A general route to pyridine-modified salicylaldehydes via Suzuki coupling

Article abstract of DOI:10.1016/S0040-4039(01)00106-X

An efficient method for the preparation of 5-(3-pyridyl)- and 5-(4-pyridyl)salicylaldehydes by the palladium-catalyzed cross-coupling reaction of either 4-pyridylboronic acid or diethyl-(3-pyridyl)borane and bromosalicylaldehydes is described.

Full text of DOI:10.1016/S0040-4039(01)00106-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2093–2096
A general route to pyridine-modified salicylaldehydes via Suzuki
coupling
Gregory A. Morris and SonBinh T. Nguyen*
Department of Chemistry and Institute for Environmental Catalysis, Northwestern University, Evanston, IL 60208, USA
Received 21 November 2000; accepted 12 January 2001
Abstract—An efficient method for the preparation of 5-(3-pyridyl)- and 5-(4-pyridyl)salicylaldehydes by the palladium-catalyzed
cross-coupling reaction of either 4-pyridylboronic acid or diethyl-(3-pyridyl)borane and bromosalicylaldehydes is described.
© 2001 Published by Elsevier Science Ltd.
Our interest in the design of cyclic supramolecular
structures of the Fujita1,2 and Stang3 varieties led us to
investigate the synthesis of a bifunctional salen tem-
plate containing pendant Lewis base groups. Our pri-
mary target was a salen-type ligand featuring a pair of
5,5%-pyridyl groups oriented at 180° with respect to each
other that we envisioned would have the potential to be
used as ‘edges’ in the construction of a supramolecular
complex. It was thought that this highly functionalized
of stannylpyridines and aryl halides,5 and the Pd-cata-
lyzed coupling of pyridylboranes and aryl halides.6 Yet,
after each of these methods gave disappointing results
in our laboratory, we were left searching for better
ways to synthesize the desired 3- and 4-arylpyridines.
Our
first
attempt
at
preparing
the
5-(4-
pyridyl)salicylaldehyde 1 involved a Ni-catalyzed cross-
coupling between aryl Grignard 27 and 4-bromopy-
ridine 3 to produce the heterobiaryl product 4 (Eq. (1)).
Even though we took great care in the procedure,
including titrating the Grignard reagent and taking
several steps to ensure that the 4-bromopyridine was
dry after free-basing,8 we were unable to obtain yields
greater than 42% for the coupling. In addition to using
Ni(dppp)Cl2 as a catalyst, we also tried Ni(dppe)Cl2,
Ni(dppf)Cl2, and Ni(PPh3)2Cl2 but were not able
improve on our initial yields. Since others have
reported similar problems due to the well-known insta-
bility of 4-halopyridines,4,9–11 we decided to seek other
means for the synthesis of 4. Although the reverse
Ni-catalyzed cross-coupling could, in theory, be accom-
plished, the nucleophilicity of the necessary reagent,
4-pyridylmagnesium bromide, has been shown to be
significantly weaker than that of typical phenyl or alkyl
Grignard reagents.12 Furthermore, 4-pyridylmagnesium
ligand could be synthesized by reacting
a 5-(4-
pyridyl)salicylaldehyde (1) with a vicinal diamine. Since
salicylaldehydes containing a pyridyl functionality were
not known, we decided to explore the synthetic possi-
bilities for introducing pyridyl substituents.
We set out to prepare a variety of pyridylsalicylalde-
hydes by
a
Ni- or Pd-mediated cross-coupling
approach. Because we wanted to access a variety of
substituted salen ligands in the most efficient manner,
our strategy emphasized the use of a single easily
accessible pyridyl-substituted coupling agent in con-
junction with several 3-substituted salicylaldehydes. A
review of the literature revealed a number of such
methods that might be applicable for the synthesis of
the targeted heterobiaryl framework, including Ni- or
Pd-catalyzed coupling of halopyridines and arylmetallic
compounds (Mg, Zn),4 the Pd-catalyzed cross-coupling
(1)
* Corresponding author. Tel.: 847.467.3347; fax: 847.491.7713; e-mail: stn@chem.nwu.edu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00106-X

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G. A. Morris, S. T. Nguyen / Tetrahedron Letters 42 (2001) 2093–2096
bromide must be obtained through a transmetalation
procedure with ethyl or phenylmagnesium bromide,12–14
leaving a halide as a byproduct that could potentially
interfere in the subsequent coupling reaction.
Pd(PPh3)4 as a catalyst, we were able to achieve yields
of only 28%. When we used Pd2(dba)3 with (2-furyl)3P
in THF,16 we were able to improve the yield only
slightly to 32%. While we were aware that there have
been reports of the successful use of trimethyl-(4-
pyridyl)stannane in cross-coupling reactions,17 we ruled
out this reagent due to the unnecessary risks associated
with handling the trimethylstannane reagents.
Next, we investigated the Pd-catalyzed coupling of aryl
halide 5 and tributyl-(4-pyridyl)stannane 615 as a way to
prepare the heterobiaryl product 4 (Eq. (2)). Using
Table 1. Formation of aryl pyridines
Pd catalyst
Ar%B(R)2+ArB ꢀꢀꢀꢀꢀꢀꢀꢀꢁ Ar%ꢀAr
a
4-Pyridylboronic acid (1.1 equiv.), Na2CO3 (1.5 equiv.), Pd(dppf)Cl2 (0.05 equiv.) refluxed for 3–5 h in N2-degassed DME:H2O (3:1) v/v), TLC
analyzed.
b
c
Diethyl-(4-pyridl)borane (1.1 equiv.), NaOH (3 equiv.), Bu4NBr (0.5 equiv.), Pd(PPh3)4(0.05 equiv., refluxed for 3–5 h in THF, TLC analyzed.
Phenylboronic acid (1.1 equiv.), Na2CO3 (1.5 equiv.), Pd(dppf)Cl2 (0.05 equiv.) refluxed for 3–5 h in N2-degassed DME:H2O (3:1) v/v), followed
by TLC.
d
e
f
Prepared by literature procedure.23
Available from Aldrich.
Prepared by literature procedure.24
g
Yields are given for pure products isolated by flash chromatography on silica gel.

G. A. Morris, S. T. Nguyen / Tetrahedron Letters 42 (2001) 2093–2096
2095
(2)
(3)
(4)
Finally, we decided to examine the Pd-catalyzed cross-
coupling reactions of aryl halide 5 with organoboron
reagents as a way to prepare 4. We decided on this
coupling direction because it would allow us to synthe-
size a series of salicylaldehydes from a single pyridylbo-
rane.18 We initially planned to use diethyl-(4-
pyridyl)borane as a coupling reagent. However, the
preparation of this compound proved to be difficult, as
we were unable to reproduce the results of a literature
procedure.6 While we were eventually able to make
diethyl-(4-pyridyl)borane using an alternative proce-
dure,19 the crude yield was a disappointing 41%. As a
result, we turned to the commercially available 4-
pyridylboronic acid 7.20 We were pleased that the
Pd(dppf)Cl2-catalyzed cross-coupling reaction between
7 and aryl halide 5 provided heterobiaryl compound 4
in 74% yield (Eq. (3) and Table 1). The coupled product
4 could then be converted to the targeted salicylalde-
hyde 1 using a two-step procedure consisting of depro-
tection of the hydroxymethyl group followed by
oxidation to the aldehyde.
boron reagents are known to undergo more facile
protodeboronation.22
In conclusion, we have shown that the Pd-catalyzed
cross-coupling reaction between either 4-pyridylboronic
acid or diethyl-(3-pyridyl)borane and bromosalicylalde-
hydes can provide direct access to a variety of highly
functionalized 3- and 4-arylpyridines. This procedure is
quite versatile and makes use of commercially available
organoboron reagents.
Acknowledgements
This work was supported by the National Science
Foundation’s Partnership in Nanotechnology initiative
(NSF grant cCHE-9811334) and by the EMSI pro-
gram of the National Science Foundation and the
Department of Energy (NSF grant cCHE-9810378) at
the Northwestern University Institute for Environmen-
tal Catalysis. STN thanks the Dreyfus Foundation, the
du Pont Company, the Beckman Foundation, and the
Packard Foundation for financial support. We grate-
fully acknowledge Frontier Scientific chemical company
for providing samples of 4-pyridylboronic acid.
Even more gratifying was the fact that salicylaldehyde 1
could also be obtained directly through the Pd(dppf)-
Cl2-catalyzed cross-coupling reaction between bromo-
aldehyde 8 and boronic acid 7 in 67% yield (Eq. (4)).
Thus, this methodology enabled us to prepare the
target biaryl compound in a single step. This method
could be readily applied to a variety of bromosalicyl-
aldehydes such as 9, which produced the biaryl alde-
hyde 10 in 66% yield.21
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G. A. Morris, S. T. Nguyen / Tetrahedron Letters 42 (2001) 2093–2096
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