Unlocking carbene reactivity by metallaphotoredox α-elimination.

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates1,2. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon-metal bond. However, these methods are usually prohibitive because of reagent safety concerns, limiting their broad implementation in synthesis3-6. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to metal to forge the initial carbon-metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Here we realize this strategy through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N-H, S-H and P-H bonds from abundant and bench-stable carboxylic acids, amino acids and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

Nonsymmetrical Bis-Azine Biaryls from Chloroazines: A Strategy Using Phosphorus Ligand-Coupling.

Distinct approaches to synthesize bis-azine biaryls are in demand as these compounds have multiple applications in the chemical sciences and are challenging targets for metal-catalyzed cross-coupling reactions. Most approaches focus on developing new reagents as the formal nucleophilic coupling partner that can function in metal-catalyzed processes. We present an alternative approach using pyridine and diazine phosphines as nucleophilic partners and chloroazines where the heterobiaryl bond is formed via a tandem SNAr-phosphorus ligand-coupling sequence. The heteroaryl phosphines are prepared from chloroazines and are bench-stable solids. A range of bis-azine biaryls can be formed from abundant chloroazines using this strategy that would be challenging using traditional approaches. A one-pot cross-electrophile coupling of two chloroazines is feasible, and we also compared the phosphorus-mediated strategy with metal-catalyzed coupling reactions to show advantages and compatibility.

Halogenation of the 3-position of pyridines through Zincke imine intermediates.

Pyridine halogenation reactions are crucial for obtaining the vast array of derivatives required for drug and agrochemical development. However, despite more than a century of synthetic endeavors, halogenation processes that selectively functionalize the carbon-hydrogen bond in the 3-position of a broad range of pyridine precursors remain largely elusive. We report a reaction sequence of pyridyl ring opening, halogenation, and ring closing whereby the acyclic Zincke imine intermediates undergo highly regioselective halogenation reactions under mild conditions. Experimental and computational mechanistic studies indicate that the nature of the halogen electrophile can modify the selectivity-determining step. Using this method, we produced a diverse set of 3-halopyridines and demonstrated late-stage halogenation of complex pharmaceuticals and agrochemicals.

Pyridylphosphonium salts as alternatives to cyanopyridines in radical-radical coupling reactions.

Radical couplings of cyanopyridine radical anions represent a valuable technology for functionalizing pyridines, which are prevalent throughout pharmaceuticals, agrochemicals, and materials. Installing the cyano group, which facilitates the necessary radical anion formation and stabilization, is challenging and limits the use of this chemistry to simple cyanopyridines. We discovered that pyridylphosphonium salts, installed directly and regioselectively from C-H precursors, are useful alternatives to cyanopyridines in radical-radical coupling reactions, expanding the scope of this reaction manifold to complex pyridines. Methods for both alkylation and amination of pyridines mediated by photoredox catalysis are described. Additionally, we demonstrate late-stage functionalization of pharmaceuticals, highlighting an advantage of pyridylphosphonium salts over cyanopyridines.

Facile Pyridine S N Ar Reactions via N-Phosphonium-Pyridinium Intermediates.

Here we report that N-phosphonium pyridinium intermediates are unusually reactive for pyridine S N Ar reactions. Specifically, forming phosphonium salts from halopyridines typically requires elevated temperatures and Lewis acid additives. The alternative activation mode described in this paper permits C-P bond formation to occur at ambient temperatures in many cases, and functions across a broad range of substrates.

Heterobiaryl synthesis by contractive C-C coupling via P(V) intermediates.

Heterobiaryls composed of pyridine and diazine rings are key components of pharmaceuticals and are often central to pharmacological function. We present an alternative approach to metal-catalyzed cross-coupling to make heterobiaryls using contractive phosphorus C-C couplings, also termed phosphorus ligand coupling reactions. The process starts by regioselective phosphorus substitution of the C-H bonds para to nitrogen in two successive heterocycles; ligand coupling is then triggered via acidic alcohol solutions to form the heterobiaryl bond. Mechanistic studies imply that ligand coupling is an asynchronous process involving migration of one heterocycle to the ipso position of the other around a central pentacoordinate P(V) atom. The strategy can be applied to complex drug-like molecules containing multiple reactive sites and polar functional groups, and also enables convergent coupling of drug fragments and late-stage heteroarylation of pharmaceuticals.