Low-valent niobium-catalyzed reduction of α,α,α- trifluorotoluenes

Article abstract of DOI:10.1021/ol070249m

Equation presented In the presence of 5 mol % of niobium(V) chloride, α,α,α-trifluorotoluene derivatives were reduced with lithium aluminum hydride to give toluene derivatives in good yields. Stepwise, partial reduction of bis(trifluoromethyl)benzene derivative was also demonstrated.

Full text of DOI:10.1021/ol070249m

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1497-1499
Low-Valent Niobium-Catalyzed
Reduction of -Trifluorotoluenes
r,r,r
Kohei Fuchibe, Yoshitaka Ohshima, Ken Mitomi, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin UniVersity, 1-5-1 Mejiro
Toshima-ku, Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received February 1, 2007
ABSTRACT
In the presence of 5 mol % of niobium(V) chloride,
r,r,r-trifluorotoluene derivatives were reduced with lithium aluminum hydride to give
toluene derivatives in good yields. Stepwise, partial reduction of bis(trifluoromethyl)benzene derivative was also demonstrated.
The carbon-fluorine bond is one of the most stable single
bonds that constitute organic molecules.1 Fluorine substitu-
ents in organic compounds, in general, remain intact under
various vigorous conditions, and development of efficient
methods to transform the C-F bonds into new C-C bonds2
or C-X bonds3 has therefore attracted a great deal of
attention from synthetic organic chemists.
Although various stoichiometric and catalytic reductions of
perfluoroarenes,9 fluoroarenes,10 fluoroalkanes,10a and fluoro-
alkenes9d,11 have been reported to date, efficient and widely
applicable methods are still required.
It is well-recognized that R,R,R-trifluorotoluenes are one
of the most inert examples among a wide range of organo-
fluorine compounds. The trifluoromethyl groups on the
Reductions of the C-F bonds into C-H bonds are also
important transformations4 not only because of the funda-
mental importance on the C-F bond activation chemistry5
but also because of the close relationship to destruction of
atmospheric pollutants6 such as chlorofluorocarbons (CFCs,
ozone depletion)7 and perfluoroalkanes (greenhouse gases).8
(5) (a) Richmond, T. G. In ActiVation of UnreactiVe Bonds and Organic
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10.1021/ol070249m CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/13/2007

Table 1. Reduction of Trifluorotoluene Derivatives
a Conditions: NbCl5 (5 mol %), DME, reflux. b Starting materials were not recovered. c NMR yield (CH2Br2 was used as an internal standard). d NbCl5
(100 mol %).
aromatic rings are scarcely affected12 and efficient reduction
of the formally benzylic C-F bonds has not been realized
until very recently.13
We have reported niobium(V) chloride-catalyzed reduction
of fluorobenzene derivatives with lithium aluminum hydride
in recent years.14 The low-valent niobium,15 which is
generated in situ, was found to be of high efficiency and the
corresponding benzene derivatives were obtained in high
yields. Here, we disclose reduction of R,R,R-trifluorotoluene
derivatives by means of the low-valent niobium catalyst.
A DME (1,2-dimethoxyethane) solution of 4-phenyl-
R,R,R-trifluorotoluene 1a and 4 molar amounts of lithium
aluminum hydride was refluxed in the presence of 5 mol %
of niobium(V) chloride for 4 h. The reaction was quenched
with water at 0 °C and the desired 4-phenyltoluene 2a was
obtained in 96% yield (Scheme 1). Without niobium(V)
Scheme 1
(12) (a) Amii, H.; Hatamoto, Y.; Seo, M.; Uneyama, K. J. Org. Chem.
2001, 66, 7216. (b) Saboureau, C.; Troupel, M.; Sibille, S.; Pe´richon, J. J.
Chem. Soc., Chem. Commun. 1989, 1138. (c) Clavel, P.; Le´ger-Lambert,
M.-P.; Biran, C.; Serein-Spirau, F.; Bordeau, M.; Roques, N.; Marzouk, H.
Synthesis 1999, 829. (d) Ferraris, D.; Cox, C.; Anand, R.; Lectka, T. J.
Am. Chem. Soc. 1997, 119, 4319.
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2005, 127, 2852.
(14) (a) Fuchibe, K.; Akiyama, T. Synlett 2004, 1282. See our preceding
C-C bond forming reactions using the CF3 group, also: (b) Fuchibe, K.;
Akiyama, T. J. Am. Chem. Soc. 2006, 128, 1434. (c) Fuchibe, K.; Mitomi,
K.; Akiyama, T. Chem. Lett. 2007, 36, 24.
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Org. Lett., Vol. 9, No. 8, 2007

chloride, the reduction did not proceed to completion and
partially reduced product 3 was obtained in 53% yield.
The low-valent niobium-catalyzed reduction could be
applied to various R,R,R-trifluorotoluene derivatives and the
corresponding toluene derivatives were obtained in good
yields (Table 1).16 Phenyl trifluorotoluenes bearing substit-
uents such as methyl and fluorine gave the corresponding
products 2a-f in high yields (entries 1-6). It is noteworthy
that the aromatic C-F bonds remained intact under the
reaction conditions (entries 5 and 6). Not only phenyl
trifluorotoluenes but also the parent trifluorotoluene 1g and
benzyl trifluorotoluene 1h also gave the corresponding
products 2g and 2h, respectively (entries 7 and 8). When
chlorotrifluorotoluene 1i was subjected to the conditions, both
the C-F bonds and the C-Cl bond were reduced to give
m-phenyltoluene 2b in 81% yield (entry 9). On the other
hand, when the reduction of 1i was performed with a reduced
amount of lithium aluminum hydride (6 versus 3 molar
amounts), partial reduction products 4 and 1b, in which no
chlorine atom survived, were obtained (entry 10). The C-Cl
bond in 1i was found to be reduced prior to the C-F bonds.
Reduction of 4,4′-bis(trifluoromethyl)biphenyl 1j also pro-
ceeded successfully and 2c was obtained in 58% yield (entry
11).
Scheme 2
which are prepared by chlorination of the corresponding
toluenes.19 The low-valent niobium-catalyzed partial reduc-
tion is thus a potentially useful method to produce aromatic
compounds that possess both the CH3 group and the CF3
group.
In conclusion, a variety of R,R,R-trifluorotoluenes could
be reduced by the combined use of 5 mol % of niobium(V)
chloride and lithium aluminum hydride. The corresponding
toluenes were obtained in good yields. Both complete and
partial reduction of bis(trifluoromethyl)benzene derivative
was also demonstrated.
Acknowledgment. This work was supported in part by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan
(No. 18750036). This work was also supported by the
Saneyoshi scholarship foundation (No. 1818).
Selective, stepwise reduction of bis(trifluoromethyl)-
benzene 1k was also accomplished (Scheme 2). With large
excess amounts of lithium aluminum hydride, 1k gave
completely reduced product 2d in 78% yield. In contrast,
1k gave a partial reduction product 1d in 77% yield with 3
molar amounts of the reducing agent. One of the most general
methods to prepare R,R,R-trifluorotoluene derivatives is
fluorine-chlorine exchange of R,R,R-trichlorotoluenes,17,18
Supporting Information Available: 1H and 13C NMR
spectra of 2 and 1d, and chracterization data of 3 and 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Typical Procedure. To a DME solution of 1a (308 mg, 1.39 mmol)
and NbCl5 (18 mg, 0.068 mmol) was added solid lithium aluminum hydride
(208 mg, 5.47 mmol) carefully. The mixture was magnetically stirred and
allowed to reflux for 4 h. The reaction was quenched with water at 0 °C
and a small amount of sodium tartrate (ca. 200 mg) was added for ease of
extraction. Products were extracted with ethyl acetate three times and the
combined organic layers were dried over anhydrous sodium sulfate. The
organic solvents were removed under reduced pressure and purification by
column chromatography (SiO2, hexane) gave 2a (218 mg, 1.33 mmol, 96%
yield) as a colorless crystal. The 1H and 13C NMR spectra were in complete
agreement with those in the literature (Tao, B.; Boykin, D. W. J. Org. Chem.
2004, 69, 4330).
OL070249M
(18) Other methods to access R,R,R-trifluorotoluenessoxidative substitu-
tions of dithioacid derivatives: (a) Furuta, S.; Kuroboshi, M.; Hiyama, T.
Bull. Chem. Soc. Jpn. 1999, 72, 805. (b) Matthews, D. P.; Whitten J. P.;
McCarthy J. R. Tetrahedron Lett. 1986, 27, 4861. Metal-mediated coupling
reactions: (c) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969, 10,
4095. (d) Kitazume, T.; Ishikawa, N. Chem. Lett. 1982, 11, 137. See also:
(e) Su, D.-B.; Duan, J.-X.; Chen, Q.-Y. Tetrahedron Lett. 1991, 32, 7689.
(19) (a) Harvey, P. G.; Smith, F.; Stacey, M.; Tatlow, J. C. J. Appl. Chem.
1954, 4, 319. (b) Marsh, F. D.; Farnham, W. B.; Sam, D. J.; Smart, B. E.
J. Am. Chem. Soc. 1982, 104, 4680.
(17) (a) Simons, J. H.; Lewis, C. J. J. Am. Chem. Soc. 1938, 60, 492.
(b) Bloodworth, A. J.; Bower, K. J. Tetrahedron Lett. 1987, 28, 5347.
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