Angewandte
Chemie
DOI: 10.1002/anie.201002191
Arynes
Preparation and Regioselective Diels–Alder Reactions of
Borylbenzynes: Synthesis of Functionalized Arylboronates**
Takashi Ikawa, Akira Takagi, Yurio Kurita, Kozumo Saito, Kenji Azechi, Masahiro Egi,
Keisuke Kakiguchi, Yasuyuki Kita, and Shuji Akai*
Arylboronates currently represent one of the most widely
used classes of synthetic intermediates because of the
generation. Although the addition of tBuLi to 2-boryl-6-
bromo-4-methylphenyl triflate generated 1 (R = Me), which
was immediately and effectively trapped by 2-butylfuran (2a)
to give a 92:8 mixture of the regioisomeric cycloadducts 4 and
4’(R=Me) in 67% yield, the use of tBuLi hampered the
compatibility of various functional groups. 2-Boryl-4-methyl-
6-trimethylsilylphenyl triflate was another potential precur-
sor; however, its treatment with fluoride ions resulted in the
exclusive generation of the 3-silylbenzyne. We finally discov-
ered that 2-boryl-6-iodophenyl triflate 6a served as an
excellent precursor of 1a (R = H) and was sufficiently
compatibile with various functional groups. Thus, the addition
of 1.2 equivalents of iPrMgCl·LiCl[10] to 6a in Et2O at À788C
led to generation of 1a, which instantaneously underwent the
Diels–Alder reaction with 2a to give a 90:10 mixture of 4a
(R = H) and 4a’ (R = H) in a total yield of 88% (Scheme 1).
The use of the 2-boryl-6-iodophenyl triflates has another
advantage that enabled us to prepare precursors with various
À
À
À
versatile transformation of their C B bonds to C C, C N,
[1]
À
and C O bonds. Arylboronic acids have also been utilized
in a variety of applications in saccharide sensing[2] and
medicinal chemistry.[3] While arylboronic acid derivatives
have been mainly prepared by the borylation of boron-free
compounds,[4] the construction of carbon frameworks from
boron-containing reactive species provides alternative syn-
theses of arylboronic acid derivatives. In particular, the latter
approach is useful for the preparation of polyfunctionalized
compounds, some of which are otherwise difficult to pre-
pare.[5]
Herein we describe the preparation of 3-borylbenzynes 1,
and their Diels–Alder reaction with furans 2 or pyrroles 3 to
produce highly functionalized arylboronic acid derivatives (4
and 5, Tables 1 and 2). The following two points are also
worth noting from the viewpoint of benzyne chemistry:
Firstly, the boryl groups (Bpin = pinacol-
boryl) were found to favor the highly
regioselective Diels–Alder reactions of
unsymmetrically substituted benzynes
with furans 2 or pyrroles 3, in contrast
to most of the previously reported
cases.[6-8] Secondly, the regioselectivities
of the Diels–Alder reaction of 1 resem-
bled those of the 3-silylbenzynes,[9] but
Scheme 1. Generation of borylbenzyne 1 and its Diels–Alder reaction with n-butylfuran (2a).
the boryl groups exerted different effects
than the silyl groups.
We investigated the efficient preparation of several
precursors of the 3-borylbenzynes 1 and also benzyne
labile functional groups without the use of strong bases such
as nBuLi (see below).[11] By starting from another precursor
7a, in which the positions of the iodide and sulfonyloxy
groups were interchanged, the same mixture of 4a and 4a’
was obtained in the same ratio. Although we could not
directly observe 1a because of its extreme instability, all these
results strongly suggest the generation of 1a and its excellent
reactivity as a dienophile in the Diels–Alder reaction.
Another noteworthy result was the high regioselectivity of
the Diels–Alder reaction, in which the major product 4a (anti
adduct) had the two substituents (boryl and nBu groups) at a
maximum distance. The steric repulsion between the boryl
and nBu groups does not seem to be sufficient to explain this
high level of selectivity.[12]
Because the use of 6a led to a better yield than 7a
(Scheme 1), we investigated the Diels–Alder reaction of
various borylbenzynes 1, generated from 6, and the
2-substituted furans 2 (Table 1). The Diels–Alder reaction
of 2b, which has a methyl group as a small substituent in the
2-position, gave a significantly high regioselectivity (4b/4b’ =
[*] Dr. T. Ikawa, A. Takagi, Y. Kurita, K. Saito, K. Azechi, Dr. M. Egi,
Prof. Dr. S. Akai
School of Pharmaceutical Sciences, University of Shizuoka
52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526 (Japan)
Fax: (+81)54-264-5672
E-mail: akai@u-shizuoka-ken.ac.jp
Dr. K. Kakiguchi, Prof. Dr. Y. Kita[+]
Graduate School of Pharmaceutical Sciences
Osaka University, Osaka 565-0871 (Japan)
[+] Current Address: School of Pharmaceutical Sciences
Ritsumeikan University, Shiga, 525-8577 (Japan)
[**] This work was supported by KAKENHI (No. 19890182) and a Grant-
in-Aid for the Global COE Program from MEXT. T.I. is also grateful
for receiving the Daicel Chemical Industry Award in Synthetic
Organic Chemistry (Japan). Prof. Dr. Philip Hawke is acknowledged
for assistance in preparation of this manuscript.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2010, 49, 5563 –5566
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5563