δ-C-H Halogenation Reactions Enabled by a Nitrogen-Centered Radical Precursor

Abstract

Nitrogen-centered radicals are versatile synthetic intermediates with the ability to undergo diverse reactions such as hydrogen atom transfer (HAT), β-scission, and addition across unsaturated systems. A long-standing impediment to the wider adoption of these intermediates in synthesis has been the difficulty of their generation. Herein we disclose a new hydrazonyl carboxylic acid precursor to nitrogen-centered radicals and its application toward remote C-H fluorination and chlorination reactions of sulfonyl-protected alkyl amines via 1,5-HAT.

Figure 1

A: Radical HAT as a general means for remote C–H functionalization. B: Our prior development of an oxime precursor to alkoxy radicals for remote C–H halogenation reactions. C: Development of a new hydrazonyl carboxylic acid precursor enables the remote C–H halogenation of sulfonamides.

Figure 2

Preparation of a new hydrazonyl carboxylic acid precursor to nitrogen-centered radicals.

Figure 3

Scope of the δ-C–H fluorination reaction. Yields reported are isolated yields of the monofluorinated products, which may be mixtures of regioisomers. In all cases, except 2e (δ:ε=1:1), the δ-fluorinated product was the major regioisomer (>90%). For some substrates, the formation of δ,δ-difluorinated product was also observed. Substrate 1k was diastereomerically enriched (69:31 d.r.). See experimental section for further details.

Figure 4

Scope of the δ-C–H chlorination reaction. Yields reported are isolated yields. 3f was obtained as a 72:28 mixture of δ:ε-chlorinated products. Product 3d proved unstable to purification and spontaneously cyclized to the corresponding pyrrolidine 3dʹ. Substrate 1k was diastereomerically enriched (69:31 d.r.). See experimental section for further details.

Figure 5

A Proposed catalytic cycle for remote C–H halogenation reactions on the basis of cyclic voltammetry and fluorescence quenching studies. For X = F, Y = 1-(chloromethyl)-1,4-diazabicyclo[2.2.2]octane-1,4-diium ditetrafluoroborate. For X = Cl, Y= ethyl dichloroacetyl. B Quantum yield measurements for the two reactions.