ARTICLES https://doi.org/10.1038/s41929-021-00652-8 Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer Bartosz Górski1,3, Anne-Laure Barthelemy 1,3, James J. Douglas 2, Fabio Juliá 1 ✉ and Daniele Leonori 1 ✉ Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature. The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues. itrogen-rich molecules form the structural basis of almost species10. The potential of these two elementary steps to assemble a every pharmaceutical and agrochemical lead, as well as broad array of sp3 C–Y bonds (Y = C, N, O, S, halogen) represents a many other high-value products like food additives and powerful opportunity for modular fragment coupling11. N 1 organic materials . A large fraction of these chemotypes contain Despite these prominent features, copper catalysis has seen lim- bonds between nitrogenated residues and saturated carbons, which ited applications to the amination of unactivated alkyl halides12,13. makes the development of methods for sp3 C–N bond construction As shown in Fig. 1c, the overall amination using a [Cu(i)–amido] integral to both academia and industry (Fig. 1a)2–4. species would require initial single-electron transfer (SET) reduc- One classical method is N-alkylation with alkyl (pseudo) tion of the halide, followed by radical capture to give the [alkyl– halides using textbook SN2 (bimolecular nucleophilic substitu- Cu(iii)–amido] complex that undergoes fast reductive elimination. tion) chemistry; however, this reactivity has major limitations in Although radical recombination and reductive elimination are complex molecular settings5. Indeed, while substitutions on pri- very facile, the low reduction potential of unactivated alkyl halides mary substrates are easy to perform, extension to secondary and (Ered < −2 V versus saturated calomel electrode (SCE)) thwarts their tertiary substrates is challenging due to their increased steric hin- activation by Cu(i), ultimately limiting synthetic applications. This drance. The requirement for forcing conditions (strong bases, high lack of reactivity contrasts with the ubiquitous applicability of acti- temperatures) often results in low yields and leads to competitive vated substrates, such as α-carbonyl and benzylic halides14,15, that E2-elimination to alkene by-products. The intrinsic difficulties are much easier to reduce (Ered > −1.5 V versus SCE) and therefore in SN2 reactivity are underscored by the fact that, among all the readily engage in Cu-catalysis. N-nucleophilic substitutions reported in the literature, 93% take In an effort to address this issue, two main approaches have place on primary alkyl halides and only 6% and 1% involve second- emerged in recent years, both relying on the use of photochem- ary and tertiary substrates, respectively (Fig. 1b and Supplementary istry to aid the radical generation step. Fu and Peters reported Fig. 30). Furthermore, the limited pool of substitutions at second- pioneering works using photochemistry to engage unactivated ary centres is largely biased towards the use of activated electro- alkyl and aryl halides in C–N bond formations16–18. In these philes (for example, benzylic, α-carbonyl), making the frequency of examples, photoexcitation of the transient amido–Cu(i) complex nucleophilic displacement at unactivated secondary halides <1.5%. (amido = carbazole, indole, amide) is required to access a highly As a result, the preferred route to assemble C–N bonds on second- reducing species from which SET reduction of the organic halides ary sp3 centres is largely based on the use of ketones via reductive is possible. This strategy, which hinges on the photochemical per- aminations6,7, but this is only feasible for the reaction of alkylamines formance of the amido–Cu(i) complex and is therefore highly and cannot be extended to other valuable N-nucleophiles such as dependent on the N-nucleophile structure, activates the alkyl azoles, amides and carbamates. halide by SET and often requires high-energy UV-light irradia- The limitations of these polar approaches have recently trig- tion (hν = 254 nm)19. gered the exploration of alternative reactivity modes based on radi- An alternative avenue for copper-catalysed aminative cal chemistry. In this context, copper catalysis has demonstrated cross-coupling relies on the combination with visible-light pho- a unique versatility in orchestrating coupling reactions involving toredox catalysis and the use of carboxylic acids or their activated carbon-radical intermediates5,8. The success of these transforma- derivatives as alkyl radical precursors20–22. In these cases, radical tions generally relies on the ability of Cu(ii) complexes to trap car- generation by SET reduction is facile (Ered > −1.5 V versus SCE), bon radicals at near diffusion-controlled rates9, and then undergo but the extension of this approach to unactivated alkyl halides is facile reductive elimination from the resulting high-valent Cu(iii) challenging. 1Department of Chemistry, University of Manchester, Manchester, UK. 2Early Chemical Development, Pharmaceutical Sciences R&D, AstraZeneca, Macclesfield, UK. 3These authors contributed equally: Bartosz Górski, Anne-Laure Barthelemy. ✉e-mail: [email protected]; [email protected] NATURE CATALYSIS | VOL 4 | JULY 2021 | 623–630 | www.nature.com/natcatal 623 ARTICLES NATURE CATALYSIS a OPh X N S 2 N H N Effective for 1° or N activated 2° alkyl halides NH2 N N O N N N N N N N N HN CN Reductive O Common for alkylamines amination N O but not feasible for N-heteromatics O Imbruvica Xeljanz Kytril Anticancer Immunosuppressant Antiemetic b c Unactivated 2° alkyl halide (I) (II) 27% [Cu] N [Cu] N (III) I [Cu] N Total frequency of N S 2 reactions N SET Radical Reductive using activation capture elimination N-nucleophiles Challenging Facile Facile Activated 2° alkyl halide 73% ‡ R I R N R Halogen-atom transfer (XAT) R N X X X XAT bypasses challenges in –δ I +δ R redox catalysis R Primary : 93% Secondary : 6% Tertiary: 1% Facile Fig. 1 | Relevance and assembly of sp3 C–N bonds. a, Molecules containing sp3 C–N bonds are widespread among many high-value materials. However, these bonds are still challenging to assemble. b, Analysis of substitution reactions involving N-nucleophiles and alkyl halides. c, The use of copper catalysis in the amination of unactivated alkyl halides is hampered by the initial SET reduction. Here we demonstrate that XAT using α-aminoalkyl radicals can be used to bypass this issue and enable catalytic sp3 C–N bond formation. Overall, the limited capacity to access strong reducing species 3-chloroindazole 2. Starting with a Cu(i) catalyst, base-aided azole remains the key element restricting general application of copper coordination is expected to afford the [Cu(i)–2] complex A. At this catalysis in amination chemistry. From this perspective, a strategy stage, we postulated that the known ground-state SET between able to circumvent the problematic alkyl halide SET reduction, Cu(i) and a peroxide B could be used to simultaneously obtain a while still benefitting from the ability of copper to forge sp3 C–N [Cu(ii)–2] complex C and an electrophilic O-radical, D28. This spe- bonds by reductive elimination, might provide a powerful tool cies would have the appropriate philicity and reactivity profile to towards achieving the assembly of complex nitrogenated motifs. undergo HAT selectively at the α-N position of alkyl amine E29. The Recently, ourselves23,24 and the group of Doyle25,26 have demon- activated nature (bond-dissociation energy (BDE) = 91 kcal mol−1)30 strated that alkyl radicals can be accessed from the corresponding and hydridic character of this C–H bond should lead to a halides by exploiting the ability of α-aminoalkyl radicals to trigger polarity-matched process resulting in the α-aminoalkyl radical F. halogen-atom-transfer (XAT) reactions. This blueprint for radical This species is the key agent for the homolytic activation of iodide 1 generation is facilitated by the interplay of strong polar effects in through XAT and would generate the alkyl radical G (and iminium the transition state of the halide abstraction step27 and can be used H). At this point, fast capture of radical G by C would provide the as part of C–C bond-forming strategies such as Giese alkylation high-valent [alkyl–Cu(iii)–2] species I from which reductive elimi- and Heck-type olefination. We recently questioned if this reactivity nation is facile. This last step would forge the targeted sp3 C–N bond mode could be integrated with copper catalysis to enable sp3 C–N in 3 and regenerate the Cu(i) catalyst. bond formation. Such a strategy would benefit from a carbon–halo- The realization of this approach is not without challenges, gen bond-activation step