Scheme 2.11 Site‐specific intermolecular γ‐C(sp3)–H functionalization of ketones via iminyl radicals.
Source: Jiang and Studer [36], Morcillo et al. [37], and Davies et al. [38].
2.3.2.2 1,5‐HAT via Amidyl and Sulfamidyl Radicals
A related approach for nitrogen radical generation was then used by the Leonori group to introduce a range of functionalities at the γ‐position of amides and at the δ‐position of protected amines using carboxylic acid‐containing hydroxyamides 49 (Scheme 2.12) [37]. In analogy to their previous work on iminyl radicals, photoinduced oxidation of 49 under basic conditions enabled amidyl radical generation, followed by 1,5‐HAT and distal carbon radical functionalization. In this case, halogenating agents such as NCS and selectfluor allowed introduction of γ chlorine and fluorine atoms, while S‐containing phthalimides enabled direct thioetherification. More importantly, 2‐iodoxybenzoic acid (IBX) reagents were successful to achieve remote C—C bond formation and introduce CN as well as alkyne functionalities. This strategy enabled the selective modification of tertiary, secondary, and even primary centers and was also used for the late‐stage functionalization of small dipeptides.
A very powerful approach for distal functionalization of amides has been possible from the corresponding N–H substrates using photoinduced proton‐coupled electron transfer (PCET). As initially demonstrated by Knowles and coworkers, this activation mode bypasses the need to install a stoichiometric electrophore on the substrates and therefore streamlines the preparation of the desired reaction products. This strategy has been initially used to trigger cyclization reactions [39], and also used in interrupted HLF‐type reactivity as demonstrated by the groups of Knowles and Rovis (Scheme 2.13) [40, 41]. Following a reductive‐quenching photoredox cycle and in the presence of a suitable base, 50 was effectively oxidized by photoinduced PCET generating the amidyl radical 51. This species was exploited in a 1,5‐HAT transposition and the resulting carbon radical 52 reacted with a Michael acceptor (53), thus assembling a distal sp3–sp3 C—C bond. Owing to electron‐poor nature of the intermediate α‐ester radical 53, the photoredox cycle was closed by SET with the reduced Ir(II) photocatalyst that delivered the stabilized anion 54 that was protonated. The design of the amide substrates was critical to the feasibility and the overall success of the PCET as the carbonyl functionality must be able to acidify the N–H proton enough to encourage the deprotonation step. This somewhat controlled the nature of the amidyl radicals that could be generated. Nevertheless, this methodology displayed strong functional group tolerance as demonstrated by the number of Michael acceptors and functionalized amides that could be used.
Scheme 2.12 Nitrogen radical mediated remote functionalization of amides and amines.
Source: Modified from Morcillo et al. [37].
Scheme 2.13 Amide‐directed selective C—C bond formation at C(sp3)—H bonds.
Source: Choi et al. [40] and Chu and Rovis [41].
This PCET reactivity for amidyl radical generation and 1,5‐HAT has also been exploited by Tamber to achieve remote amide allylation using allyl chlorides and a Ni(0) cocatalyst (Scheme 2.14) [42].
A powerful expansion of this PCET strategy for amidyl radical generation and 1,5‐HAT has been recently introduced by Rovis and coworkers, who merged the photoredox manifold with nickel catalysis (Scheme 2.15) [43]. This dual catalytic process used alkyl bromides as coupling partners and enabled a site‐selective C–H alkylation delivering products 55. Mechanistically, the trifluoroacetic acid (TFA)‐amide was oxidized through PCET by the excited Ir(III) catalyst upon visible light irradiation to form the amidyl radical 56. This species underwent 1,5‐HAT, delivering the carbon radical 57. At the same time, oxidative addition of a nickel(I) complex 58 to the alkyl bromide resulted in an alkyl–Ni(III) complex 59 that was proposed to undergo SET with the reduced photocatalyst. This event would close the photoredox cycle and generate an alkyl–Ni(II) species 60 that could be intercepted by 57. This radical transmetalation enabled access to a dialkyl–Ni(III) intermediate 61 from which reductive elimination is facile. This final step would forge the key sp3–sp3 C—C bond and close the nickel cycle. Although this reactivity is restricted to the use of primary alkyl bromides as coupling partners, the authors demonstrated its ability to construct a broad range of remotely alkylated products.
Scheme 2.14 Remote amide allylation using allyl chlorides and Ni(0) cocatalyst.
Source: Modified from Xu and Tambar [42].
Scheme 2.15 Regioselective cross‐coupling of C(sp3)—H bonds and alkyl bromides under a combination of photoredox and nickel catalysis.
2.3.3 Photoinduced Bond Homolysis
The weak nature of N—X (X = halogen) bonds has historically been of fundamental importance for the development of HLF reactions. However, the requirement for prior synthesis of N‐iodo or N‐bromo amines, which are sometimes unstable, represented a significant limitation.
In a series of elegant reports Muñiz and coworkers developed conditions for HLF conversion of unfunctionalized N‐Ts amines 62 into the corresponding pyrrolidines 63 by using substoichiometric amounts of I2 and the I(III) reagent PhI(mCBA)2 as the oxidant (Scheme 2.16) [44–46]. These processes are believed to be initiated by the reaction of I2 with PhI(mCBA)2 that leads to the formation of I(mCBA) 64, the active catalyst. Following detailed mechanistic studies, the authors suggested that this species promoted the in situ formation of an N‐iodo–N‐Ts amine 65, which underwent facile N—I bond homolysis upon visible light irradiation. Following
