The reactions proceed via the intermediacy of [CuCF3] species.
The introduction of CF3 groups into molecules has a tremendous influence on the
properties of compounds [1]. Considerable efforts have, therefore, been made to
develop new reactions for the introduction of CF3 groups [2]. Various transition metal-
mediated transformations of ArX [3] or ArH [4] to ArCF3 have been reported in this
context. Alternative methods [5], such as those involving electrophilic [6] or radical-
based [7] trifluoromethylation processes, have also been developed. One of the most
effective methods for aromatic trifluoromethylations involves Cu [8]. Such trans-
formations generally occur via reaction of aryl iodides with a [CuCF3] species [9]. The
latter are either pre-synthesized [10] or formed in situ (see Scheme 1). The use of
Ruppertꢁs reagent (Me3SiCF3) along with KF and CuI constitutes one of the most
widely applied methods to form [CuCF3][11][12]. A similarly mild method was
recently reported by Gooßen and co-workers, involving borate salts (see Scheme 1)
[13]. In addition, CHF3 can readily be converted to [CuCF3], as recently shown by
Grushin and co-workers [14].
Scheme 1. Examples of Syntheses of [CuCF3] and Its Reaction with ArI
We herein report our finding that tributyl(trifluoromethyl)stannane, Bu3SnCF3, is
also efficient in Cu-mediated trifluoromethylation reactions. We found that using CuI,
ꢂ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

2232
Helvetica Chimica Acta – Vol. 95 (2012)
Bu3SnCF3, and KF along with a coordinating solvent, such as the mixture DMF/N-
methylpyrrolidin-2-one (NMP) 1:1, allows the conversion of a variety of aryl iodides to
ArCF3 under relatively mild conditions in 24 h. Table 1 gives a compilation of
stoichiometric experiments that we performed in this context. Electron-rich as well as
electron-deficient aryl iodides were trifluoromethylated in good yields.
Table 1. Examples of ArI Couplings under Stoichiometric Reaction Conditions
Entry
Ar
Yield [%] of producta)
1
2
3
4
5
6
7
8
9
4-NO2ꢀC6H4
4-BnO2CꢀC6H4
4-MeOꢀC6H4
4-MeꢀC6H4
87
91
96
99
95
98
96
87
82
4-ClꢀC6H4
Naphthalen-1-yl
Pyridin-3-yl
4-[Ph(CH2)3O]ꢀC6H4
4-tBuꢀC6H4
a) Determined by 19F-NMR vs. internal standard (4,4’-difluoro-1,1’-biphenyl).
With 19F-NMR studies, we observed that [CuCF3] species form readily at room
temperature under these reaction conditions (CuI, Bu3SnCF3, KF), indicating that the
CuI-mediated trifluoromethylation involving stannane proceeds via the intermediacy
of [CuCF3]. We observed peaks at d ꢀ 29.3 ppm and ꢀ 32.2 ppm in (D7)DMF which
are similar to those signals reported previously by Kolomeitsev and co-workers for
[CuCF3], i.e., ꢀ 28.8 ppm for (CF3Cu · KBr) and ꢀ 32.4 ppm for [(CF3)2Cu]ꢀ Kþ
[15][16]1). In the absence of a fluoride salt, the signals associated with [CuCF3] are
observed only at higher temperature (758).
In the presence of KF, we found that the subsequent reaction of [CuCF3] with ArI
to ArCF3 is the more difficult step and requires elevated temperature for efficient
conversion. Electron-poor aryl iodides react more rapidly with [CuCF3] than electron-
rich analogs: after 2 h reaction time at 808, 1-(tert-butyl)-4-iodobenzene (1) showed
44% conversion, while benzyl 4-iodobenzoate (3) was nearly fully consumed (75%) in
the same time (see Scheme 2; the remaining material was predominantly unreacted
starting material, and less than 2% of side-products (e.g., ArCF2CF3) were detected).
The trifluoromethylations with stannane, therefore, seem to mirror the reactivity of
the CuI-mediated trifluoromethylations of aryl iodides involving Ruppertꢁs reagent
[11][12]. Given that the analogous reactivity is observed as with Ruppertꢁs reagent, we
were intrigued to compare the relative reactivity of the stannane reagent with Ruppertꢁs
reagent, testing i) the relative ease of [CuCF3] formation and ii) the overall efficiency
of the reaction. In Scheme 3, the results are outlined. After 20 min at room
Using CuBr instead of CuI, we also observed the peak at 29.3 ppm in 19F-NMR.
1
)

Helvetica Chimica Acta – Vol. 95 (2012)
2233
Scheme 2. Reactivity Comparison of Electron-Rich vs. Electron-Deficient ArI
temperature, 53% of Ruppertꢁs reagent had been consumed, while, under identical
conditions, only 30% of the Bu3SnCF3 had reacted. This suggests that [CuCF3]
formation proceeds slightly more readily in the case of Ruppertꢁs reagent. However,
after 30 h reaction time with PhI at room temperature (Scheme 3), almost identical
overall conversions to ArCF3 had taken place (13 – 16% yield), indicating that the
stannane is similarly effective as Ruppertꢁs reagent in CuI-mediated trifluoromethy-
lations of ArI.
Scheme 3. Comparison of the Reactivity of Me3SiCF3 vs. Bu3SnCF3, Testing the Ease of Formation of
[CuCF3] (Step 1) and Overall Reaction Efficiency (Step 2)
In a manner similar to the reactions performed with Ruppertꢁs reagent, drawbacks
also apply for the stannane-mediated trifluoromethylations, i.e., moisture sensitivity
(protonation of [CuCF3]) and a tendency to undergo side-reactions are encountered.
For example, ArCF2CF3 side-products were detected. It has previously been suggested
that these form as a consequence of [CuCF3] decomposition to CF2 carbenes, which in
turn react with [CuCF3] to give pentafluoro derivatives [2][8]. This side-reaction was
also encountered under catalytic reaction conditions. In Table 2, our preliminary, un-
optimized experiments, involving 10 – 20 mol-% loading of CuI together with
phenanthroline and KF in a mixture of NMP and DMF, are compiled. A reaction
temperature of 508 was found to give the best conversions (ca. 60% yield of ArCF3; see
Entries 4 and 5). Amii and co-workers previously demonstrated such catalytic
conditions to be effective for trifluoromethylations with Ruppertꢁs reagent [12].

2234
Helvetica Chimica Acta – Vol. 95 (2012)
Table 2. CuI-Catalyzed Trifluoromethylation of ArI Involving Bu3SnCF3
Entry
Catalyst loading [mol-%]
Temperature [8]
Yield [%] of product
1
2
3
4
5
10
20
10
10
20
80
80
25
50
50
30
37
21
56
60
To gain further mechanistic insights and to test for the potential intermediacy of
radicals, we applied our reaction conditions to aryl iodide 5 (Scheme 4). Substrate 5 was
previously shown to undergo a very rapid cyclization upon aryl radical formation
(generated either via electron-transfer-induced reductive bond cleavage of CꢀI or
through reaction with a radical-chain carrier) [17]. However, no cyclized product was
detected in our hands, and uncyclized product 6, arising from direct trifluoromethy-
lation of the CꢀI bond, was isolated instead2), indicating that, if aryl radicals were to be
involved in the mechanism, their lifetime would be extremely short. This suggests that
trifluoromethylation is likely to occur via s-bond methathesis or direct oxidative
addition of the nucleophilic [CuCF3] species to CꢀI.
Scheme 4. Test for the Intermediacy of Radicals
In conclusion, it was demonstrated that (trifluoromethyl)stannane reagents, such as
Bu3SnCF3, are effective trifluoromethylation agents in CuI-mediated transformations
of ArI. The reactions proceed via the [CuCF3] intermediates and show promise for
catalytic reaction conditions. The formation of organocopper species has frequently
been implicated in cross-coupling reactions, such as the Stille reaction [18]. Our direct
detection of [CuCF3] species and their facile formation from a stannane precursor may
provide support of the latter proposals.
REFERENCES
[1] S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; K. Mꢀller, C. Faeh,
F. Diederich, Science 2007, 317, 1881; W. K. Hagmann, J. Med. Chem. 2008, 51, 4359.
[2] O. A. Tomashenko, V. V. Grushin, Chem. Rev. 2011, 111, 4475.
2
)
The side-product ArCF2CF3 (5%) was also detected.

Helvetica Chimica Acta – Vol. 95 (2012)
2235
[3] V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc. 2006, 128, 12644; V. V. Grushin, W. J. Marshall, J.
Am. Chem. Soc. 2006, 128, 4632; G. G. Dubinina, W. W. Brennessel, J. L. Miller, D. A. Vicic,
Organometallics 2008, 27, 3933; V. V. Grushin, Acc. Chem. Res. 2012, 43,160; E. J. Cho, T. D. Senecal,
T. Kinzel, Y. Zhang, D. A. Watson, S. L. Buchwald, Science 2010, 328, 1679.
[4] X. Wang, L. Truesdale, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132, 3648; N. D. Ball, J. W. Kampf, M. S.
Sanford, J. Am. Chem. Soc. 2010, 132, 2878; N. D. Ball, J. B. Gary, Y. Ye, M. S. Sanford, J. Am. Chem.
Soc. 2011, 133, 7577.
[5] F. Swarts, Bull. Acad. R. Med. Belg. 1892, 24, 309; H. S. Booth, H. M. Elsey, P. E. Burchfield, J. Am.
Chem. Soc. 1935, 57, 2066; Y. Ye, S. H. Lee, M. S. Sanford, Org. Lett. 2011, 13, 5464.
[6] T. Umemoto, S. Ishihara, Tetrahedron Lett. 1990, 31, 3579; T. Umemoto, Chem. Rev. 1996, 96, 1757;
S. G. K. Prakash, A. K. Yudin, Chem. Rev. 1997, 97, 757; J.-A. Ma, D. Cahard, Chem. Rev. 2004, 104,
6119; I. Kieltsch, P. Eisenberger, A. Togni, Angew. Chem., Int. Ed. 2007, 46, 754; J.-A. Ma, D.
Cahard, Chem. Rev. 2008, 108, PR1.
[7] A. P. Stefani, M. Szwarc, J. Am. Chem. Soc. 1962, 84, 3661; J. M. Birchall, G. P. Irvin, R. A. Boyson, J.
Chem. Soc., Perkin Trans. 2 1975, 435; H. Kimoto, S. Fujii, L. A. Cohen, J. Org. Chem. 1984, 49, 1060;
´
Y. Girard, J. G. Atkinson, P. C. Belanger, J. J. Fuentes, J. Rokach, C. S. Rooney, D. C. Remy, C. A.
Hunt, J. Org. Chem. 1983, 48, 3220; B. R. Langlois, E. Laurent, N. Roidot, Tetrahedron Lett. 1991, 32,
7525; D. A. Nagib, D. W. C. MacMillan, Nature 2011, 480, 224; Y. Ji, T. Brueckl, R. D. Baxter, Y.
Fujiwara, I. B. Seiple, S. Su, D. G. Blackmond, P. S. Baran, Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14411; N. Iqbal, S. Choi, E. Ko, E. J. Cho, Tetrahedron Lett. 2012, 53, 2005; E. Mejꢃa, A. Togni, ACS
Catal. 2012, 2, 52; Y. Li, A. Studer, Angew. Chem., Int. Ed. 2012, 51, 8221.
[8] V. C. R. McLoughlin, J. Thrower, Tetrahedron 1969, 25, 5921; Y. Kobayashi, I. Kumadaki,
Tetrahedron Lett. 1969, 10, 4095; D. J. Burton, Z.-Y. Yang, Tetrahedron 1992, 48, 189; M. A.
McClinton, D. A. McClinton, Tetrahedron 1992, 48, 6555; D. J. Burton, L. Lu, Top. Curr. Chem. 1997,
193, 45; M. Schlosser, Angew. Chem., Int. Ed. 2006, 45, 5432; S. Roy, B. T. Gregg, G. W. Gribble, V.-
D. Le, S. Roy, Tetrahedron 2011, 67, 2161; K. Sato, A. Tarui, M. Omote, A. Ando, I. Kumadaki,
Synthesis 2010, 1865.
[9] D. M. Wiemers, D. J. Burton, J. Am. Chem. Soc. 1986, 108, 832.
[10] Y. Usui, J. Noma, M. Hirano, S. Komiya, Inorg. Chim. Acta 2000, 309, 151; G. G. Dubinina, H.
Furutachi, D. A. Vicic, J. Am. Chem. Soc. 2008, 130, 8600; G. G. Dubinina, J. Ogikubo, D. A. Vicic,
Organometallics 2008, 27, 6233; I. Kieltsch, G. G. Dubinina, C. Hamacher, A. Kaiser, J. Torres-Nieto,
J. M. Hutchison, A. Klein,Y. Budnikova, D. A. Vicic, Organometallics 2010, 29, 1451; O. A.
´
Tomashenko, E. C. Escudero-Adan, M. Martꢃnez Belmonte, V. V. Grushin, Angew. Chem., Int. Ed.
2011, 50, 7655; H. Morimoto, T. Tsubogo, N. D. Litvinas, J. F. Hartwig, Angew. Chem., Int. Ed. 2011,
50, 3793.
[11] H. Urata, T. Fuchikami, Tetrahedron Lett. 1991, 32, 91; F. Cottet, M. Schlosser, Eur. J. Org. Chem.
2002, 327.
[12] M. Oishi, H. Kondo, H. Amii, Chem. Commun. 2009, 1909.
[13] T. Knauber, F. Arikan, G.-V. Rçschenthaler, L. J. Gooßen, Chem. – Eur. J. 2011, 17, 2689; B. A. Khan,
A. E. Buba, L. J. Gooßen, Chem. – Eur. J. 2012, 18, 1577.
[14] A. Zanardi, M. A. Novikov, E. Martin, J. Benet-Buchholz, V.-V. Grushin, J. Am. Chem. Soc. 2011,
133, 20901.
[15] A. Kꢀtt, V. Movchun, T. Rodima, T. Dansauer, E. B. Rusanov, I. Leito, I. Kaljurand, J. Koppel, V.
Pihl, I. Koppel, G. Ovsjannikov, L. Toom, M. Mishima, M. Medebielle, E. Lork, G.-V.
Rçschenthaler, I. A. Koppel, A. A. Kolomeitsev, J. Org. Chem. 2008, 73, 2607.
[16] M. M. Kremlev, W. Tyrra, A. I. Mushta, D. Naumann, Y. L. Yagupolskii, J. Fluorine Chem. 2010, 131,
212.
[17] J. A. Murphy, T. A. Khan, S.-Z. Zhou, D. W. Thomson, M. Mahesh, Angew. Chem., Int. Ed. 2005, 44,
1356; T. A. Khan, R. Tripoli, J. J. Crawford, C. G. Martin, J. A. Murphy, Org. Lett. 2003, 5,
2971.
[18] N. J. Long, C. K. Williams, Angew. Chem., Int. Ed. 2003, 42, 2586; Y. Fujikura, K. Sonogashira, N.
Hagihara, Chem. Lett. 1975, 1067; K. Osakada, T. Yamamoto, Coord. Chem. Rev. 2000, 198, 379; P.

2236
Helvetica Chimica Acta – Vol. 95 (2012)
Espinet, A. M. Echavarren, Angew. Chem., Int. Ed. 2004, 43, 4704; L. S. Liebeskind, J. Srogl, J. Am.
Chem. Soc. 2000, 122, 11260; Y. Wang, D. J. Burton, Org. Lett. 2006, 8, 1109.
Received August 10, 2012