Niobium-catalyzed activation of CF3 group on alkene: Synthesis of substituted indenes

Article abstract of DOI:10.1246/cl.2010.867

A CF₃ group attached to an alkene functionality was activated by a zero-valent niobium catalyst to generate niobium alkenylcarbenoid species. The niobium carbenoid species then underwent insertion to an internal aromatic C-H σ bond to give inde

Full text of DOI:10.1246/cl.2010.867

doi:10.1246/cl.2010.867
Published on the web July 10, 2010
867
Niobium-catalyzed Activation of CF3 Group on Alkene: Synthesis of Substituted Indenes
³
Kohei Fuchibe, Kohei Atobe, Yukari Fujita, Keiji Mori, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588
(Received May 24, 2010; CL-100495; E-mail: takahiko.akiyama@gakushuin.ac.jp)
A CF3 group attached to an alkene functionality was
activated by a zero-valent niobium catalyst to generate niobium
alkenylcarbenoid species. The niobium carbenoid species then
underwent insertion to an internal aromatic C-H · bond to give
indene derivatives in good yields. Isomerization in terms of the
alkene geometry was also observed.
Table 1. Cyclization of trifluoropropenes (1)
H
H
NbCl5 30 mol%
NaAlH4 4 equiv
H
CF3
7
Ph
Ar
Ph
6
1,4-dioxane, reflux
R
R 5
Ar
4
2
1, Ar = C6H4R
Entry Ar
Time/h Yield (R)/%a
1
Ph, 1a
Ph, 1a
Ph, 1a
p-Tol, 1b
C6H4(p-OMe), 1c
C6H4(p-F), 1d
3,5-Dimethylphenyl, 1e
4
4
4
2
5
1
3
80 (6-H), 2a
72 (6-H), 2a
54 (6-H), 2a
63 (6-Me), 2b
52 (6-OMe), 2c
56 (6-F), 2dd
CF3 groups have played important roles in a range of
organic molecules for a long time.1 Molecules bearing CF3
group(s) in their structures, in general, exhibit enhanced (altered)
activities and stabilities, and various useful materials, such as
pharmaceuticals2 and ligands for metal catalysis,3 have been
created and utilized.4,5
2b
3c
4
5
6
7
54 (5,7-Me2), 2e
The CF3 group is now rapidly gaining importance in
synthesis and practical applications despite the fact that its C-F
bonds are highly inactive.6,7 For instance, magnesium-promoted
formation of ¢,¢-difluorosilyl enol ethers and N-silylenamines
from trifluoromethyl ketones and trifluoromethyl imines has
provided new synthetic routes for various difluoromethylene
compounds.8 Substitution reactions of fluorines of the CF3 group
were found to proceed smoothly by the use of catalytic9a and
stoichiometric9b,9c amounts of aluminum compounds. Reduc-
tions of halogenated hydrocarbons are of environmental im-
portance,10 and a highly efficient hydrodefluorination process for
trifluorotoluenes has been achieved by a silylium catalyst.11,12
We have also reported that a zero-valent niobium species
generated in situ smoothly activates C-F bonds of the CF3
groups on aromatic nuclei.13-16 Deuterium labeling experiments
suggested that a niobium fluorocarbenoid species is involved in
the catalytic cycle and that insertion of the carbenoid center to
the neighboring C-H · bond affords products.13c Biologically
important N-fused indoles, in particular, could be synthesized
efficiently with our transition metal-catalyzed method.13d
In contrast to recent progress in the reactions of CF3 groups
attached to carbonyl and aromatic functionalities, reactions of
CF3 groups attached to an alkene functionality have not been
fully developed yet. Although nonmetal-catalyzed, SN2¤-type
reactions of 3,3,3-trifluoropropenes are known,17 transition
metal-catalyzed activation of alkenylated CF3 groups has been
quite limited.18 We wish to report herein the first, direct
activation of the CF3 groups attached to an alkene functionality
by a niobium catalyst. Substituted indenes, which are of
importance from viewpoints of medical and material sciences,
were synthesized from trifluoropropenes (Scheme 1).19,20
aTrifluoropropenes 1 were consumed completely. b10 mol %
NbCl5. cLiAlH4 was used. dDefluorinated indenes were not
detected by 19F NMR analysis.
Requisite 3,3,3-trifluoropropenes 1 were prepared according
to a method developed by Hiyama and co-workers,21 and were
treated with a niobium catalyst. To a dioxane solution of ¢,¢-
diphenyltrifluoropropene 1a and niobium(V) chloride (30
mol %) was added 4 molar equivalents of solid sodium
aluminum hydride (Table 1, Entry 1).13d,16 After refluxing for
4 h, the reaction was quenched with pH 7 phosphate buffer.
Chromatographic purification of the products afforded phenyl-
indene 2a in 80% yield, which suggests that the CF3 group was
successfully activated. 1H NMR analysis showed that only a
trace amount of the conventional reduction product (non
fluorine-substituted propene) was formed. The reaction also
proceeded readily when the catalyst loading was decreased to
10 mol % (Entry 2).
Use of lithium aluminum hydride in place of sodium
aluminum hydride gave a diminished yield of 2a (54% yield,
Entry 3). Treatment of isolated 2a with lithium aluminum
hydride alone resulted in 44% recovery of 2a (not shown),
whereas 2a was recovered in 58% yield when treated with
sodium aluminum hydride. It is likely that the decomposition of
the product in the reaction medium was promoted when a more
reactive lithium congener was used.22
Other 1,1-homodiarylated trifluoropropenes also afforded
the corresponding indenes in good yields.23 Not only parent 1a
but also electron-donating and electron-withdrawing p-tolyl-, p-
methoxyphenyl-, and p-fluorophenyl-substituted trifluoropro-
penes 1b-1d afforded the corresponding indenes 2b-2d in good
yields (Entries 4-6). Sterically demanding 1e also worked well
(Entry 7). It is noted that the CF3 group was selectively activated
in preference to the aromatic C-F moiety under the reaction
conditions (Entry 6).24
F
F
H H
Niobium Catalyst
F
Ar2
Ar1
Ar2
H
R
R
Ar1
Substituents ¡ to the CF3 group also exhibited wide
generality (Table 2). Substituted phenyl- and heteroaryltrifluo-
Scheme 1.
Chem. Lett. 2010, 39, 867-869
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

868
Table 2. Cyclization of trifluoromethylalkenes (2)
H
H
NbCl5 30 mol%
NaAlH4 4 equiv
H
CF3
R
R
1,4-dioxane, reflux
Ph
Ph
1
2
Entry
R
Time/h
Yield/%
1
2
3
4
p-MeOC6H4, 1f
p-FC6H4, 1g
2-Thienyl, 1h
Me, 1i
2
2
2
2
80, 2f
71,a 2g
83, 2h
53, 2i
a7% yield of 2,3-diphenylindene was obtained.
NbCl5 30 mol%
NaAlH4 4 equiv
CF3
Ph
Ph
Ph
Ph
+
1,4-dioxane
p-tol
Figure 1. ORTEP diagram of 4.
p-tol
reflux, 2 h
As above
3
4
NbCl5
CF3
H–
1j (single E isomer)
1k (single Z isomer)
from 1j; 77% (3:4 = 43:57)
from 1k; 71% (3:4 = 45:55)
Ar
R1
(NaAlH4)
1
H2
CF3
Ph
Ph
Ph
Ph
H2
Nb(0)
MeO
R2
+
2 F–
Anis
Anis
H–
(NaAlH4)
5
6
(Anis = C6H4(p-OMe))
F
1l (single E isomer)
1m (single Z isomer)
from 1l; 73% (5:6 = 58:42)
from 1m; 77% (5:6 = 55:45)
H
Ar
C6H4R2
· Nb(n)
Nb(n)
R1
Scheme 2.
Fluorine-substituted niobium carbenoid
ropropenes 1f-1h gave the corresponding 2f-2h in good yields
(Entries 1-3). Not only 2-arylated trifluoropropenes but also 2-
alkylated trifluoropropene 1i afforded the corresponding indene
2i (Entry 4).
A
C–H insertion
H
F
hydro-
Ar
defluorination
R1
Ar
1,1-Heterodiarylated trifluoropropenes also gave the corre-
sponding indenes and in this case, unexpected isomerization in
terms of the alkene geometry took place (Scheme 2); (E)-1,2-
diphenyl-1-p-tolyl-3,3,3-trifluoropropene (1j) (single E-isomer)
gave a 43:57 mixture of phenyltolylindene 3 and methyldiphen-
ylindene 4 in 77% yield. Isomer 1k (single Z-isomer) also gave
essentially the same isomeric mixture. These phenomena were
also observed when E- and Z-trifluoropropenes 1l and 1m were
used. The structure of 4 was determined by X-ray crystal
structure analysis (Figure 1).25
The formation of indenes and the geometric isomerization
described in Scheme 2 can be explained by our presumed
catalytic cycle (Scheme 3). Reduction of niobium(V) chloride
with sodium aluminum hydride gives Nb(0) species.26 Fluorine-
substituted alkenylcarbenoid intermediates A are reductively
formed from the Nb(0) species and substrates 1.13c The
carbenoid intermediates A undergo intramolecular insertion to
an aromatic C-H · bond27 to give fluoroindene intermediates
B,28 liberating niobium species in higher oxidation state [Nb(n)].
Re-reduction of the liberated Nb(n) to Nb(0) initiates again the
catalytic cycle, and fluoroindenes B are hydrodefluorinated in
situ to give products 2 after aqueous work-up.13c Isomerization
of the alkene geometry of A27b and the C-H insertion of the
thus-formed isomeric fluorine-substituted alkenylcarbenoid in-
R1
C6H4R2
C6H4R2
2
B (not observed)
Scheme 3.
termediates (not shown) afford the isomeric indenes. The E- and
Z-alkenylcarbenoid intermediates are in equilibrium, based on
the fact that the same isomeric mixtures 3/4 and 5/6 were
obtained regardless of the alkene geometry of 1j-1m.
In summary, we have developed a niobium-catalyzed
method for the activation of the CF3 group on alkene
functionality. Treatment of 3,3,3-trifluoropropenes with zero-
valent niobium species successfully gave substituted indenes in
good yields. Niobium alkenylcarbenoid species are presumed to
be generated as key intermediates.29
This work is supported by the Asahi Glass Foundation.
References and notes
³
Present address: Department of Chemistry, Graduate School of
Pure and Applied Sciences, University of Tsukuba, Tsukuba,
Ibaraki 305-8571
Chem. Lett. 2010, 39, 867-869
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

869
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Chem. Lett. 2010, 39, 867-869
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/