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5-bromo-1,2,3-triazine under the standard reaction conditions,
furnishing the corresponding 3-nitrile pyridines 13eâ 16e in good
yields rather than Î -amino pyridines. In addition, various triazines
could also be converted into the 3-nitriles products in high yields
17eâ 19e. Furthermore, this selectivity was not suppressed by
varying the reaction conditions, and the results show that the
ketones are more reactive than the substituted acetonitriles. Next,
we investigated the preparation of bi- and terpyridines, which are
known to coordinate with a wide variety of metal ions, and
considerable progress has been made in their homogeneous
catalysis [4]. They are also common in natural products and
pharmaceuticals [1,2]. However, traditionally, the synthesis of
these compounds requires non-trivial multistep synthesis or
metal-catalyzed coupling reactions. Therefore, the development
of new methods to synthesize bi- and terpyridines easily is highly
attractive. Interestingly, the reaction of the various 1,2,3-triazines
with β-pyridine ketone ester generated the expected 2,2'-
bipyridine products 20eâ 22e in high yields. Similarly, reactions
with β-(2-methyl-pyridine) ketone and β-isoquinoline afforded
the corresponding bipyridines 23eâ 24e in excellent yields,
indicating that the current transformation is insensitive to the
steric bulk of the substituents. Fortunately, the reactions of 1,2,3-
triazines with diketones also afforded the 2,2':6',2â -terpyridine
products 25eâ 26e in good yields, further expanding the service-
ability of this transformation.
In general, the resulting substituted pyridines are convenient
precursors for subsequent modification or transformation. As
shown in Scheme 4, we applied this method to synthesize
bioactive molecules and pharmaceuticals. Compound 2c could be
converted into imidazo[1,2-a]pyridine structural unit f via a simple
cyclization reaction (Scheme 4a). The f is a synthetic precursor of
bioactive molecule SC-53606, which is a selective 5-HT4 receptor
antagonist [13]. Moreover, we applied this reaction to the synthesis
of the marketed pharmaceutical etoricoxib, which is used to treat
osteoarthritis, rheumatoid arthritis, acute gouty arthritis, and
ankylosing spondylitis, and can also be used to treat acute pain and
chronic musculoskeletal pain [14]. The first synthesis was
accomplished by Merck in a six-step sequence starting from 3-
bromo-5-chloropyridin-2-ol [14a]. Fortunately, using our method,
the gram-scale reaction of 5-chloro-1,2,3-triazine 2a with the
corresponding ketone delivered etoricoxib 27e in 82% yield in one
step (Scheme 4b). The divergent synthesis of etoricoxib with B ring
modification were also expediently achieved by using various
1,2,3-triazines, these compounds (28eâ 31e) are attractive as
potential feedstocks for the structureâ activity relationship (SAR)
studies of etoricoxib analogues. These transformations also proved
to be effective for the synthesis of 2,3-diaryl substituted pyridines.
Furthermore, to demonstrate the utility of 5-bromopyridines as
effective coupling partners, we explored their application in the
synthesis of bioactive bipyridine compound h, which is a selective
orexin 2 receptor antagonist (2-SORA) for the treatment of
insomnia [15]. Specifically, the ammonolysis reaction of the ester
and Suzuki cross-coupling afforded compound h, demonstrating
the tolerance of our method toward a polypyridine systems
(Scheme 4c).
Inverse electron demand Dielsâ Alder reactions is a type of
pericyclic reactions, in which the driving force is heat (thermal
reaction) or light (photochemical reaction) [7e,7g]. However, our
reactions can also be performing at room temperature. Therefore,
we consider that our reaction is more likely to be a stepwise
nucleophilic addition process. Based on our experimental results, a
possible mechanism is proposed in Scheme 5. Initially, in the
presence of a base, the intermediate I or I' is formed by the addition
of substituted acetonitriles or ketones to the C4-position of 1,2,3-
triazines, respectively. Moreover, the intramolecular nucleophilic
addition of nitrogen anion to the cyano or carbonyl group results in
strained bridged-ring intermediate II or II', followed by the release
of N2, thus forming intermediate III or III'. Finally, the former
intermediate forms Î -amino pyridines c through isomerization of
the Câ=âN double bond, whereas the latter forms pyridines e with
the generation of H2O.
In summary, we have developed a cascade nucleophilic addition
reaction with 1,2,3-triazines and substituted acetonitriles or
ketones for convenient access to a range of pyridine-containing
products. Synthetically important bi- and terpyridines were also
effectively obtained using this method. In particular, the marketed
pharmaceutical etoricoxib, as well as its analogues were synthe-
sized in one step with high yields. The developed method was also
employed for the synthesis of several bioactive molecules. In
general, this strategy is highly practical for the synthesis of
pharmaceuticals and bioactive compounds. Thus, we anticipate
that our methods will be widely used by the synthetic chemistry
community.
Scheme 4. Synthetic applications.
Scheme 5. The proposed mechanism.
Please cite this article in press as: Y. Zhang, et al., Access to pyridines via cascade nucleophilic addition reaction of 1,2,3-triazines with activated
Zhang, Yuan
