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Melvin, Patrick R., et al. Organic Letters 21.5 (2019): 1350-1353.
Tetramethylammonium fluoride (Me₄NF) has been applied as an effective nucleophilic fluoride source in the mild deoxyfluorination of benzaldehydes and α-ketoesters using sulfuryl fluoride (SO₂F₂) under ambient conditions. This methodology enables the selective conversion of carbonyl groups into difluoromethyl- and α-gem-difluoroester-substituted (hetero)arene products with high efficiency.
A wide substrate scope was demonstrated, including aryl, heteroaryl, ortho-substituted aromatics, pyridine, quinoline derivatives, and α-ketoesters. Comparative studies with conventional deoxyfluorination reagents, such as DAST, revealed that the SO₂F₂/Me₄NF system afforded comparable or superior yields across numerous substrate classes, highlighting the reagent's effectiveness. Notably, substrates bearing sterically hindered ortho-substituents and heterocyclic moieties exhibited significantly enhanced conversion and selectivity.
The reaction proceeds under mild, room-temperature conditions, offering operational simplicity and broad functional group tolerance. Me₄NF functions as a stable, cost-effective fluoride source, facilitating the nucleophilic displacement of hydroxyl groups by fluoride in carbonyl-containing compounds without requiring elevated temperatures or harsh reaction conditions.
This study demonstrates the strategic utility of Me₄NF in carbonyl deoxyfluorination reactions, providing a versatile and scalable approach for the synthesis of fluorinated intermediates relevant in pharmaceuticals and agrochemicals. The combination of high selectivity, broad applicability, and operational convenience establishes Me₄NF as a valuable reagent for modern synthetic fluorination methodologies.
Inamoto, Kiyofumi, et al. Tetrahedron 70.43 (2014): 7917-7922.
Tetramethylammonium fluoride (TMAF) has been applied as an efficient activator in the deprotonative functionalization of heteroarenes, enabling C-H bond activation under mild, room-temperature conditions. This methodology exploits TMAF in combination with aminosilanes to generate onium amide bases in situ, which serve as highly reactive deprotonating agents.
In a representative reaction, benzothiazole was deprotonated in the presence of TMAF and tris(trimethylsilyl)amine ((TMS)₃N) in DMF, followed by addition of electrophiles such as ketones or aldehydes. The process efficiently formed C-C addition products in good yields. Subsequent workup and purification via standard extraction and silica gel chromatography afforded the desired functionalized heteroarenes with high selectivity.
Mechanistic insights suggest that TMAF facilitates the formation of onium amide bases that selectively abstract acidic C-H protons of heteroarenes, generating nucleophilic species that undergo subsequent addition to electrophiles. The reaction exhibits broad applicability, accommodating various heteroaryl substrates and electrophilic partners, highlighting TMAF's versatility as a mild, non-metallic activator for C-H functionalization.
This study demonstrates that TMAF provides a practical, high-efficiency strategy for heteroarene derivatization, offering operational simplicity and avoiding harsh conditions. Its use in deprotonative functionalization represents a valuable advancement in synthetic methodology, particularly for the construction of complex heteroaryl frameworks relevant to pharmaceuticals, agrochemicals, and materials science.
Cheng, Hong-Gang, et al. Organic letters 22.1 (2019): 331-334.
Tetramethylammonium fluoride (TMAF) has emerged as a highly effective, selective methylating agent capable of transforming a broad range of nucleophilic substrates-including amides, indoles, pyrroles, imidazoles, alcohols, and thiols-under operationally simple conditions. This methodology distinguishes itself from conventional methylation strategies by eliminating hazardous reagents and offering a wide substrate scope with streamlined purification.
In the reported protocol, substrates (0.40 mmol) are treated with TMAF (1.0 mmol) in toluene at 100 °C or in N-methyl-2-pyrrolidone (NMP) at 160 °C. Reaction times vary from 3 to 72 hours depending on substrate class. Upon completion, workup involves straightforward filtration or aqueous extraction, yielding the corresponding methylated products in high purity.
Computational investigation indicates that TMAF promotes a concerted methylation-deprotonation pathway, in which the fluoride ion activates the tetramethylammonium cation to deliver a methyl group directly to the nucleophilic site. This mechanism provides enhanced selectivity and minimizes side-product formation.
The demonstrated versatility of TMAF across heterocycles, carbonyl derivatives, and heteroatom-containing functional groups highlights its value as a mild, metal-free reagent for methyl installation. This method provides chemists with a practical and scalable alternative for constructing methylated scaffolds relevant to pharmaceuticals, natural product derivatives, and advanced materials.
