A regioselective cycloaddition route to isoxazoleboronic esters

Article abstract of DOI:10.1039/b103319k

Alkynylboronates participate in 1,3-dipolar cycloaddition reactions with nitrile oxides to provide isoxazoleboronic esters with excellent levels of regiocontrol; additionally, these potentially valuable synthetic intermediates have been shown to participa

Full text of DOI:10.1039/b103319k

A regioselective cycloaddition route to isoxazoleboronic esters†
Mark W. Davies,a Robert A. J. Wybrow,a Christopher N. Johnsonb and Joseph P. A. Harrity*a
a Department of Chemistry, University of Sheffield, Sheffield, UK S3 7HF.
E-mail: j.harrity@Sheffield.ac.uk; Fax: +44 (0)114 273 8673; Tel: (0)114 222 9496
b Medicinal Chemistry, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK CM19 5AW
Received (in Cambridge, UK) 12th April 2001, Accepted 26th June 2001
First published as an Advance Article on the web 1st August 2001
Table 1 1,3-Dipolar cycloadditionsa
Alkynylboronates participate in 1,3-dipolar cycloaddition
reactions with nitrile oxides to provide isoxazoleboronic
esters with excellent levels of regiocontrol; additionally,
these potentially valuable synthetic intermediates have been
shown to participate efficiently in Suzuki coupling reac-
tions.
Aromatic boronic esters are amongst the most valuable and
widely used synthetic intermediates in modern organic chem-
istry due to their ability to participate in functional group
transformations and carbon–carbon bond forming reactions.1
These compounds are generally accessed via a functional group
interconversion strategy from a starting aryl halide or triflate.2
However, the requirement of these precursors can prove
problematic when more highly substituted or heavily function-
alised boronic ester products are required. Accordingly, in an
effort to develop novel and efficient routes to complex
arylboronates, we have recently been exploring the possibility
of employing cycloaddition/benzannulation reactions of boron
containing alkynes.3 In connection with this study, we wish to
report herein our recent findings on the [3+2] cycloaddition
reaction of alkynylboronates with nitrile oxides towards the
assembly of highly substituted isoxazoleboronic esters.
Entryb R1
R2 Product
Yield (%)
The cycloaddition reaction of nitrile oxides with alkynyl-
boronates has received scant attention in the literature to-date.
Indeed, we are aware of only a single report whereby dibutyl
ethynylboronate provided the corresponding isoxazole as a
single regioisomer.4 However and importantly, only this
terminal alkynylboronate was examined and the effect of
acetylenic alkyl substituents on regioselectivity was not de-
scribed. In contrast, the employment of alkynylstannanes is well
documented.5 However, this approach suffers from ready
protodestannylation of the heterocyclic product, as well as the
associated problems of handling toxic organotin species. In an
effort to further clarify the effectiveness of alkynylboronates as
precursors to isoxazoleboronic esters, to examine the
regiochemistry of substituted boron containing alkynes and to
establish the utility of isoxazoleboronic esters in carbon–carbon
bond forming processes, we undertook a study of the scope of
the cycloaddition reaction as outlined in Table 1.
We decided to initiate our studies on the scope of alkynyl-
boronate [3+2] cycloaddition reactions with mesitylenecarbo-
nitrile oxide 1 (R1 = Mes), which is known to be stable towards
dimerisation.6 As outlined in Entry 1, we were pleased to find
that 2-ethynyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane7 2 (R2
= H), underwent a smooth cycloaddition reaction to provide the
isoxazole 4a bearing the boronic ester unit in the 5-position in
59% yield, with only 23% of the alternative regioisomer 3a. On
changing the alkyne substituent R2 = H to R2 = Me (Entry 2)
the reaction proceeded cleanly to provide a single regioisomer
of 3b, remarkably, with complete reversal in regiochemistry.
Finally, the use of longer chain alkyl and phenyl substituents
also provided the 4-substituted boronic esters as single
regioisomers in good yield.8 We briefly examined the scope of
nitrile oxides in the cycloaddition process and were pleased to
a Regiochemical assignments made on the basis of diagnostic 13C
resonances. Additionally, these assignments have been supported by X-ray
data for compounds 3b and 3c, which will be the subject of a future
c
disclosure. b For experimental conditions, see ref. 8. 23% of 3a was
isolated. d 6% of 3e was islolated. e Estimated by 1H NMR.9
find that this technique was applicable to phenyl and alkyl
substituted 1,3-dipole substrates (Entries 5–7), the isoxazole
† Electronic supplementary information (ESI) available: full experimental
procedures. See http://www.rsc.org/suppdata/cc/b1/b103319k/
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Chem. Commun., 2001, 1558–1559
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b103319k

products 4e, 3f–g, were again formed with excellent levels of
regioselectivity and followed the same insertion pattern estab-
lished with the mesitylenecarbonitrile oxide in Entries 1–4.
Notably, and in contrast to the stannylated isoxazoles, boronic
esters 3 and 4 were isolated as white crystalline solids which
could be readily purified by standard chromatographic tech-
niques without problematic protodeboronation side reactions.
The regiochemical outcomes outlined in Table 1 are
consistent with literature reports of electron deficient alkyne
[3+2] cycloaddition reactions with nitrile oxides. Specifically,
whereas terminal propiolates generally give a mixture of
regioisomers which favours that bearing the ester moiety in the
5-position,10 substituted propiolates and alkynyl ketones pro-
vide the regioisomeric products with the electron withdrawing
group in the 4-position with high levels of selectivity.11
Nonetheless, from a synthetic standpoint, this methodology
provides a quick and direct method for the assembly of
isoxazoleboronic esters which avoids problematic metallation
of the heterocyclic nucleus.12
With a rapid and efficient entry into isoxazoleboronic esters
in hand, we decided to confirm their effectiveness as synthetic
intermediates for Suzuki coupling reactions. As outlined in
Scheme 1, isoxazoles 3b and 3d were found to undergo smooth
and efficient Pd-catalysed coupling with bromobenzene and
allyl bromide to give 5 and 6 respectively in excellent yields.
We therefore anticipate that this efficient two step procedure
holds great promise for the regioselective assembly of a range of
functionalised highly substituted isoxazole products.13 Addi-
tionally, as exemplified in Scheme 2, attempts to prepare 5 by
direct [3+2] cycloaddition of prop-1-ynylbenzene failed to
produce any of the cycloaddition product, even after prolonged
reaction times. Therefore, not only does the cycloaddition–
coupling technique permit the regioselective formation of
highly substituted isoxazole products, it also circumvents
limitations associated with preparing 4,5-dialkyl or -diaryl
substituted isoxazoles through the employment of unactivated
alkyne substrates.
In conclusion, we report a novel and flexible approach to
highly substituted isoxazoles through a key [3+2] cycloaddition
reaction of nitrile oxides with alkynylboronates. The investiga-
tion of related cycloaddition reactions is currently underway in
our laboratories and will be reported in due course.
The authors are grateful to the EPSRC for a studentship (M.
W. D.) and to GlaxoSmithKline and the University of Sheffield
for generous financial support.
Notes and references
1 For comprehensive reviews, see: A. Suzuki, Pure Appl. Chem., 1994,
66, 213; N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
2 M. Valtier and B. Carboni, in Comprehensive Organometallic Chem-
istry II, ed. E. W. Abel, F. G. A. Stone and G. Wilkinson, Pergamon,
Oxford, 1995, Vol. 11, p. 191; T. Ishiyama, Y. Itoh, T. Kitano and N.
Miyaura, Tetrahedron Lett., 1997, 38, 3447; M. Murata, T. Oyama, S.
Watanabe and Y. Masuda, J. Org. Chem., 2000, 65, 164.
3 M. W. Davies, C. N. Johnson and J. P. A. Harrity, Chem. Commun.,
1999, 2107; M. W. Davies, C. N. Johnson and J. P. A. Harrity, J. Org.
Chem., 2001, 66, 3525.
4 G. Bianchi, A. Cogoli and P. Grünanger, J. Organomet. Chem., 1966, 6,
598.
5 T. N. Mitchell, A. El-Faragy, S. N. Moschref and E. Gourzoulidou,
Synlett, 2000, 223; T. Sakamoto, Y. Kondo, D. Uchiyama and H.
Yamanaka, Tetrahedron, 1991, 47, 5111.
6 C. Grundman and J. M. Dean, J. Org. Chem., 1965, 30, 2809.
7 Prepared according to the procedure developed by Brown: H. C. Brown,
N. G. Bhat and M. Srebnik, Tetrahedron Lett., 1988, 29, 2631.
8 Typical experimental procedure as exemplified by the synthesis of 3d:
a solution of 2,4,6-trimethylbenzonitrile N-oxide (0.50 g, 3.1 mmol) and
4,4,5,5-tetramethyl-2-phenylethynyl-1,3,2-dioxaborolane (1.41 g, 6.2
mmol) in Et2O (50 ml) was heated at reflux for 64 h. The reaction
mixture was filtered through Celite and concentrated by rotary
evaporation. Purification of the resulting residue by silica gel chromato-
graphy provided isoxazole 3d (0.78 g, 64%) as a white crystalline solid;
mp 87.7–88.2 °C; dH (250 MHz, CDCl3) 1.11 (12H, s, CH3), 2.13 (6H,
s, Ar-CH3), 2.32 (3H, s, Ar-CH3), 6.89 (2H, s, Ar-H), 7.43–7.48 (3H, m,
Ar-H), 8.05–8.13 (2H, m, Ar-H); dC (62.9 MHz, CDCl3) 20.1, 21.2,
24.3, 83.8, 127.1, 127.5, 127.6, 128.5, 128.6, 130.3, 137.2, 138.1, 166.9,
174.4; umax/cm21 3054 (w), 2981 (m), 1570 (m), 1144 (m). (Calc. for
C24H28BNO3: C, 74.05; H, 7.25; N, 3.60. Found C, 73.94; H, 7.23; N,
3.45%). For full experimental procedure see Supplementary Informa-
tion.
9 Product could not be separated from the nitrile oxide dimer by silica gel
chromatography.
10 V. P. Sandanayaka and Y. Yang, Org. Lett., 2000, 2, 3087
11 R. R. Sauers, L. M. Hadel, A. A. Scimone and T. A. Stevenson, J. Org.
Chem., 1990, 55, 4011; M. Hojo, K. Tomita and A. Hosomi,
Tetrahedron Lett., 1993, 34, 485; F. A. Fouli, M. M. Habashy, A. F. El-
Kafrawy, A. J. A. Youseef and M. M. El-Adly, J. Prakt. Chem., 1987,
329, 1116.
Scheme 1 Suzuki coupling reactions.
12 For an excellent review on the metallation of isoxazoles, see: B. Iddon,
Heterocycles, 1994, 37, 1263.
13 Disubstituted alkynes have been shown to undergo incorporation with
low levels of regioselectivity: P. Pevarello, R. Amici, M. Colombo and
M. Varasi, J. Chem. Soc., Perkin Trans. 1, 1993, 18, 2151.
Scheme 2
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