Electrochemical or Photoredox Activation of Latent Electrophiles: Three-Component Mumm Rearrangement Cascade Reactions from Alkoxyamines

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Alkoxyamines, such as those derived from 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), are bench-, air-, and moisture-stable compounds. They are directly accessible from a broad range of chemical feedstocks, including activated alkanes, (1) aldehydes, (2,3) alkenes, (4) organohalides, (5) and carboxylic acids (Figure 1A). (6−8) TEMPO-based alkoxyamines (TAs) are most commonly exploited synthetically in polymer chemistry, where they serve as radical initiators or mediators. (9) In these reactions, heating at elevated temperatures facilitates homolytic bond cleavage, which affords a carbon-centered radical and the persistent radical TEMPO. (10) In contrast, the broader applications of TAs in small molecule synthesis remain largely unrealized. (11)

Figure 1

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In 2006, Braslau and O’Brya discovered that cerium ammonium nitrate mediated oxidative cleavage of alkoxyamines which enabled nucleophilic substitution reactions at 70 °C. (12) A decade later, the Knowles group reported that the photoredox-catalyzed one-electron oxidation of certain TAs (A) at ambient temperature generates transient cationic radicals A^+• that undergo mesolytic cleavage to form carbocations (Figure 1B). (13) Exploiting this mode of activation allowed trapping of these electrophiles by an array of nucleophiles, facilitating substitution reactions under mild conditions. (13) In 2018, we combined cyclic voltammetry, EPR spectroscopy and theoretical calculations to demonstrate that mesolytic cleavage of TAs affords carbocations under mild electrochemical conditions. (14) We, subsequently, showed that additional modes of reactivity are possible, including mesolytic cleavage to carbon-centered radicals or S_N2 reactions with weak nucleophiles including common solvents and electrolytes. (2,15) In 2019, we exploited electrochemical activation to reveal the previously inaccessible latent electrophilicity of TEMPO–Me, developing a new methylating agent (Figure 1B). (16) Notably, this reactivity was exclusively restricted to electrosynthesis and was unattainable by photoirradiation or chemical oxidation.

Although photoredox catalysis has enabled alkylations employing TAs with a relatively large number of nucleophiles, (4,13,17−19) the scope of analogous electrochemical methods is confined to carboxylates (Figure 1B). (16,20,21) Nevertheless, cyclic voltammetry indicates that a much wider scope of reactivity is accessible under electrochemical conditions. (2,15) Expanding the range of nucleophiles is therefore crucial for fully realizing the potential of TAs in electrosynthesis and organic synthesis more generally.

The Mumm rearrangement is a multicomponent cascade reaction in which nucleophilic trapping of a carbocation by a nitrile (e.g., CH₃CN) forms a nitrilium ion that is then captured, in situ, by a carboxylic acid. Subsequent rearrangement affords an imide product (Figure 1C). (22) Recently, a handful of Mumm rearrangement protocols have been reported in which anodic oxidation is utilized to access carbocations from activated alkenes, benzylic C(sp³)–H substrates, or via decarboxylation of carboxylic acids. (23−27) In this proof of concept study, we demonstrate that electrochemical triggers enable TAs to serve as synthetically useful, latent carbocations in three-component Mumm rearrangement cascade reactions to generate functionalized imides and imidates. Our work emphasizes that electrochemical activation of TAs can facilitate transformations in which multiple bonds are formed in a single operation─i.e., reactivity beyond the direct alkylation of carboxylic acids. (28) In addition, we investigate and develop analogous photoredox-catalyzed methodology and demonstrate that TAs can serve as masked amides, which can be selectively revealed under relatively mild conditions.

Our investigation commenced with an optimization study examining the reaction of alkoxyamine (1a) and benzoic acid (2a) in an appropriate electrolyte (Table 1). We determined that the reaction of these substrates (1:1.5 ratio of 2a/1a) in an anhydrous electrolyte solution (ⁿBu₄NPF₆ and CH₃CN) employing an undivided cell equipped with graphite working electrodes operating at 10 mA under an argon atmosphere delivered imide 4a in 88% yield after 16 h (Table 1, entry 1). These optimal conditions required very high electron equivalents (29.8 F/mol; current density: ∼5 mA/cm²). (29,30) Shorter reaction times provided lower product yields due to incomplete conversion (41% yield after 4 h; and 74% yield after 12 h), while reaction in air afforded imide 4a in 80% yield (entries 2–4). When we performed the transformation using a nonanhydrous, bench-grade electrolyte in the presence of activated molecular sieves 4Å and air, we obtained a 59% yield (entry 5). (31) Rapid alternating polarity electrolysis (RAP) at 25 Hz (every 0.04 s) did not promote the reaction and returned unreacted starting materials (entry 6). Galvanostatic electrolysis at either 5 or 15 mA did not provide enhanced results (entries 7 and 8). Potentiostatic electrolysis applied at either 1.6 and 1.8 V vs Ag/AgCl afforded product 4a in 40% and 64% yields, respectively (entries 9 and 10). The substitution of ⁿBu₄NPF₆ for either ⁿBu₄NOAc or ⁿBu₄NBF₄ gave lower yields (entries 11 and 12), while a blended solvent system (3:1 CH₂Cl₂/CH₃CN) provided product 4a in 75% yield (entry 13). We found that employing either 1:1 or 1:1.5 ratios of 1a/2a resulted in diminished efficiency (entries 14 and 15). Finally, reaction in a divided cell using a protocol in which compounds 1a and 2a were initially introduced into the anodic chamber delivered imide 4a in 73% yield (entry 16).

Table 1. Influence of Reaction Parameters on Electrochemically-Promoted Mumm Rearrangementsd

^a

¹H NMR yield of 4a using 1,3,5-trimethoxybenzene as internal standard.

^b

Isolated yield.

^c

1 mmol scale, 3 h.

^d

Standard conditions: 0.2 mmol 2a, 1.5 equiv 1a, ⁿBu₄NPF₆ (4 mL of a 0.1 M anhydrous CH₃CN solution), undivided cell equipped with graphite working electrodes, 10 mA, 16 h, Ar.

With the optimized reaction conditions in hand, we initially explored the substrate scope with respect to the carboxylic acid partner (Figure 2). The more sterically encumbered reactant 2-ethylbenzoic acid provided imide 4b in 74% yield. Electronically diverse para-substituted benzoic acids bearing either electron-donating (methoxy) or electron-withdrawing (benzoyl, bromo, and nitro) groups were tolerated under the reaction conditions (4c–4f). Unsurprisingly, we found that employing a divided cell considerably improved the yield of nitro-containing imide 4f. meta-Disubstituted benzoic acids were compatible (4g and 4h), and 2-naphthoic acid afforded the corresponding imide 4i in 74% yield. Notably, pivalic acid and adamantane carboxylic acid were tolerated by our protocol (4j and 4k). The structure of 4k was confirmed by X-ray crystal diffraction. These findings are significant because previously reported electrochemically promoted Mumm rearrangement methods have been typically restricted to aromatic acid substrates. (23−27)

Figure 2

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The alkoxyamine scope was also examined. TAs bearing para-fluoro- and para-phenyl-substituted groups efficiently delivered respective imides 4l and 4m (Figure 2). 4-Chlorobenzyl-substituted TA, which represents an activated primary electrophile afforded imide 4n in a low 31% yield. The generation of tertiary carbocations, such as those derived from cumenyl, tert-butyl and 1-adamantyl systems, gave the corresponding imides (4o–4q) in synthetically useful yields. A cyclohexene-containing TA also engaged in the transformation to furnish imide 4r in 63% yield. In comparison, the cyclohexyl-based TA analogue gave product 4s in a poor yield at low conversion in an undivided cell (12% yield; 96% yield brsm). This improved to a 28% yield of imide 4s when the reaction was performed in a divided cell. Interestingly, imide 4t could not be prepared under undivided cell conditions and isopropyl benzoate was formed in preference (19% NMR yield). However, imide 4t was obtained in a 45% yield under divided cell conditions. Poor conversion was observed in the synthesis of imide 4u. Our approach also furnished derivatives of the drugs ibuprofen and flurbiprofen (4v and 4w) in 74% and 44% (85% brsm) yields, respectively.

Based on the alkoxyamine scope, supported by cyclic voltammetry on representative substrates (Supporting Information), we conclude that our protocol is generally tolerated by alkoxyamines that undergo facile oxidative cleavage to carbocations. Even the cyclohexyl-based TA substrate which, based on cyclic voltammetry (see Figure S7, Supporting Information), undergoes slow cleavage to carbocations, nonetheless gives high selectivity for product 4s (96% yield brsm under undivided cell conditions). In this case, we posit that low conversion arises from the partially reversible nature of the alkoxyamine oxidation. The protocol fails for carbocations that are especially prone to decomposition, such as from 2-THF-containing substrate 1ac (Figure 3). Yields are probably also somewhat diminished by competing E1 elimination from the respective tertiary carbocation intermediates that lead to 4o and 4p. As anticipated, the protocol fails for substrates bearing electron-withdrawing groups (such as 1ad and 1ae). Based on our previous studies, (14) these systems are expected to undergo oxidative cleavage to carbon-centered radicals.

Figure 3

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Consistent with our synthetic experiments and cyclic voltammetry studies, we propose a mechanism in which reaction is initiated via one-electron oxidation of the TA at the anode leading to mesolytic cleavage that generates a carbocation. TEMPO is formed as a byproduct of this process. We suspect that the relatively low Faradaic efficiency we often observe in this chemistry principally derives from the unproductive cycling of TEMPO/TEMPO⁺ across electrodes. Thus, we anticipate that reduction of nitroxide species serve as the primary cathodic processes. Consistent with this, we observed vast differences in the Faradaic efficiency of experiments performed in undivided and divided cells using 1a, 2a (1.0 mmol), and CH₃CN: 18.9 vs 1.11 F/mol, respectively (see: p S-13, Supporting Information). The undivided cell experiment required a reaction time of 50 h, in comparison to 3 h for the equivalent process performed in a divided cell.

We examined the nitrile scope using a predominantly dichloromethane-based electrolyte. Acetonitrile-d₃ afforded imide 4x in 58% yield under these conditions (Figure 2). Reactions employing aromatic nitriles, such as benzonitrile, 4-bromobenzonitrile, 4-methoxybenzonitrile, and 2-thiophenecarbonitrile, were slower and provided respective products 4y, 4z, 4aa, and 4ab in low yields at low conversion. In all cases, the yields calculated relative to the recovered starting material are high, indicating good selectivity. The lower conversions compared with the analogous reactions with acetonitrile are attributed to changes in solution conductivity arising from the use of mixed nitrile/dichloromethane solvents; yields for these may be improved through further optimization of the reaction conditions. (32)

As noted earlier, photoredox activation of alkoxyamines has also been exploited to generate carbocations under mild conditions. (13,17,18) This prompted us to examine the utility of this alterative strategy to facilitate Mumm rearrangement cascades from alkoxyamines. To this end, irradiating an acetonitrile solution of TA 1 and aryl carboxylic acid 2 with blue light in the presence of iridium photoredox catalyst B afforded imides 4a, 4d, 4p, and 4q in excellent yields (Figure 4). In contrast to the electrochemical conditions, product 4n could not be prepared from 4-chlorobenzyl-substituted TA under photoredox activation (no conversion of the starting material was observed). We also noted that photoredox activation enabled efficient capture of nitrilium with hexafluoroisopropanol (HFIP), affording somewhat unstable imidate 4af. Limited formation of product 4af was observed via electrosynthesis (∼16% yield, as judged by ¹H NMR spectroscopy), in comparison. These results emphasize that, although carbocations can be generated from TAs via either photochemical or electrochemical triggers, notable differences remain in observed reaction outcomes depending on the method used to promote the initial redox event. This discovery suggests interesting opportunities for complementary or divergent reactivity are possible in these manifolds.

Figure 4

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Consistent with previous reports, (24) we could selectively convert imide 4a to either benzamide 5 or acetamide 6 by judicious selection of reaction conditions (eq 1). This demonstrates that TAs can serve as masked amides that can be selectively revealed under relatively mild conditions over 2 steps.

In summary, our work highlights that either electrochemical or photoredox triggers can induce oxidative mesolytic cleavage of TAs 1 under mild conditions to establish three-component Mumm rearrangement cascade reactions. These new protocols broaden the scope of alkoxyamines in chemical synthesis and the extension of these strategies to more complex systems remain ongoing in our laboratories.