An Alkyne Diboration/6π-Electrocyclization Strategy for the Synthesis of Pyridine Boronic Acid Derivatives

Article abstract of DOI:10.1002/anie.201601084

A new and efficient synthesis of pyridine-based heteroaromatic boronic acid derivatives is reported through a novel diboration/6π-electrocyclization strategy. This method delivers a range of functionalized heterocycles from readily available starting materials.

Full text of DOI:10.1002/anie.201601084

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201601084
German Edition: DOI: 10.1002/ange.201601084
Synthetic Methods
An Alkyne Diboration/6p-Electrocyclization Strategy for the Synthesis
of Pyridine Boronic Acid Derivatives
Helena Mora-Radó, Laurent Bialy, Werngard Czechtizky, María MØndez, and
Joseph P. A. Harrity*
Abstract: A new and efficient synthesis of pyridine-based
heteroaromatic boronic acid derivatives is reported through
a novel diboration/6p-electrocyclization strategy. This method
delivers a range of functionalized heterocycles from readily
available starting materials.
N
itrogen-based heterocyclic compounds constitute impor-
tant building blocks for organic synthesis since they are found
in many pharmaceutical and agrochemical targets. In this
regard, heteroaromatic boronic acid derivatives are one of the
most valuable classes of intermediates in synthetic chemis-
try.[1] Their value lies in their unique combination of high
stability and rich reactivity, allowing them to participate in
a wide range of functionalization reactions. Traditional
Scheme 1. The diboration/6p-electrocyclization strategy.
B2pin2 =(bispinacolato)diboron.
and condensation with O-methylhydroxylamine.[9] To our
delight, all substrates underwent smooth diborylation under
Pt catalysis to deliver the corresponding products in good to
excellent yields (Scheme 2). The scope of the chemistry was
found to be quite general with a range of substituents
tolerated on the alkyne and aryl rings. A relatively high
catalyst loading (10 mol%) was used when investigating the
scope of the reaction method so that the reactions were
complete in 30 min. However, we found that it was possible to
lower the catalyst loading to 3 mol% and that this had only
a minor effect on the reaction yield over a slightly increased
reaction time of 2.5 h.
approaches to these compounds relied on elaboration of
[2]
À
À
preformed scaffolds through C X or C H borylation.
Complementary strategies, such as cycloaddition reactions[3]
and annelative borylations,[4] have become more established,
and allow functionalized aromatic boronic acid scaffolds to be
made available in a direct manner.
The synthesis of pyridines through 6p-electrocyclization
reactions represents an interesting and alternative means for
the bespoke synthesis of this class of heterocyclic intermedi-
ates, and the reaction is compatible with a range of common
functional groups such as esters, aldehydes, and ethers.[5,6]
Importantly, in the context of boronic acid derivatives, we
envisaged that we could take advantage of catalytic dibor-
ylation methodology[7] to transform readily available yne-ene-
oximes into pyridine boronic esters. As shown in Scheme 1,
central to our objective was the activation of the alkyne
substrate towards electrocyclization whilst simultaneously
incorporating useful functionality. Moreover, we expected
that this process would selectively eliminate only one of the
two boronic ester moieties; thereby obviating the common
problem of differentiating between the two boronate units
generated by diboration chemistry.[8]
The substrates for this study were readily prepared in two
steps from 2-bromo aryl aldehydes by Sonogashira coupling
[*] H. Mora-Radó, Prof. J. P. A. Harrity
Department of Chemistry, University of Sheffield
Sheffield, S3 7HF (UK)
E-mail: j.harrity@sheffield.ac.uk
Dr. L. Bialy, Dr. W. Czechtizky, Dr. M. MØndez
Sanofi, Industrial Park Hoechst
65926 Frankfurt am Main (Germany)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601084.
Scheme 2. Diboration of 2-alkynyl aryloximes. [a] Reaction conducted
with 3 mol% Pt catalyst over 2.5 h.
5834
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 5834 –5836

Angewandte
Communications
Chemie
With a range of 1-azatrienes in hand, we turned our
attention to the pyridine-forming 6p-electrocyclization step.
o-DCB (ortho-dichlorobenzene) proved to be the optimal
solvent to perform this transformation and a reaction temper-
ature of 2008C led to complete conversion within 16 h
(Scheme 3). Pleasingly, all substrates underwent the key
Scheme 4. One-pot diboration/electrocyclization.
a similar sequence could also be achieved with aryloximes.
Specifically, isoquinoline 14 could be prepared directly from
the corresponding alkyne on circa 0.5 g scale by utilizing
a telescoped diboration/electrocyclization sequence.
We next decided to explore the suitability of ketoximes to
deliver more substituted heterocyclic products. As shown in
Scheme 5, condensation of 27 with O-methylhydroxylamine
provided a 4:1 mixture of oxime isomers (E/Z)-28 that could
be separated by chromatography. The major isomer was
Scheme 3. 6p-electrocyclization to form isoquinolines. [a] Reaction
conducted at 1808C for 16 h. o-DCB=1,2-dichlorobenzene; TBS=tert-
butyldimethylsilyl.
cyclisation step giving rise to a large number of functionalized
isoquinoline derivatives after elimination of MeOBpin. We
observed that the silyl-substituted triene 1 (yielding com-
pound 11) required the use of slightly lower temperatures to
avoid protodesilylation, and the free alcohol bearing sub-
strate 3 required protection as a TBS-ether[9] to avoid
protodeborylation during the electrocyclization process to
form compound 13. Notably, chemoselective electrocycliza-
tion was observed in the reactions of 15 and 16, and the
corresponding naphthalenes were not detected through the
potentially competing 6p-cyclization in these cases.
Scheme 5. 6p-electrocyclization of (E/Z)-oxime isomers. Tol.=toluene.
We were able to extend our studies to include aliphatic 1-
azatrienes and our results are shown in Scheme 4. Substrates
21, 22, and 25 were prepared in a similar manner as before,[9]
and the O-methyl oximes were subjected to B2pin2 in the
presence of the Pt catalyst. In each of these cases, however,
we were unable to isolate the intermediate diborylation
products, and instead these reactions directly furnished the
cyclized pyridine boronates 23, 24, and 26 in good yields at
1208C. The one-pot diboration/electrocyclization observed in
substrates 21, 22, and 25 reflects the increased reactivity of
aliphatic substrates towards pyridine formation. Nonetheless,
assigned as (E)-28 on the basis of comparative 1H NMR
spectroscopy[9] and the propensity of acetophenone oximes to
adopt the (E)-configuration.[10] We decided to subject the
individual oxime isomers to the diboration/electrocyclization
sequence. In the reaction, (E)-28 underwent efficient con-
version to the azatriene (E)-29 which was smoothly converted
into isoquinoline 30 in high yield. In contrast, (Z)-28 provided
the corresponding diborylation product (Z)-29 in low yield.
Moreover, and to our surprise, this substrate was found to be
inert to electrocyclization.
Angew. Chem. Int. Ed. 2016, 55, 5834 –5836
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5835

Angewandte
Communications
Chemie
HRMS ESI calculated for C18H22BNO2: m/z 295.1853, found:
295.1856.
The dependence of oxime stereochemistry on the effi-
ciency of electrocyclization of azatrienes is intriguing and has
not been documented to our knowledge. The reason could be
steric in nature and related to the lower reactivity of (Z)-1-
substituted butadienes in Diels–Alder reactions.[11] Further
investigations as to the underlying causes of this phenomenon
are currently underway.
Keywords: boronic esters · diboration · electrocyclic reactions ·
nitrogen heterocycles · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5834–5836
Angew. Chem. 2016, 128, 5928–5930
The potential of the heterocyclic boronic esters to be
further exploited for synthesis was next investigated by
employing two representative organoboron transformations.
Specifically, as highlighted in Scheme 6, compound 14 was
oxidized to the corresponding phenol 31 or could be
converted into azido product 32 in good yield in both cases.
[1] Boronic Acids: Preparation and Applications in Organic Syn-
thesis Medicine and Materials, Vol. 1, 2nd ed. (Ed.: D. G. Hall),
Wiley-VCH, Weinheim, 2011.
[2] For selected examples, see: a) T. Ishiyama, M. Murata, N.
Miyaura, J. Org. Chem. 1995, 60, 7508; b) I. A. I. Mkhalid, J. H.
Barnard, T. B. Marder, J. M. Murphy, J. F. Hartwig, Chem. Rev.
2010, 110, 890; c) A. Del Grosso, P. J. Singleton, C. A. Muryn,
M. J. Ingleson, Angew. Chem. Int. Ed. 2011, 50, 2102; Angew.
Chem. 2011, 123, 2150.
[3] a) S. P. J. T. Bachollet, J. F. Vivat, D. C. Cocker, H. Adams,
J. P. A. Harrity, Chem. Eur. J. 2014, 20, 12889; b) D. F. P. CrØpin,
J. P. A. Harrity, J. Jiang, A. J. H. M. Meijer, A.-C. M. A. Nassoy,
P. Raubo, J. Am. Chem. Soc. 2014, 136, 8642; c) V. Gandon, D.
Leboeuf, S. Amslinger, K. P. C. Vollhardt, M. Malacria, C.
Aubert, Angew. Chem. Int. Ed. 2005, 44, 7114; Angew. Chem.
2005, 117, 7276; d) G. Hilt, K. I. Smolko, Angew. Chem. Int. Ed.
2003, 42, 2795; Angew. Chem. 2003, 115, 2901; e) Y. Yamamoto,
J.-i. Ishii, H. Nishiyama, K. Itoh, J. Am. Chem. Soc. 2004, 126,
3712; f) H. Wang, C. Grohmann, C. Nimphius, F. Glorius, J. Am.
Chem. Soc. 2012, 134, 19592.
[4] a) D. J. Faizi, A. Issaian, A. J. Davis, S. A. Blum, J. Am. Chem.
Soc. 2016, 138, 2126; b) E. Chong, S. A. Blum, J. Am. Chem. Soc.
2015, 137, 10144; c) A. J. Warner, J. R. Lawson, V. Fasano, M. J.
Ingleson, Angew. Chem. Int. Ed. 2015, 54, 11245; Angew. Chem.
2015, 127, 11397; d) J. Huang, S. J. F. Macdonald, J. P. A. Harrity,
Chem. Commun. 2010, 46, 8770.
Scheme 6. Representative functionalization reactions of 14.
DCM=CH2Cl2.
In conclusion we report a new and efficient synthesis of
pyridine-based heteroaromatic boronic acid derivatives
through a novel diboration/6p-electrocyclization pathway.
This strategy allows rapid access to bicyclic pyridines,
although the suitability of this method to access monocyclic
heterocycles will likely require further method development.
Moreover, this method has raised an intriguing result that the
cyclization of oxime-derived trienes appears to depend on the
substrate stereochemistry. Further studies to establish the
generality of this observation together with the underlying
causes are underway and will be reported in due course.
[5] a) S. J. Markey, W. Lewis, C. J. Moody, Org. Lett. 2013, 15, 6306;
b) T. Hosokawa, N. Shimo, K. Maeda, A. Sonoda, S.-I. Muraha-
shi, Tetrahedron Lett. 1976, 17, 383; c) T. Kumemura, T. Choshi,
A. Hirata, M. Sera, Y. Takahashi, J. Nobuhiro, S. Hibino, Chem.
Pharm. Bull. 2005, 53, 393.
[6] For related examples involving in situ generation of unsaturated
oximes, see: a) D. A. Colby, R. G. Bergman, J. A. Ellman, J. Am.
Chem. Soc. 2008, 130, 3645; b) S. Liu, L. S. Liebeskind, J. Am.
Chem. Soc. 2008, 130, 6918; c) K. Parthasarathy, M. Jeganmo-
han, C.-H. Cheng, Org. Lett. 2008, 10, 325; d) R. M. Martin,
R. G. Bergman, J. A. Ellman, J. Org. Chem. 2012, 77, 2501.
[7] T. Ishiyama, N. Matsuda, N. Miyaura, A. Suzuki, J. Am. Chem.
Soc. 1993, 115, 11018.
[8] a) S. D. Brown, R. W. Armstrong, J. Am. Chem. Soc. 1996, 118,
6331; b) H. Prokopcovµ, J. Ramírez, E. Fernµndez, C. O. Kappe,
Tetrahedron Lett. 2008, 49, 4831.
[9] Further details are contained within the Supporting Information.
[10] G. J. Karabatsos, N. Hsi, Tetrahedron 1967, 23, 1079.
[11] We thank a reviewer for this suggestion. For an example of
comparative Diels – Alder reactions of E/Z-1-substituted buta-
dienes, see : H. Adams, J. C. Anderson, R. Bell, D. N. Jones,
M. R. Peel, N. C. O. Tomkinson, J. Chem. Soc. Perkin Trans.
1 1998, 3967.
Experimental Section
Typical diboration/electrocyclization procedure as exemplified by the
formation of 14: B2pin2 (640 mg, 2.5 mmol) was added to a stirred
solution of (E)-2-(2-cyclopropylethynyl)benzaldehyde O-methyl
oxime (456 mg, 2.3 mmol) in toluene (15 mL). Then [Pt(PPh3)4]
(132 mg, 0.12 mmol, 5 mol%) was added and the reaction was stirred
at 1208C for 1 h. The reaction mixture was allowed to cool to room
temperature and 1,2-Cl2C6H4 was added (30 mL). The reaction
mixture was stirred at 2008C for a further 16 h. The solution was
allowed to cool to room temperature and was filtered through a pad
of silica gel. The residue was purified by flash column chromatog-
raphy on silica gel eluting with petroleum ether (40/60 v/v) and ethyl
acetate to afford 3-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
1
olan-2-yl)isoquinoline 14 (480 mg, 71%) as an orange oil. H NMR
(400 MHz, CDCl3): d = 9.09 (s, 1H), 8.11 (dd, J = 8.5, 1.0 Hz, 1H),
7.84 (d, J = 8.0 Hz, 1H), 7.62 (ddd, J = 8.5, 7.0, 1.5 Hz, 1H), 7.45 (ddd,
J = 8.0, 7.0, 1.0 Hz, 1H), 2.61–2.54 (m, 1H), 1.49 (s, 12H), 1.22–1.18
(m, 2H), 1.02–0.96 ppm (m, 2H); 13C NMR (101 MHz, CDCl3): d =
160.7, 153.8, 139.5, 130.4, 128.0, 126.3, 126.1, 125.5, 84.3, 25.0, 16.6,
9.9 ppm; 11B NMR (128 MHz, CDCl3): d = 32.8 ppm (br); FTIR: u =
Received: January 30, 2016
Revised: February 19, 2016
Published online: April 5, 2016
2978 (m), 1619 (m), 1562 (m), 1495 (m), 1235 (s), 1134 (s) cmÀ1
.
5836
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 5834 –5836