a more electrophilic species 78, thus reinforcing the polar effect and resulting in a more favorable 1,5‐HAT process. The resulting carbon radical 79 was proposed to undergo an Fe(III)‐mediated azide transfer to give the product 80 and regenerate the active Fe(II) catalyst. This methodology tolerated several functionalities including alkenes, heterocycles, nitriles, and substituted aromatics. Furthermore, by using N‐acyloxy imidates, valuable β‐azido alcohols (after further hydrolysis) could also be obtained.
Scheme 2.21 Iron‐catalyzed remote C(sp3)–H azidation of ketones via iminyl and imidate radicals.
Source: Modified from Torres‐Ochoa et al. [59].
Cook and coworkers reported the direct Csp3–H fluorination of N–fluoroamides 81, employing Fe(OTf)2 as the catalyst (Scheme 2.22) [60]. The mechanistic studies suggest that Fe(II) could directly cleave the N—F bond to generate an amidyl radical, which underwent nitrogen‐to‐carbon radical relay. Fe‐mediated fluorine transfer gave the products in generally high yields, also showing significant functional group tolerance.
Using a similar strategy, Zhu and coworkers designed a copper‐catalyzed variant, which allowed for a remote arylation using preformed N‐fluoroamides 82 (Scheme 2.23) [61]. Mechanistically, the authors proposed that Cu(I)‐mediated reductive cleavage of the amide N—F bond generated the amidyl radical 83, which underwent 1,5‐HAT from the benzylic position. Simultaneously, the Cu(II) species underwent transmetalation with the arylboronic acid 84, generating an Ar–Cu(II) species. This intermediate was intercepted by the carbon radical 85 to give an Ar, alkyl–Cu(III)complex 86 from which reductive elimination is facile. This step generated the desired arylated product 87 along with the active Cu(I) catalyst. The methodology showed excellent functional group compatibility around the aromatic rings and could also be applied to heteroaromatic substrates. This Cu(I)/(II)/(III) manifold was also extended to the functionalization of nonbenzylic positions. However, these reactions generally gave lower yields owing to the increased flexibility of the chain when compared to the substrates with an embedded aromatic, which have a rigid and defined conformation.
Scheme 2.22 Amide‐directed fluorination of C—H bonds catalyzed by iron.
Source: Modified from Groendyke et al. [60].
Scheme 2.23 Copper‐catalyzed remote arylation of C(sp3)—H bonds via amidyl radicals.
Source: Modified from Li et al. [61].
Scheme 2.24 Enantioselective remote C–H cyanation of amines via copper‐catalyzed radical relay.
Nagib and coworkers have recently provided a solution to the asymmetric synthesis of 3‐aryl substituted piperidines 88 using an interrupted HLF reaction (Scheme 2.24) [62]. By employing a Cu(I) catalyst in the presence of a chiral Box ligand, the authors achieved a rare example of enantioselective remote cyanation of N‐fluoroamides 89 in high yields and excellent enantioselectivities. These cyanated products 90 were then converted in just two steps into the corresponding piperidines. The authors proposed a mechanism where an initial transmetalation between the Cu(I) catalyst and Me3SiCN provided a Cu(I) intermediate capable of reducing the N—F bond in the amide starting materials. This step gave the amidyl radical 91 that underwent N‐to‐C radical relay via 1,5‐HAT. The incipient carbon radical 92 was intercepted by the Cu(II)CN species to give an alkyl–Cu(III)CN 93 intermediate, from which a stereoselective reductive elimination provided the product and regenerated the Cu(I) catalyst. Although this chemistry is only compatible with the functionalization of benzylic positions, the authors applied it to the preparation of a range of cyanated substrates, all synthesized in good yields and enantioselectivities. Next, they subjected a number of products to a two‐step reduction with i‐Bu2AlH (to form a hemiaminal), followed by Et3SiH to furnish the desired C‐3 arylated piperidine products.
2.5 Summary and Conclusions
Nitrogen radicals are powerful intermediates in synthetic chemistry. Their ability to undergo selective H‐atom transfer reactions represents a valuable tool for the assembly and functionalization of organic molecules. Although the large body of work and examples are already available, several challenges are still unsolved. For example, the ability to control in a general sense the stereochemical outcome of these transformations is currently not possible but would be highly desirable. Furthermore, these processes have rarely been used in large‐scale settings, especially at an industrial level, so further work would be required to identify reaction protocols that can be translated into process development. Finally, an area where continuous development and application is required involves the use of these strategies for the late‐stage modification of complex and bioactive materials. The ability to selectively target specific and unactivated sp3‐centers, where a functionality can be introduced, would represent a powerful tool in order to better explore chemical space around lead molecules.
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