Table 1. Benzannulation toward Perfluoroalkylbenzenesa
Scheme 1. Alternative Strategies toward Fluoroarenes
the explosive nature of the required starting fluoro al-
kynes.8 We envisioned that the Pd-catalyzed [4 þ 2] cross-
benzannulation reaction between conjugated enynes and
diynes9,10 might provide an alternative route for the facile
synthesis of fluorinated benzene cores (Scheme 1). In this
case, the fluorine atom could be introduced at the alkene
moiety of an enyne coupling partner, thus avoiding the
employment of fluoro alkynes. Importantly, compared
with other vinyl halides, vinyl fluorides are less reactive
toward the oxidative addition of low-valent transition
metals,11 which would allow the Pd(0)-catalyzed benzan-
nulation process of fluoro enynes 2 to proceed without
accompanying defluorination. Herein, we wish to report
an efficient synthesis of aryl fluorides, as well as perfluo-
roalkyl arenes, from acyclic precursors employing a
Pd-catalyzed [4 þ 2] cycloaddition strategy.
To test our benzannulation strategy for fluoroarenes,
we first examined the cycloaddition of trifluoromethyle-
nynes with the aid of a recently developed highly efficient
catalytic system.12 Gratifyingly, a cross-benzannulation
reaction between enyne 4a and diphenyldiyne 3a, in the
presence of 1% of a Pd-catalyst, afforded the desired
(8) (a) Middleton, W. J.; Sharkey, W. H. J. Am. Chem. Soc. 1959, 81,
803. (b) Viehe, H. G.; Merenyi, R.; Oth, J. F. M.; Valange, P. Angew.
Chem., Int. Ed. Engl. 1964, 3, 746.
a Reaction conditions: 4 (0.6 mmol), 3 (0.5 mmol), IPrPdAllCl
(1 mol %), (2-furyl)3P (2 mol %), CsOPiv (2 mol %), toluene (1 M),
100 °C, 16ꢀ24 h. b Isolated yields, %. c Reaction conditions: 4a
(0.75 mmol), 3c (0.5 mmol), Pd2(dba)3 (5 mol %), (2-furyl)3P (10 mol %),
toluene (1 M), 100 °C; NMR yield, %.
ꢀ
(9) For transition-metal-free [4 þ 2] benzannulation, see: (a) Danheiser,
R. L.; Gould, A. E.; Fernandez de la Pradilla, R.; Helgason, A. L. J. Org.
Chem. 1994, 59, 5514. (b) Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc.
2005, 127, 5776. (c) Hayes, M. E.; Shinokubo, H.; Danheiser, R. L. Org. Lett.
2005, 7, 3917. For Pd-catalyzed [4 þ 2] benzannulation, see: (d) Saito, S.;
Salter, M. M.; Gevorgyan, V.; Tsuboya, N.; Tando, K.; Yamamoto, Y.
J. Am. Chem. Soc. 1996, 118, 3970. (e) Gevorgyan, V.; Takeda, A.;
Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 11313. (f) Gevorgyan, V.;
Sadayori, N.; Yamamoto, Y. Tetrahedron Lett. 1997, 38, 8603. (g)
Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.; Radhakrishnan,
U.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 6391. (h) Rubina, M.;
Conley, M.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 5818. For Co-
trifluoromethyl-containing arene 5aa in 84% yield in a
highlyregio- and chemoselectivemanner(Table1, entry1).
Analogously, the reaction between enyne 4a and dialkyl-
substituted diyne 3b proceeded with good efficiency
(entry 2). Employment of alkyl substituted enyne 4d
afforded the corresponding trifluoromethylarene 5da in
high yield (entry 3). However, 3,5-dialkyl substituted tri-
fluoromethylarene 5db was obtained in 72% yield along
with 15% of the homo-benzannulation product of 4d
(entry 4). Presumably, the high reactivity of enyne 4d and
the low reactivityofdiyne 3bbothaccounted for thisresult.
Similarly to trifluoromethylarenes, arylalkynes bearing a
perfluoroalkyl chain can also be obtained with high effi-
ciency via the benzannulation reaction of enynes 4b and 4c
(entries 5, 6). Importantly, unsymmetrically substituted
silyldiyne 3c reacted with enyne 4a to produce trifluoro-
methylarene 5ac (entry 7) with perfect regioselectivity.
Base-free reaction conditions were employed in this case
to avoid loss of the fragile alkynylsilyl ether functionality.
Although hydrolytically unstable, product 5ac possesses a
valuable ortho-alkynyl arylsilyl ether functionality that can
€
catalyzed [4 þ 2] benzannulation, see: (i) Punner, F.; Hilt, G. Chem.
Commun. 2012, 3617.
(10) For synthetic application, see: (a) Gevorgyan, V.; Quan, L. G.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 1244. (b) Gevorgyan, V.; Quan,
L. G.; Yamamoto, Y. J. Org. Chem. 2000, 65, 568. (c) Saito, S.; Uchiyama,
N.; Gevorgyan, V.; Yamamoto, Y. J. Org. Chem. 2000, 65, 4338. (d) Rubin,
M.; Markov, J.; Chuprakov, S.; Wink, D. J.; Gevorgyan, V. J. Org. Chem.
2003, 68, 6251. (e) Nakao, Y.; Hirata, Y.; Ishihara, S.; Oda, S.; Yukawa, T.;
Shirakawa, E.; Hiyama, T. J. Am. Chem. Soc. 2004, 126, 15650. (f)
Gevorgyan, V.; Tsuboya, N.; Yamamoto, Y. J. Org. Chem. 2001, 66,
2743. (g) Saito, S.; Tsuboya, N.; Yamamoto, Y. J. Org. Chem. 1997, 62,
5042. (h) Weibel, D.; Gevorgyan, V.; Yamamoto, Y. J. Org. Chem. 1998,
63, 1217. (i) Liu, J. X.; Saito, S.; Yamamoto, Y. Tetrahedron Lett. 2000, 41,
4201. (j) Gevorgyan, V.; Tando, K.; Uchiyama, N.; Yamamoto, Y. J. Org.
Chem. 1998, 63, 7022. (k) Lewis, F. D.; Zuo, X.; Gevorgyan, V.; Rubin, M.
J. Am. Chem. Soc. 2002, 124, 1366. (l) Lewis, F. D.; Sajimon, M. C.; Zuo,
X.; Rubin, M.; Gevorgyan, V. J. Org. Chem. 2005, 70, 10447. For cascade
reactions, see: (m) Gevorgyan, V.; Radhakrishnan, U.; Takeda, A.;
Rubina, M.; Rubin, M.; Yamamoto, Y. J. Org. Chem. 2001, 66, 2835. (n)
Xi, C.; Chen, C.; Lin, J.; Hong, X. Org. Lett. 2005, 7, 347.
(11) Chelucci, G. Chem. Rev. 2012, 112, 1344.
(12) Zatolochnaya, O. V.; Galenko, A. V.; Gevorgyan, V. Adv.
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