Tailored cobalt-salen complexes enable electrocatalytic intramolecular allylic C–H functionalizations

Oxidative allylic C–H functionalization is a powerful tool to streamline organic synthesis as it minimizes the need for functional group activation and generates alkenyl-substituted products amenable to further chemical modifications. The intramolecular variants can be used to construct functionalized ring structures but remain limited in scope and by their frequent requirement for noble metal catalysts and stoichiometric chemical oxidants. Here we report an oxidant-free, electrocatalytic approach to achieve intramolecular oxidative allylic C–H amination and alkylation by employing tailored cobalt-salen complexes as catalysts. These reactions proceed through a radical mechanism and display broad tolerance of functional groups and alkene substitution patterns, allowing efficient coupling of di-, tri- and even tetrasubstituted alkenes with N- and C-nucleophiles to furnish high-value heterocyclic and carbocyclic structures. Oxidative allylic C–H functionalizations minimise the need for functional group activation and generate alkenyl-substituted products amenable to further chemical modifications. Here the authors report an oxidant-free, electrocatalytic approach to achieve intramolecular oxidative allylic C–H amination and alkylation by employing tailored cobalt-salen complexes as catalysts.

C atalytic allylic C-H functionalizations are particularly attractive transformations because they maximize step-and atom-economy and the retained or newly formed alkenyl moiety is available for versatile further transformations [1][2][3] . Intramolecular variants of these transformations can provide rapid access to functionalized hetero-and carbocycles. These allylic C-H functionalization reactions are generally catalyzed by noble metals such as Pd, Ru, and Ir and involve either the formation of an allylmetal complex via C-H activation followed by it being attacked by a tethered nucleophile, or sequential nucleometallation and βhydride elimination (Fig. 1a) [1][2][3] . A noticeable drawback of the allyl-metal pathway is that its application to an internal alkene substrate usually produces a mixture of regioisomers, limiting most reactions to terminal alkenes 3,4 . The nucleometallation pathway, on the other hand, is compatible with internal alkenes and has been extensively studied since 1970s for the synthesis of N-heterocycles [5][6][7][8][9] . These intramolecular oxidative amination reactions, referred to as Aza-Wacker cyclizations, can be achieved under mild conditions using palladium catalysis with oxygen as the terminal oxidant, although the cyclization of densely substituted alkenes remains challenging [10][11][12][13][14][15] .
Radical cyclizations are broadly compatible with various alkene substitution patterns because of the high reactivities of the open shell species 16,17 . However, radical-mediated catalytic allylic C-H functionalizations with nucleophiles remain rare due to the lack of catalysts for oxidative radical formation and termination 18 . Nonetheless, since the first report in 1980s, there has been a plethora of studies on intramolecular allylic C-H alkylation of 1,3-dicarbonyl compounds with stoichiometric Mn(III) and Cu (II) salts, which serve the purposes of oxidizing the substrate to a C-radical and converting the cyclized alkyl radical to an alkene, respectively ( Fig. 1b) 19,20 . Following a similar mechanism, we have accomplished Cu(II)-catalyzed intramolecular allylic C-H amination with DMP as the terminal oxidant (Fig. 1c) 21 . The use of stoichiometric sacrificial oxidants poses a significant challenge to product isolation and reaction scale-up 22 . In addition, 3°alkyl radicals are easily oxidized to carbocations by the Cu(II) salts, resulting in by-product formation and yield reduction 23 .
An ideal approach to dehydrogenative transformations is through H 2 evolution without using any chemical oxidants 24,25 , which can be conveniently achieved via organic electrochemistry [26][27][28][29][30][31][32][33][34][35][36][37][38][39] . We 40,41 and others 42 have reported electrochemical allylic C-H amination Fig. 1 Intramolecular oxidative allylic C-H functionalization. a Transition-metal catalyzed allylic C-H functionalization usually proceeds through C-H activation to form allyl-metal species or nucleometallation/β-hydride elimination. b Mn(III)/Cu(II)-mediated intramolecular allylic C-H alkylation of 1,3dicarbonyl compounds. c DMP-promoted, Cu(II)-catalyzed intramolecular allylic C-H amination. d Proposed electrocatalytic approach to achieve intramolecular allylic C-H functionalization. The electrocatalyst facilitates both the initial substrate oxidation and the conversion of the cyclized alkyl radical to an alkene. e Electrocatalytic intramolecular allylic C-H amination and alkylation enabled by tailored cobalt-salen complexes. DMP Dess-Martin periodinane, Cu(eh) 2 copper(II) 2-ethylhexanoate. through direct electrolysis or Cu(II)-mediation, which is highly useful but far from perfect. On the one hand, direct electrolysis is often incompatible with disubstituted internal alkenes 40 ; on the other hand, electrolysis in the presence of Cu(II) requires inconvenient divided cells to avoid Cu(II) reduction and a large excess of supporting salts to increase conductivity 22,42 . In addition, both approaches rely on direct oxidation of substrates on the anode, which necessitates a high anodic potential and consequently limits the scope of functional groups allowed. Furthermore, there is no efficient electrochemical methods for the allylic alkylation reaction. Building on our experience in the electrocatalytic generation of Nand C-centered radicals 17,[43][44][45] , we argue that the aforementioned challenges can be addressed by electrocatalytic allylic C-H functionalization (Fig. 1d).
In this work, we report an efficient and broadly applicable electrocatalytic strategy for the intramolecular allylic C-H amination and alkylation in undivided cells, by employing tailored cobalt-salen complexes as catalysts, which are low in oxidation potentials and well suited for converting alkyl radicals to alkenes (Fig. 1e).

Results and discussion
Reaction development. The electrocatalytic cyclization of carbamate 1 bearing a removable N-PMP group 46 was chosen as a model reaction for optimization (Table 1 and Supplementary  Table 1). We chose to screen a wide variety of cobalt(II) salen complexes as catalysts because they are known to oxidize alkyl radicals to alkenes 47,48 , and share similar oxidation potentials as ferrocene 49 , which had been previously employed to catalyze the electrooxidative generation of N-and C-centered radicals 43,44 . The electrolysis was conducted under a constant current in a three-necked round-bottomed flask equipped with a reticulated vitreous carbon (RVC) anode and a platinum plate cathode. The optimal conditions comprised cobalt-salen complex [Co]-1 as a catalyst, Na 2 CO 3 as a basic additive, and Et 4 NPF 6 as supporting electrolyte, in a mixed solvent of MeCN/MeOH (5:1). Under these conditions, the desired product 2 was obtained in 86% yield as the only observed diastereomer and regioisomer (Table 1, entry 1). Both the Co-catalyst (entry 2) and heating (entry 3) were critical for product formation, whereas omitting Na 2 CO 3 hampered the conversion of 1 and thus decreased the yield of 2 to 52% (entry 4). Reduction of the amount of [Co]-1 to 5 mol% did not affect the yield of 2 but led to the formation of a small amount of side product 2′ (4% yield) that was inseparable from 2 (entry 5). While K 2 CO 3 was similarly effective as Na 2 CO 3 , other bases such as NaOPiv, NaHCO 3 , K 2 HPO 4 , and LiOMe were less efficient in promoting the formation of 2 (Supplementary Table 1). The use of Cs 2 CO 3 as a base resulted in the decomposition of the carbamate 1 to generate MeOCONHPMP in 60% yield and no formation of 2 (Supplementary Table 1). The amount of Et 4 NPF 6 could be reduced to 0.1 equiv. without affecting the reaction efficiency (entry 6). Replacing [Co]-1 with another Co-catalyst that differs in electronic and steric properties, such as [Co]-2, [Co]-3, or [Co]-4, led to sub-optimal results (entry 7). We also tested several other cathode materials and found brass (entry 8) and nickel (entry 9) to be equally suitable as platinum, but not graphite (entry 10), probably because of its high overpotential for proton reduction. Pleasingly, the electrolysis could be performed under air without any apparent yield loss (entry 11).
We next applied our electrochemical method on a decagram scale to further demonstrate its utility. With the help of larger electrodes to allow for higher electric current, we successfully synthesized 10.3 g of 2 in 71% yield, and 12.2 g of 63 in 88% yield (Fig. 4a), the latter of which even improved over what we accomplished on the milligram scale (78%). The scalability of our method coupled with versatile known transformations of the alkene-bearing cyclic carbamate and urea products to valuable structures such as vicinal amino alcohols and diamines makes the electrosynthesis attractive for synthetic applications 40,46,52 . Additional merits of our approach included mitigated sensitivity to steric hindrance and enhanced selectivity in the H-elimination step compared to the use of Cu(II) salts. For example, while the Co-catalyzed electrochemical reaction of trisubstituted alkene 83 afforded the intended allylic amination product 18, a similar but Cu(II)-catalyzed reaction of the analogous 84 ended up in cascade cyclization to give 85 (Fig. 4b). These results suggested that the Co-catalyst that we used was more efficient than Cu(II) in catalyzing the oxidation of sterically hindered 2°alkyl radical intermediates to alkenes. The alkylation of 1,2-disubstituted alkene 86 produced a regioisomeric mixture of 54 and 87 with the use of stoichiometric Mn(III)/Cu(II) salts 23 , but furnished 54 exclusively under electrocatalytic conditions (Fig. 4c). Additionally, Mn(III)/Cu(II)-mediated reaction of 88 formed undesired 89 due to overoxidation of the 3°alkyl radical intermediate to a carbocation and its subsequent solvolysis (Fig. 4d) 23 ; in contrast, this was not observed with Co-catalysis.
Mechanistic investigation. As part of the mechanistic studies, the cyclopropane-bearing substrate 90 was cyclized under the standard reaction conditions to furnish a pair of ring-opening products 91 and 92, suggesting the involvement of an alkyl radical 93 (Fig. 5a) 53 . Reaction of 1 with 3 equiv. of preformed [Co III ] + 95 in the presence of Cs 2 CO 3 under reflux afforded 2 in 20% yield with 78% unreacted 1 (Fig. 5b). Meanwhile, no reaction occurred at rt. or when an insoluble base such as Na 2 CO 3 was employed. These results suggested that 95 could oxidize 1 to 2 but required heating and a base. Cyclic voltammetry (Fig. 5c) revealed that the electrocatalyst [Co]-1 (red trace) could undergo reversible singleelectron oxidation (E p/2 = 0.31 V) to [Co III ] + or reduction (E p/2 = −1.25 V) to [Co I ] − in MeCN/MeOH (5:1). The low oxidation potential of [Co]-1 underpinned the broad functional group tolerance of the electrocatalytic method. While the voltammogram of [Co II ]/[Co III ] + in the presence of 1 remained largely unchanged regardless of whether Na 2 CO 3 was added (without Na 2 CO 3 , cyan trace; with Na 2 CO 3 , olive trace), the employment of NaOMe as a substitute base caused the curve to shift negatively and the reduction wave to disappear, but no catalytic current was observed (black trace). Combined, we deduced that the electrochemically generated [Co III ] + reacted with the conjugate base of 1 but without reverting to [Co]-1 at rt 54 . Interestingly, preparative electrolysis of 1 without using an alkaline additive afforded 2 in 52% yield (see Table 1, entry 4). We speculated that MeO − generated at the cathode might have served as a base to promote substrate oxidation 43,45 .
Based on the above information, we formulated a possible mechanism for our electrocatalytic allylic C-H amination reaction. The Co-catalyst [Co II ] is first oxidized to [Co III ] + at the anode 55  In summary, we have developed an electrocatalytic approach for intramolecular allylic C(sp 3 )-H amination and alkylation. These reactions are catalyzed by molecular cobalt-salen complexes, which oxidize the substrate to initiate radical cyclization and convert the cyclized alkyl radical to the alkene product. The favorable redox potential of the cobalt catalyst, coupled with its high reactivity for the oxidation of 2°and 3°alkyl radical intermediate, contributes to broad reaction compatibility with a diverse range of functional groups and alkene substitution patterns, thereby enabling the efficient synthesis of various high-value alkene-bearing cyclic structures. The synthetic utility of our method is further enhanced by its scalability and elimination of external chemical oxidants. We are convinced that the use of tunable cobalt-salen complexes as molecular electrocatalysts for the oxidative formation and termination of radicals will create vast opportunities for reaction discovery.

Methods
Representative procedure for allylic C-H amination. The substrate (0.2 mmol, 1 equiv.), Et 4 NPF 6 (0.2 mmol, 1 equiv.), Na 2 CO 3 (0.2 mmol, 1 equiv.), and [Co]-1 (0.02 mmol, 0.1 equiv.) were placed in a 10 mL three-necked round-bottom flask. The flask was equipped with a condenser, a reticulated vitreous carbon (RVC) anode (100 PPI, 1 cm × 1 cm x 1.2 cm), and a platinum plate (1 cm × 1 cm × 0.1 cm) cathode ( Supplementary Fig. 3a). The flask was flushed with argon. MeCN (5 mL) and MeOH (1 mL) were added. The electrolysis was carried out at reflux using a constant current of 10 mA until complete consumption of the substrate (monitored by TLC or 1 H NMR). The reaction mixture was cooled to rt. H 2 O (30 mL) and EtOAc (30 ml) were added. The phases were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic solution was dried over anhydrous MgSO 4 , filtered, and concentrated under reduced pressure. The residue was chromatographed through silica gel eluting with EtOAc/hexanes to give the product. All new compounds were fully characterized (see the Supplementary Methods).