Exploring N-centered umpolung reactivity in photoredox-catalyzed amidation with an α-iminoester

Abstract

The synthesis of amides and their derivatives has gained significant attention from the scientific community in recent decades due to the presence of amide moieties in many bioactive organic molecules. Pursuing sustainable chemistry using cost-effective starting materials under mild reaction conditions is intriguing and challenging. In this context, we present a method for the direct synthesis of amides from α-keto acids and α-iminoesters. This approach employs an Ir-based photocatalyst to enable redox-neutral C–N bond formation at room temperature through N-center umpolung chemistry. This straightforward protocol is compatible with a broad range of functional groups, allowing for the efficient production of amides from aromatic keto acids and imines as coupling partners in an atom-economical manner.

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Introduction

Acyl radicals are versatile synthetic intermediates used for the construction of various C–C and C–heteroatom bonds for rapid generation of molecular complexity.^1,2 Various sources have been employed for the generation of acyl radicals; among them, α-keto acids are the most convenient ones due to their ease of oxidation, followed by a facile decarboxylation process to provide acyl radicals. Visible light photoredox catalysis has achieved considerable success in generating acyl radicals from α-keto acids.^2,3

On the other hand, imines are flexible functional groups and significant structural motifs commonly observed in many organic molecules.⁴ Typically, the imine C-center is electrophilic in nature and the majority of conventional polar or radical reactivity is concentrated on this electrophilic C-center.⁵ The reverse of this conventional chemistry, the so-called umpolung chemistry, is another gateway to reverse the reactivity of imines to provide easy access to compounds that may not be possible following a traditional reactivity. Over the past decade, photoredox catalysis has gained much attention to initiate the radical reactivity of C=N via single electron transfer (SET). A SET process generates a radical anion intermediate that typically exists in two distinct resonating forms (Scheme 1). The C-centered radicals are typically involved in radical–radical cross coupling and radical Giese-type addition reactions (Scheme 1B and C),^6–8 whereas the other resonating form with carbanion character is also explored to react with electrophiles to construct C–C and C–heteroatom bonds (Scheme 1E). The N-center in both resonating forms either gets protonated or abstracts a hydrogen atom.⁹ The N-centered umpolung reactivity of imines thus remains less explored; nevertheless, Shu and co-workers utilized this N-centered umpolung reactivity to develop a dual photoredox/N-heterocyclic carbene (NHC)-catalyzed synthesis of amides. The critical point was the oxidation of the Breslow intermediate for radical–radical coupling with the generated N-centered radical (Scheme 1D).¹⁰

Scheme 1 Photocatalytic diverse functionalization of an imine.

We envision that a readily available α-keto acid can be a good source of acyl radicals that may directly connect with the N-center of imines following radical umpolung chemistry without the need for any NHC catalyst. We speculate that radical–radical cross coupling between an acyl radical and an N-centered radical can efficiently construct a C–N bond. In contrast, acyl radical addition to the N-center in an umpolung fashion is also expected in a strategically designed imine. This thought process must overcome the classical electrophilic nature of the C=N bond to suppress the radical addition to the C-center, which requires a balanced blueprint in the imine structure. Herein, a tactically designed α-iminoester is used for amide bond formation in the presence of a visible-light photoredox catalyst. It is worth mentioning the importance of amide bond formation, as amides serve as important functionalities in peptide chemistry, drug molecules, agrochemicals, and organic materials and as significant intermediates for functional group modification.^11–14 The current protocol will provide an alternative redox-neutral direct access to amides following an intriguing concept of umpolung chemistry in a straightforward and atom-economical fashion.

Results and discussion

We began our investigation for the reaction development by taking phenylglyoxalic acid 1a and different substituted imines, such as N-1,1-triphenylmethanimine (2t), (E)-N,1-diphenylethan-1-imine (2u), dimethyl 2-((tosyloxy)imino)malonate (2v), methyl (Z)-2-(benzoylimino)-2-phenylacetate (2w), and methyl (Z)-2-phenyl-2-(tosylimino)acetate (2x) as reaction partners. In all the above cases, the imines failed to produce any desired products. However, when methyl (Z)-2-phenyl-2-(phenylimino)acetate (2a) was used as an α-iminoester, the reaction proceeded smoothly to produce the desired product. After immense optimization of the reaction conditions, we finalized the use of Ir[dF(CF₃)ppy₂(dtbpy)]PF₆ as a photocatalyst and K₂HPO₄ as an additive in a solvent mixture of DCM/H₂O (0.1 M) (1 : 1) by irradiating the mixture with 456 nm Kessil blue LEDs, obtaining the desired amide product 3aa in an excellent isolated yield of 87% (Table 1, entry 1). Prior to obtaining these optimized reaction parameters, screening of different catalysts was performed, where we used [Ir(ppy)₂(dtbbpy)]PF₆ as a photocatalyst to catalyze the reaction to produce a yield of 41%. Thereafter, an exhaustive trial with different solvents, like DCE, DME, 1,4-dioxane, CH₃CN and many others, was carried out generating the desired product in an isolated yield of not more than 41%. For more details, see ESI Table S4.† In the optimization of bases, we observed that none of the bases except 2,6-lutidine (2.5 equiv.,) recorded a yield of 41% in DCE. Despite our endeavours to enhance the reaction yield our efforts proved futile when we substituted the base with K₂HPO₄ and the catalyst with Ir[dF(CF₃)ppy₂(dtbpy)]PF₆. This led us to consider the involvement of the solubility parameter, which thus prompted us to add water as a co-solvent with DCE and vary the ratio of DCE/H₂O; an optimized solvent parameter was established with a DCE/H₂O ratio of 1 : 1, which significantly increased the yield from 41 to 60% (Table 1, entries 2 and 3). When we used DCM as a solvent instead of DCE, the corresponding yield increased to 62% (Table 1, entry 4). Further scaling down the equivalency of K₂HPO₄ from 2.5 equiv. to 1.2 equiv. increased the yield up to 67% (Table 1, entry 5). A gradual increase in the reaction time from 16 hours to 72 hours produced the desired product 3aa with an isolated yield of 87% (compare Table 1, entries 5–7 with 1). An excess amount of α-iminoester (2a, 3 equiv.) is necessary for a higher yield, as we observed partial hydrolysis of the α-iminoester (2a) during the course of the reaction. From control experiments, we deduced that water is important in combination with the organic solvent DCM along with light, a base, and a catalyst to achieve an optimum yield of the product (Table 1, entries 8 to 13). Furthermore, when the reaction was performed in an open atmosphere, a sudden decline in the yield was observed indicating that O₂ might be interfering with the reaction (Table 1, entry 14).

Table 1 Optimization study and reaction set-up^a

Entry	Deviations from standard reaction conditions	Yield^b (%)
a Unless otherwise mentioned all reactions were carried out on a 0.1 mmol scale at room temperature for 16 to 72 h. b Yield measured by ^1H NMR analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as the internal standard. c Isolated yield in parentheses. d Reaction time, 16 h; DCE, 0.2 M; 1a and 2a (equiv.) ratio, 1 : 1.5. e Reaction time, 24 h.
1	None	90 (87)^c
2	[Ir(ppy)2(dtbbpy)]PF6, 2,6-lutidine (2.5 equiv.)	41 (40)^c^,^d
3	K2HPO4 (2.5 equiv.), DCE/H2O, 16 h	60
4	K2HPO4 (2.5 equiv.), DCM/H2O, 16 h	62
5	16 h	67
6	24 h	73
7	48 h	80
8	Only water	27^e
9	Only DCM	15^e
10	Only DCE	17^e
11	No light	n.r.^e
12	No base	n.r.^e
13	No catalyst	n.r.^e
14	Open air	56

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With the optimized conditions in hand, we shifted our focus to explore the extent of this transformation. This reaction exhibits a diverse substrate scope with good functional group tolerance (Scheme 2). When it comes to the imine component, imines with different substitution patterns performed well, giving the desired C–N coupling products (3aa to 3ha) in good to excellent yields ranging from 50% to 95%. Additionally, both electron-withdrawing and electron-donating substituents of aryl imines at the C-aryl center and the N-aryl center were successfully incorporated under the standard reaction conditions, giving rise to the corresponding amides with yields ranging from 66% to 92% (3aa to 3ao). It was found that electron-withdrawing groups such as 3,5-trifluoromethyl (3ab), 3,5-diester (3ac), and m-trifluoromethoxy (3ae) worked smoothly to deliver the desired products with good to excellent yields (55% to 85%). Furthermore, to diversify the substrate scope, we incorporated various substituents such as p-trifluoromethoxy (3ah), p-methoxy (3ai), and o-methyl (3an) as well as EWGs such as m-trifluoromethyl (3al) and o-bromo (3am) on the C-aryl center of the iminoester (3ah–3an) and these when coupled with 1a gave good to excellent yields between 75% and 89%. Further incorporation of heterocyclic moieties like thiophene (3ao) gave an excellent yield of 92% of the desired product. To extend the scope of the iminoester, we varied the ester part by replacing the methyl group of esters with ethyl (3ap), isopropyl (3aq), benzyl (3ar) and menthol (3as) groups forming C–N coupled products with yields ranging from 50% to 86%. The diversification of the acid coupling partner was also explored by incorporating both electron-withdrawing groups such as p-trifluoromethyl (3da), m-trifluoromethyl (3ga), and o-chloro (3ea), and electron-donating groups like o-methyl (3fa) and thiophene (3ha). It was found that attaching EDGs significantly increased the nucleophilicity of the acyl radical favouring increased reactivity with the iminoester furnishing higher yields of up to 95%. Arenes with alkyl groups and halogens as substituents at either the meta- or the para-position of the aryl ring afforded moderate to good yields (77% to 95%) of the desired amide product. To understand the practicability of the reaction on a larger scale we performed a model reaction on an elevated scale of 1 mmol, obtaining 70% isolated yield of product 3aa. Unfortunately, the reaction of the iminoester with an aliphatic keto acid did not produce any desired products. The acyl radical generated from aliphatic keto acid after decarboxylation may be engaged in further decarbonylation to generate an alkyl radical; however, we are unable to observe any product formation from the alkyl radical.¹⁵

Scheme 2 Substrate scope. ^a All reactions were carried out on a 0.1 mmol scale under irradiation with 456 nm Kessil light using 1.0 equiv. of 1 and 3.0 equiv. of 2. Yields refer to isolated yields.

To establish the mechanistic aspect of the reaction, we performed several control experiments. To begin with, we set up the standard reaction protocol in the presence of TEMPO (2 equiv.) as a source of the radical scavenger. We observed a complete shutdown of the reaction and detected the formation of radical trapping product V between an acyl radical and TEMPO as well as IX between an imine and TEMPO (Scheme 3A). The former (V) was isolated in 72% yield and characterized by NMR, while the latter was characterized using HRMS data of the crude reaction mixture. From these experiments, we conclude the formation of both the acyl and the N-centered radical intermediates. Fluorescence quenching experiments were conducted with various components like acids, additives and imines. The mixture of an acid and additive (α-keto carboxyl anion, I) and an α-iminoester exhibited a significant quenching effect on the excited photocatalyst.¹⁶ However, among them, the carboxyl anion showed an exceptionally high quenching effect on the excited photocatalyst (Scheme 3B). This observation supports that the reaction proceeds through the reductive quenching pathway of the Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆ catalyst, resulting in the formation of [Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆]˙⁻. To further confirm the source of the proton in our desired product 3aa, we performed the reaction using optimized reaction parameters; however, this time we thoughtfully replaced DCM/H₂O with DCM/D₂O. There was 95% deuterium incorporation, as confirmed by the characterization data with an 85% isolated yield of the deuterated product (4) (Scheme 3C). From this experiment, it is clear that the source of the proton during the reductive acylation process is water. Next, a light on–off experiment indicated that the use of light sources throughout the experiment is necessary. Furthermore, we measured the quantum yield for the model reaction and two other reactions, affording good to moderate yields. We found that the quantum yield was 1.8 for the model reaction, 2.0 for 3ao and 1.0 for 3ea. Although, in some cases, the quantum yield value is more than 1, the lower quantum yield value and its substrate dependency indicate that a radical chain process may be possible; however, the chain is not an efficient one. A continuous initiation is required to conduct the overall process.¹⁷

Scheme 3 Mechanistic study.

Based on literature studies and mechanistic investigations, we proposed a plausible mechanism favoring the formation of our product. Firstly, the photocatalyst [Ir[dF(CF₃)ppy]₂(dtbbpy)PF₆] upon visible light irradiation is excited to convert to its excited state form. The photoexcited species is a strong electron acceptor (vs. SCE i.e., potential versus saturated calomel electrode in CH₃CN).^18,19 The α-keto acid after deprotonation generates α-keto carboxyl anion I (E^red_peak = +1.08 V vs. SCE in DCM), which subsequently undergoes single electron transfer (SET) to the excited photocatalyst, forming an α-keto carboxyl radical.^19,20 This carboxyl radical quickly releases CO₂ to generate acyl radical species II. Subsequently to complete the catalytic cycle, iminoester 2a (E^red_1/2 = −1.24 V vs. SCE in DCM) undergoes a SET process by accepting an electron from the reduced photocatalyst (E^III/II_1/2 = −1.37 V vs. SCE in CH₃CN),¹⁸ generating intermediate VI, which can also remain in another resonating form, VII. Furthermore, upon protonation N-centered radical intermediate VIII is generated. Radical cross-coupling between two radicals VIII and II produces the desired product 3aa. This radical intermediate VIII and acyl radical II are trapped in the presence of TEMPO, generating the corresponding TEMPO adducts IX and V, respectively. Alternatively, this acyl radical, being nucleophilic in nature,²¹ may add to the N-center of the iminoester in an umpolung fashion to generate C-center radical III. Subsequently, this intermediate III, which is an α-amino radical,²² can be easily reduced by Ir^II species to form intermediate carbanion IV with the regeneration of the photocatalyst Ir^III (E^III/II_1/2 = −1.37 V vs. SCE in CH₃CN).¹⁸ Thereafter, protonation in the presence of water delivers the desired amide product 3aa (Scheme 4).

Scheme 4 Proposed reaction mechanism of the reaction.

This methodology was utilized to develop a one-pot sequential synthesis, which generalizes the method by reducing the intermediates. To our delight, we successfully obtained the expected product 3aa with an isolated yield of 75% using commercially available chemicals (Scheme 5). Importantly, keto acids were utilized for the synthesis of α-iminoester derivatives and as precursors for acyl radicals.

Scheme 5 One-pot sequential synthesis.

Conclusions

In conclusion, we report a mechanistically interesting and strategically developed C–N bond formation process utilizing the concept of radical umpolung chemistry on the N-center of α-iminoester derivatives. The commercially and readily available α-keto acid is chosen as the source of acyl radicals, which are added directly to the imine N-center in an umpolung fashion. A radical chain mechanism is also proposed based on mechanistic investigation. Radical polar cross-over is justified by the structural requirement of the modified α-iminoester, where both the aryl and ester parts are necessary to observe the desired reactivity. Due to the low quantum yield value, we cannot rule out the possibility of radical cross-coupling between an acyl radical and N-centered radical. The broad substrate scope and mild reaction conditions are the key features of this newly developed methodology. We hope that this newly designed protocol will attract substantial attention to scaffold-oriented radical umpolung chemistry.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors wish to acknowledge financial assistance from the SERB, DST, India (CRG/2022/007790). P. M. and R. P. thank the UGC CSIR for their fellowship. S. D. is a postgraduate student.

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4qo01515k

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