Palladium-catalyzed trifluoroethylation of terminal alkynes with 1,1,1-trifluoro-2-iodoethane

Article abstract of DOI:10.1021/ol400099h

An efficient C_sp-CH₂CF₃ bond-forming reaction via Pd-catalyzed 2,2,2-trifluoroethylation of aryl and alkyl terminal alkynes has been developed. This protocol proceeds under mild conditions using the readily available and cheap reagent CF₃CH₂I as the source of the CH₂CF₃ group. Various terminal aryl alkynes as well as alkylacetylenes can be transformed into the corresponding trifluoroethylated products in good-to-excellent yields. The method is tolerant of carbonyl, nitro, ester, cyano, and even formyl groups.

Full text of DOI:10.1021/ol400099h

ORGANIC
LETTERS
2013
Vol. 15, No. 4
936–939
Palladium-Catalyzed Trifluoroethylation
of Terminal Alkynes with 1,1,1-Trifluoro-
2-iodoethane
Yi-Si Feng,† Chuan-Qi Xie,† Wen-Long Qiao,† and Hua-Jian Xu*,†,‡
School of Chemical Engineering, School of Medical Engineering, Hefei University
of Technology, Key Laboratory of Advanced Functional Materials and Devices,
Anhui Province, Hefei 230009, P. R. China
hjxu@hfut.edu.cn
Received January 12, 2013
ABSTRACT
An efficient CspꢀCH2CF3 bond-forming reaction via Pd-catalyzed 2,2,2-trifluoroethylation of aryl and alkyl terminal alkynes has been developed.
This protocol proceeds under mild conditions using the readily available and cheap reagent CF3CH2I as the source of the CH2CF3 group. Various
terminal aryl alkynes as well as alkylacetylenes can be transformed into the corresponding trifluoroethylated products in good-to-excellent yields.
The method is tolerant of carbonyl, nitro, ester, cyano, and even formyl groups.
The incorporation of fluorine atoms into organic mole-
cules can profoundly influence their chemical and biological
activities, such as lipophilicity, metabolic stability, and bio-
availability.1 As a result, much attention has been paid to
the development of an appropriate method for the incor-
poration of fluoroalkyl groups into functional organic
structures.2 In this context, considerable progress has been
made in the use of 1,1,1-trifluoro-2-iodoethane (CF3CH2I)
to form Csp ꢀCH2CF3 or Csp ꢀCH2CF3 bonds.3 For in-
stance, McLoughlin and Thrower groups reported Cu(0)-
promoted 2,2,2-trifluoroethylation reactions of iodoaromatic
compounds with CF3CH2I in 1969.4 Recently, the Hu5 and
Zou6 groups respectively reported the palladium-catalyzed
† Hefei University of Technology.
‡ Key Laboratory of Advanced Functional Materials and Devices.
(1) Recent reviews: (a) Uneyama, K.; Katagiri, T.; Amii, H. Acc.
Chem. Res. 2008, 41, 817. (b) Hagmann, W. K. J. Med. Chem. 2008, 51,
4359. (c) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (d) Hu, J.;
Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. (e) Lectard, S.;
Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010, 352, 2708. (f)
Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455. (g)
Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475.
(2) Recent examples: (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang,
Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679. (b) Zhu, R.;
Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 12462. (c) Parsons, A. T.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9120. (d) Cho, E. J.;
Buchwald, S. L. Org. Lett. 2011, 13, 6552. (e) Ye, Y.; Sanford, M. S.
J. Am. Chem. Soc. 2012, 134, 9034. (f) Ye, Y.; Lee, S.; Sanford, M. S. Org.
Lett. 2011, 13, 5464. (g) Ball, N. D.; Gary, J. B.; Ye, Y.; Sanford, M. S.
J. Am. Chem. Soc. 2011, 133, 7577. (h) Loy, R. N.; Sanford, M. S. Org.
Lett. 2011, 13, 2548. (i) Ball, N. D.; Kampf, J. W.; Sanford, M. S. J. Am.
Chem. Soc. 2010, 132, 2878. (j) Janson, P. G.; Ghoneim, I.; Ilchenko,
N. O.;Szabo, K. J. Org. Lett. 2012, 14, 2882. (k) Xu, J.;Fu, Y.;Luo, D.-F.;
Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Liu, L. J. Am. Chem. Soc.
2011, 133, 15300. (l) Xu, J.; Xiao, B.; Xie, C.-Q.; Luo, D.-F.; Liu, L.; Fu,
Y. Angew. Chem., Int. Ed. 2012, 51, 12551. (m) Xu, J.; Luo, D.-F.; Xiao,
B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem. Commun. 2011, 47, 4300.
(n)Hu, M.-Y.;Ni, C.-F.; Hu, J.-B. J. Am. Chem. Soc. 2012, 134, 15257. (o)
Shen, X.; Zhang, W.; Ni, C.-F.; Gu, Y.-C.; Hu, J.-B. J. Am. Chem. Soc.
2012, 134, 16999. (p) Zhao, Y.-C.; Huang, W.-Z.; Zheng, J.; Hu, J.-B.Org.
Lett. 2011, 13, 5342. (q) He, Z.-B.; Luo, T.; Hu, M.-Y.; Cao, Y.-J.; Hu,
J.-B. Angew. Chem., Int. Ed. 2012, 51, 3944. (r) Chu, L.-L.; Qing, F.-L.
J. Am. Chem. Soc. 2010, 132, 7262. (s) Morandi, B.; Carreira, E. M.
Angew. Chem., Int. Ed. 2010, 49, 938.
3
2
(3) (a) Solladie-Cavallo, A.; Suffert, J. Tetrahedron Lett. 1984, 25,
1897. (b) Solladie-Cavallo, A.; Farkhani, D.; Fritz, S.; Lazrak, T.;
Suffert, J. Tetrahedron Lett. 1984, 25, 4117. (c) Solladie-Cavallo, A.;
Suffert, J. Synthesis 1985, 659. (d) Schneider, M. R. J. Med. Chem. 1986,
29, 1494. (e) Solladi-Cavallo, A.; Farkhani, D.; Dreyfuss, A. C.; Sanch,
F. Bull. Soc. Chim. Fr. 1986, 6, 906. (f) Matsubara, S.; Mitani, M.;
Utimoto, K. Tetrahedron Lett. 1987, 28, 5857. (g) Hammond, G. B.;
Plevey, R. G.; Sampson, P.; Tatlow, J. C. J. Fluorine Chem. 1988, 40, 81.
(h) Long, Z.-Y.; Chen, Q.-Y. Tetrahedron Lett. 1998, 39, 8487. (i)
Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398. (j) Balsells,
J.; Waters, M.; Hansen, K.; Kieczykowski, G. R.; Song, Z. J. Synthesis
2007, 2779. (k) Takai, K.; Takagi, T.; Baba, T.; Kanamori, T. J. Fluorine
Chem. 2007, 128, 120.
(4) McLoughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921.
(5) Zhao, Y.-C.; Hu, J.-B. Angew. Chem., Int. Ed. 2012, 51, 1033.
(6) Liang, A.-P.; Li, X.-J.; Liu, D.-F.; Li, J.-Y.; Zou, D.-P.; Wu,
Y.-J.; Wu, Y.-S. Chem. Commun. 2012, 48, 8273.
r
10.1021/ol400099h
Published on Web 02/01/2013
2013 American Chemical Society

2,2,2-trifluoroethylation of organoboronic acids and esters
with readily available 1,1,1-trifluoro-2-iodoethane.
Table 1. Optimization of the Reaction Conditionsa
Notably, trifluoroethylatedacetylenesare usefulorganic
intermediates. While methods for the construction of
Csp-CH2CF3 bonds have remained rare, the Shibata group
has documented a copper-mediated protocol for the pre-
paration of 1-nitro-4-(4,4,4-trifluorobut-1-ynyl)benzene,
but the yield was only 36% (Scheme 1a).7 In addition,
the copper-catalyzed direct 2,2,2-trifluoroethylation of
terminal alkynes with pregenerated 2,2,2-trifluorodia-
zoethane was reported by the Ma group in 2012. The
drawback of this method is the need to preprepare the
gaseous 2,2,2-trifluorodiazoethane from 2,2,2-trifluoroethy-
lamine hydrochloride and sodium nitrite (Scheme 1b).8
Meanwhile, the Szabo group developed a copper-mediated
trifluoromethylation of propargylic halides and trifluoro-
acetates, which require prefunctionalization of terminal
alkynes (Scheme 1c).9 Herein, we describe a direct
palladium-catalyzed method for 2,2,2-trifluoroethylation
of terminal alkynes with readily available 1,1,1-trifluoro-2-
iodoethane (CF3CH2I). The direct trifluoroethylation of
CspꢀH bonds represents a straightforward and functional
group tolerant protocol applicable for preparation of a
broad range of trifluoroethylated acetylenes in moderate-
to-excellent yields.
Scheme 1. Synthetic Protocols of Trifluoroethylated Acetylenes
a Unless otherwise noted, the reactions were carried out with I
(0.5 mmol), CF3CH2I (2 equiv), base (2 equiv), Pd2(dba)3 (5 mol %),
ligand (20 mol %), and toulene (1 mL) under Ar, 80 °C, 24 h. b 10 mol %
of Pd(OAc)2, PdCl2, and Pd(PPh3)4 were used. c Under air.
Our study began with the cross-coupling of phenylace-
tylene (I) with the CF3CH2I. Initially we examined direct
2,2,2-trifluoroethylation in the presence of Pd2(dba)3
(5 mol %), Xantphos (20 mol %), and Cs2CO3 (2.0 equiv)
in 1,4-dioxane at 80 °C, which is similar to previously
reported reaction conditions.5 Fortunately, the desired
product was detected, although the yield was very low
(Table 1, entry 1). With the aim of improving the desired
product yield, different organic solvents were examined,
and PhCH3 gave the best yield compared with other
solvents (Table 1, entries 2ꢀ6). To our surprise, screening
different monodentate and bidentate phosphine ligands
(Table 1, entries 7ꢀ11) led to the discovery that DPEphos
was an effective ligand, forming the product in 72% yield
(Table 1, entry 11). Reasoning that a base might play an
important role in this reaction, we tested several inorganic
(Table1, entries 12ꢀ15) and organic bases (Table1, entries
16 and 17). It was found that 1,4-diazabicyclo[2.2.2]octane
(Dabco) could provide the most efficient yield of 86%
(Table 1, entry 17), while otherorganic and inorganicbases
(7) Kawai, H.; Furukawa, T.; Nomura, Y.; Tokunaga, E.; Shibata,
N. Org. Lett. 2011, 13, 3596.
(8) Liu, C.-B.; Meng, W.; Li, F.; Wang, S.; Nie, J.; Ma, J.-A. Angew.
Chem., Int. Ed. 2012, 51, 6227.
(9) Zhao, T. S. N.; Szabo, K. J. Org. Lett. 2012, 14, 3966.
Org. Lett., Vol. 15, No. 4, 2013
937

Table 2. Pd-Catalyzed Trifluoroethylation of Terminal Alkynes
to 1,1,1-Trifluoro-2-iodoethanea
Scheme 2. Reduction and Oxidation Reaction of Aryl and Alkyl
2,2,2,-Trifluoroethylation Product
were less effective. Finally, an examination of different
palladium sources revealed that palladium(II) catalysts
were less effective compared to the Pd2(dba)3 catalyst
(Table 1, entries 18 and 19). However, other palladium(0)
catalysts, suchasPd(PPh3)4, gaveonly a low yield (Table 1,
entry 20). Obviously, both palladium catalyst and ligand
were essential for reaction efficiency, as hardly any detect-
able product was observed in the absence of Pd2(dba)3 or
DPEphos (Table 1, entries 21and 22). Only a trace amount
of the target product was obtained when the reaction was
carried out under aerobic conditions (Table 1, entry 23).
With the optimal protocol in hand, we next investigated
the substrate scope of this 2,2,2-trifluoroethylation reac-
tion. We found that various terminal aryl alkynes (1aꢀ1l)
and alkyl alkynes (1mꢀ1s) could be transformed to the
corresponding products in good-to-excellent yields (Table 2).
Both electron-rich (1aꢀ1e) and electron-deficient (1fꢀ1l)
aryl alkynes gave the expected trifluoroethylation products
in moderate-to-good yields. Many synthetically important
functional groups, such as alkoxy, alkyl, nitrile, carbonyl,
nitro, ester, amide, and especial formyl groups, were well-
tolerated under the optimal conditions (1bꢀ1c, 1f, 1g, 1i, 1h,
1jꢀ1k, 1p, 1n). Moreover, adjacent heteroatom substituted
alkyl alkynes (1mꢀ1q) reacted with CF3CH2I under our
conditions to give the products in higher yield, up to 95%.
Alkyl alkynes with O,N-heteroatoms at the β-position
(1r, 1s) were also tolerated and gave the products in
moderate-to-excellent yields.
Application of this new trifluoroethylative method in
the synthesis of organofluorine compounds which would
otherwise be difficult to access was tested (Scheme 2). We
chose 4-(4,4,4-trifluorobut-1-yn-1-yl)benzonitrile (3f) and
2-((5,5,5-trifluoropent-2-yn-1-yl)oxy)naphthalene (3m) as
model substrates, which can be hydrogenated to the
fluorinated alkanes 3f0 and 3n0 using a 10% Pd/C catalyst
and H2 at room temperature. Next, the oxidation reaction
of 4-(4,4,4-trifluorobut-1-yn-1-yl)-1,10-biphenyl (3a) was
a Reaction conditions: 1 (0.5 mmol), CF3CH2I (2 equiv), Pd2(dba)3
(5 mol %), DPEphos (20 mol %), and Dabco (2 equiv) in toluene (1 mL),
80 °C, Ar, 24 h. b Isolated yields. c Yields were determined by 19FNMRwith
an internal standard (benzotrifluoride).
investigated with the oxidant Ce(SO4)2 4H2O and H2SO4
(concd) at 70 °C, producing the corresponding ketone
3
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Org. Lett., Vol. 15, No. 4, 2013

compound 3a0 in moderate yield. These encouraging results
indicated that the present method provides an efficient
approach for the preparation of diverse organofluorine
compounds.
by the amine (Dabco), forming a new square planar Pd
complex D.10ꢀ12 Probably the CfD process in the catalytic
cycle is relatively facile under Cu-free catalytic Sonogashira
reaction conditions. A reason for this can be the electron-
withdrawing nature of the CF3 group, which is beneficial for
formation of complex Dfrom complex C. Finally, complex D
affords the product alkynyl-CH2CF3 through reductive
elimination.12,14
Scheme 3. A Possible Mechanism for the Catalytic
2,2,2-Trifluoroethylation Reaction
In conclusion, we have successfully developed the
palladium-catalyzed 2,2,2-trifluoroethylation reaction of
alkyl and aryl terminal alkynes using the readily available
reagent CF3CH2I. The reaction can be carried out under
mild conditions and is compatible with many functional
groups, even the formyl group. This reaction provides a
straightforward, practically useful way to prepare various
trifluoroethylated alkynes.
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation
of China (Nos. 21272050, 21072040, 21071040) and the
Program for New Century Excellent Talents in University
of the Chinese Ministry of Education (NCET-11-0627).
Supporting Information Available. Standard experi-
mental procedure and characterization data of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
A plausible reaction mechanisim for Pd-catalyzed tri-
fluoroethylation of alkynes with CF3CH2I is presented in
Scheme 3. Initially, the palladium complex A10ꢀ12 would be
generated by the reaction of the Pd precursor with ligands.
Subsequently, the PdII intermediate B13 is formed via oxi-
dative addition of complex A to CF3CH2I. Then, ligand
dissociation followed by complexation with the alkyne occurs
to form the intermediate complex C (η2-RCtCH);Pd
(CF3CH2)XL.10,12 The ligated alkyne is then deprotonated
(13) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(b) Fujita, K.-I.; Yamashita, M.; Puschmann, F.; Alvarez-Falcon,
M. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
9044. (c) Zuideveld, M. A.; Swennenhuis, B. H. G.; Boele, M. D. K.;
Guari, Y.; van Strijdonck, G. P. F.; Reek, J. N. H.; Kamer, P. C. J.;
Goubitz, K.; Fraanje, J.; Lutz, M.; Spek, A. L.; van Leeuwen, P. W. N.
M. J. Chem. Soc., Dalton Trans. 2002, 2308. (d) Li, Z.; Fu, Y.; Zhang,
S.-L.; Guo, Q.-X.; Liu, L. Chem.;Asian J. 2010, 5, 1475–1486. (e) Li, Z.;
Fu, Y.; Guo, Q.-X.; Liu, L. Organometallics 2008, 27, 4043. (f) Klingensmith,
L. M.; Strieter, E. R.; Barder, T. E.; Buchwald, S. L. Organometallics
2006, 25, 82. (g) Amii, H.; Kageyama, K.; Kishikawa, Y.; Hosokawa,
T.; Morioka, R.; Katagir, T.; Uneyama, K. Organometallics 2012, 31,
1281.
(10) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874.
(11) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.;
Hughes, D. L. Org. Lett. 2003, 5, 4191.
(12) (a) Garcia-Melchor, M.; Pacheco, M. C.; Najera, C.; Lledos, A.;
Ujaque, G. ACS Catal. 2012, 2, 135. (b) Shang, R.; Yang, Z.-W.; Wang,
Y.; Zhang, S.-L.; Liu, L. J. Am. Chem. Soc. 2010, 132, 14391.
(14) Culkin, D. A.; Hartwig, J. F. Organometallics 2004, 23, 3398.
The authors declare no competing financial interest.
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