We screened ruthenium catalysis for [2 þ 2þ2] cycload-
dition reaction of trifluoromethyl-substituted internal al-
kyne 1a as the model substrate from among the commercial
Table 1. Ruthenium-Catalyzed Cyclotrimerization of 1-(4-
Methylphenyl)-3,3,3-trifluoropropyne (1a)
a
8
sources listed in Table 1. Although [Ru-1] {dichlorobis(μ-
chloro)bis[(1,2,3,6,7,8-η)-2,7-dimethyl-2,6-octadiene-1, 8-
3
a
diyl]diruthenium}, Cp*RuCl(cod),
3b,d-g
[RuCp(CH3-
are known as
3
c
3h
CN) ]PF and [RuCp*(CH CN) ]PF
6
3
6
3
3
effective ruthenium catalysts for the trimerization of term-
inal alkynes, the reactions of 1a by these ruthenium catalysts
resulted in no reaction or very low yields (entries 1-4). On
9
12
,10
the other hand, we found that the Ru (CO)
formed the
desired benzene derivatives 2a in 35% isolated yield with a
5% regioselectivity. The yield from the trimerization of 1a
3
9
was still insufficient, but the regioselectivity was higher than
that of previous reports. On the basis of this preliminary
result, we confirmed that Ru (CO) is a promising ruthe-
b
yield (%)
3
12
c
entry
[Ru/L]
of 2a and 3a
2a:3a
nium precatalyst to produce the trifluoromethyl group
substituted benzene derivative with a high regioselectivity.
Therefore, we next attempted to optimize the reaction of 1a
by Ru (CO) with several phosphine ligands. Typically, the
1
2
3
4
5
6
7
8
9
Cp*RuCl(cod)
[RuCp(CH CN)
CN)
<5
0
ND
-
-
3
3
]PF
6
[RuCp*(CH
[Ru-1]
3
3
]PF
6
0
3
12
0
-
reaction was carried out as follows: in the presence of 3.3
mol % of Ru (CO) with a phosphine ligand (2.5, 5, or 10
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
Ru
3
3
3
3
3
3
3
3
3
(CO)12
(CO)12/10% PPh
35
7
95:5
95:5
95:5
3
12
3
mol %), an alkyne 1a was mixed in CH CN at 80 °C for 12
3
(CO)12/5% PPh
3
56
32
18
42
55
n
h. The reaction by the addition of 10 mol % of PPh (Ru/
3
(CO)12/5% P Bu
3
90:10
91:9
PPh = 1:1) decreased the yield to 7% (entry 6). However,
3
(CO)12/5% DPPE
1
0
(CO)12/2.5% DPPE
(CO)12/5% 2-DPPBN
(CO)12/5% 2-DPPBN
(CO)12/10% 2-DPPBN
78:22
>98:2
>98:2
97:3
an increased isolated yield (56%) was observed without
reducing the regioselectivity when 5 mol % of PPh (Ru/
11
3
d
e
1
2
3
84 (95)
11
PPh = 2:1) was added to the reaction mixture (entry 7).
3
1
45
n
Other phosphine ligands, for example P Bu or DPPE, were
3
a
Reaction conditions: 1a (0.2 mmol), 10 mol % for Cp*RuCl(cod),
RuCp(CH CN) ]PF and [RuCp*(CH CN) ]PF , 5 mol % for [Ru-1],
.3 mol % for Ru (CO)12, 0.4 mL of CH CN (0.5 M). Isolated yield.
Ratio was determined by H and/or F NMR of the crude materials.
not effective for the cyclotrimerization of 1a (entries 8-10).
Finally, we found that the reaction with 2-(diphenylphos-
phino)benzonitrile (2-DPPBN) gave the best result for the
desired cyclotrimerization. The reaction of 3.3 mol % of
Ru (CO) with 5 mol % of 2-DPPBN exhibited the
[
3
3
6
3
3
6
b
3
3
3
c
1
19
d
e
3
CH CN (0.1 mL, 2 M). NMR yield is in parentheses.
3
12
5
a
selective formation (>98% regioselectivity) of an unsym-
metrical benzene derivative 2a in 55% yield (entry 11).
Changing the concentration of the reaction mixture from
internal alkyne. They reported that the reaction was
catalyzed by a nickel catalyst, and the trifluoromethyl group
substituted benzene derivatives were quantitatively formed
with a 70% regioselectivity. Very recently, Konno and
Ishihara discovered that the rhodium catalyst produced the
cyclotrimerized benzene derivatives in moderate to good
0.5 to 2 M significantly increased the yield, and we thus
succeeded in obtaining 2a as a single regioisomer in an 84%
isolated yield (95% NMR yield) (entry 12). Again, the
reaction with 10 mol % of 2-DPPBN decreased both the
yield and regioselectivity (entry 13), so the ratio of ruthe-
nium to ligand (Ru/2-DPPBN=2:1) is very important when
5b
yields with up to an 88% regioselectivity. On the other
hand, during the course of our research on ruthenium-
6
catalyzed reactions and the stereoselective reaction of fluo-
11
7
rine-containing compounds, we found that Ru (CO)
forming the active ruthenium species.
3
12
We next examined the [2 þ 2 þ 2] cyclotrimerization of
various trifluoromethylated internal alkynes 1b-i under the
optimized reaction conditions, and the results are summarized
in Table 2. For the reaction of 1c-e, which has an electron-
withdrawing group at the para-position on the benzene ring,
small amounts of symmetrical products 3c-e were formed
coordinated with 2-(diphenylphosphino)benzonitrile (2-
DPPBN) and effectively catalyzed a [2 þ 2 þ 2] cyclotrimer-
ization of the trifluoromethyl group substituted internal
alkynes in high yields with an almost perfect regioselectivity.
(
5) (a) M u€ ller, C.; Lachicotte, R. J.; Jones, W. D. Organometallics
002, 21, 1975–1981. (b) Konno, T.; Moriyasu, K.; Kinugawa, R.;
Ishihara, T. Org. Biomol. Chem. 2010, 8, 1718–1724.
6) (a) Kawatsura, M.; Kamesaki, K.; Yamamoto, M.; Hayase, S.;
2
(8) Konno, T.; Chae, J.; Kanda, M.; Nagai, G.; Tamura, K.;
Ishihara, T.; Yamanaka, H. Tetrahedron 2003, 59, 7571–7580.
(
Itoh, T. Chem. Lett. 2010, 39, 1050–1051. (b) Kawatsura, M.; Ata, F.;
Hirakawa, T.; Hayase, S.; Itoh, T. Tetrahedron Lett. 2008, 49, 4873–
3
(9) Ru (CO)12 is known to react with hexafluoro-2-butyne and forms
cyclopentadienone-ruthenium complex, see: Bruce, M. I.; Knight, J. R.
J. Organomet. Chem. 1968, 12, 411–413.
4875. (c) Kawatsura, M.; Ata, F.; Hayase, S.; Itoh, T. Chem. Commun.
2
007, 4283–4285. (d) Kawatsura, M.; Ata, F.; Wada, S.; Hayase, S.;
(10) Ru
3
(CO)12 is also an active catalyst for several types of [2 þ 2þ2]
Uno, H.; Itoh, T. Chem. Commun. 2007, 298–300.
7) (a) Kawatsura, M.; Hirakawa, T.; Tanaka, T.; Ikeda, D.; Hayase,
S.; Itoh, T. Tetrahedron Lett. 2008, 49, 2450–2453. (b) Kawatsura, M.;
Wada, S.; Hayase, S.; Itoh, T. Synlett 2006, 2483–2485.
cycloadditions, see: Yamamoto, Y.; Itoh, K. In Ruthenium in Organic
Synthesis; Murahashi, S.-I, Ed.; Wiley-VCH: Weinheim, 2004; pp 95-128.
(11) The ratio of Ru to phosphine (2:1) is crucial to attain both a high
yield and regioselectivity, but the details are unknown at this time.
(
1
002
Org. Lett., Vol. 13, No. 5, 2011