Visible-light-promoted radical amidoarylation of arylacrylamides towards amidated oxindoles

Abstract

A visible-light-promoted intermolecular radical amidation/cyclization of arylacrylamides was realized by using N-aminopyridinium salts as the source of amidyl radicals. The reaction exhibits a broad scope and good functional group tolerance, and a variety of amide-tethered-oxindoles were prepared in this way in moderate to good yields.

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C–N bond-forming reactions have drawn persistent interest from chemists because of the importance of nitrogen-containing compounds in materials science and in medicinal chemistry. Among the various strategies used for the construction of C–N bonds, those mediated by nitrogen-centered radicals have been gaining prominence, with accumulating studies showing that the high reactivity of N-radicals can be exploited to tackle a number of challenging synthetic problems.¹ Multiple methods have been developed for the generation of N-radicals under mild conditions, which greatly enhances their usefulness in organic synthesis.²

The radical amination of alkenes constitutes a highly valuable type of reaction for the preparation of nitrogen-containing compounds.³ Significant progress has been made over the past few years, which is to a great extent attributable to the employment of visible-light photoredox catalysis.⁴ For instance, excellent protocols have been reported for the anti-Markovnikov hydroamination^2f,5,6 and amination/difunctionalization (Scheme 1a).^7–10 It is noteworthy that primary amidyl radicals, which have been sparingly employed to react with alkenes because of a lack of an effective means of generation, have begun to be used for the construction of the C–N bond.^6–9 Despite this advancement, most of the investigations in this line have focused on protected amidyl radicals, and intermolecular olefin amidation with aryl and alkyl-attached primary amidyl radicals has been much less explored. In view of the great synthetic potential of amidyl radicals as well as the structural importance of amides, it would be highly desirable to broadly investigate the reactivity and efficacy of common amidyl radicals towards the addition of alkenes.

Scheme 1 Photochemical protocols for the intermolecular addition of primary amidyl radicals to alkenes.

Oxindoles represent an important class of naturally occurring heterocycles that show highly effective biological and physiological activities.¹¹ Oxindoles can be efficiently prepared from N-phenylacrylamides via radical addition/intramolecular aromatic substitution.¹² Our previous study shows that by reacting aminium radicals with N-phenylacrylamides, aminated oxindoles can be accessed readily in good yields.¹³ Considering the significance of the amidyl group in medicinal chemistry, it would be desirable to incorporate the amidyl group into oxindoles by this strategy. Chang et al. reported an effective photochemical protocol for the preparation of amidated oxindoles through the reaction of benzoyl azides with N-phenylacrylamides.¹⁴ We envisioned that by reacting amidyl radicals with N-phenylacrylamides, the scope of the reaction could be expanded. N-Aminopyridinium salts have recently been demonstrated to be highly efficient precursors toward N-centered radicals (Scheme 1b);^15,16 they were expected to fulfill our need to deliver the primary aryl and alkyl amidyl radicals under mild conditions. Indeed, our results verified the viability of our design, and the reaction of N-phenylacrylamides with N-aminopyridinium salts was performed under blue light irradiation with fac-Ir(ppy)₃ as the photocatalyst (Scheme 1b). It is worth noting that the reaction exhibited good functional tolerance, and the alkyl-substituted amido group can be introduced into the oxindole motif as well as the aryl and heteroaryl-substituted amido group.

Initially, we selected N-phenylacrylamide 1a and N-aminopyridinium salt 2a as the model substrates to investigate the feasibility of the reaction under visible-light irradiation (40 W Kessil blue LEDs, 50% intensity) in the presence of a photocatalyst (Table 1). A systematic survey of the reaction conditions with variation in the photocatalyst, solvent and base revealed the optimum conditions to be: fac-Ir(ppy)₃ as the photocatalyst, K₃PO₄ as the base in 1,2-dichloroethane (DCE) at room temperature, and blue-light irradiation for 36 h. Under these conditions, the desired product 3a was isolated in good yield (with 2a as the limiting substrate). The structure of 3a was confirmed by X-ray crystallographic analysis (CCDC no. 2122102†).¹⁷ Other catalysts, such as Cu(dap)₂Cl and eosin Y, were ineffective under the current conditions (Table 1, entries 2 and 3). Replacing DCE with MeCN, dichloromethane (DCM), or CHCl₃ resulted in lower yields (entries 4–6). Additionally, the yield was diminished when K₂CO₃ or Et₃N was used as the base or in the absence of a base (entries 7–9). Control experiments indicate that both photocatalyst and light irradiation are necessary for the reaction to take place (entries 10 and 11).

Table 1 Optimization of the reaction conditions^a

Entry	Deviation from the standard conditions	Yield^b (%)
a Reaction conditions: 1a (0.15 mmol, 1.5 equiv.), 2a (0.1 mmol, 1.0 equiv.), K3PO4 (0.12 mmol, 1.2 equiv.), fac-Ir(ppy)3 (2.0 mol%), DCE (1.0 mL), 40 W Kessil blue LEDs (50% intensity), room temperature, 36 h, under an argon atmosphere. b Isolated yields. c The reaction was conducted at the 0.2 mmol scale. d Reaction time was 24 h. Detailed information concerning the screening of the reaction conditions is presented in Tables S1–S5 in the ESI.†
1	Standard conditions	81 (78^c)
2	Eosin Y instead of Ir(ppy)3	Trace^d
3	Cu(dap)2Cl instead of Ir(ppy)3	N.R.
4	MeCN instead of DCE	56
5	DCM instead of DCE	74
6	CHCl3 instead of DCE	64
7	K2CO3 instead of K3PO4	64
8	Et3N instead of K3PO4	41
9	No base	61
10	In the dark	N.R.
11	No photocatalyst	N.R.

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To test the generality of this reaction, the scope of arylacrylamides 1 was investigated, and the results are shown in Scheme 2. Both electron-donating and electron-withdrawing groups on the N-phenyl ring were well tolerated, and the corresponding products were obtained in moderate to good yields. Notably, a broad range of functional groups such as the halo (3g–3k) and cyano (3n) groups were well tolerated, which offers the potential for further transformations. This protocol is applicable to gram-scale preparation. As such, 3a was obtained in 61% yield upon isolation when the reaction was performed at the 4.0 mmol scale. However, the expected product 3v was not obtained when the N-unprotected acrylamide was used as the substrate. In this case, the reaction only delivered a complex mixture.

Scheme 2 Scope of arylacrylamides. The reactions were conducted at the 0.2 mmol scale. Isolated yield. ^a 1a (6.0 mmol, 1.5 equiv.), 2a (4.0 mmol, 1.0 equiv.), base (4.8 mmol, 1.2 equiv.), fac-Ir(ppy)₃ (2.0 mol%), DCE (30 mL), 40 W Kessil blue LEDs (100% intensity), room temperature, 42 h, under argon atmosphere. ^b A complex mixture was generated.

We next turned our attention to examine the scope of N-aminopyridinium salts 2 under the standard conditions (Scheme 3). It can be seen that a range of substrates bearing electron-donating and electron withdrawing groups on the phenyl ring of pyridinium salts can be converted to the expected products (3ab–3ah), and heteroaryl aminopyridinium salts such as pyridine (3ai and 3aj) and furan (3ak) were also suitable substrates for the present reaction. Moreover, alkyl and alkyloxyl-substituted amidyl groups can be introduced into the oxindole motif as well, although the yields of 3al–3ap were considerably lower than those obtained using their aryl-substituted counterparts. The lower yields of 3al–3ap might be attributed to the presence of competitive pathways (C–H abstraction from the solvent, for example) that N-alkyl amidyl radicals are liable to undergo. This method did not work for the N-disubstituted aminopyridinium salt 2r, possibly as a result of steric hindrance caused by the N-methyl group.

Scheme 3 Scope of aminopyridinium salts. The reactions were conducted at the 0.2 mmol scale. Isolated yields. ^a No reaction took place.

The present reactions are believed to take place following the radical pathway shown in Scheme 4. Taking the reaction of 1a with 2a as an example, it can be seen that the reaction is initiated by the single electron transfer between the N-aminopyridinium salt 2a and the excited [Ir(III)]*, which generates radical A and [Ir(IV)]. Radical A then undergoes fragmentation to give the amidyl radical B, which is subsequently trapped by 1a to produce the radical intermediate C. The latter undergoes cyclization to afford radical D. Oxidation by [Ir(IV)] converts D to the carbocation E, from which 3a is finally generated by deprotonation. K₃PO₄ has a beneficial effect on the reaction, probably because it can enhance the basicity of the system to make the deprotonation easier. This radical mechanism was supported by the inhibition experiment with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-butyl-4-methylphenol (BHT) (Scheme 5). The reaction of 1a and 2a was completely inhibited in the presence of 2.0 equiv. of TEMPO, and the yield of 3a was significantly decreased when 2.0 equiv. of BHT was added into the reaction vessel. In the latter case, the BHT-trapped product 4 was also detected by HRMS. That the reaction could not take place without fac-Ir(ppy)₃ and light irradiation (Table 1, entries 10 and 11) reveals the necessity of photoexcitation of the catalyst during the reaction.

Scheme 4 Proposed mechanism.

Scheme 5 Inhibition experiment.

In summary, we have developed an effective protocol for the preparation of amidyl-attached oxindoles via photoinduced and fac-Ir(ppy)₃-catalyzed amidoarylation of arylacrylamides with N-aminopyridinium salts as the amidyl radical precursors. This method allows a variety of substituted arylacrylamides and N-aminopyridinium salts to be converted to the desired products in moderate to good yields. Further attempts to expand the synthetic scope of the intermolecular radical amidation of unactivated olefins are ongoing in our laboratory.

Author contributions

Y.-Z. Wang and W. Yu contributed to the conceptualization of this study. Y.-Z. Wang carried out all the experimental work. Y.-Z. Wang and W. Yu wrote the manuscript. Y.-Z. Wang, W.-J. Lin, H.-C. Liu and W. Yu reviewed the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank the National Natural Science Foundation of China (no. 21772077) and the State Key Laboratory of Applied Organic Chemistry for financial support.

Notes and references

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17. CCDC 2122102† (N-((1,3-dimethyl-2-oxoindolin-3-yl)methyl)benzamide, 3a) contains the supplementary crystallographic data for this paper.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2122102. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d2qo00127f

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