Cooperative N-heterocyclic carbene/photocatalysis: visible-light-promoted tandem α-sp³ C–H activation and reductive N-alkylation of tetrahydroisoquinoline

Abstract

While N-heterocyclic carbenes (NHCs) play a vital role as organocatalysts due to their umpolung reactivity toward carbonyl or imine carbons, activation of sp³-carbons via single-electron transfer (SET) processes remains challenging and underdeveloped. Recently, the coupling of NHC catalysis with photocatalysis for the SET process has gained attention. Herein, we report visible-light and NHC-catalyzed tandem α-sp³ C–H activation and reductive N-alkylation of tetrahydroisoquinoline (THIQ) with o-hydroxybenzaldehydes. The key step in this process is the formation of a photoactive species between o-hydroxybenzaldehydes and a base, which functions as a self-photocatalyst, eliminating the need for an external photocatalyst or photoactivator. The subsequent reaction of photoactive species with NHCs leads to the Breslow intermediate, followed by intramolecular hydrogen atom transfer (HAT) and benzylic activation to form N-benzylated 3,4-dihydroisoquinolin-1(2H)-ones. The salient features of this work include the use of sunlight as a visible-light source and molecular oxygen as an oxidant under mild reaction conditions, highlighting the green chemistry aspects of this approach.

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Introduction

N-heterocyclic carbenes, frequently employed as ligands for transition metals, are superior to their phosphine and imine counterparts due to their unique electronic properties, steric requirements and susceptibility to oxidation, making them front-runners in transition-metal catalysis.^1,2 In 1943, Ukai et al. demonstrated that coenzyme thiamine (vitamin B1) can be employed as a catalyst for the benzoin reaction.³ Later, Breslow elucidated the mechanism, which paves the way for the origin of NHCs as organocatalysts.⁴ The applicability of NHCs as organocatalysts can be attributed to their umpolung reactivity towards electrophilic carbonyl or imine carbons to generate several reactive intermediates like the Breslow intermediate, the aza-Breslow intermediate, acyl azolium, enolates, homoenolates, etc. via a two-electron reaction pathway.^5–9 However, electrophiles containing sp³-carbons are difficult to activate via NHC catalysis. The first report on an NHC-catalyzed single-electron transfer (SET) pathway appeared in 2001, featuring the crystal structure of the free radical intermediate.¹⁰ Since then, only a few reports have explored NHC-catalyzed SET pathways using various single-electron oxidants^11–17 or reductants,^18,19 making this approach rather limited. To enhance the effectiveness of NHC catalysis beyond single-catalyst systems, many research groups have successfully combined NHCs with other catalytic systems with ease, thus adding another dimension to their applicability via cooperative catalysis.^20–27

Likewise, there has been remarkable interest in visible-light-promoted photochemical transformations as they offer an environmentally benign alternative energy source and align with the green chemistry principles.^28–33 A noteworthy aspect of visible-light-mediated processes is their ability to generate highly reactive radical intermediates under mild and environmentally benign reaction conditions. Sunlight offers a sustainable alternative to thermal activation, being an abundant, non-hazardous energy source with zero carbon emissions, thus aligning well with the principles of green chemistry. Additionally, employing atmospheric oxygen as an oxidant minimizes the need for toxic peroxide-based oxidants and reduces by-product formation, thereby improving reaction rates and selectivity.³⁴ In recent years, there are few reports on synthetic strategies under neutral and oxidative conditions using cooperative NHC/light catalysis. The first report on NHC/light cooperative catalysis appeared in 2012 when DiRocco and Rovis reported a chiral NHC/Ru(III) dual catalytic system for the asymmetric acylation of N-aryl tetrahydroisoquinolines (THIQs) using m-dinitrobenzene as the oxidant.³⁵ Subsequently, numerous organic transformations utilizing NHC–visible-light cooperative catalysis have been reported, employing either metal-based^36–44 or metal-free^45–51 photocatalysts. Recent developments have shown that NHC-catalyzed photochemical reactions can be performed without the need for an external photocatalyst or photoactivator. In these cases, intermediates/complexes obtained from the interaction between the NHCs and a suitable substrate can absorb light, generating photo-excited species that undergo subsequent reactions with other substrates to produce the desired product. This strategy introduces a novel activation mode for NHC organocatalysis, allowing them to generate short-lived intermediates from intrinsically photo-inactive substrates.^52,53

The possible pathways for photo–NHC catalysis performed in the absence of photocatalysts are shown in Scheme 1. In the first case, Breslow/acyl azolium intermediates formed between the NHCs and the reactant absorb light and are converted to their excited state and react subsequently with another reagent via the SET pathway to form the desired products (Scheme 1a).^54–57 Light was employed to generate nitrene/carbene intermediates from the corresponding diazo compounds, which on reaction with NHCs, form enolate/Breslow intermediates followed by reaction with suitable substrates to generate the desired products (Scheme 1b).^58–60 Photo–NHC-catalysis can also proceed via the formation of an electron donor–acceptor (EDA) complex that absorbs light, facilitating the reaction (Scheme 1c).^61,62

Scheme 1 Possible pathways of photo–NHC catalysis.

In this context, we envision that NHC catalysis can be coupled with visible-light for the activation of the benzylic sp³ C–H bond under environmentally benign conditions in the absence of photocatalysts or photosensitizers based on our expertise in oxidative NHC catalysis^63–67 and visible-light-mediated synthesis of biologically significant compounds.⁶⁸ We envisage that simultaneous α-sp³ C–H activation and reductive N-alkylation of THIQ with aldehydes can be achieved via photo/NHC catalysis under visible-light and using molecular oxygen as the oxidant.

Our research was driven by the hypothesis that simultaneous α-sp³ C–H activation and reductive N-alkylation of tetrahydroisoquinoline (THIQ) could be achieved under aerobic photo/NHC catalytic conditions.

This idea stemmed from our previous work on the amidation of primary amines using NHC catalysis with NBS as an oxidant (Scheme 2a).⁶³ Encouraged by these findings, we aimed to extend the methodology into the photochemical domain, focusing on the amidation of THIQ under visible-light and aerobic conditions, thereby contributing to the advancement of NHC-catalyzed transformations (Scheme 2b).

Scheme 2 Origin of the proposed hypothesis.

Results and discussion

To validate our proposed hypothesis for the tandem α-sp³ C–H activation and reductive N-alkylation of THIQ with aldehydes under photo/NHC-catalysis, o-hydroxybenzaldehyde (1a) and THIQ 2a were taken as the model substrates, and the results are tabulated in Table 1. After extensive optimisation of the reaction parameters (see the SI), we identified the use of NHC-A (20 mol%) as the catalyst and Et₃N (1.1 equiv.) as the base in CH₃CN under sunlight and in an open atmosphere as the optimal conditions, yielding the desired N-benzylated 3,4-dihydroisoquinolin-1(2H)-one 3a in 76% isolated yield (entry 1). The expected product can be obtained with other NHC catalysts, albeit with diminished yields (entries 2–6 and the SI). Other organic bases also proved effective for this reaction, but the yields were comparatively lower than those achieved with Et₃N and a similar trend was observed with inorganic bases as well (entries 7–11 and the SI). When tert-butyl hydroperoxide (TBHP) was used as the oxidant instead of oxygen, only 30% of the desired product 3a was formed, with 3,4-dihydroisoquinolin-1(2H)-one 8 emerging as the major product (entry 12). When the reaction was conducted in the absence of light and under an N₂ atmosphere, it failed completely (entries 13 and 14 and the SI). A similar observation was made in the absence of either NHCs or a base as the catalyst (entries 15 and 16). These control experiments revealed that light, O₂, and NHCs are essential for the desired α-sp³ C–H activation and reductive N-benzylation of THIQ. Finally, instead of light as the source of energy, when the reaction was performed under thermal heating conditions, only 59% of the desired product was observed (entry 17). Under thermal dark conditions, the product formation was not observed, which indicates that light is essential for the formation of the product (entry 18).

Table 1 Optimization of the reaction conditions^a

Entry	Variation from the standard conditions	Yield of 3a (%)
a Reaction conditions: 1a (1.0 equiv.), 2a (2.0 equiv.), NHC precatalyst (20 mol%), and base (1.1 equiv.) at rt in CH3CN (2.0 mL) under irradiation with sunlight in open air for 4 h. b 3,4-Dihydroisoquinolin-1(2H)-one 8 was formed along with the product. c In the dark. d Under an N2 atmosphere by degassing air.
1	None	76
2	B instead of A	67
3	C instead of A	65
4	D instead of A	42
5	E instead of A	31
6	F instead of A	Trace
7	Cs2CO3 as a base	34
8	K2CO3 as a base	—
9	t-BuOK as a base	62
10	DBU as a base	31
11	DIPEA as a base	70
12	TBHP instead of air	30^b
13	No light	ND^c
14	N2 instead of O2	ND^d
15	No NHC	ND
16	No Et3N	ND
17	80 °C instead of light	59
18	80 °C instead of light (in the dark)	—

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With the optimized reaction conditions in hand, we then set out to investigate the scope of the visible-light and NHC-catalysed redox reaction by varying structurally different o-hydroxybenzaldehydes (Scheme 3). The key step in this reaction is the in situ formation of a photoactive species generated through the interaction between o-hydroxybenzaldehydes and the base, which is crucial for light absorption and subsequent transformations. Thus, the reaction failed with simple aldehydes without o-hydroxy substituents or with other o-substituted benzaldehydes (see the SI) and works well with substituted o-hydroxybenzaldehydes as the substrates.

Scheme 3 Substrate scope for the tandem α-sp³ C–H activation and reductive N-alkylation of THIQ. Reaction conditions: 1a–l (1.0 equiv.), 2 (2.0 equiv.), NHC precatalyst A (20 mol%), and Et₃N (1.1 equiv.) at rt in 2.0 mL of CH₃CN under sunlight and open air.

Irrespective of the electronic nature and position of the substituent, the desired products were obtained in moderate to good yields. When 3-ethoxy-2-hydroxybenzaldehyde 1b was used as the substrate, the desired product 3b was obtained in a moderate yield of 65%, whereas with 5-methyl-2-hydroxybenzaldehyde 1c, only 46% of the corresponding product 3c was obtained. Notably, 5-fluoro-, chloro-, bromo-, and iodo-substituted o-hydroxybenzaldehydes (1d–1g) were successfully converted into the desired products 3d–3g with yields ranging from 72% to 80%. Additionally, 5-nitro-2-hydroxybenzaldehyde 1h was converted into the expected product 3h with an excellent yield of 81%. In similar lines, with 3-nitro-2-hydroxybenzaldehyde 1i, the yield of the corresponding product 3i is slightly lowered. 1-Hydroxy-2-naphthaldehyde 1j could be coupled with THIQ to give the expected product 3j in 59% yield. Moreover, the reaction was compatible with highly functionalized 3,5-dichloro- and 3,5-dibromo-2-hydroxybenzaldehydes (1k, 1l), affording the products in 86% and 83%, respectively (3k and 3l).

Apart from 2-hydroxybenzaldehydes, when the reaction was performed with other visible light-absorbing aldehydes, the reaction proceeded to give different products (Scheme 4). For instance, when the reaction was carried out with furan-2-carboaldehyde (1m) and thiophene-2-carbaldehyde (1n), instead of the expected redox product, the corresponding N-aroylated products 3m′ and 3n′ were obtained in 43% and 38%, respectively. Instead of THIQ, when piperidine 2b was taken as the secondary amine, we observed the amidation products 3o′–3q′ in moderate to good yields. In the case of 2-nitrobenzaldehyde (1o), instead of the expected redox product, the corresponding dual-oxidised α-sp³ C–H activated N-benzoylated product of THIQ 4a was obtained in good yield. When THIQ (2a) was reacted with 2-aminobenzylalcohol 5, 5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one 6 was obtained as the product. This suggested that the reaction proceeds via the α-sp³ C–H activation of THIQ and subsequent intramolecular cyclization to afford the observed product. When 4-nitrobenzaldehyde (1r) was used as the coupling partner, the expected redox product (3r) was observed along with the N-benzoylated product of THIQ (3r′).

Scheme 4 Substrate scope of amidation under standard reaction conditions: 1, (1.0 equiv.), 2 (2.0 equiv.), NHC precatalyst A (20 mol%), and Et₃N (1.1 equiv.) at rt in 2.0 mL of CH₃CN under sunlight and open air.

Likewise, when 2-phenylacetonitrile (1s) was used as the alkyl source, a similar outcome was observed, yielding both the redox product (3s) and the N-benzoylated product of THIQ (3s′) in nearly equal ratios (Scheme 5). In order to gain insight into the mechanism of this reaction, we carried out several experiments, as shown in Scheme 6. When THIQ 2a was reacted with 2-hydroxy-3-nitrobenzaldehyde 1i under standard reaction conditions, the intermediate 2-((3,4-dihydroisoquinolin-2(1H)-yl)methyl)-6-nitrophenol 7 was obtained, which was isolated and confirmed by ¹H-NMR and HRMS along with the expected product 3i (Scheme 6a). The isolated intermediate 7, when treated under the standard reaction conditions in the presence of atmospheric O₂, was converted to the expected product 3i. The radical mechanism can be ascertained by performing the reaction employing radical quenching reagents under the standard reaction conditions. When 1.0 equiv. of TEMPO was added to the reaction, a significant decrease in the product yield was observed (Scheme 6b) and with 3.0 equiv. of TEMPO, the reaction failed completely, indicating that the reaction proceeds via a radical pathway (Scheme 6c). This observation was further substantiated by the reaction with 1.0 equiv. of BHT, where the reaction failed to deliver the product miserably; BHT-adduct 9 (see the SI) was detected by ESI-HRMS (Scheme 6d). The radical quenching behavior for this photo–NHC redox process was studied by carrying out the reaction in the presence of 2a using 2-diphenyl-1-picrylhydrazyl (DPPH) as a radical scavenger. When the Breslow intermediate was added to this, the absorption wavelength (λ_max = 518 nm) corresponding to DPPH showed a hypochromic shift, which indicates that I is responsible for radical initiation due to photoexcitation (Scheme 6e and Fig. 1). Furthermore, when the reaction was monitored in the presence of a triplet state quencher, benzophenone, the reaction did not proceed as expected under these conditions (Scheme 6f).^36,47

Scheme 5 Substrate scope of other alkylating agents under standard reaction conditions: 1o–q, 5 (1.0 equiv.), 2a (2.0 equiv.), NHC precatalyst A (20 mol%), and Et₃N (1.1 equiv.) at rt in 2.0 mL of CH₃CN under sunlight and open air.

Scheme 6 Control experiments. Standard conditions: 1 (1.0 equiv.), 2 (2.0 equiv.), NHC precatalyst A (20 mol%), and Et₃N (1.1 equiv.) at rt in 2.0 mL of CH₃CN under sunlight and open air.

Fig. 1 Radical quenching experiment. Absorbance spectra were recorded in CH₃CN as a solvent in 1 × 10⁻⁶ M solution: DPPH (green lined), 2a with DPPH (orange dotted), Breslow intermediate I, 2a with DPPH (red dashed), and A* (NHC), 1a, and 2a (purple lined).

To identify the origin of fluorescence in our reaction, we combined different reactants and observed their fluorescence behaviour (see the SI). Among various combinations, we found that treating o-hydroxybenzaldehyde with Et₃N resulted in a fluorescent solution and we combined various substituted o-hydroxybenzaldehydes with Et₃N and recorded their emission spectra (see the SI). Of these, 3,5-dichloro-2-hydroxybenzaldehyde (1k) shows greater intensity, making it a suitable compound for further photochemical studies. If the reaction was carried out in the absence of the Breslow intermediate, significant excitation followed by quenching was not observed, which indicates that the formed Breslow intermediate is the photoactive species and gets excited (Fig. 2).

Fig. 2 Emission spectra of reactant 1k under standard reaction conditions in 1 × 10⁻³ M solution. Determination of photoactive species.

Then, luminescence quenching experiments were performed at different time intervals (Fig. 3). Initially, upon adding 1k with Et₃N, the emission intensity increases followed by the addition of NHC (0–15 min). From this we have concluded that a photoactive species was formed when 1k reacts with Et₃N and further addition of NHC resulted in the Breslow intermediate that can absorb light and gets converted into the excited Breslow intermediate. Upon adding THIQ to the reaction mixture, we observed significant quenching, which was further supported by the excitation studies (see the SI). When 2a was added to the Breslow intermediate, a significant change in the absorption and excitation spectra was observed. This may be attributed to the formation of an excited state complex, which could be either a radical cation/anion or an electron donor–acceptor pair.

Fig. 3 Emission spectra of reactant 1k under standard reaction conditions in 1 × 10⁻³ M solution at a time interval of 0 min–8 h. For the first 1 h, the spectra were recorded every 15 min followed by a time interval of 1 h.

The light on–off experiments indicated that the reaction proceeded via a catalytic radical mechanism rather than a radical chain pathway (Fig. 4).⁵⁴

Fig. 4 Light on–off experiment under standard reaction conditions: the dark circle represents the reaction carried out in the dark and the Sun represents the reaction carried out in sunlight at a time interval of 1 h.

The adaptability of the present strategy for the synthesis of N-benzylated 3,4-dihydroisoquinolin-1(2H)-ones has been investigated using the optimized product on a gram scale. The reaction of 3,5-dichloro-2-hydroxybenzaldehyde 1k and THIQ 2 under the optimized reaction conditions gave the desired product 3k in a good yield of 79% (Scheme 7). In order to establish the environment-friendliness of the present redox process, various green chemistry metrics were calculated, as shown in Table 2, and they show notably high values, with the AE, AEf, E-factor, RME and PMI for 3k.⁶⁹ Based on the control experiments and fluorescence studies, we have confirmed the in situ formation of photoactive species and have proposed a plausible mechanism for this dual-NHC/photocatalysis activation of THIQ (Scheme 8). Initially, o-hydroxybenzaldehyde (1) reacts with the base, generating 1′, which exhibits fluorescence.⁷⁰ The base generates free carbene from the NHC precatalyst and aids in the formation of the Breslow photoactive species I. THIQ (2a) reacts with the Breslow intermediate (I) in the presence of molecular oxygen to form an excited state complex II*,⁷¹ which subsequently generates intermediate III.^72,73 Proton transfer from the nitrogen of the THIQ moiety to the benzylic oxygen leads to intermediate IV, which on dehydration generates intermediate V (confirmed by ESI-HRMS of intermediate Vk and isolation of compound 7). An intramolecular 1,3 hydride shift gives VI and further nucleophilic addition of a water molecule forms intermediate VII.⁷⁴ Intramolecular hydrogen atom transfer (HAT) and the removal of a proton in the presence of a base lead to the formation of intermediate VIII with the regeneration of NHCs.⁷⁵ Finally, removal of hydrogen radicals by the superoxide radical anion⁷³ leads to the final product 3.

Scheme 7 Gram-scale synthesis.

Scheme 8 Plausible mechanistic pathway for the tandem α-sp³ C–H activation and reductive N-alkylation of THIQ.

Table 2 Green chemistry metrics calculation, atom economy (%), atom efficiency (AEf) (%), E-factor, process mass intensity (PMI), and reaction mass efficiency (RME) (%) for 3k

Atom economy (%)	AEf (%)	E-Factor	PMI	RME (%)
83.03	71.38	4.09	5.09	60.6

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Conclusions

In summary, a visible-light and NHC-catalyzed tandem α-sp³ C–H activation and reductive N-alkylation of THIQ with o-hydroxybenzaldehydes has been demonstrated at room temperature for the first time. The reaction follows a intramolecular hydrogen atom transfer mechanism coupled with benzylic oxidation, with molecular oxygen acting as the oxidant. Mechanistic and fluorescence quenching experiments suggest the in situ formation of photoactive species between o-hydroxybenzaldehyde and Et₃N, which serves as a self-photocatalyst, thus eliminating the need for external photo-catalysts or photo-activators. The emission intensity of the photoactive species 1′ correlates directly with the efficiency of the NHC/visible-light-photocatalyzed process. We expect this tandem NHC/visible-light photocatalysis strategy to pave the way for a plethora of NHC- and visible-light-catalyzed carbon–heteroatom bond formation processes. Further mechanistic aspects for this tandem α-sp³ C–H activation and reductive N-alkylation will be explored in due course.

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the SI. SI includes: General information, optimisation of reaction conditions, Crystal data, control experiments, Experimental section, Characterization of compounds and copies of ¹H-NMR, ¹³C NMR spectral for all the products. See DOI: https://doi.org/10.1039/d5qo01032b.

CCDC 2430429 contains the supplementary crystallographic data for this paper.⁷⁶

Acknowledgements

C. U. M. acknowledges financial support from the Council of Scientific and Industrial Research (CSIR-ASPIRE): 01WS(032)/2023-24/EMR-II/ASPIRE and SASTRA in house research funding: SASTRA-TRR-SCBT. This work was also supported by Anusandhan National Research Foundation (ANRF), New Delhi, India, for the award of a core research grant: CRG/2021/006424 and DST-FIST (SR/FST/CS-I/2018/62) for NMR analysis.

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