Direct C-H Hydroxylation of N-Heteroarenes and Benzenes via Base-Catalyzed Halogen Transfer.

Hydroxylated (hetero)arenes are valued in many industries as both key constituents of end products and diversifiable synthetic building blocks. Accordingly, the development of reactions that complement and address the limitations of existing methods for the introduction of aromatic hydroxyl groups is an important goal. To this end, we apply base-catalyzed halogen transfer (X-transfer) to enable the direct C-H hydroxylation of mildly acidic N-heteroarenes and benzenes. This protocol employs an alkoxide base to catalyze X-transfer from sacrificial 2-halothiophene oxidants to aryl substrates, forming SNAr-active intermediates that undergo nucleophilic hydroxylation. Key to this process is the use of 2-phenylethanol as an inexpensive hydroxide surrogate that, after aromatic substitution and rapid elimination, provides the hydroxylated arene and styrene byproduct. Use of simple 2-halothiophenes allows for C-H hydroxylation of 6-membered N-heteroarenes and 1,3-azole derivatives, while a rationally designed 2-halobenzothiophene oxidant extends the scope to electron-deficient benzene substrates. Mechanistic studies indicate that aromatic X-transfer is reversible, suggesting that the deprotonation, halogenation, and substitution steps operate in synergy, manifesting in unique selectivity trends that are not necessarily dependent on the most acidic aryl position. The utility of this method is further demonstrated through streamlined target molecule syntheses, examples of regioselectivity that contrast alternative C-H hydroxylation methods, and the scalable recycling of the thiophene oxidants.

Nucleophilic C-H Etherification of Heteroarenes Enabled by Base-Catalyzed Halogen Transfer.

We report a general protocol for the direct C-H etherification of N-heteroarenes. Potassium tert-butoxide catalyzes halogen transfer from 2-halothiophenes to N-heteroarenes to form N-heteroaryl halide intermediates that undergo tandem base-promoted alcohol substitution. Thus, the simple inclusion of inexpensive 2-halothiophenes enables regioselective oxidative coupling of alcohols with 1,3-azoles, pyridines, diazines, and polyazines under basic reaction conditions.

Organic Superbases in Recent Synthetic Methodology Research.

Organic superbases are a distinct and increasingly utilized class of Brønsted base that possess properties complementary to common inorganic bases. This Concept article discusses recent applications of commercial organic superbases in modern synthetic methodologies. Examples of the advantages of organic superbases in three areas are highlighted, including the discovery of new base-catalyzed reactions, the optimization of reactions that require stoichiometric Brønsted base, and in high-throughput experimentation technology.

Base-catalyzed aryl halide isomerization enables the 4-selective substitution of 3-bromopyridines.

The base-catalyzed isomerization of simple aryl halides is presented and utilized to achieve the 4-selective etherification, hydroxylation and amination of 3-bromopyridines. Mechanistic studies support isomerization of 3-bromopyridines to 4-bromopyridines proceeds via pyridyne intermediates and that 4-substitution selectivity is driven by a facile aromatic substitution reaction. Useful features of a tandem aryl halide isomerization/selective interception approach to aromatic functionalization are demonstrated. Example benefits include the use of readily available and stable 3-bromopyridines in place of less available and stable 4-halogenated congeners and the ability to converge mixtures of 3- and 5-bromopyridines to a single 4-substituted product.

Catalytic α-Selective Deuteration of Styrene Derivatives.

We report an operationally simple protocol for the catalytic α-deuteration of styrenes. This process proceeds via the base-catalyzed reversible addition of methanol to styrenes in DMSO -d6 solvent. The concentration of methanol is shown to be critical for high yields and selectivities over multiple competing side reactions. The synthetic utility of α-deuterated styrenes for accessing deuterium-labeled chiral benzylic stereocenters is demonstrated.

Synthesis and characterization of a deuterium labeled stercobilin: A potential biomarker for autism.

Stercobilin is an end-stage metabolite of hemoglobin, a component of red blood cells. It has been found that there is a significantly lower concentration of stercobilin in the urine of people diagnosed with autism spectrum disorders, suggesting potential use as a biomarker. In vitro, we have synthesized stercobilin from its precursor bilirubin through a reduction reaction proceeded by an oxidation reaction. In addition, we have isotopically labeled the stercobilin product with deuterium using this protocol. Nuclear magnetic resonance investigations show the products of the unlabeled stercobilin (Rxn 1) and the deuterated stercobilin (Rxn 2) both had a loss of signals in the 5.0- to 7.0-ppm range indicating proper conversion to stercobilin. Changes in the multiplicity of the sp3 region of the proton nuclear magnetic resonance suggest proper deuterium incorporation. Mass spectrometry studies of Rxn 1 show a difference in fragmentation patterns than that of Rxn 2 proposing potential locations for deuterium incorporation. This isotopologue of stercobilin is stable (>6 mo), and further analysis permits investigation for its use as a biomarker and potential quantitative diagnostic probe for autism spectrum disorders.