Electroredox Carbene Organocatalysis with iodine cocatalyst

Oxidative carbene organocatalysis, inspired from Vitamin B1 catalyzed oxidative activation from pyruvate to acetyl coenzyme A, have been developed as a versatile synthetic method. To date, the α-, β-, γ-, δ- and carbonyl carbons of (unsaturated)aldehydes have been successfully activated via oxidative N-heterocyclic carbene (NHC) organocatalysis. In comparison with chemical redox or photoredox methods, electroredox methods, although widely used in mechanistic study, were much less studied in NHC catalyzed organic synthesis. Herein, an electroredox NHC organocatalysis system with iodine cocatalyst was developed. With the help of non-uniform distribution of electrolysis system, NHC and iodine, which was normally not compatible in chemical reaction, cooperated well in the electrochemical system. This cocatalyst system provided general solutions for electrochemical single-electron-transfer (SET) oxidation of Breslow intermediate towards versatile transformations. Radical clock experiment and cyclic voltammetry results suggested an anodic radical coupling pathway.

different NHC catalysts (imidazolium, triazolium NHCs), different activation modes (α-, β-, γ-, or δ-carbon functionalization) and enantioselective transformations were still waiting for a general and e cient electrochemical oxidation system. Inspired by the proposed concept of coupled electrolysis in Lin's work 50 in 2018, herein we developed a general electrochemical catalytic system for oxidative carbene organocatalysis. As shown in Fig. 1b, Breslow intermediate was anodic oxidized to radical cation intermediate 51,52 I (Fig. 1b, anodic event A), while iodine radical 53 was also generated on anode (Fig. 1b, anodic event B). The coupling of these two radicals gave intermedaite II, which further affording acyl azolium intermediate after an eliminative regeneration of iodine anion. It is worth to note that iodine can poison carbene catalyst 54,55 (Fig. 1c) and was never applied as oxidant in NHC organocatalysis. However, with the help of non-uniform distribution of electrolysis system 56 , the generation of iodine radical was well kinetically controlled to undergo radical coupling with NHC attached radical intermediate I near anode, without poisoning NHC. This cocatalyst strategy provide new possibility for electrochemical reaction to use the cocatalyst systems which are not compatible in normal chemical reactions. The radical clock experiment of cis-2-phenylcyclopropane-1carbaldehyde gave difference results with traditional chemical oxidant DQ or our electrochemical cocataltic oxidation system. Radical intermediate in our system was believed to undergo a reversible ringopening of cyclopropane, to give the transester product (Fig. 1d). Substrate scope. With optimized conditions in hand, the substrate scope of the model reaction was investigated (Fig. 2). Functional groups in the aromatic ring of the hydrazones such as uoro, methoxy and bromo substituents worked well (3a-3d). 3-pyridyl and 2-furyl substituents in the hydrazone substrates were also tolerated (3e and 3f). Various aryl substituents of the α,β-unsaturated aldehydes were all suitable for this transformation, giving the desired products in good yields with excellent ee (3g-3j). Substrates with different ester substituents were also tolerated, affording the corresponding products with good results (3k and 3l).
Encouraged by the success of electrochemical oxidative reaction on enal γ-carbon, we next evaluated the electrochemical approach for the oxidative β-carbon reaction of enal. As exempli ed in Fig. 3, in the model reaction 60 of formal [3+3] annulation of enals (4) and 1,3-dicarbonyls (5), both imidazolium catalyst B and triazolium catalsyt C were applicable in our anodic coupled electrolysis system (The optimized condition with two catalyst was slightly different in base and solvent, see Supplementary Information for details). Reactions of different 1,3-dicarbonyl compounds with cinnamaldehyde gave the lactone products effectively (6a-6e). Reactions of 2,4-pentandione and enals with different aromatic substituents also successfully afford the corresponding products in moderate yield (6f-6i).
The electrocatalytic protocol for oxidative enal α-carbon atom functionalization was also studied. The formal [2+4] annulation of aliphatic aldehydes 7 and α,β-unsaturated ketones 8 was chosen as a model reaction 15,16 and the results were shown in Fig. 4 (see Supplementary Information for details of condition optimization). Different aliphatic aldehydes reacted with chalcone smoothly, and gave the lactone products in good yield with excellent enantioselectivity (9a-9d). Variation in the chalcone skeleton with different aromatic substituents had little in uence on the of this reaction, and a broad range of groups, such as uoro, chloro, methyl, methoxy and furyl groups were viable to get excellent ee (9e-9i).
For oxidative functionalization of aldehyde carbonyl carbon, an NHC-catalyzed dynamic kinetic resolution of hemiacetal was selected as a model reaction 61 and the results were shown in Fig. 5 (see Supplementary Information for details of condition optimization). One of the biggest challenge of this reaction was to prevent the anodic oxidation of hemiacetal 11 towards phthalic anhydride. Fortunately, the anodic coupled electrolysis system was well kinetically controlled. The oxidation of Breslow intermediate was prior to that of hemiacetal 11, no phthalic anhydride byproduct was observed. Different aromatic aldehydes were appliable in the reaction, giving chiral acetal product 12a-12d with excellent ee.
Miscellaneous reactions and gram-scale synthesis. To further investigate the generality of our catalytic system, additional examples of different model reactions were tried and the results were summarized in Fig. 6. To our delight, the anodic couple electrolysis system was quite general for different reactions, including δ-carbon functionalization of enal 13 towards multisubstituted benzene 14 (Fig. 6a), β-carbon functionalization of enal 4a towards chiral lactam 16 (Fig. 6b) and γ-carbon functionalization of enal 1a towards multicyclic product 18 (Fig. 6c). Brief screening of solvent could nd acceptable condition for these reactions (see Supplementary Information for details). The corresponding products were obtained in moderate yield with excellent ee. An initial test towards scale-up synthesis was also studied. As shown in Fig. 6d, the reaction of 1a and 2a on a 5 mmol scale underwent smoothly for 83.5 hours, giving the desired product 3a 62% yield with 96% ee. In comparison, the traditional chemical oxidant strategy of this reaction may need at least 3 gram of oxidant DQ and will generate the same amount of reductive byproduct (diphenyl diphenone). These results further demonstrate the generality and e ciency of the electrochemical oxidation system.
Mechanistic studies. Some controlled experiments were carried out for mechanistic study, the results were summarized in Fig. 7. In the presence of 50 mol% I 2 , the [4+2] annulation of enal 1a and hydrazone 2a was fully suppressed (Fig. 7a). When 10 mol% I 2 was subjected to the optimized reaction conditions (20 mol% NHC), half of the NHC catalyst A were believed to be poisoned and the result was nearly the same with the reaction with 10% NHC catalyst A (Fig. 7b). This result told us that the poisoned catalyst was probably inert in the reaction. The poisoned catalyst iodination poisoned effect of NHC catalyst was irreversible. Another possible pathway involving iodination of enal substrate was also excluded by the iodination control test (Fig. 7d). To further con rm the existence of key radical intermediate (Fig. 1 (Fig. 7e). Aldehyde cis-20 with cyclopropyl group was conducted in the anodic coupled electrolysis system to undergo a NHC catalyzed oxidative esteri cation reaction. As we expected, due to the radical isomerization towards a more thermal dynamically stabled transstructure (Fig. 7e), ester product trans-21 was obtained as main product. In comparison, cis-20 did not isomerize to trans-20 in the reaction system. And the reaction with traditional chemical oxidant strategy only gave non-isomerized product cis-21. These results clearly showed that the SET oxidation of Breslow intermediate in our anodic coupled electrolysis system is completely different from the traditional electron paired oxidation with chemical oxidant DQ.
The electrochemical properties of different reactants and reagents were investigated in cyclic voltammetry experiments (Fig. 8). In summary, we have developed a modular method of anodic coupled electrolysis system in which NHC catalysis is merged with cooperative iodine anion and electrocatalysis. With the help of non-uniform distribution of electrolysis system, NHC and iodine, which was normally not compatible in chemical reaction, cooperated well in the electrochemical cocatalyst system. This electrochemistry incorporated EtOAc, which was combined with the crude mixture. After concentrated under reduced pressure, the crude residue was puri ed via ash column chromatography to afford the desired product 6.
General produce for electrochemical [3+3] annulation of 4 with 5 by the catalysis of NHC C. The ElectraSyn vial (5 mL) with a stir bar was charged with α,β-unsaturated aldehydes 4 (0.1 mmol, 1.0 equiv.), NHC C (0.02 mmol, 20%), K 2 CO 3 (0.02 mmol, 20%.), n-Bu 4 NI (0.1 mmol, 1.0 equiv.) and 1,3dicarbonyl derivatives 5 (0.2 mmol, 2.0 equiv.) followed by anhydrous CH 3 CN (1.5 mL) and t-BuOH (1.5 mL). The ElectraSyn vial cap equipped with anode (graphite) and cathode (Pt) were inserted into the mixture. After pre-stirring for 2 minutes, the Electrasyn vial was connected to the Electrasyn 2.0 and the reaction mixture was electrolyzed under a constant current of 0.8 mA for a total reaction time of 10 hours accompanied by magnetic stirring. The ElectraSyn vial cap was removed, and electrodes were rinsed with EtOAc, which was combined with the crude mixture. After concentrated under reduced pressure, the crude residue was puri ed via ash column chromatography to afford the desired product 6.
General pressure, the crude residue was puri ed via ash column chromatography to afford the desired product 9.
General produce for electrochemical asymmetric acylation of hydroxyphthalide by carbene-catalyzed dynamic kinetic resolution. The ElectraSyn vial (5 mL) with a stir bar was charged with aldehydes 10 (0.18 mmol, 1.8 equiv.), NHC A (0.02 mmol, 20%), DIEA (0.1 mmol, 100%.), n-Bu 4 NI (0.1 mmol, 1.0 equiv.) and hydroxyphthalide 11 (0.1 mmol, 1.0 equiv.) followed by anhydrous THF (3.0 mL). The ElectraSyn vial cap equipped with anode (Pt) and cathode (Pt) were inserted into the mixture. After pre-stirring for 2 minutes, the Electrasyn vial was connected to the Electrasyn 2.0 and the reaction mixture was electrolyzed under a constant current of 1 mA for a total reaction time of 6 hours accompanied by magnetic stirring. The ElectraSyn vial cap was removed, and electrodes were rinsed with EtOAc, which was combined with the crude mixture. After concentrated under reduced pressure, the crude residue was puri ed via ash column chromatography to afford the desired product 12.      Miscellaneous reactions and gram-scale synthesis.

Supplementary Files
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