COMMUNICATION
Boronic acid catalyzed ene carbocyclization of acetylenic
dicarbonyl compoundsw
Meiling Li,a Ting Yangb and Darren J. Dixon*a
Received (in Cambridge, UK) 26th November 2009, Accepted 8th February 2010
First published as an Advance Article on the web 25th February 2010
DOI: 10.1039/b924899d
The discovery and development of an efficient ene carbocyclization
of 1,3-dicarbonyl compounds bearing pendent terminal alkyne
substituents under 3-nitrobenzeneboronic acid catalysis is
described. The reaction is efficient, easy to perform and general
to a wide range of ketoester substrates.
carbocyclization of 1a and the results are summarised in
Table 1. Indeed many benzeneboronic acids were catalytically
active, as was the Lewis acid tris(pentafluorophenyl)borane 4f
which gave good conversion (95%) after 16 hours in boiling
toluene. However, boric acid 4a gave only 8% conversion
under the same conditions. Of the benzeneboronic acids those
bearing electron withdrawing groups afforded better reactivity
than those with electron donating groups, presumably due to
their increased acidity.13 The most efficient was found to be
3-nitrobenzeneboronic acid (entry 7, Table 1). In order to
identify the optimal conditions, a further screen of catalyst
loading using 3-nitrobenzeneboronic acid was also performed.
Complete conversion was achieved with 5 and 10 mol%
boronic acid 4g in 16 h and 20 h respectively. When 2 mol%
of boronic acid 4g was used, a slower reaction rate was
observed (45% conversion after 48 h in boiling toluene).
With optimal conditions established, a range of a-pentynyl-
b-ketoesters was readily prepared14 and treated with 5 mol%
of 3-nitrobenzeneboronic acid in boiling toluene. The results
are presented in Table 2.
The carbocyclization of 1,3-dicarbonyl compounds to pendent
alkyne functionality, first discovered by Eglinton and Whiting1
and then developed by Conia and Perchec,2 has received much
attention in recent years.3 The reaction allows the formation of
cyclopentanes bearing a methylene substituent adjacent to the
newly formed quaternary centre and can be conducted under
thermal2 conditions, strong mineral acid,4 base,1 or metal ion
catalysis.5–9 Nevertheless, the application of the ene carbo-
cyclization of acetylenic dicarbonyl compounds in organic
synthesis is limited because of the harsh experimental
conditions that are often required. Recently, the use of
transition metal catalysis has allowed a notable improvement
to the reaction conditions. For example, Cu(I),4,10 Au(I),5
Ni(II)6 all proved to be efficient catalysts for the cyclization
of alkynoic esters.11 Other than the use of strong mineral acids
or alkoxide bases, to the best of our knowledge, no other
transition-metal free method has been reported to efficiently
catalyze the ene carbocyclization of acetylenic dicarbonyl
compounds. Herein we wish to describe the discovery
and development of the ene carbocyclization of acetylenic
dicarbonyl compounds catalyzed by aryl boronic acids.
During some recent investigations in our laboratories,10 we
required b-ketoester derivative 3 and, to us, a direct route from
1b was attractive. Following the report of Tale et al., we
attempted the transesterification of 1b with cyclohexanol in
the presence of 5 mol% 3-nitrobenzeneboronic acid 4g.12 To
our surprise, the cyclized product 2b was formed in 89% yield,
and no evidence of the expected ester 3 was detected in the
1H-NMR spectrum of the crude reaction mixture (Scheme 1).
Having uncovered a new catalytic process, we decided to
explore the scope and mechanism of this reaction and herein
we report our findings.
As expected from our initial discovery (Scheme 1) and
the subsequent optimization study (Table 1), linear and
a-branched aliphatic keto-esters were good substrates and were
efficiently transformed to the corresponding carbocyclic
products (Table 2, entries 1–4). Both electron rich and electron
deficient aryl ketone substrates reacted smoothly and
efficiently. However, prolonged reaction times were required
for aryl ketones substituted with para-electron donating
groups (Table 2, entry 11) while ortho- and meta-substituted
aromatic substrates gave comparable reaction rates. The ester
moiety had minimal influence on the reaction rate and methyl,
ethyl, benzyl and tert-butyl esters were all well-tolerated. Also
a keto-amide substrate 1o proved to be an excellent substrate,
affording the carbocyclic product in 75% isolated yield
(Table 2, entry 15). The 3-nitrobenzeneboronic acid catalysis
Initially a range of catalysts related to 3-nitrobenzene-
boronic acid were screened for catalytic activity in the ene
a Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: Darren.Dixon@chem.ox.ac.uk; Fax: +44 (0)1865 285002;
Tel: +44 (0)1865 275648
b School of Chemistry, The University of Manchester, Oxford Road,
Manchester, M13 9PL, UK
w Electronic supplementary information (ESI) available: Experi-
mental procedures and spectral data for compounds 2a–q. See DOI:
10.1039/b924899d
Scheme 1 Discovery of the boronic acid catalyzed ene carbocyclization
of acetylenic dicarbonyl compounds.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 2191–2193 | 2191
Li, Meiling
