Synthesis of fluoro- and perfluoroalkyl arenes via palladium-catalyzed [4 + 2] benzannulation reaction

Article abstract of DOI:10.1021/ol401057z

An efficient entry into densely substituted fluorinated and perfluoroalkylated benzene derivatives via chemo- and regioselective Pd-catalyzed [4 + 2] cross-benzannulation is presented. The synthetic utility of these products for the synthesis of various aromatic and heteroaromatic compounds is also demonstrated. This strategy offers a viable and quite general alternative to existing fluorination and perfluoroalkylation methods for securing these valuable molecules.

Full text of DOI:10.1021/ol401057z

ORGANIC
LETTERS
2013
Vol. 15, No. 10
2562–2565
Synthesis of Fluoro- and Perfluoroalkyl
Arenes via Palladium-Catalyzed [4 þ 2]
Benzannulation Reaction
Olga V. Zatolochnaya and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607, United States
vlad@uic.edu
Received April 18, 2013
ABSTRACT
An efficient entry into densely substituted fluorinated and perfluoroalkylated benzene derivatives via chemo- and regioselective Pd-catalyzed
[4 þ 2] cross-benzannulation is presented. The synthetic utility of these products for the synthesis of various aromatic and heteroaromatic
compounds is also demonstrated. This strategy offers a viable and quite general alternative to existing fluorination and perfluoroalkylation
methods for securing these valuable molecules.
Due to their unique physical, chemical, and biological
properties, fluoride and perfluoroalkyl-containing aro-
matic compounds are garnering increasing attention in
various research areas.1 In recent years, substantial
progress toward the synthesis of aryl fluorides 1 has been
achieved2 (Scheme 1). A variety of transition metal
mediated strategies, as well as metal-free procedures, have
beenadded tothe traditionalfluorinationmethods, suchas
BalzꢀSchiemann and aromatic nucleophilic substitution
reactions. All these approaches employ fluorination of
pre-existing aromatic precursors with either nucleophilic
or electrophilic fluorine sources. On the other hand,
cycloaddition methods serve as a powerful tool set for
the rapid assembly of aromatic cores.3 Although several
examples are known for introduction of perfluoroalkyl
groups4 onto a benzene ring via a [2 þ 2 þ 2] cycloaddition
reaction of perfluoroalkylated alkynes,5,6 to the best of our
knowledge, construction of aryl fluorides via similar meth-
ods has not been previously described,7 presumably due to
(4) For selected reviews on trifluoromethylation of aromatic com-
pounds, see: (a) Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975.
(b) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D.; Roy, S. Tetrahedron
2011, 67, 2161. (c) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475. See also ref 2d, 2e.
(5) For Rh-catalyzed [2 þ 2 þ 2] cycloaddition, see: (a) Garcia, J. J.;
Sierra, C.; Torrens, H. Tetrahedron Lett. 1996, 37, 6097. (b) Tanaka, K.;
Hara, H.; Nishida, G.; Hirano, M. Org. Lett. 2007, 9, 1907. (c) Konno, T.;
Moriyasu, K.; Kinugawa, R.; Ishihara, T. Org. Biomol. Chem. 2010, 8,
1718. For Ru-catalyzed [2 þ 2 þ 2] cycloaddition, see: (d) Kawatsura, M.;
Yamamoto, M.; Namioka, J.; Kajita, K.; Hirakawa, T.; Itoh, T. Org. Lett.
€
(1) For selected reviews, see: (a) Muller, K.; Faeh, C.; Diederich, F.
Science 2007, 317, 1881. (b) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (c) Jeschke, P. Chem-
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Chem. Rev. 2008, 108, 1501.
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8610. (c) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (d) Furuya, T.;
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Chem. Commun. 2012, 48, 2929.
€
2011, 13, 1001. For Ni-catalyzed [2 þ 2 þ 2] cycloaddition, see: (e) Muller,
C.; Lachicotte, R. J.; Jones, W. D. Organometallics 2002, 21, 1975.
(6) For synthesis of perfluoroalkylarenes using DielsꢀAlder reac-
tion, see: (a) Wong, H. N. C. Synthesis 1984, 787. (b) Abubakar, A.;
Booth, B.; Suliman, N.; Tipping, A. J. Fluorine Chem. 1992, 56, 359. (c)
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r
10.1021/ol401057z
Published on Web 05/08/2013
2013 American Chemical Society

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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Org. Lett., Vol. 15, No. 10, 2013
2563

Table 2. Scope of Enynes for the Synthesis of Fluoroarenesa
Scheme 2. Scope of Diynes for the Synthesis of Fluoroarenes
p-alkynylaryl fluoride 1aa in 85% yield (Table 2, entry 1).
Likewise, fluoro enyne 2b provided the cross-
benzannulation product 1ba in good yield (entry 2).
As expected, enyne 2c bearing an electron-donating
group delivered the corresponding fluoroarene with mod-
erate efficiency12 (entry 3). Substrates 2d,e substituted at
the propargylic position were smoothly converted to the
corresponding fluoroarene derivatives (entries 4, 5). Simi-
larly, alkyl substituted fluoro enynes were competent sub-
strates for the benzannulation reaction (entries 6, 7).
Differently substituted alkyl enynes possessing valuable
functionalities, such as silyloxy (entry 8), amino (entries 5,
9), cyano (entry 10), and ester (entry 11) groups, were well
tolerated under these reaction conditions.
Next, the reactivity of different diynes toward this
benzannulation with enyne 2a was examined (Scheme 2).
Thus, employment of either electron-deficient (3d) or
electron-rich (3e) symmetrical diaryldiynes, as well as
dialkyl-substituted diyne (3b), led to the formation of
fluorinated arenes in good yields. 3-Fluoroenyne 2a also
underwent benzannulation with unsymmetrically substi-
tuted silyldiyne 3c. In this case, the hydrolytically unstable
product was isolated as the desilylated adduct 1ac, after
treatment with TBAF in a one-pot fashion.
Notably, this benzannulation strategy, which leads to
alkynyl-containing arenes, offers a unique opportunity for
accessing various aromatic and heteroaromatic scaffolds.
It seems particularly attractive for the synthesis of mole-
cules possessing a modifiable silyl group at the aryl ring.
Accordingly, we explored further transformations of
trifluoromethyl-containing o-alkynylsilyl ether 5ac, the
product of the benzannulation of enyne 4a and diyne 3c
(Table 1, entry 7). Given the hydrolytical instability of 5ac,
it was used crude.13 ortho-Alkynylbiaryls are valuable sub-
strates in the synthesis of polycyclic aromatic scaffolds.14
Thus, benzannulation product 5ac was desilylated to
afford the corresponding o-alkynylbiaryl 6 in 76% yield
via a one-pot operation (Scheme 3). It was found that 6
a Reaction conditions: 2 (0.6 mmol), 3 (0.5 mmol), IPrPdAllCl
(1 mol %), (2-furyl)3P (2 mol %), CsOPiv (2 mol %), toluene (1 M),
120 °C, 16ꢀ24 h. b Isolated yields, %.
be further utilized in the synthesis of various aromatic
scaffolds (vide infra).
(13) See Supporting Information for details.
(14) (a) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130,
5636. (b) Chernyak, N.; Gevorgyan, V. Adv. Synth. Catal. 2009, 351,
Encouraged by these results, we turned our attention
to the synthesis of aryl fluorides via the benzannulation
of fluoro-containing enynes 2. To our delight, 3-fluoro-
1-phenylenyne 2a underwent a facile benzannulation
reaction with diphenyldiyne 3a, thus giving access to
€
1101. (c) Furstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264. (d)
€
Mamane, V.; Hannen, P.; Furstner, A. Chem.;Eur. J. 2004, 10, 4556.
(e) Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677. (f)
Yao, T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511.
2564
Org. Lett., Vol. 15, No. 10, 2013

Scheme 3. Synthesis of Trifluoromethyl-Containing Aromatic and Heteroaromatic Compounds
underwent smooth Pd-catalyzed 5-exo-dig cyclization14a
followed by hydrogenation to form the corresponding
fluorene 7. Alternatively, arylative 5-exo-dig cyclization14b
of 6 afforded unsymmetrically substituted fluorene 8 as a
single stereoisomer. Electrophilic 6-endo-dig cyclization14c,d
under gold catalysis delivered the CF3-containing phenan-
threne 9 in excellent yield. Iodo-containing phenanthrene 10
was efficiently assembled from 6 via an ICl-induced 6-endo-
dig cyclization.14e,f
Naturally, we were interested in exploring the advan-
tages provided by the silyl group located at the ortho-
position to the triple bond. Thus, reduction of the silyl
ether groupwith DIBAL-H providedaccess tohydrosilane
11 in 75% yield over the two-step sequence. This com-
pound represents not only a hydrolytically stable analog of
5ac but also a potential substrate for the synthesis of
benzosilols.15 Alternatively, silver fluoride mediated elec-
trophilic halogenation of 5ac afforded haloarenes 12a and
12b in good yields. ortho-Alkynyliodide 12a was efficiently
converted to a densely substituted indole 13 via the
Pd-catalyzed amination/cyclization sequence.16 Notably,
the overall procedure allows for the synthesis of 6-sub-
stituted indole in just three steps starting from acyclic
precursors 4a and 3c. Additionally, Sonogashira cross-
coupling of 12a with trimethylsilylacetylene afforded the
Bergman cyclization precursor 14. Finally, the Tamao
oxidation of 5ac under mildly basic conditions offered
an access toward o-alkynylphenol 15, leaving the triple
bond unaffected. Further electrophilic cyclization under
Pt-catalysis17 delivered the benzofuran 16. Interestingly,
under forcing oxidation conditions, an unprecedented
direct transformation of o-alkynylsilylbenzene 5ac into
benzofuran 16 was observed.
In conclusion, an efficient and selective method for the
synthesis of fluoro- and perfluoroalkylaromatic compounds
via the Pd-catalyzed [4 þ 2] cross-benzannulation reaction
has been developed. This cycloaddition strategy proved to be
effective for the rapid construction of aromatic fluorides
from easily available acyclic starting materials. Significantly,
many of these products can be easily transformed into a
variety of diverse aromatic and heteroaromatic structures.
Acknowledgment. The support of the National Science
Foundation (CHE-1112055) is gratefully acknowledged.
(15) (a) Yamaguchi, S.; Xu, C.; Tamao, K. J. Am. Chem. Soc. 2003,
125, 13662. (b) Ilies, L.; Tsuji, H.; Sato, Y.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 4240. (c) Ilies, L.; Tsuji, H.; Nakamura, E. Org. Lett.
2009, 11, 3966.
Supporting Information Available. Experimental pro-
cedure and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Ackermann, L. Org. Lett. 2005, 7, 439. (b) Ackermann, L.;
€
Barfußer, S.; Potukuchi, H. K. Adv. Synth. Catal. 2009, 351, 1064. (c)
Ackermann, L.; Sandmann, R.; Schinkel, M.; Kondrashov, M. V.
Tetrahedron 2009, 65, 8930. (d) Ackermann, L.; Song, W.; Sandmann,
R. J. Organomet. Chem. 2011, 696, 195.
€
(17) Furstner, A.; Davies, P. W. J. Am. Chem. Soc. 2005, 127, 15024.
The authors declare no competing financial interest.
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