Benzylic Oxidation and Fluorination of Aromatic Heterocycles: A Synthetic Gap
Nitrogen
containing heterocycles are among the most prevalent components of medicinally
relevant molecules.1 An analysis of FDA approved drugs done by Njarðarson
and coworkers in 2013, concluded that 59% of small-molecule pharmaceuticals
contain a nitrogen heterocycle.1 Among the
25 most common nitrogen heterocycles in small-molecule drugs are thiazoles
(12%), imidazoles (10%), benzimidazoles (5%) and isoxazoles (4%).1 Sulfur-based drugs are also highly
prominent in the pharmaceutical industry with 8% containing a thiophene.2 Thiazoles are also common
sulfur-containing heterocycles in small-molecule therapeutics.2
Some common pharmaceuticals
which contain these aromatic heterocycles are Zyprexa
is an antipsychotic drug that contains a thiophene with an isolated benzylic
position primed for functionalization. It also encompasses four basic nitrogen sites
which could bind a metal center or become oxidized under harsh reaction
conditions. The ubiquity of these scaffolds highlights the importance of accessing these heterocycles as it is crucial
to the drug development and discovery processes. Together, this has generated a need for robust yet mild
methodologies for derivatization.
A continuous trend in drug advancement has been the introduction of fluorine to existing scaffolds since the first FDA approved example in the 1950s.2 Fluorine can be found in 15% of the top 20 drugs as it can provide increased lipophilicity, bioavailability and metabolic stability.2 Such chemical modifications can improve target affinities and perturb other chemical properties such as toxicity and bioavailability ultimately affecting drug potency. The antibiotic flucloxacillin and the mood disorder medication Risperdal both show a common example of drug modification via fluorination of an arene. Methods for selective fluorination of hetero-benzylic positions would provide a new means of introducing fluorine to preexisting drug scaffolds.
A continuous trend in drug advancement has been the introduction of fluorine to existing scaffolds since the first FDA approved example in the 1950s.2 Fluorine can be found in 15% of the top 20 drugs as it can provide increased lipophilicity, bioavailability and metabolic stability.2 Such chemical modifications can improve target affinities and perturb other chemical properties such as toxicity and bioavailability ultimately affecting drug potency. The antibiotic flucloxacillin and the mood disorder medication Risperdal both show a common example of drug modification via fluorination of an arene. Methods for selective fluorination of hetero-benzylic positions would provide a new means of introducing fluorine to preexisting drug scaffolds.
Typically employed methods for benzylic oxidations often involve
the use of stoichiometric reagents such as chromium7,8, manganese10
and hypervalent iodine.11 A handful of metal catalyzed methods have
been developed for benzylic oxidation of pyridines with selenium12, iron13
and copper.14 However, the collective scope of these procedures demonstrates
few other heterocyclic substrates are compatible. Heterocycles contain easily oxidizable heteroatoms,
are prone to epoxidation, and halogenation.
Some benzylic oxidation methods employ harsh oxidants
such as Oxone15 and peroxides16 which are unsuitable for nitrogen and sulfur atoms as well as electron rich π-bonds. The leading explanation for low
reactivity in these reactions is heteroatoms near the resulting ketone chelating to the metal
center preventing re-oxidation of the active catalytic species.9 Other heterocyclic substrates can bind to the metal center shutting the
reaction down completely.
Some isolated examples of hetero-benzylic oxidation involve the use of stoichiometric selenium, manganese, or chromium which are not ideal for large scale synthesis. A few metal-free methods exist4, often using highly basic conditions5 or halogens6 which suffer from limited scopes and low functional group tolerance. Light and iodine6, activated carbon17 and cesium carbonate18, have been shown to oxidize benzylic positions of select aromatic heterocycles. These methods are largely limited to doubly benzylic positions without other sensitive functionalities or complex scaffolds.
Fortunately, these electron rich aromatic heterocycles are a convenient functional handle for radical based functionalizations. The use of N-hydroxyphthalimide (NHPI) catalysts for C-H oxidation of aliphatic substrates has been well studied.7,8 NHPI catalysts combined with cobalt and/or manganese co-catalysts7,8,19 are powerful tools for C-H oxidation of both aliphatic and allylic substrates. A recent publication by Stahl and coworkers demonstrated aerobic oxidation of pyridines using a NHPI/cobalt catalyst.9 However, this transformation was not efficient for other heterocyclic substrates due to catalyst deactivation by chelating products as previously stated. A modified metal-free process, could therefore allow for benzylic oxidation of a broader scope of heterocycles.
Some isolated examples of hetero-benzylic oxidation involve the use of stoichiometric selenium, manganese, or chromium which are not ideal for large scale synthesis. A few metal-free methods exist4, often using highly basic conditions5 or halogens6 which suffer from limited scopes and low functional group tolerance. Light and iodine6, activated carbon17 and cesium carbonate18, have been shown to oxidize benzylic positions of select aromatic heterocycles. These methods are largely limited to doubly benzylic positions without other sensitive functionalities or complex scaffolds.
Fortunately, these electron rich aromatic heterocycles are a convenient functional handle for radical based functionalizations. The use of N-hydroxyphthalimide (NHPI) catalysts for C-H oxidation of aliphatic substrates has been well studied.7,8 NHPI catalysts combined with cobalt and/or manganese co-catalysts7,8,19 are powerful tools for C-H oxidation of both aliphatic and allylic substrates. A recent publication by Stahl and coworkers demonstrated aerobic oxidation of pyridines using a NHPI/cobalt catalyst.9 However, this transformation was not efficient for other heterocyclic substrates due to catalyst deactivation by chelating products as previously stated. A modified metal-free process, could therefore allow for benzylic oxidation of a broader scope of heterocycles.
An organic radical initiator and a novel NHPI catalyst
could achieve the desired benzylic oxidation on a variety of aromatic
heterocycles. An optimal substitution pattern on the arene ring of
the NHPI can alter the reactivity of the catalyst to match the desired
substrates and increase its solubility in organic solvents. These changes could
lower catalyst loadings, increase reaction rates, and allow for open air
conditions through a more oxygen permeable solvent.
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