Chichibabin‐Type Phosphonylation of 2‐(Hetero)aryl Pyridines: Selective Synthesis of 4‐Phosphinoyl Pyridines via an Activated N‐Benzylpyridinium Salt

Abstract

A direct C−H phosphonylation of pyridine by N‐benzylating activation is reported, which afforded 4‐pyridylphosphine oxides with high regioselectivity, without the employment of metal catalyst or expensive activator. By increasing the electrophilicity of pyridinium with electron‐withdrawing substituents on the N‐benzyl group, the phosphonylation process could be realized at room temperature. Control experiments and NMR investigation confirmed the interaction between DBU and diphenylphosphine oxide which generated the true phosphorus nucleophile. Moreover, DFT calculations offered enough insight into an intermolecular cooperative dehydrogenation‐debenzylation mechanism, which helped to elucidate the origin of C4‐regioselectivity in this metal‐free Chichibabin‐type phosphonylation.

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004–2024

“…N-Ethoxypyridinium salts 792 can be selectively phosphonylated at C-4 through a visible lightpromoted reaction that uses diphenylphosphine oxide, quinolinone Q (795, Figure 12) as photocatalyst, an oxidant such as K 2 S 2 O 8 and NaHCO 3 as a base (Table 4). 404 4-Phosphinoylpyridines 794 can also be achieved in moderate to good yields through of 2susbtituted N-benzylpyridinium bromides in the presence of 2 equiv of DBU in 1,4-dioxane at 100 °C in an air-open 405 Using polyethylene glycol (PEG) as a solvent and trialkyl phosphites 797 as a phosphorus source, some N-heterocyclic halides 796 and 799 are converted to the corresponding phosphonate derivatives 798 and 800 through a Michaelis− Arbuzov reaction (Scheme 143). The presence of PEG in this reaction has several advantages: it decreases the reaction time, allows mild experimental conditions, is environmentally friendly and can be recovered and reused due to its thermal stability.…”

“…N-Ethoxypyridinium salts 792 can be selectively phosphonylated at C-4 through a visible light-promoted reaction that uses diphenylphosphine oxide, quinolinone Q ( 795 , Figure ) as photocatalyst, an oxidant such as K 2 S 2 O 8 and NaHCO 3 as a base (Table ). 4-Phosphinoylpyridines 794 can also be achieved in moderate to good yields through a direct C–H phosphonylation of 2-susbtituted N-benzylpyridinium bromides in the presence of 2 equiv of DBU in 1,4-dioxane at 100 °C in an air-open flask …”

C3-selective C–H thiolation of quinolines via an N-arylmethyl activation strategy

“…Our group previously realized the nucleophilic C2-trifluoromethylation, C2-polyfluoroarylation, and C4-phosphorylation of pyridines using an operationally simple N -alkyl pyridinium salt activation strategy. 14 In continuation of our effort on the exploration of the further application of this activation strategy and development of a new protocol for achieving the C3–H thiolation of quinoline, we report herein a novel quinoline C3–H thiolation system with a broad substrate scope and good functional group compatibility enabled by an N -benzyl or N -naphtha-1-ylmethyl quinolinium salt activation strategy (Scheme 1C). Notably, this reaction proceeds via C3-selective radical addition to afford the key radical cation intermediate, and then an auto-deactivation process (heterolysis or homolysis of the N–C bond) takes place to afford the product.…”

Transition Metal-Free Regioselective Phosphonation of Pyridines: Scope and Mechanism

“…In contrast to transition metal and photocatalytic methods outlined above, the use of polar chemistry to achieve selective C-4 phosphonation has not been extensively investigated . As part of our interest to develop mechanistically driven approaches for the formation of C–P, − we hypothesized that the use of oxidative Chichibabin-type reaction, that is, nucleophilic addition of a phosphine oxide anion to an activated pyridine followed by oxidative aromatization, would provide a straightforward access to C-4 phosphonated pyridines through the mechanism outlined in Scheme …”