Ru(II)-Catalyzed Chemo- and Regioselective Cyclotrimerization of Three Unsymmetrical Alkynes through Boron Temporary Tether. One-Pot Four-Component Coupling via Cyclotrimerization/Suzuki-Miyaura Coupling

Article abstract of DOI:10.1021/ja049673y

The Ru(II)-catalyzed [2+2+2] cyclotrimerization of alkynylboronates, propargyl alcohol, and terminal alkynes proceeded chemo- and regioselectively to give rise to arylboronates, which were subjected to Suzuki?Miyaura cross-coupling with aryliodides to aff

Full text of DOI:10.1021/ja049673y

Published on Web 03/10/2004
Ru(II)-Catalyzed Chemo- and Regioselective Cyclotrimerization of Three
Unsymmetrical Alkynes through Boron Temporary Tether. One-Pot
Four-Component Coupling via Cyclotrimerization/Suzuki-Miyaura Coupling
Yoshihiko Yamamoto,*,† Jun-ichi Ishii,† Hisao Nishiyama,† and Kenji Itoh‡
Department of Applied Chemistry and Department of Molecular Design and Engineering,
Graduate School of Engineering, Nagoya UniVersity, Chikusa, Nagoya 464-8603, Japan
Received January 19, 2004; E-mail: yamamoto@apchem.nagoya-u.ac.jp
The transition-metal-catalyzed [2+2+2] alkyne cyclotrimeriza-
tion is a straightforward approach to construct substituted benzenes
from simple acyclic precursors.1 One crucial disadvantage of this
potentially useful methodology is the difficulty in controlling
chemo- and regioselectivity. Although the selective cyclotrimer-
ization of three different alkyne components was accomplished
using stoichiometric transtion-metal reagents,2 the development of
catalytic variants is highly important from the viewpoint of atom-
economy.3 In this context, intramolecular approaches utilizing
diynes or triynes have been explored as a promising tool to afford
selectively polycyclic arenes.4 However, additional synthetic opera-
tions are required, if the resultant polycyclic framework is not
desirable. An unnecessary ring moiety must be cleaved and
transformed into required side chains. Moreover, the preparation
of polyalkyne substrates equipped with a cleavable tether as well
as substituents or functional groups at appropriate positions might
be troublesome. One effective strategy to address this issue is the
temporary connecting of monoalkynes with a disposable tether
group.5 In this Communication, we report the chemo- and regio-
selective catalytic cyclotrimerization of unsymmetrical three alkyne
components by means of the temporary tethering approach with
ruthenium catalysis (Scheme 1).
ruthenacycle intermediate 5.10 At the outset, 1.1 equiv of propargyl
alcohol 3 was added dropwise over 15 min to a solution of 5 mol
% 1, 1-hexynylboronate 2a, and 4 equiv of 1-hexyne 4a in 1,2-
dichloroethane (DCE) at room temperature, and the solution was
1
stirred for 24 h. In the H NMR spectrum of the crude product
mixture, the absorptions of aromatic and benzylic methylene protons
were observed together with those of two n-butyl chains, indicative
of the cyclotrimerization of the three alkyne components taking
place. Unfortunately, the expected arylboronate 6 could not be
obtained in pure form, due to the facile exchange of the boronate
ligands. Accordingly, we further attempted the Suzuki-Miyaura
coupling11 of crude 6. Thus, 6 was treated with 5 mol % Pd(PPh3)4,
1.5 equiv of p-iodoacetophenone 7a, and K2CO3 in refluxing THF/
H2O for 24 h to give rise to the desired 8aaa in 32% yield together
with a protodeboration product 9 in 22% yield. Significantly, both
of these products were obtained as a single regioisomer.12 To
minimize the protodeboration, the cross-coupling was optimized,
and we found that the reaction completed within 2 h in toluene/
H2O at 70 °C to afford 8aaa exclusively in 71% yield. The
couplings with less reactive iodobenzene 7b and p-iodoanisole 7c
required prolonged reaction time of 20 h. In addition, the desired
product 8aac was accompanied by the phenyl-substituted product
8aab as a result of the aryl-group interchange between the
phosphorus-bound phenyl groups and the p-methoxyphenyl ligand.13
When the combination of tricyclohexylphosphine and Pd2(dba)3 was
employed instead of Pd(PPh3)4, 8aac was successfully obtained as
a sole product in 70% yield.
Having optimized the coupling conditions, the generality of the
one-pot four-component coupling was examined as summarized in
Table 1. With a shorter reaction time of 5 h, the cyclotrimerization
of 2a, 3, and 4a proceeded satisfactorily, and the biphenyl derivative
8aaa was obtained in 73% yield after the Suzuki-Miyaura coupling
with 7a (run 1). Similarly, 7b and 7c underwent cross-coupling
with the same arylboronate intermediate to furnish 8aab and 8aac
in comparable yields (runs 2 and 3). Although a longer reaction
time was required to ensure the cross-coupling with 2-iodopyridine
Scheme 1
We have previously reported that the cycloaddition of unsym-
metrical 1,6-diynes with terminal monoalkynes proceeded at room
temperature in the presence of a Ru(II) precatalyst, Cp*RuCl(cod)
1, to afford bicyclic benzenes with excellent chemo- and regiose-
lectivity.6 To realize Ru(II)-catalyzed cyclotrimerization of three
different monoalkynes, we chose a temporary tether through a
C-B-O linkage7-9 rather than widely prevalent C-Si-O or
O-Si-O linkages,5 because relatively long Si-C and Si-O bonds
might cause a deleterious effect on the formation of a key
† Department of Applied Chemistry.
‡ Department of Molecular Design and Engineering.
9
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J. AM. CHEM. SOC. 2004, 126, 3712-3713
10.1021/ja049673y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 1. One-Pot Four-Component Couplings
coupling (runs 10 and 11). Although the cyclotrimerization of these
boronates with 3 and 4a requires longer reaction time as compared
to that with 2a, the Suzuki-Miyaura coupling of the resultant
arylboronates with 7a successfully gave rise to biaryl products 8baa
and 8caa in 63% and 66% yields, respectively.
In conclusion, the catalytic intermolecular cyclotrimerization of
three different unsymmetrical alkynes was accomplished by means
of the ruthenium catalysis and the temporary tethering approach
with the C-B-O linkage. The crude arylboronates were further
applied to the Suzuki-Miyaura coupling with various aryl iodides
using Pd2(dba)3/PCy3 as a catalyst precursor in aqueous toluene to
afford biaryls. As a result, the novel four-component coupling
approach to highly substituted biaryls was successfully established
by combining these two operations into a sequential one-pot process.
Acknowledgment. We gratefully acknowledge financial support
(14750677) from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
Supporting Information Available: Experimental procedure and
analytical data for biaryls 8 and 9 (PDF and CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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a In DCE (4 mL), 2, 3 (1.1 equiv), and 4 (4 equiv) were reacted in the
presence of 5 mol % 1 under Ar at room temperature. b A crude arylboronate
was reacted with 7 (1.5 equiv) in toluene/H2O in the presence of 2.5 mol
% Pd2(dba)3 and 11 mol % PCy3.
7d and 2-iodothiophene 7e, the desired hetero-biaryls 8aad and
8aae were obtained in 53% and 69% yields, respectively (runs 4
and 5).
With respect to alkyne components, terminal alkynes bearing
chloro, ester, or ether functionalities 4b-d can be employed to
obtain the corresponding biaryls in 69-76% yields (runs 6-8).
Interestingly, methyl propargyl ether 4b caused no deleterious effect.
This implies that the boron-tethered diyne intermediate was
selectively formed with the alcohol 3 rather than with the ether
4b. Gaseous propyne 4e (1 atm) was also selectively incorporated
into the final biaryl product 8aea in good yield (run 9).
Two more alkynylboronates bearing an ether or a chloroalkyl
substituent 2b and 2c were subjected to the one-pot four-component
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of 1,7-diynes or monoalkynes (see ref 6).
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supported by 1H NMR spectroscopy as well as the X-ray analysis of a
2,4-dinitrophenylhydrazone derived from 8i (see Supporting Information).
(13) Goodson, F. E.; Wallow, T. I.; Novak, B. M. J. Am. Chem. Soc. 1997,
119, 12441-12453.
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