A [4+2] cycloaddition strategy to pyridine boronic ester derivatives

Article abstract of DOI:10.1021/ol7029189

Alkynylboronate cycloadditions of 1,4-oxazin-2-ones and 2-pyrazinones provide a direct and regioselective route to functionalized pyridine boronic ester derivatives.

Full text of DOI:10.1021/ol7029189

ORGANIC
LETTERS
2008
Vol. 10, No. 5
781-783
A [4
+ 2] Cycloaddition Strategy to
Pyridine Boronic Ester Derivatives
Patrick M. Delaney,† Jianhui Huang,† Simon J. F. Macdonald,‡ and
Joseph P. A. Harrity*,†
Department of Chemistry, UniVersity of Sheffield, Brook Hill,
Sheffield S3 7HF, United Kingdom, and GlaxoSmithKline Research and DeVelopment,
Gunnels Wood Road, SteVenage, Hertfordshire, SG1 2NY, United Kingdom
j.harrity@sheffield.ac.uk
Received December 3, 2007
ABSTRACT
Alkynylboronate cycloadditions of 1,4-oxazin-2-ones and 2-pyrazinones provide a direct and regioselective route to functionalized pyridine
boronic ester derivatives.
Aromatic and heteroaromatic boronic esters are an extremely
valuable class of synthetic intermediates in modern organic
chemistry.1 Although these compounds undergo many trans-
formations, the Suzuki-Miyaura cross-coupling with aryl/
heteroaryl halides is arguably the most widely studied within
academia and the fine chemicals industry.2 Moreover, among
the plethora of biaryl compounds that can be prepared by
this strategy, pyridine-containing compounds are of signifi-
cant importance because of their biological activity3 and
widespread employment in catalysis both as ligands4 and as
nucleophilic promoters.5 However, the use of pyridines as
the boronic acid component in Suzuki coupling is relatively
uncommon, most likely because of problems associated with
their preparation. For example, they can show significant
water solubility, thereby necessitating an additional step to
convert from the boronic acid to the corresponding ester.
Moreover, Li-halogen exchange-based approaches can be
hampered by the acidity of the substrate bromopyridines.6
We envisaged an alternative strategy to pyridine boronic
esters that employed an alkynylboronate cycloaddition as
outlined in Scheme 1. Such cycloadditions have become
increasingly popular,7 and to-date, metal-mediated8 and
metal-catalyzed9 processes have been developed, as well as
(6) For a discussion and lead references see: (a) Tyrrell, E.; Brookes,
P. Synthesis 2004, 469. (b) Thompson, A. E.; Batsanov, A. S.; Bryce, M.
R.; Saygili, N.; Parry, P. R.; Tarbit, B. Tetrahedron 2005, 61, 5131. (c)
Campeau, L.-C.; Fagnou, K. Chem. Soc. ReV. 2007, 36, 1058.
(7) For recent overviews see: (a) Hilt, G.; Bolze, P. Synthesis 2005,
2091. (b) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun. 2006,
2209.
(8) (a) Ester, C.; Maderna, A.; Pritzkow, H.; Siebert, W. Eur. J. Inorg.
Chem. 2000, 1177. (b) Davies, M. W.; Johnson, C. N.; Harrity, J. P. A. J.
Org. Chem. 2001, 66, 3525. (c) Gandon, V.; Leca, D.; Aechtner, T.;
Vollhardt, K. P. C.; Malacria, M.; Aubert, C. Org. Lett. 2004, 6, 3405. (d)
Gandon, V.; Leboeuf, D.; Amslinger, S.; Vollhardt, K. P. C.; Malacria,
M.; Aubert, C. Angew. Chem., Int. Ed. 2005, 44, 7114. (e) Geny, A.;
Leboeuf, D.; Rouquie´, G.; Vollhardt, K. P. C.; Malacria, M.; Gandon, V.;
Aubert, C. Chem.-Eur. J. 2007, 13, 5408.
(9) (a) Hilt, G.; Smolko, K. I. Angew. Chem., Int. Ed. 2003, 42, 2795.
(b) Hilt, G.; Luers, S.; Smolko, K. I. Org. Lett. 2005, 7, 251. (c) Hilt, G.;
Hess, W.; Schmidt, F. Eur. J. Org. Chem. 2005, 2526. (d) Yamamoto, Y.;
Ishii, J.-i.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2004, 126, 3712. (e)
Yamamoto, Y.; Ishii, J.-i.; Nishiyama, H.; Itoh, K. Tetrahedron 2005, 61,
11501. (f) Yamamoto, Y.; Hattori, K.; Ishii, J.-i.; Nishiyama, H. Tetrahedron
2006, 62, 4294.
† University of Sheffield.
‡ GlaxoSmithKline.
(1) Boronic Acids; Hall, D.G., Ed.; Wiley-VCH: Weinheim, Germany,
2005.
(2) (a) Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201. (b) Hassan,
J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002,
102, 1359. (c) Suzuki, A. Pure Appl. Chem. 1994, 66, 213.
(3) Balasubramanian, M.; Kealy, J. G. In ComprehensiVe Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 5, p 245.
(4) Chelucci, G. Chem. Soc. ReV. 2006, 35, 1230 and references cited
therein.
(5) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5346.
10.1021/ol7029189 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/05/2008

Scheme 1
Table 1. Cycloaddition Reactions of Alkynyl Boronic Esters
with 3,5-Dihalo-2H-1,4-oxazin-2-ones
entry
R1
R2
product
yield (a:b)
1
2
3
4
5
6
7
8
9
H (1a)
Cl (1b)
Br (1c)
H (1a)
Cl (1b)
Br (1c)
H (1a)
Cl (1b)
Br (1c)
Ph (2a)
Ph (2a)a
Ph (2a)
Bu (2b)
Bu (2b)a
Bu (2b)
H (2c)
3
4
5
6
7
8
9
10
11
72% (5:1)
78% (5:1)
74% (20:1)
67% (2:1)
82% (9:1)
82% (10:1)
88% (1:2)
84% (1:1)
83% (3:2)
techniques based on pericyclic10 reactions. In the context of
pyridine synthesis, we envisaged that the cycloaddition of
an alkynylboronate with a 1,4-oxazin-2-one would furnish
the desired heteroaromatic product after loss of CO2. This
scheme provided the prospect of a direct synthesis of pyridine
boronic esters under neutral conditions that avoided aqueous
workup steps. We report herein our preliminary studies on
this novel strategy with regard to its scope and regioselec-
tivity.
H (2c)a
H (2c)
a Reaction run in o-dichlorobenzene (DCB) at 190 °C for 4 h.
that delivered generally higher levels of regiocontrol. In this
context, the Hoornaert group demonstrated that substituted
pyridines and pyridones could be prepared by the cyclo-
addition of alkynes with 2[1H]-pyrazinones;13 we therefore
decided to explore this chemistry in an effort to uncover the
reaction chemoselectivity (formation of pyridine versus
pyridone) and regioselectivity (Scheme 2).
We first decided to investigate the scope and regioselec-
tivity of cycloadditions of readily accessible 1,4-oxazin-2-
ones 1a-c with alkynylboronates of varying steric size.11
Indeed, heating a toluene solution of 1a with phenyl-
acetylene-derived substrate 2a resulted in smooth cyclo-
addition and generation of pyridine boronic ester 3 in high
yield (entry 1, Table 1). Moreover, we were pleased to find
that the reaction provided useful levels of regiocontrol for
isomer 3a. The 3-chloro-oxazin-2-one gave very similar
results (entry 2). However, 3-bromo-oxazin-2-one provided
the corresponding product with enhanced regiocontrol for
the 4-boronate isomer 5a (entry 3). Changing alkyne
substrates to 2b provided 6 in good yield but with dis-
appointing levels of regioselectivity. Interestingly, oxazinone
1b provided significantly better regiocontrol whereas, again,
1c proved to generate the pyridine boronic ester 8 in high
yield and with excellent levels of control for regioisomer a.
Finally, the terminal alkyne 2c reacted with dienes 1a-c in
excellent yield but with poor selectivity. Nonetheless, we
were interested to note that once again, a preference for
regioisomer a was strongest when bromide 1c was em-
ployed.12
Scheme 2
We prepared azadiene 1213a and explored its cycloaddition
with alkynylboronates 2a-d. Our results are highlighted in
Table 2. We were delighted to find that the cycloadditions
proceeded in high yield to provide the 2-pyridone boronic
ester rather than the pyridine product.14 Moreover, we
observed a single regioisomer in each case where the boronic
ester was incorporated in the 5-position.15 The 2-pyridone
boronic esters prepared by this route have little precedent in
Although we were encouraged by the potential of oxazi-
nones to furnish functionalized pyridines, we decided to
investigate alternative heterodienes in an effort to expand
the product scope and in the hope of uncovering processes
(10) (a) Moore, J. E.; Davies, M. W.; Goodenough, K. M.; Wybrow, R.
A. J.; York, M.; Johnson, C. N.; Harrity, J. P. A. Tetrahedron 2005, 61,
6707. (b) Helm, M. D.; Moore, J. E.; Plant, A.; Harrity, J. P. A. Angew.
Chem., Int. Ed. 2005, 44, 3889. (c) Moore, J. E.; York, M.; Harrity, J. P.
A. Synlett 2005, 860. (d) Delaney, P. M.; Moore, J. E.; Harrity, J. P. A.
Chem. Commun. 2006, 3323. (e) Browne, D. L.; Helm, M. D.; Plant, A.;
Harrity, J. P. A. Angew. Chem., Int. Ed. 2007, 46, 8656.
(11) For cycloadditions of these and other oxazinones with various
hydrocarbon based acetylenes see: (a) Meerpoel, L.; Deroover, G.; Van
Aken, K.; Lux, G.; Hoornaert, G. Synthesis 1991, 765. (b) Van, Aken, K.
J.; Lux, G. M.; Deroover, G. G.; Meerpoel, L.; Hoornaert, G. J. Tetrahedron
1994, 50, 5211.
(12) The regiochemistry of compounds 5, 7, 8 were determined by nOe
and that of 9 was based on 1H NMR coupling constants. The regiochemistry
of compound 3 was assigned by 1H NMR coupling constants after
protodeboronation with CsF/EtOH/MeCN. The regiochemistry of 6, 10, and
11 are tentatively made by analogy. Compounds 4 and 5 were analyzed by
X-ray crystallography. This assignment data is available in the Supporting
Information.
(13) (a) Tutonda, M.; Vanderzande, D.; Hendrickx, M.; Hoornaert, G.
Tetrahedron 1990, 46, 5715. (b) Pawar, V. G.; De Borggraeve, W. M.
Synthesis 2006, 2799.
(14) The cycloaddition of alkyne 2d (Table 2, entry 4) provided a minor
amount (∼5%) of the corresponding pyridine product.
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Org. Lett., Vol. 10, No. 5, 2008

Scheme 3
Table 2. Synthesis of Di-, Tri-Substituted Pyridone Boronic
Esters
entry
R
product
yield
1
2
3
4
Ph (2a)
Bu (2b)
H (2c)
13a
13b
13c
13d
64%
81%
77%
84%
Me3Si (2d)
the literature, and further studies into the scope of this
interesting transformation are ongoing in our laboratories.
Having developed two complementary approaches to
pyridine-based boronic esters, we wished to confirm that
these intermediates could be further elaborated and chose to
investigate representative cross-coupling reactions. This
process was of particular significance given the congested
nature of the boronic esters and/or the presence of halide
groups in these substrates that could potentially give rise to
competing dimerization processes. We began by investigating
the cross-coupling of substrate 5. As outlined in Scheme 3,
we were pleased to find that the Suzuki-Miyaura reaction
of pyridine 5 proceeded efficiently to provide 14 and 15,
and we were unable to detect products resulting from
homocoupling. In addition, we found that the cross-coupled
products could be efficiently de-halogenated to provide 3,4,5-
trisubstituted pyridines 16 and 17. Moreover, partial reduction
to the 2-chloropyridine 18 was successfully achieved in the
case of 15 by carrying out the reduction with fewer
equivalents of LAH. Finally, with regard to the 2-pyridone
boronic esters, we confirmed the potential of these interme-
diates as substrates for Suzuki coupling by performing the
Pd-catalyzed cross-coupling of 13b. Subsequent substitution
at the chloride was also feasible but required rather harsh
conditions to provide 19 in good overall yield.
In conclusion, we report herein a new approach to
functionalized pyridine-based boronic esters that exploits [4
+ 2] cycloaddition reactions of alkynylboronates. This
strategy allows a diverse range of intermediates to be
generated in good yield and obviates many of the problems
associated with using strong bases or aqueous workup
procedures.
Acknowledgment. We are grateful to the EPSRC and
GSK for financial support.
Supporting Information Available: Full experimental
details for the syntheses reported are provided together with
spectroscopic and X-ray crystallographic assignment data.
This material is available free of charge via the Internet at
http://pubs.acs.org
(15) The regiochemistry of compounds 13b, d was determined by nOe
and that of 13c was based on 1H NMR coupling constants. The regiochem-
istry of 13a is tentatively made by analogy.
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