Zirconium-mediated selective synthesis of 1,2,4,5-tetrasubstituted benzenes from two silyl-substituted alkynes and one internal alkyne

Article abstract of DOI:10.1021/ol901153p

Selective synthesis of 1,2,4,5-tetrasubstituted benzenes was achieved via formation of 2,5-bis(trimethylsilyl)zirconacyclopentadienes from 2 equiv of TMS-substituted alkynes with Cp₂ZrBu₂ and Cu-mediated formation of 1,4-disilylbenze

Full text of DOI:10.1021/ol901153p

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3318-3321
Zirconium-Mediated Selective Synthesis
of 1,2,4,5-Tetrasubstituted Benzenes
from Two Silyl-Substituted Alkynes and
One Internal Alkyne
Shi Li,† Hongmei Qu,† Lishan Zhou,† Ken-ichiro Kanno,† Qiaoxia Guo,‡
Baojian Shen,‡ and Tamotsu Takahashi*,†
Catalysis Research Center, Hokkaido UniVersity, and SORST, Japan Science and
Technology Agency (JST), Kita-ku, Sapporo 001-0021, Japan, and Petroleum
UniVersity-Hokkaido UniVersity Joint Laboratory, Department of Chemical
Engineering, China UniVersity of Petroleum, Beijing, China
tamotsu@cat.hokudai.ac.jp
Received May 24, 2009
ABSTRACT
Selective synthesis of 1,2,4,5-tetrasubstituted benzenes was achieved via formation of 2,5-bis(trimethylsilyl)zirconacyclopentadienes from 2
equiv of TMS-substituted alkynes with Cp2ZrBu2 and Cu-mediated formation of 1,4-disilylbenzene by cycloaddition of zirconacyclopentadienes
to disubstituted alkynes. Preparation of 1,2,3,4,9,10-hexasubstituted pentacene and 2,3,6,11-tetrasubstituted naphthacene derivatives were
demonstrated by a homologation or coupling method using tetrasubstituted benzene.
It is well-known that benzene derivatives have been
synthesized by cyclotrimerization of alkynes using transi-
tion-metal complexes.1 One of the major problems of the
reactions is the difficulty in regioselective intermolecular
cyclotrimerization with unsymmetrical alkynes to give
multisubstituted benzene derivatives. As shown in Scheme
1, when two terminal alkynes react with transition metals,
the corresponding metalacycles are obtained as a mixture
of three possible regioisomers.2 The following cyclization
with one internal alkyne affords a mixture of three benzene
derivatives.
stituted benzenes with excellent selectivity in high yields as
shown in Scheme 2.3 These reactions can be applied for
synthesis of hexa-, penta-, and 1,2,3,5-tetrasubstituted ben-
zenes with excellent selectivity and high yields. But there
are no reports for preparation of 1,2,4,5-tetrasubstituted
benzene derivatives via coupling of two terminal alkynes
and one internal alkyne with zirconocene.
(2) For the transition-metal-mediated cyclotrimerization with terminal
alkynes, see: (a) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaka, K.; Hirano,
M. Chem. Eur. J. 2005, 11, 1145. (b) Kirss, R. U.; Ernst, R. D.; Arif, A. M.
J. Organomet. Chem. 2004, 689, 419. (c) Gao, Y.; Puddephatt, R. J. Inorg.
Chim. Acta 2003, 350, 101. (d) Opstal, T.; Verpoort, F. Synlett 2003,
314. (e) Navarro, J.; Sagi, M.; Sola, E.; Lahoz, F. J.; Dobrinovitch, I. T.;
Katho, A.; Joo, F.; Oro, L. A. AdV. Synth. Catal. 2003, 345, 280. (f) Melis,
K.; De Vos, D.; Jacobs, P.; Verpoort, F. J. Organomet. Chem. 2002, 659,
159.
Previously, our group reported the zirconium-mediated
cycloadditions of different alkynes to prepare highly sub-
† Hokkaido University.
‡ China University of Petroleum.
(3) (a) Takahashi, T.; Xi, Z.; Yamazaki, A.; Liu, Y.; Nakajima, K.;
Kotora, M. J. Am. Chem. Soc. 1998, 120, 1672. (b) Takahashi, T.; Kotora,
M.; Xi, Z. J. Chem. Soc., Chem. Commun. 1995, 361. (c) Takahashi, T.;
Tsai, F.-Y.; Liu, Y.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 1999,
121, 11093. (d) Takahashi, T.; Ishikawa, M.; Huo, S. J. Am. Chem. Soc.
2002, 124, 388.
(1) (a) Schore, N. E. Chem. ReV. 1988, 88, 1081. (b) Schore, N. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A.,
Eds.; Pergamon: Tokyo, 1991; Vol. 5, p 1144. (c) Grotjahn, D. B. In
ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G. A.,
Wilkinson, G., Eds.; Pergamon: New York, 1995; Vol. 12, p 741.
10.1021/ol901153p CCC: $40.75
Published on Web 07/08/2009
 2009 American Chemical Society

Scheme 1
Scheme 3
The reason is the poor regioselectivity in the zirconacycle
formation with two terminal alkynes and intolerance of the
low-valent zirconocene species for the acidic hydrogen of
the terminal alkyne employed.
of CuCl at room temperature. The NMR analysis of the
reaction mixture revealed that the formation of the corre-
sponding benzene 4d and Dewar benzene 3d in 18 and 45%
yields, respectively. It is worth noting that Dewar benzene
3d was afforded as a major product regardless of its highly
strained structure. The 13C NMR spectrum of 3d in CDCl3
showed a characteristic quaternary carbon signal appeared
at 57.1 ppm, which was assignable to the bridgehead carbon
of Dewar benzene. Fortunately, the Dewar benzene 3d was
quantitatively converted to the benzene 4d after heating in
toluene at 100 °C for 3 h.5 Totally, the desired benzene
derivative 3d was obtained in 63% yield from silylalkyne
1d. Finally, the silyl groups were removed cleanly by
treatment with 2 equiv of TBAF in THF for 1 h, and the
corresponding 1,2,4,5-tetrasubstituted benzene 5d was ob-
tained in 90% yield.
Scheme 2
Scheme 4
Our strategy for a synthesis of 1,2,4,5-tetrasubstituted
benzene as a single product was shown in Scheme 3. For
this purpose, silylalkynes seem to be suitable because of their
characteristic properties. The reaction of Cp2Zr(II) species
with silylalkynes proceeds with excellent regioselectivity to
afford the corresponding 2,5-disilyl-substituted zirconacy-
clopentadienes as single products in high yields.4 Cycload-
dition reaction of the 2,5-disilylzirconacyclopentadiene with
an internal alkyne followed by removal of the introduced
silyl groups can afford the desired tetrasubstituted benzene
derivative.
Unexpectedly, the formation of a Dewar benzene deriva-
tive 3 was found in the cycloaddition reaction of 2,5-disilyl-
substituted zirconacyclopentadiene 2 with dimethyl acety-
lenedicarboxylate (DMAD) in the presence of CuCl (Scheme
4). At the beginning, the above-mentioned strategy was
examined with 1-trimethylsilyl-1-hexyne (1d, R ) Bu) as a
starting material. Silylalkyne 1d was treated with Cp2ZrBu2
in THF to produce 2,5-disilyl-substituted zirconacyclopen-
tadiene 2d, which was cyclized with DMAD in the presence
The results of the reactions with various alkynes are
summarized in Table 1. In most cases, the Dewar benzenes
3 were obtained as major products along with their benzene
isomers 4. On the other hand, in the reactions with decyl-
or 2-thienyl-substituted silylalkynes, only the corresponding
benzene isomers were formed (entries 8 and 10). The two
benzene isomers 3 and 4 were easily separable by a silica
gel chromatography except for entries 9, 11, and 12. To
obtain the desired 1,2,4,5-tetrasubstituted benzene 5, the
(5) (a) Sakurai, H.; Ebata, K.; Kabuto, C.; Sekiguchi, A. J. Am. Chem.
Soc. 1990, 112, 1799. (b) Maier, G.; Neudert, J.; Wolf, O. Angew. Chem.,
Int. Ed. 2001, 40, 1674. (c) Maier, G.; Neudert, J.; Wolf, O.; Pappusch, D.;
Sekiguchi, A.; Tanaka, M.; Matsuo, T. J. Am. Chem. Soc. 2002, 124, 13819.
(4) (a) Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989, 111,
2870. (b) Ashe, A. J., III; Kampf, J. W.; Al-Taweel, S. M. J. Am. Chem.
Soc. 1992, 114, 372.
Org. Lett., Vol. 11, No. 15, 2009
3319

separation of 3 and 4 is not necessary, since a simple heating
of the mixture caused the facile conversion of Dewar benzene
3 into benzene 4 quantitatively. The following desilylation
with TBAF produced the desired benzene 5 in a good total
yield based on silylalkyne 1.
Scheme 6
Table 1. Formation of Dewar Benzenes 3 and Benzenes 4 and
1,2,4,5-Tetrasubstituted Benzenes 5
yieldsa (%)
entry product
R1
R2
R3
3
4
5
1
2
3
4
5
6
7
8
9
a
b
c
d
e
f
g
h
i
Me
Et
Pr
CO2Me CO2Me 17 39 53
CO2Me CO2Me 51 26 70
CO2Me CO2Me 42 21 59
CO2Me CO2Me 45 18 57
CO2Me CO2Me 48 25 69
CO2Me CO2Me 34 30 58
CO2Me CO2Me 21 21 40
Bu
C5H11
C6H13
C8H17
presenceofCuClaffordedthecorrespondingdicopper-hexatriene
intermediate 6 via transmetalation from Zr to Cu followed
by Michael addition to DMAD. After intramolecular Michael
addition, the corresponding dicopper-cyclohexadiene inter-
mediate 7 is formed. Copper metals in 7 move to allylic
positions to give sterically stable form 8. These two species
are interconvertible by migration of copper metals. From 7,
benzene 4 is formed and from 8, Dewar benzene 3 is formed.
As shown in Scheme 7, when the reaction of zirconacy-
clopentadiene 2d with DMAD and CuCl was carried out at
-78 °C and quenched at the same temperature, linear triene
9 was formed in high yield. If the reaction mixture was
warmed from -78 °C to room temperature, the correspond-
ing benzene and Dewar benzene were obtained. This suggests
that both benzene and Dewar benzene derivatives are formed
via the same intermediate, linear triene 9.
C
10H21
Ph
2-thienyl CO2Et
CO2Me CO2Me
0
29 27
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
28 56 76
10
11
12
j
k
l
0
53
53
64 60
Me
Me
Ph
Me
6
8
55
58
a Isolated yields based on silylalkynes.
In the case of 2,5-bis(silylated) bicyclic zirconacyclopen-
tadienes prepared from bis(silylated) diynes, the formation
of Dewar benzene isomers was not observed. Only benzene
derivatives were obtained in high yields as we reported.3a
Probably the steric effect of the side ring of the bicyclic
zirconacycle inhibited the formation of Dewar benzene
derivatives.
It was reported that the Dewar benzenes were formed as
minor products in the copper-mediated cycloaddition of
tetraalkyl-substituted
zirconacyclopentadienes
with
arylpropiolates.6a Zirconium(η6-benzene)(AlCl4)2-catalyzed
cyclotrimerization of 2-butyne was also known for the
formation of hexamethyl Dewar benzene.6b
Scheme 7
Scheme 5
Substituted naphthacenes and pentacenes have attracted
much attention as soluble organic materials such as semi-
conductors.7 We have developed a homologation method,8
a double-homologation method,9 and a coupling method10
for the formation of substituted naphthacenes and pentacenes.
Preparation of 2,3,6,11-tetraalkylnaphthacenes was dem-
onstrated by a coupling method using 1,2,4,5-tetrasubstituted
benzenes as shown in Scheme 8. Reduction of 3,4,5,6-
When dimethylphenylsilyl group was used for the reaction
instead of trimethylsilyl group, a similar result was obtained
as shown in Scheme 5.
Scheme 6 showed a possible mechanism for benzene and
Dewar benzene formation. As we reported previously,3a the
reaction of zirconacyclopentadiene 2 with DMAD in the
(7) (a) Gundlach, D. J.; Lin, Y.-Y.; Jackson, T. N.; Nelson, S. F.; Schlom,
D. G. IEEE Electron DeVice Lett. 1997, 18, 87. (b) Lin, Y.-Y.; Gundlach,
D. J.; Nelson, S. F.; Jackson, T. N. IEEE Electron DeVice Lett. 1997, 18,
606. (c) Lin, Y.-Y.; Gundlach, D. J.; Nelson, S. F.; Jackson, T. N. IEEE
Trans. Electron DeVices 1997, 44, 1325. (d) Nelson, S. F.; Lin, Y.-Y.;
Gundlach, D. J.; Jackson, T. N. Appl. Phys. Lett. 1998, 72, 1854.
(6) (a) Calderazzo, F.; Pampaloni, G.; Pallavicini, P. Organometallics
1991, 10, 896. (b) Dufkova, L.; Kotora, M.; Cisarova, I. Eur. J. Org. Chem.
2005, 2491.
3320
Org. Lett., Vol. 11, No. 15, 2009

tetrasubstituted phthalates 4 with LiAlH4, hydrolysis with 2
N H2SO4, and successive bromination of the resulting diol
with PBr3 gave cleanly dibromo-o-xylenes 10. The NMR
analysis of these steps showed that the protodesilylation
occurred at the bromination step, probably due to HBr
generated from the reaction of the alcohol with PBr3 or
contaminated in it. Alkynylation of 10 with 1-hexynyllithium
afforded 12. The Zr,Cu-mediated coupling of diyne 12 with
1,2-diiodobenzene afforded dihydronaphthacene derivatives
13. Finally, dihydronaphthacenes 13 were aromatized with
1 equiv of DDQ at 100 °C in toluene. The desired
naphthacenes 14 were obtained as a yellow solid in moderate
yields.
Scheme 9
Scheme 8
in the homologation procedures as described before. The
tetrahydropentacene 17f reacted with the excess of DDQ (3
equiv) to give the Diels-Alder adduct. To recover the
pentacene, the pentacene-DDQ adduct was treated with 50
equiv of γ-terpinene at 100 °C in toluene. The pentacene
18f was isolated in a good yield as a blue solid by a column
chromatography.10 The naphthacenes 14c,d and pentacene
18f are stable under nitrogen and have good solubility in a
variety of organic solvents.
In summary, a synthetic method was developed for 1,2,4,5-
tetrasubstituted benzenes from silylalkynes and an internal
alkyne with the Zr,Cu system. The sequence included the
unexpected Dewar benzene formation in the reaction of 2,5-
disilyl-substituted zirconacyclopentadienes with DMAD in
the presence of CuCl. Dewar benzenes were quantitatively
converted to the corresponding benzenes by heating, and the
removal of the silyl groups afforded the desired 1,2,4,5-
tetrasubstituted benzenes. These 1,2,4,5-tetrasubstituted ben-
zenes were converted into soluble substituted pentacenes and
naphthacenes by homologation and coupling method.
Preparation of 1,2,3,4,9,10-hexasubstituted pentacene de-
rivative 18f from 1,2,4,5-tetrasubstituted benzene was also
demonstrated by a homologation method as shown in Scheme
9. Reaction of dibromo-o-xylene prepared by the same way
as 10c,d from 4f with trimethylsilylethyllithium or -magne-
sium halide did not lead to the formation of desired diyne
12f. Therefore, dibromide was converted to diiodo-o-xylene
11f. Diiodo-o-xylene 11f cleanly reacted with trimethylsi-
lylethynylmagnesium bromide in the presence of CuCl to
give the desired diyne 12f. The diyne 12f was treated with
Cp2ZrBu2 (Negishi reagent) followed by the reaction with
DMAD in the presence of CuCl to afford dihydroanthracene
derivative 15f. The tricyclic skeleton of 15f could be again
extended to pentacyclic compound 17f by the same combi-
nation of procedures as for 15f. Similar desilylation occurred
Acknowledgment. We thank Mr. Qingguang Zheng
(Petroleum University-Hokkaido University Joint Labora-
tory) for his experimental assistance.
(8) (a) Takahashi, T.; Kitamura, M.; Shen, B.; Nakajima, K. J. Am.
Chem. Soc. 2000, 122, 12875. (b) Takahashi, T.; Li, S.; Huang, W.; Kong,
F.; Nakajima, K.; Shen, B.; Ohe, T.; Kanno, K. J. Org. Chem. 2006, 71,
7967. (c) Li, S.; Zhou, L.; Song, Z.; Bao, F.; Kanno, K; Takahashi, T.
Heterocycles 2007, 73, 519. (d) Takahashi, T.; Li, Y.; Hu, J.; Kong, F.;
Nakajima, K.; Zhou, L.; Kanno, K. Tetrahedron Lett. 2007, 48, 6726.
(9) (a)Takahashi,T.;Li,Z.Jpn.KokaiTokkyoKoho2004,JP2004-331534.
(b) Stone, M. T.; Anderson, H. L. J. Org. Chem. 2007, 72, 9776. (c) Li, S.;
Li, Z.; Nakajima, K.; Kanno, K.; Takahashi, T. Chem. Asian J. 2009, 4,
294.
Supporting Information Available: Experimental pro-
cedure, spectral data, and NMR charts for all new com-
pounds. These materials are available free of charge via the
Internet at http://pubs.acs.org.
(10) Takahashi, T.; Kashima, K.; Li, S.; Nakajima, K.; Kanno, K J. Am.
Chem. Soc. 2007, 129, 15752.
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