Highly regioselective [2+2+2] cycloaddition of terminal alkynes catalyzed by titanium complexes of p-tert-butylthiacalix[4]arene

Article abstract of DOI:10.1016/j.tetlet.2005.12.034

Mono- and dinuclear titanium complexes of p-tert-butylthiacalix[4]arene were applied as a catalyst for [2+2+2] cycloaddition of terminal alkynes. They showed high catalytic activity and regioselectivity toward 1,3,5-trisubstituted benzenes over 1,2,4-trisubstituted isomers. The regioselectivity was rationalized in terms of the steric effect of the thiacalixarene skeleton and the coordination of the bridging sulfur atom to the titanium center.

Full text of DOI:10.1016/j.tetlet.2005.12.034

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1157–1161
Highly regioselective [2+2+2] cycloaddition of terminal
alkynes catalyzed by titanium complexes
of p-tert-butylthiacalix[4]arene
*
*
Naoya Morohashi, Katsuya Yokomakura, Tetsutaro Hattori and Sotaro Miyano
Department of Environmental Studies, Graduate School of Environmental Studies, Tohoku University,
6
-6-11 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan
Received 10 November 2005; revised 1 December 2005; accepted 2 December 2005
Available online 27 December 2005
Abstract—Mono- and dinuclear titanium complexes of p-tert-butylthiacalix[4]arene were applied as a catalyst for [2+2+2] cyclo-
addition of terminal alkynes. They showed high catalytic activity and regioselectivity toward 1,3,5-trisubstituted benzenes over
1
,2,4-trisubstituted isomers. The regioselectivity was rationalized in terms of the steric effect of the thiacalixarene skeleton and
the coordination of the bridging sulfur atom to the titanium center.
Ó 2005 Elsevier Ltd. All rights reserved.
Soon after the discovery of a practical synthesis of
p-tert-butylthiacalix[4]arene (1), in which the four meth-
ylene bridges of conventional p-tert-butylcalix[4]arene
in this line, we have recently reported that syn-(3) and
anti-dinuclear titanium(IV) complexes (4) can be readily
prepared by simply mixing thiacalixarene 1 with TiCl in
4
(
2) are replaced by epithio linkages, many researchers
dichloromethane and syn-complex 4 showed high cat-
alytic activity in the Mukaiyama-aldol reaction, indi-
cating the double-activation ability of complex 4 as a
have embarked on the study of this new host compound.
With the progress of research, it has become clear that
the thiacalixarene and its derivatives are not a simple
substitute for the conventional calixarenes but that they
should be recognized as quite unique host molecules of
4
bidentate Lewis acid toward aldehydes.
1
vast possibilities to be developed. One of the most note-
HO
HO
OH
OH
worthy features of thiacalixarenes is their coordination
ability toward metal ions without the need to modify
the upper and/or lower rim, as is the case for the con-
ventional calixarenes. This is attributed to the coordina-
tion of the sulfur to a metal center in cooperation with
the phenoxy oxygens, as revealed by solvent extraction
X
X
X
X
But
But
But
But
1: X = S
2: X = CH2
2
studies and X-ray crystallographic analyses. Further-
more, thiacalixarenes can form not only mono- but also
polynuclear metal complexes by virtue of the hetero-
geneous coordination sites. Therefore, our attention has
been focused on designing polynuclear metal complexes
of the thiacalixarenes, which may be useful for metal
catalysts. As the first successful example of our efforts
3
On the other hand, highly regiocontrolled cyclotrimeri-
zation of alkynes is an attractive method for the prepa-
5
,6
ration of multi-substituted benzenes. Recently, Ladipo
and co-workers reported that the titanium complex of
a methylene-bridged calix[4]arene (5) catalyzed the
cyclotrimerization of terminal alkynes to give 1,2,4-
7
trisubstituted benzenes selectively. Herein, we report
Keywords: Calixarene; Titanium complex; Alkyne cyclotrimerization.
*
Corresponding authors. Tel./fax: +81 22 795 7263; e-mail addresses:
morohashi@orgsynth.che.tohoku.ac.jp; hattori@orgsynth.che.tohoku.
ac.jp
that titanium complexes of thiacalix[4]arenes show the
opposite regioselectivity, giving 1,3,5-trisubstituted benz-
enes in good to excellent yield.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.034

1158
N. Morohashi et al. / Tetrahedron Letters 47 (2006) 1157–1161
Cl
Cl
sulfur atoms strongly affect the regioselectivity, as well
Cl Cl
Ti
Cl
Cl
But
But
S
as the catalytic activity. However, it should be noted
that both the sulfur-bridged bisphenol 8 and its methyl-
ene-bridged analog 9 showed similar 1,2,4-selectivity to
that obtained with TiCl4 (entries 6–9). Therefore, it
may be concluded that the steric environment imposed
by the thiacalixarene skeleton is also important for the
1,3,5-selectivity.
Ti
Ti
O
O
O
O
O
S O
S
S
S
S
S
S
O
O
But
Ti
But
But
But
But
Cl
Cl
But
3
4
Cl
But
But
Cl Ti
The cyclotrimerization of ethynylbenzene was carried
out in toluene at room temperature with 0.25 mol %
catalyst loading (15.0 lmol) in the presence of finely cut
O
O
O O
Si
8
sodium metal (0.2 mmol) to activate the catalyst. syn-
Me
Dinuclear titanium complex 3 gave a mixture of 1,3,5-
and 1,2,4-triphenylbenzene in the ratio of 77:23 in good
yield (65%) (Table 1, entry 1). Both the regioselectivity
and the product yield were significantly improved by
changing the catalyst from syn-complex 3 to anti-com-
plex 4 (entry 2). It has been reported that titanium com-
plex 5, bearing a calix[4]arene ligand of 1,2-alternate
conformation, catalyzed the cyclotrimerization of ethyn-
ylbenzene to give the 1,3,5- and 1,2,4-regioisomers in
But
But Me
5
Pri
Pri Si
O
i
Pr
Si
i
Pr
O
OH
OH
HO
HX O
O
X
X
X
X
7
the ratio of 1:99. Therefore, it is interesting to note that
But
But
complexes 4 and 5, both having a calixarene skeleton of
the same conformation, showed opposite regioselectivi-
ties to each other. In order to gain insight into the origin
of the regioselectivity, performance of bisphenol-type
ligands 6–9 was examined. The titanium complex was
But
But
But
But
6: X = S
8: X = S
9: X = CH2
7: X = CH2
generated in situ by the treatment of TiCl with a ligand
4
The cyclotrimerization of other terminal alkynes was
examined by using anti-complex 4 as a catalyst (Table
in toluene for 30 min before the addition of ethynyl-
benzene and sodium metal (entries 3–8). The complex
2
). Reaction of 4-ethynyltoluene proceeded smoothly
0
9
of O,O -disiloxane-1,3-diyl-bridged thiacalixarene 6
to give the 1,3,5-trisubstituted benzene in excellent yield
with high regioselectivity (entry 1). On the other hand,
showed high 1,3,5-selectivity (entry 3), which was com-
parable to that achieved with anti-complex 4. On the
1
-ethynyl-4-(trifluoromethyl)benzene, as well as ali-
9
other hand, its methylene-bridged analog 7 showed
phatic alkynes, did not give the desired compounds even
high 1,2,4-selectivity (entries 4 and 5), although the reac-
tion was sluggish and required higher temperature to be
completed. These observations indicate that the bridging
at elevated temperature (entries 2–5). We reasoned that
10
a titanacyclopentadiene intermediate
(vide infra)
(
Fig. 1) would not be formed from dichloride 4 with
these alkynes and therefore tried pretreating the dichlo-
ride with sodium phenylacetylide before addition of the
Table 1. Cyclotrimerization of ethynylbenzene catalyzed by titanium
complexes
1
1
alkynes (entries 6–12). By using this method, 1-ethyn-
yl-4-(trifluoromethyl)benzene gave the trisubstituted
benzenes with almost complete 1,3,5-selectively, though
in poor yield (entry 6). Elongation of the reaction time
did not improve the product yield, leaving a large por-
tion of the substrate intact, which may be attributed to
the deactivation of the catalyst during the course of
the reaction. On the other hand, aliphatic alkynes gave
the corresponding 1,3,5-trisubstituted benzenes in good
yield with varying regioselectivity (entries 7–9). The
reaction of ethynyltrimethylsilane was sluggish even at
Ph
Ph
Ph
cat.
PhC
CH
+
Na, toluene
r.t., 20 h
(
6.00 mmol)
Ph
Ph
Ph
a
Entry
Cat. (lmol)
Yield (%)
1,3,5-isomer:
b
1
,2,4-isomer
1
2
3
4
3 (15.0)
4 (15.0)
65
95
93
12
94
95
85
94
<44
77:23
85:15
83:17
6:94
6 (100)–TiCl
7 (100)–TiCl
7 (100)–TiCl
8 (100)–TiCl
9 (100)–TiCl
9 (100)–TiCl
4
4
4
4
4
4
(90.0)
(90.0)
(90.0)
(90.0)
(90.0)
(90.0)
5
0 °C to give the 1,3,5-trisubstituted benzene in poor
c
yield, while more bulky 3,3-dimethyl-1-butyne did
not give the desired compounds under the conditions
(entries 10 and 11).
5
1:99
6
7
8
32:68
33:67
35:65
37:63
c
9
TiCl
4
(90.0)
The alkyne cyclotrimerization with titanium complex 5
is believed to involve a titanacyclopentadiene intermedi-
ate, which undergoes a Diels–Alder-type reaction with
an alkyne molecule to give a 7-titana-2,5-norbornadiene
a
b
c
Isolated yield.
1
Determined by H NMR analysis.
The reaction was carried out at 80 °C for 1 h.

N. Morohashi et al. / Tetrahedron Letters 47 (2006) 1157–1161
Table 2. Cyclotrimerization of alkynes catalyzed by complex 4
1159
R
R
R
4
RC
CH
+
Na, toluene
R
R
R
a
b
Entry
Alkyne
4-MeC
Temp. (°C)
Time (h)
Yield (%)
1,3,5-isomer:1,2,4-isomer
1
2
3
4
5
6
H
4
C„CH
23
23
80
23
80
23
23
23
23
50
50
23
3.5
15
15
15
15
3.5
15
15
15
15
15
20
95
0
0
0
0
30
73
73
71
14
0
95:5
—
—
—
—
ꢀ100:0
75:25
78:22
95:5
100:0
—
4-CF
4-CF
3
C
C
6
6
H
H
4
C„CH
C„CH
3
4
BuC„CH
BuC„CH
c
6
3
4-CF C
6
H
4
C„CH
c
7
8
PrC„CH
BuC„CH
c
c
9
OctC„CH
Me SiC„CH
c
10
11
12
3
t
c
c
Bu C„CH
PhC„CMe
0
—
a
b
c
Isolated yield.
Determined by H NMR analysis.
Sodium phenylacetylide was added.
1
Cl
Cl
Cl
Cl
But
But
But
Ti
Ti
O
O
But
O
S
S
S
O O
S O
O
S
But
O
But
R
But
But
R
R
R
R
Ti
But
Ti
But
But
R
Ti
But
O
But
O
O
But
S O
S O
S O
O
O
O
But
But
But
O
O
O
But
But
But
A
B
C
Figure 1. Schematic representation of possible regioisomers of the titanacyclopentadiene intermediate.
complex.7b Reductive elimination of the 1,4-cyclohexa-
diene-3,6-diyl ligand gives the cyclotrimerization prod-
uct. The stereochemical course of the reaction in this
study can be rationalized by the preferential formation
of a thermodynamically stable titanacyclopentadiene
and the sterically favored approach of the third alkyne
molecule to the intermediate: Figure 1 shows possible
regioisomers of the titanacyclopentadiene A–C, having
different steric environments from each other. It seems
that both complexes B and C are less stable than com-
plex A because of the steric repulsion between the two
substituents on the 1,3-butadiene-1,4-diyl ligand (B)
and that between each of the substituents and the calix-
arene ligand (C), respectively. Therefore, the thermo-
dynamically most stable complex A will selectively form
and mediate the reaction. This may be supported by
the fact that 1,3,5-trisubstituted benzenes are major
products, because complexes B and C should exclusively
afford 1,2,4-trisubstituted benzenes, regardless of the
manner in which the complexes react with the alkyne
molecule. The titanacyclopentadiene ring in complex A
is oriented toward the calixarene ring, owing to the coor-
dination of a bridging sulfur atom to the titanium center,
and forms a cavity passing through the calixarene ring in
cooperation with the two benzene rings of the thiacalix-
arene moiety. The third alkyne molecule will approach
the metalacycle from the same side to the cavity in such
ways that the alkynyl group is almost parallel to the cal-
ixarene ring and that the substituent resides apart from
the 1-substituent on the 1,3-butadiene-1,4-diyl ligand to
avoid steric repulsion (Scheme 1). The resulting 1,3,5-tri-
substituted 7-titana-2,5-norbornadiene complex should

1160
N. Morohashi et al. / Tetrahedron Letters 47 (2006) 1157–1161
R
R
R
Ti
O
But
R
R
O
But
R
S
R
O
2
H
R
R
R
Ti
O
But
But
O
O
But
But
S
A
O
H
R
But
O
But
R
H
Ti
But
O
But
R
S
O
O
But
O
But
Scheme 1.
selectively afford the 1,3,5-trisubstituted benzene. On
the other hand, the titanacyclopentadiene intermediate
generated from complex 5 reportedly has a tetrahedral
titanium center, to which a 1,3-disubstituted 1,3-butadi-
ene-1,4-diyl ligand is coordinated, directing the 1-substi-
tuent outside the calixarene ring to avoid steric
repulsion. The third alkyne molecule approaches the
metalacycle with the substituent pointing outside the
calixarene ring to give a 1,2,4-trisubstituted 7-titana-
Chem. Lett. 1999, 219; (d) Morohashi, N.; Iki, N.;
Sugawara, A.; Miyano, S. Tetrahedron 2001, 57, 5557.
. (a) Bilyk, A.; Hall, A. K.; Harrowfield, J. M.; Hosseini, M.
3
4
W.; Skelton, B. W.; White, A. H. Aust. J. Chem. 2000, 53,
8
95; (b) Katagiri, H.; Morohashi, N.; Iki, N.; Kabuto, C.;
Miyano, S. Dalton Trans. 2003, 723; (c) Takemoto, S.;
Tanaka, S.; Mizobe, Y.; Hidai, M. Chem. Commun. 2004,
7
8
38.
. Morohashi, N.; Hattori, T.; Yokomakura, K.; Kabuto,
C.; Miyano, S. Tetrahedron Lett. 2002, 43, 7769.
2
,5-norbornadiene complex, which explains the 1,2,4-
5. Reviews: (a) Schore, N. E. Chem. Rev. 1988, 88, 1081; (b)
Schore, N. E. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; Vol. 5, pp 1129–
selectivity. Therefore, it may be concluded that the
coordination of the sulfur atom strongly affects the steric
environment around the titanium center in the titana-
cyclopentadiene intermediate, leading to the observed
high 1,3,5-selectivity.
1
2
162; (c) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100,
901.
6
. For example: (a) Takahashi, T.; Xi, Z.; Yamazaki, A.; Liu,
Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 1998,
1
20, 1672; (b) Sigman, M. S.; Fatland, A. W.; Eaton, B. E.
In conclusion, we have shown here that the titanium
complexes of p-tert-butylthiacalix[4]arene can be used
as an efficient catalyst for the cyclotrimerization of
terminal alkynes to afford 1,3,5-trisubstituted benzenes
regioselectively. One of the most important factors to
determine the regioselectivity was assumed to be the
coordination of the bridging sulfur to the titanium center.
J. Am. Chem. Soc. 1998, 120, 5130; (c) Suzuki, D.; Urabe,
H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925; (d)
Tanaka, R.; Nakano, Y.; Suzuki, D.; Urabe, H.; Sato, F.
J. Am. Chem. Soc. 2002, 124, 9682; (e) Oshiki, T.;
Nomoto, H.; Tanaka, K.; Takai, K. Bull. Chem. Soc.
Jpn. 2004, 77, 1009; (f) Fabbian, M.; Marsich, N.;
Farnetti, E. Inorg. Chim. Acta 2004, 357, 2881; (g)
Yamamoto, Y. J. Synth. Org. Chem. Jpn. 2005, 63,
1
12.
7
. (a) Ozerov, O. V.; Ladipo, F. T.; Patrick, B. O. J. Am.
Chem. Soc. 1999, 121, 7941; (b) Ozerov, O. V.; Ladipo, F.
T.; Patrick, B. O. J. Am. Chem. Soc. 2000, 122, 6423; (c)
Ladipo, F. T.; Sarveswaran, V.; Kingston, J. V.; Huyck,
R. A.; Bylikin, S. Y.; Carr, S. D.; Watts, R.; Perkin, S.
J. Organomet. Chem. 2004, 689, 502.
References and notes
1
2
. Reviews: (a) Iki, N.; Miyano, S. J. Incl. Phenom. Macro-
cycl. Chem. 2001, 41, 99; (b) Iki, N.; Miyano, S. Nippon
Kagaku Kaishi 2001, 609; (c) Morohashi, N.; Iki, N.;
Miyano, S. J. Synth. Org. Chem. Jpn. 2002, 60, 550; (d)
Lhot a´ k, P. Eur. J. Org. Chem. 2004, 1675.
. (a) Iki, N.; Morohashi, N.; Narumi, F.; Miyano, S. Bull.
Chem. Soc. Jpn. 1998, 71, 1579; (b) Mislin, G.; Graf, E.;
Hosseini, M. W.; Bilyk, A.; Hall, A. K.; Harrowfield, J.
M.; Skelton, B. W.; White, A. H. Chem. Commun. 1999,
8. Typical procedure for the cyclotrimerization of alkynes
(Table 1, entry 2): To a suspension of anti-complex 4
(14.3 mg, 15.0 lmol) in toluene (4.0 ml) were added finely
cut sodium (5.0 mg, 0.2 mmol) and ethynylbenzene
(613 mg, 6.00 mmol) and the mixture was stirred at room
temperature for 20 h. The mixture was quenched by
successive addition of methanol (2.0 ml) and 2 M HCl
3
73; (c) Iki, N.; Morohashi, N.; Kabuto, C.; Miyano, S.

N. Morohashi et al. / Tetrahedron Letters 47 (2006) 1157–1161
1161
(
2.0 ml) and extracted with chloroform. The extract was
11. Typical procedure for the cyclotrimerization of alkynes by
using a catalyst pretreated with sodium phenylacetylide
(Table 2, entry 7): sodium phenylacetylide was prepared
by treatment of ethynylbenzene (61.3 mg, 0.60 mmol) with
a large excess of finely cut sodium (100 mg, 4.35 mmol) in
toluene (4.0 ml) for 1 h. To the mixture was added anti-
complex 4 (47.7 mg, 50.0 lmol) and the resulting mixture
was stirred for 2 h before addition of 1-pentyne (2.72 g,
40.0 mmol). After stirring for 15 h, the mixture was
worked up and purified as before to give a mixture of
1,2,4- and 1,3,5-tripropylbenzene (1.99 g, 73%) in the ratio
of 25:75.
dried over MgSO and evaporated to leave a residue,
which was chromatographed on silica gel with hexane to
give a mixture of 1,2,4- and 1,3,5-triphenylbenzene
4
(
582 mg, 95%). The ratio of the 1,2,4- and 1,3,5-isomers
1
was determined to be 15:85 by H NMR analysis (CDCl
00 MHz).
3
,
5
9
. Narumi, F.; Hattori, T.; Morohashi, N.; Matsumura, N.;
Yamabuki, W.; Kameyama, H.; Miyano, S. Org. Biomol.
Chem. 2004, 2, 890.
1
0. Hill, J. E.; Balaich, G.; Fanwick, P. E.; Rothwell, I. P.
Organometallics 1993, 12, 2911.