Communications
DOI: 10.1002/anie.200703767
Cycloaddition Reactions
A Sydnone Cycloaddition Route to Pyrazole Boronic Esters**
Duncan L. Browne, Matthew D. Helm, Andrew Plant, and Joseph P. A. Harrity*
Aromatic and heteroaromatic boronic esters are among the
most valuable synthetic intermediates in modern organic
chemistry.[1] They are used throughout both industry and
academia, largely because of their ability to form carbon–
carbon bonds to various aromatic substrates through a Pd-
catalyzed cross-coupling reaction.[2] However, they also
participate in carbon–heteroatom bond formation to provide
amines and ethers as well as undergoing nucleophilic addition
reactions to imines, aldehydes, and enones.[3] Despite their
popularity, their synthesis generally requires a functional
group transformation from a starting organohalide or tri-
flate.[4] The requirement for these precursors can become
problematic if one wishes to generate highly functionalized
aromatic boronates because the starting halide/triflate may be
difficult to access or the substrateꢀs functionality may be
incompatible with conditions required to transform the
substrate into the boronic ester product. An alternative and
Scheme 1. Cycloaddition approaches to pyrazoles.
increasingly popular approach to these compounds is through
cycloaddition reactions of alkynylboronates.[5] To date, metal-
mediated[6] and metal-catalyzed[7] processes have been devel-
oped, as well as techniques based on pericyclic[8] reactions.
In an effort to expand the scope of hetereoaromatic
compounds available by this strategy, we were attracted to the
preparation of pyrazole boronic esters. Pyrazoles are com-
monly employed in the pharmaceutical and agrochemical
industries;[9] therefore, a direct and flexible route for the
synthesis of pyrazole boronic esters would allow a broad
range of analogues to be made available by exploiting the rich
chemistry available to these organoboron reagents.[10] We
contemplated three approaches towards this goal:
1) [3+2] cycloadditions of diazoalkanes; 2) [3+2] cycloaddi-
tions of nitrile imines; and 3) cycloaddition/retrocycloaddi-
tion of sydnones. We set out to establish the potential of each
approach, and our preliminary results are highlighted in
Scheme 1. Attempts to prepare nitrile imines and perform the
cycloaddition in situ[11] were unsuccessful, and a complex
mixture of unidentifiable products was obtained
(Scheme 1a). The [3+2] cycloaddition of diazoalkane deriv-
atives appeared to be a more promising alternative as
Matteson had demonstrated the feasibility of this reaction
through the cycloaddition of a terminal alkyne boronic ester
with ethyl diazoacetate.[12] Although we were able to repeat
these findings, the reaction was extremely slow and limited
only to the terminal alkyne substrate (Scheme 1b). We next
turned our attention to the cycloaddition of alkynylboronates
with sydnones.[13] Although there was no precedent for the
reaction of alkynylboronates with this class of reagent,
successful cycloadditions of these mesoionic compounds
were reported during the course of this work with alkynyl-
stannanes and -silanes.[14] To our delight, heating a mixture of
the alkynylboronate derived from phenylacetylene and N-
methylsydnone in refluxing mesitylenes provided the corre-
sponding pyrazole in good yield (Scheme 1c). Moreover, only
a single regioisomer could be identified from the reaction
mixture.[15] We therefore decided to carry out further inves-
tigations into the scope of this promising transformation.
We performed the cycloaddition of a series of alkynylbor-
onates with N-aryl sydnones to establish the reaction scope
and regioselectivity; our results are summarized in Table 1.
We were pleased to find that N-phenylsydnone 1a reacted
smoothly with a range of alkynylboronates to provide the
corresponding pyrazoles in good to high yield (entries 1–4).
We were surprised to find significant variation in reaction
regioselectivity. Whereas phenyl alkynylboronate 2a pro-
vided a single regioisomer, more modest regiocontrol was
observed with alkynes 2b and 2c, and a switch in regiochem-
istry was found when terminal alkyne 2d was employed. We
were intrigued by the possibility of modulating reaction rate
and regiochemistry by changing the electronic nature of the
sydnone and therefore opted to investigate the cycloaddition
of substrates bearing electron-rich/-deficient aryl groups. We
found that electron-rich sydnone 1b was rather sluggish in the
[*] D. L. Browne, M. D. Helm, Dr. J. P. A. Harrity
Department of Chemistry
University of Sheffield
Sheffield, S3 7HF (UK)
Fax: (+44)114-222-9346
E-mail: j.harrity@sheffield.ac.uk
Dr. A. Plant
Research Chemistry
Syngenta
Jealott’s Hill International Research Centre
Bracknell, Berkshire, RG42 6EY (UK)
[**] The authors are grateful to the EPSRC and Syngenta for financial
support.
Supporting information for this article is available on the WWW
8656
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8656 –8658
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