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2 Remote Functionalizations Using Nitrogen Radicals in H‐Atom Transfer (HAT) Reactions
Ji Hye Kim, Elizabeth M. Dauncey, and Daniele Leonori
University of Manchester, Department of Chemistry, Oxford Road, Manchester, M13 9PL, UK
2.1 Introduction
Nitrogen‐containing molecules represent a central class of compounds with applications spanning therapeutic agents, agrochemicals, food additives, and materials. Chemical methodologies able to streamline the synthesis and modification of these molecules underpin the development of high‐value products central to the well‐being of our society [1].
Nitrogen radicals are reactive intermediates with powerful applications to the synthesis of nitrogenated molecules [2]. Their reactivity can be used for direct C—N bond formation via exo‐trig cyclization (Scheme 2.1a) and addition to electron‐rich π‐system (Scheme 2.1b) or for remote sp3 carbon functionalization, exploiting their ability to partake in radical transpositions [3, 4]. From this perspective, there are two types of processes that can be used, β‐fission (Scheme 2.1c) and intramolecular 1,5‐H‐atom transfer (1,5‐HAT) (Scheme 2.1d). The former reactivity normally involves radical ring opening of small cyclic systems, while the latter enables the effective functionalization of N‐containing alkyl chains.
This chapter will discuss selected recent advances in the application of nitrogen radicals in the field of 1,5‐HAT. We will arrange the content highlighting the key mechanistic features of the HAT process and will then divide the discussion on the basis of the chemical process used to access the key nitrogen radicals. In each case, we aim to highlight the application of this radical reactivity in the assembly or the late‐stage functionalization of complex and bioactive materials.
2.2 Intramolecular 1,5‐H‐Atom Transfer (1,5‐HAT)
Nitrogen radicals are among the most efficient open‐shell intermediates known to undergo selective transpositions via intramolecular HAT [5, 6]. This reactivity can be used for the functionalization of nitrogenated alkyl chains at specific sp3 carbons that can be difficult to target by either ionic or transition‐metal‐mediated strategies [3]. The HAT process displays a strong 1,5‐selectivity, which means that the sp3 carbon δ to the nitrogen radical is the one that will be functionalized (Scheme 2.2a). This high fidelity has played a fundamental role in the application of these processes in synthetic organic chemistry.
Scheme 2.1 Radical transposition processes using nitrogen radicals.
The ability of nitrogen radicals to undergo very efficient and effective transposition is also of high historical relevance to radical chemistry and organic synthesis as a whole. Indeed, this elementary step is the key event in the named reaction developed over 100 years ago by Hoffman, Löffler, and Freitag (HLF) [7]. Interestingly, the HLF reaction represents the first known example of radical transposition process and a very effective strategy for the construction of pyrrolidine heterocycles [5, 6]. In general terms, this reactivity is based on the conversion of a protonated N‐haloamine (1) into an aminium radical (2) that undergoes very facile 1,5‐HAT, resulting in a nitrogen‐to‐carbon radical relay (Scheme 2.2b). The incipient δ‐carbon radical (3) is then halogenated (SH2) (4) as part of an efficient radical chain propagation. A final basic treatment induces an ionic cyclization reaction, leading to the construction of a pyrrolidine scaffold (5). Although this reactivity has been established over 100 years ago, there is still continuous interest in further developments and innovations especially in terms of expanding the types of functionalizations and also control the overall stereochemical outcome.
Mechanistically, 1,5‐HAT reactions of nitrogen radicals are strongly polarity‐ and enthalpy‐driven processes with stringent geometrical constraints. This means that three main factors need to be considered when approaching the design of these transformations.
Geometrical factors. The 1,5‐HAT process goes through a six‐membered ring transition state, which, depending on the 3D structure of the nitrogen radical, might favor or thwart reactivity [8]. This is seen in a classical example of HLF reactivity for the assembly of a complex‐bridged azabicyclic system (Scheme 2.3a) [9]. Although the intermediate N‐chloroamine 6 contains four different sites with 1,5‐relationship to
