Key words
pyridines - piperidines - N-heterocycles - C–H functionalization
Heterocycles are ubiquitous components of biologically active molecules. With the
need for greater efficacy and selectivity in therapeutic agents comes motivation to
create more efficient routes to these functionally complex target molecules to enable
drug discovery and development. In this Cluster, we highlight several modern strategies
that practitioners have recently advanced to tackle this challenge.
Heterocyclic structures are found throughout chemistry. While oxygen and sulfur-containing
rings are important, the most ubiquitous of these – nitrogen heterocycles – are a
prominent structural subclass in biologically active agents, found in ~60% of all
FDA approved drugs.[1] Given this prominence, it is no wonder that these structures have long stimulated
synthetic research efforts.
The Hantzsch pyridine synthesis is 140 years old,[2] but as with most transformations, substitution limitations mandate better methods
to address these deficiencies. Lei Jiao of Tsinghua has surveyed diverse approaches
to pyridine containing and pyridine derived products using a host of activation strategies
in a thorough review.[3]
One method of derivatization that Jiao covers is the Minisci reaction, the addition
of carbon radicals to pyridine-type heterocycles. Regioselectivities tend to be poor,
and sometimes unpredictable. In this Cluster, Phipps and co-workers report efforts
at overcoming this limitation with judicious choice of solvent and additive, leading
to selective and complementary Minisci additions to quinolines.[4]
As mentioned, N-heterocycles are not the only class of interest. Huang and coauthors
summarize approaches to sulfur-based heterocycles in a comprehensive review in this
Cluster.[5] A rapid and modular approach to one oxygen heterocycle – a coumarin – is described
by Sun and Hui.[6]
As important as known heterocycles are, novel ones expand our knowledge of chemical
space, potentially leading to new applcations. Chacon-Garcia and co-workers describe
a simple access to an unknown polycyclic heterocycle with handles in place for subsequent
derivatization.[7] Anderson and colleagues report a rapid assembly of indoles and indolines by a modular
cascade sequence.[8]
Patman and colleagues describe a rhodium(III)-catalyzed reaction coupling benzamides
with feedstock olefins and acetylenes.[9] In addition to the fine chemistry, of note is their dedication to a pioneer in heterocycle
synthesis and direct functionalization – the late Keith Fagnou.
Substituted pyridines continue to challenge us, as they find themselves in many diverse
targets. Liu, Hyde and co-workers at Merck report a simple strategy to assemble a
polysubstituted pyridine.[10]
Heterocycles meet spirocycles – two different substructures that have had enormous
impact in medicinal chemistry – in a manuscript by Jui and co-workers where visible
light photoredox catalysis is used to drive a pyridine-derived hydroarylation reaction.[11]
Last, pyridine functionalization methods are still highly desirable transformations
enabling access to more elaborated heterocyclic structures. McNally has recently described
numerous methods to use pyridyl phosphonium salts as intermediates en route to ligand
coupling strategies to effect substitution on the heterocycle.[12] In this Cluster, McNally reports a halide substitution approach to pyridyl phosphonium
salt formation, in a reaction that proceeds at room temperature.[13]
The approaches described in this Cluster highlight the breadth of challenge and diversity
of solution towards heterocycle synthesis and functionalization. Issues remain, and
tackling them will require further creativity and insight, along with new tools and
new reactivity.
