Photocatalytic radical cyclization of N-(o-cyanobiaryl)acrylamides with oxime esters†
Yu Liu
,
Shun-Dan Li and
Jian-Hong Fan*
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang 414006, China. E-mail: fanhnist@163.com
First published on 29th August 2024
Abstract
A visible-light-mediated radical cascade cyclization of N-(o-cyanobiaryl)acrylamides with oxime esters for the assembly of acyl-containing pyrido[4,3,2-gh]phenanthridines has been developed. The present protocol tolerates a wide range of oxime esters through a single reaction via fragmentation, radical addition, nitrile insertion, and cyclization under mild conditions.
Radical cascade reactions represent a fundamental synthetic method to forge chemical bonds and structurally intricate organic molecules in an efficient and straightforward manner from readily available substances.1 Among these, 2-cyano-3-arylaniline derived acrylamides are appealing building blocks in radical cascade cyclization reactions due to their diverse levels of reactivity for the one-pot production of polycyclic architectures. In this context, a series of oxidative radical cascade cyclization reactions of 2-cyano-3-arylaniline derived acrylamides have been established for the synthesis of phenanthridine derivatives.2 However, these methods required unfriendly strong oxidants as radical initiators and high temperatures, thereby seriously restricting their applications in synthesis. Meanwhile, photocatalytic radical reactions have been regarded as a better alternative protocol in organic synthesis owing to their efficiency and environmental friendliness.3 A few examples of radical cyclization of 2-cyano-3-arylaniline derived acrylamides enabled by photocatalysis have been documented.4 To extend the applications of this strategy in organic synthesis, handling acrylamide derivatives to execute visible-light-induced cascade cyclization protocols under mild conditions is still highly desirable.
Oxime esters have received immense attention from the synthetic community because of their unique single-electron redox activities.5–7 Typically, a carbon-centered radical could be generated from oxime esters by a single electron transfer under photocatalytic conditions to produce highly reactive iminyl radicals, followed by β-C–C bond cleavage. As such, acyl oxime esters are regarded as effective acyl radical precursors for the synthesis of acyl-containing molecules.7 For example, Wu disclosed an elegant radical cascade reaction between acyl oxime esters and acrylamides in 2019.7a Subsequently, the same group reported a multi-component difunctionalization of styrenes with acyl oxime esters, which provides an efficient synthetic method to produce β-carbonyl imides.7b Inspired by these findings, we envisioned the possibility of developing a radical cascade cyclization of 2-cyano-3-arylaniline derived acrylamides with acyl oxime esters for the synthesis of polyheterocycles. Herein, we report a photocatalytic radical cascade reaction of 2-cyano-3-arylaniline derived acrylamides with acyl oxime esters to generate acylated phenanthridine derivatives through a tandem acyl radical addition/nitrile insertion/cyclization process (Scheme 1).
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| Scheme 1 Photocatalytic radical cyclization of acrylamide derivatives with acyl oxime esters. | ||
Our study began with the reaction of N-(2-cyano-4′-methyl-[1,1′-biphenyl]-3-yl)-N-methylmethacrylamide (1a) and 3-(((4-(trifluoromethyl)benzoyl)oxy)imino)butan-2-one (2a) in the presence of Ir(ppy)3 (1 mol%) as the photocatalyst and Et3N (2.0 equiv.) as the base in CH3CN (2.0 mL) as the solvent with argon (sealed tube) under blue LED irradiation (5 W) at 25 °C for 0.5 h. Pleasingly, the desired product 3aa was produced in 81% yield (Table 1, entry 1). Control experiments revealed that light irradiation was essential for reactivity (entry 2). Surprisingly, the cascade radical cyclization could still take place without the photocatalyst (entry 3), suggesting that an electron donor–acceptor (EDA) complex might be formed in this process (see the ESI† for more details). The absence of a base resulted in a reduced yield (entry 4). The use of other photocatalysts decreased the yield (entries 5 and 6). The effect of bases was examined, and the results showed that Et3N was preferred (entry 1 vs. entries 7 and 8). Other solvents, such as THF (tetrahydrofuran), DMF (N,N-dimethylformamide), and toluene, could also favor the reaction, albeit with lower reactivity (entry 1 vs. entries 9–11).
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| Entry | Variation from the standard conditions | Yield (%) |
| a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2a (0.3 mmol, 1.5 equiv.), photocatalyst (1 mol%), base (0.4 mmol, 2.0 equiv.), solvent (2.0 mL), 5 W blue LED (λmax = 468 nm), Ar, 25 °C, 0.5 h. | ||
| 1 | None | 81 |
| 2 | No light | 0 |
| 3 | No Ir(ppy)3 | 17 |
| 4 | No Et3N | 28 |
| 5 | Ru(bpy)3Cl2 instead of Ir(ppy)3 | 55 |
| 6 | Eosin Y instead of Ir(ppy)3 | 28 |
| 7 | 2,6-Lutidine instead of Et3N | 52 |
| 8 | Na2CO3 instead of Et3N | 32 |
| 9 | THF instead of CH3CN | 51 |
| 10 | DMF instead of CH3CN | 73 |
| 11 | Toluene instead of CH3CN | 72 |
With the optimized conditions in hand, the scope of acrylamides was examined, and the results are summarized in Table 2. Initially, substrates with different N-substituted groups were tested. Acrylamides containing ethyl and benzyl groups on the nitrogen atom were suitable for this cascade cyclization, affording the corresponding products (3ba–ca) in excellent yields. The effect of the substituents on the carbon–carbon double bond was next investigated, and it was found that acrylamides (1d–e) bearing either phenyl or benzyl groups at the α-position of the carbon–carbon double bond proceeded efficiently to give products (3da–ea) in good yields under the optimal conditions. Then, we turned our attention to exploring the effect of the substituents on the aromatic motifs at the ortho-position of the cyano group. A series of substituents, such as electron-donating (methyl, methoxyl, iso-propyl, and tert-butyl), electron-neutral (phenyl), and electron-withdrawing (F, Cl, Br, trifluoromethyl, cyano, and acyl) groups, at the benzene ring were well compatible with the reaction conditions and produced the desired acyl-containing polyheterocycles (3fa–sa). The substrates (1h and 1i) with meta functionalities reacted well with oxime esters (2a) but with poor regioselectivity. Notably, α-naphthyl derived acrylamides could undergo a radical addition/nitrile insertion/cyclization reaction, giving the pentacyclic compound 3ta in a satisfactory yield.
| a Reaction conditions: 1 (0.2 mmol, 1.0 equiv.), 2a (0.3 mmol, 1.5 equiv.), Ir(ppy)3 (1 mol%), Et3N (0.4 mmol, 2.0 equiv.), CH3CN (2.0 mL), 5 W blue LED (λmax = 468 nm), Ar, 25 °C, 0.5 h. |
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Next, the generality of oxime esters was investigated (Table 3). In addition to 2a, oxime esters (2b–f) with either linear or branched alkyl chains involving ethyl, n-propyl, iso-propyl, n-butyl, and n-pentyl groups all participated in the reaction well to furnish the acyl-containing products (3ab–af) in 71–81% yields. In addition, various aroyl radicals produced from the corresponding oxime esters (2g–n) with electronically varied substituents (H, methyl, methoxyl, F, Cl, and Br) on the aromatic ring at different positions reacted smoothly with 1a under the well-established conditions. When 2-furanoacyl-substituted oxime ester (2o) was employed as the substrate, the desired product 3ao was obtained in a moderate yield.
| a Reaction conditions: 1a (0.2 mmol, 1.0 equiv.), 2 (0.3 mmol, 1.5 equiv.), Ir(ppy)3 (1 mol%), Et3N (0.4 mmol, 2.0 equiv.), CH3CN (2.0 mL), 5 W blue LED (λmax = 468 nm), Ar, 25 °C, 0.5 h. |
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Some control experiments were carried out to gain mechanistic insights into the cascade cyclization reaction. The reaction was suppressed in the presence of radical inhibitors, including TEMPO, BHT, and 1,1-diphenylethene, and the starting material 1a was recovered (Scheme 2a). Notably, the radical trapping adducts (4–6) could be detected by GC-MS or NMR analysis. These results suggest that a free radical process might be operative for this transformation. The quantum yield (Φ) of the cascade cyclization reaction resulting in product 3aa was 15.5 (Scheme 2b), indicating the involvement of a radical-chain process in product formation. In addition, Stern–Volmer quenching studies suggested that the excited photocatalyst was mainly quenched by the oxime esters (see the ESI† for more details).
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| Scheme 2 Mechanistic investigations. | ||
A possible mechanism was outlined based on the above mechanistic studies (Scheme 3). First, oxime esters 2 were reduced by the excited photocatalyst to generate acyl radical A, which attacks the C–C double bonds of 1 affording intermediate B. Then, an intramolecular nitrile insertion proceeds to furnish imine radical C, which then follows another intramolecular radical substitution to yield the delocalized radical species D. Intermediate D could be further oxidized by interaction with the oxidized PC (path a) or reduction of 2 to A (path b) for radical chain propagation. In this case, we believe that the radical-chain process is favored based on the measure of quantum yields of the transformation. Finally, deprotonation of E occurs to afford products 3 with the assistance of a base. In addition, a possible reaction mechanism involving an EDA intermediate (Table 1, entry 3) is presented in the ESI.†
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| Scheme 3 Proposed mechanism. | ||
Conclusions
In summary, a new radical cascade cyclization of N-(o-cyanobiaryl)acrylamides with oxime esters under photocatalytic conditions has been established, which provides an efficient synthetic approach toward acyl-containing phenanthridine frameworks. This method shows a broad substrate scope and good functional group tolerance. Further synthetic uses of this environmentally friendly protocol for the construction of functional polyheterocycles are currently underway in our laboratory.Author contributions
Conceptualization: Y. L.; investigation: S.-D. L. and J.-H. F.; writing – original draft: J.-H. F.; writing – review & editing: Y. L., S.-D. L., and J.-H. F.Data availability
The data underlying this study are available in the published article and its ESI.†Conflicts of interest
There are no conflicts to declare.Acknowledgements
This work was funded by the National Natural Science Foundation of China (no. 22078084 and 22201070) and the Natural Science Foundation of Hunan Province (no. 2023JJ30273).Notes and references
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Footnote |
| † Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4ob01368a |
| This journal is © The Royal Society of Chemistry 2024 |