Organic & Biomolecular Chemistry
Paper
(d) S. Sakashita, M. Takizawa, J. Sugai, H. Ito and
Y. Yamamoto, Org. Lett., 2013, 15, 4308.
Conclusions
In summary, we report a simple Brønsted acid catalysed
approach to the synthesis of diverse C2-alkenylated N-hetero-
aromatic compounds. The protocol relies on thermally pro-
moted (3 + 2) dearomatising cycloaddition between an N-oxide
and an alkene to generate an isoxazolidine. The Brønsted acid
catalyst then promotes N–O cleavage and dehydration to the
target. We believe the method has high utility because (a) it is
operationally simple, (b) the Brønsted acid catalyst is cheap,
non-toxic and sustainable, (c) the N-oxide activator disappears
during the reaction, (d) water is the sole stoichiometric by-
product of the process and (e) the functional group tolerance
is orthogonal to metal-catalysed methods. Furthermore, we have
demonstrated that the protocol can be integrated easily into
synthetic sequences to provide polyfunctionalised targets, as
exemplified by a highly concise synthesis of (−)-cuspareine
and sequential N-oxide directed C–C bond forming C–H func-
tionalisations of quinoline. Although inherently valuable, C2-
alkenylated heteroarenes also function as precursors to C2-
alkylated derivatives and as substrates for an emerging range
of metal catalysed C–C/C–H bond forming processes.24 Given
these considerations and the simplicity of our approach,
which takes advantage of an intermediate routinely used in
other contexts,1a it is likely that the protocol described here
will find wide utility in synthesis and pharmaceutical chem-
istry. In broader terms, this study demonstrates how classical
organic reactivity can still be used to provide solutions to
contemporary synthetic challenges that might otherwise be
approached using transition metal catalysis.
5 S. E. Wengryniuk, A. Weickgenannt, C. Reiher,
N. A. Strotman, K. Chen, M. D. Eastgate and P. S. Baran,
Org. Lett., 2013, 15, 792 and references cited therein.
6 An alternative method involves metal catalysed conden-
sation of 2-methyl N-heteroarenes with aldehydes or
imines. This approach requires prior installation of a
methyl substituent. Selected recent examples: (a) B. Qian,
P. Xie, Y. Xie and H. Huang, Org. Lett., 2011, 13, 2580;
(b) Z. Jamal and Y.-C. Teo, Synlett, 2014, 2049.
7 Seminal studies: (a) L.-C. Campeau, S. Rousseaux and
K. Fagnou, J. Am. Chem. Soc., 2005, 127, 18020;
(b) L.-C. Campeau, D. J. Schipper and K. Fagnou, J. Am.
Chem. Soc., 2008, 130, 3266; (c) L.-C. Campeau,
D. R. Stuart, J.-P. Leclerc, M. Bertrand-Laperle,
E. Villemure, H.-Y. Sun, S. Lasserre, N. Guimond,
M. Lecavallier and K. Fagnou, J. Am. Chem. Soc., 2009, 131,
3291.
8 Examples of C2 selective C–H alkenylations of pyridine
N-oxides: (a) K. S. Kanyiva, Y. Nakao and T. Hiyama, Angew.
Chem., Int. Ed., 2007, 46, 8872; (b) S. H. Cho, S. J. Hwang
and S. Chang, J. Am. Chem. Soc., 2008, 130, 9254;
(c) L. Ackermann and S. Fenner, Chem. Commun., 2011, 47,
430.
9 C2 selective C–H alkenylation of pyridines have also been
achieved. Selected processes: (a) Y. Nakao, K. S. Kanyiva
and T. Hiyama, J. Am. Chem. Soc., 2008, 130, 2448;
(b) P. Wen, Y. Li, K. Zhou, C. Ma, X. Lan, C. Ma and
G. Huang, Adv. Synth. Catal., 2012, 354, 2135.
10 Examples where N-oxides direct metal catalysed C–H acti-
vation and serve as the internal oxidant: (a) J. Wu, X. Cui,
L. Chen, G. Jiang and Y. Wu, J. Am. Chem. Soc., 2009, 131,
13888; (b) X. Huang, J. Huang, C. Du, X. Zhang, F. Song
and J. You, Angew. Chem., Int. Ed., 2013, 52, 12970;
(c) B. Zhou, Z. Chen, Y. Yang, W. Ai, H. Tang, Y. Wu,
W. Zhu and Y. Li, Angew. Chem., Int. Ed., 2015, 54, 12121.
See also ref. 13c and g. For a complementary strategy invol-
ving initial nucleophilic addition, see: (d) O. V. Larionov,
D. Stephens, A. Mfuh and G. Chavez, Org. Lett., 2014, 16,
864.
Acknowledgements
G. E. M. C. thanks the Bristol Chemical Synthesis Doctoral
Training Centre, funded by the EPSRC (EP/G036764/1) for a
PhD studentship. J. F. B. is indebted to the Royal Society for
the provision of a University Research Fellowship.
Notes and references
11 L. Bering and A. P. Antonchick, Org. Lett., 2015, 17,
3134.
1 (a) J. S. Carey, D. Laffan, C. Thomson and M. T. Williams,
Org. Biomol. Chem., 2006, 4, 2337; (b) V. Bonnet, F. Mongin, 12 During the preparation of this manuscript Gou, Wang and
F. Trécourt, G. Breton, F. Marsais, P. Knochel and
G. Quéguiner, Synlett, 2002, 1008.
2 For example, see: Y. Zou, G. Yue, J. Xu and J. Zhou,
Eur. J. Org. Chem., 2014, 5901.
3 For example, see: M. L. Kantam, P. V. Reddy, P. Srinivas
and S. Bhargava, Tetrahedron Lett., 2011, 52, 4490.
4 Contemporary approaches rely on modified 2-pyridyl
boron-based reagents. Selected examples: (a) K. L. Billingsley
and S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 4695;
(b) G. R. Dick, D. M. Knapp, E. P. Gillis and M. D. Burke,
co-workers reported a conceptually similar approach:
H. Xia, Y. Liu, P. Zhao, S. Gou and J. Wang, Org. Lett., 2016,
18, 1796. This protocol was strictly limited to quinoline-
based systems, and required super-stoichiometric acetic
acid (300 mol%) in combination with a large excess of the
alkene (1000 mol%) (cf. this study: C2-alkenylation of
quinoline, isoquinoline and pyridine N-oxides using just
5 mol% TsOH with 300–500 mol% of the alkene partner).
See also: R. Kumar, I. Kumar, R. Sharma and U. Sharma,
Org. Biomol. Chem., 2016, 14, 2613.
Org. Lett., 2010, 12, 2314; (c) G. R. Dick, E. M. Woerly and 13 Selected examples of quinoline N-oxide directed C8-func-
M. D. Burke, Angew. Chem., Int. Ed., 2012, 51, 2667;
tionalisation with Rh or Ir catalysts: (a) H. Hwang, J. Kim,
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Org. Biomol. Chem.