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Published in final edited form as: J Am Chem Soc. 2024 May 17;146(21):14799–14806. doi: 10.1021/jacs.4c02991

Visible Light Photocatalytic C–H Amination of Arenes Utilizing Acridine–Lewis Acid Complexes

Matthew R Lasky a, En-Chih Liu a, Matthew S Remy b, Melanie S Sanford a,*
PMCID: PMC11577968  NIHMSID: NIHMS2035657  PMID: 38759094

Abstract

This report describes the development of a visible light photocatalytic system for C(sp2)–H amination that leverages in situ-generated photocatalysts. We demonstrate that the combination of acridine derivatives and Lewis acids forms potent photooxidants that promote the C–H amination of electronically diverse arenes upon irradiation with visible (440 nm) light. A first generation photocatalyst composed of Sc(OTf)3 and acridine effects the C–H amination of substrates with oxidation potentials ≤ 2.5 V vs SCE with pyrazole, triazole, and pyridine nucleophiles. Furthermore, the simplicity and modularity of this system enables variation of both the Lewis acid and acridine to tune reactivity. This enabled the rapid identification of two second generation photocatalysts (derived from (i) Al(OTf)3 and acridine or (ii) Sc(OTf)3 and a pyridinium-substituted acridine) that catalyze a particularly challenging transformation: C(sp2)–H amination with benzene as the limiting reagent.

Graphical Abstract

graphic file with name nihms-2035657-f0001.jpg

Introduction

Over the past decade, photoredox catalysis1 has emerged as a powerful approach for the C–H amination2 of aromatic substrates using a variety of photocatalysts (PC) and nitrogen nucleophiles (Figure 1a).3,4,5 These reactions generally proceed by a mechanism involving (i) excitation of PC to generate PC*, (ii) single electron transfer (SET) between PC* and the arene substrate to generate aryl radical cation I, (iii) capture of I by a nitrogen nucleophile, and (iv) oxidative formation of the aryl amine product.3,6,7 Despite the utility of reported methods, they have several key limitations. First, pre-assembled photocatalysts are typically required, and these are often expensive to purchase and/or are accessed via multi-step synthesis. As such, the modification/tuning of the catalyst requires significant time/synthetic effort. Second, the scope of these methods is generally restricted to electron-rich arenes, based on the limited range of excited state potentials (E*red) of existing photocatalysts.1a

Figure 1.

Figure 1.

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(A) Traditional photocatalytic C(sp2)–H amination. E*red = +2.15 V vs SCE for the acridinium photocatalyst in Figure 1A.3 (B) Consecutive photoinduced electron transfer (conPET) approach for C(sp2)–H amination. (C) Electrophotocatalysis for C(sp2)–H amination; NR2 = cis-2,6-dimethylpiperidine; compact fluorescent light bulb (400–700 nm). (D) Our approach for photocatalytic C(sp2)–H amination.

Recent efforts have focused on addressing this second limitation in order to achieve the amination of less activated arenes such as toluene and benzene. This has been accomplished by using ground-state oxidants that absorb visible light (e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone)8 or by exploiting alternative pathways, such as consecutive photoinduced electron transfer (conPET)9 (Figure 1b) or electrophotocatalysis (Figure 1c).10,11 However, despite significant progress,12 existing methods still require pre-assembled catalysts, and they typically need large excesses of arene substrate to afford synthetically useful yields.

We report herein a complementary approach that leverages modular, in situ-generated photocatalysts to achieve visible light photocatalytic C(sp2)–H amination. We demonstrate that these catalysts can be assembled under the C–H amination reaction conditions by simply combining a Lewis acid [e.g., Sc(OTf)3, Al(OTf)3] and an acridine derivative.13 Further, we show that mixing-and-matching the two readily available components (Lewis acid and acridine) enables amination reactions that are challenging with existing photocatalysts (for example, those involving toluene and benzene as limiting reagents).

Results and Discussion

Our approach was inspired by a 2004 report from Fukuzumi and co-workers, who studied photoinduced electron transfer reactions of acridine in the presence of Sc(OTf)3.13 The singlet excited state of acridine (Acr) in acetonitrile (MeCN) has an E*red of +1.29 V vs SCE, which is significantly below the oxidation potential of toluene or benzene. However, Fukuzumi showed that the addition of 0.5 equiv of Sc(OTf)3 resulted in a 2: 1 complex (A)14 with a singlet excited state that is quenched by xylenes as well as toluene and benzene (Figure 2).13 Despite these promising quenching results, to date the (Acr)2Sc(OTf)3 system has only been employed as a photocatalyst in a single organic transformation: the benzylic oxidation of hexamethylbenzene using UV light irradiation.13

Figure 2.

Figure 2.

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Precedent from Fukuzumi13 demonstrating metal ion-promoted photoinduced electron transfer and our approach.

Based on Fukuzumi’s results, we hypothesized that the combination of acridine and Sc(OTf)3 could serve as an effective photocatalyst for the C–H amination of arenes via aryl radical cation intermediate I (Figure 2). However, we also recognized a key challenge for this system: Lewis basic amine nucleophiles3–5 could competitively bind to Sc(OTf)3, thus disrupting the in situ formation of photocatalyst A. As an initial qualitative assay, we spiked solutions of A (which is a vibrant yellow color) with 2 equiv of various nitrogen nucleophiles (pyrazole, pyridine, imidazole, morpholine, butylamine; see Supporting Information for complete details). As shown in Figure 3a, the yellow color persists with nucleophiles that have a pKaH lower than that of acridine, including pyrazole, triazole, and pyridine derivatives. In contrast, loss of color is observed with nucleophiles that have a higher pKaH than acridine (e.g., imidazole, 1° and 2° amines).3,5c UV-vis spectroscopy was next used to quantify the amount of A remaining in solution in the presence of 2 equiv of various nitrogen nucleophiles (Figure 3b). As expected based on the qualitative experiments in Figure 3a, the %A decreases from 97% with pyrazole to 26% with pyridine to <1% with imidazole. In the latter case, nearly quantitative formation of free acridine is observed by UV-vis spectroscopy, implicating displacement of this ligand from the Sc(OTf)3. Overall, these results provide guidance on the selection of effective nitrogen nucleophiles for A-catalyzed C–H amination.

Figure 3.

Figure 3.

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(a) Visual appearance of a solution of A in MeCN upon addition of 2 equiv of various nitrogen nucleophiles. (b) UV-vis spectra of A in the presence of 2 equiv of nitrogen nucleophile.

We next established the E*red of the 2:1 complex A in typical solvents for C–H amination reactions: MeCN and 1,2-dichloroethane (DCE). Excitation and emission spectra of A15 as well as the ground state reduction potential were obtained (see Supporting Information), and then the Rehm-Weller equation was used to calculate E*red.16 These data reveal an E*red of +2.47 V vs SCE in MeCN and +2.38 V vs SCE in DCE.17,18 For comparison, E*red for the widely used acridinium photocatalyst in Figure 1A is nearly 300 mV lower at +2.15 V vs SCE.3 In addition, the excited state lifetime (τf) of A is 32.2 ns,13 which is comparable to or longer than that of other common organic photoredox catalysts.1b,19

Based on the work in Figure 3, we initiated our studies of photocatalysis with the reaction between biphenyl and pyrazole to form aminated product 1. A solution of acridine (100 mol %), Sc(OTf)3 (50 mol %), biphenyl (1 equiv), and pyrazole (2 equiv) in MeCN was irradiated for 24 h with 440 nm Kessil LEDs under an atmosphere of O2. This afforded pyrazole product 1 in 27% yield (Table 1, entry 1). Lowering the loading of acridine (to 10 mol %) and Sc(OTf)3 (to 5 mol %) led to a decrease in yield (to 11%, entry 2). However, changing the solvent from MeCN to DCE3,4 under otherwise identical conditions, afforded 71% yield of 1 with a 1 : 2 stoichiometry of biphenyl to pyrazole (entry 3).20 This yield could be further increased to 97% by moving from 2 to 5 equiv of pyrazole relative to biphenyl (entry 4).21 Control experiments show that acridine, Sc(OTf)3, and light are all necessary to obtain more than 20% product under these conditions (entries 6–8). Moreover, if the reaction mixture is not sparged with oxygen, the yield drops to 19% (entry 9), consistent with O2 driving the trapping and re-aromatization sequence.12c,22 Fluorescence quenching studies show that the excited state of A is quenched most efficiently by the arene (biphenyl), consistent with a mechanism proceeding through an aryl radical cation intermediate.23

Table 1.

Photocatalytic C(sp2)–H Amination Optimization

graphic file with name nihms-2035657-t0002.jpg
entry acridine (mol %) Sc(OTf)3 (mol %) pyrazole (equiv) solvent yielda (1)
1 100 50 2 MeCN 27%
2 10 5 2 MeCN 11%
3 10 5 2 DCE 71%
4 10 5 5 DCE 97%
5 5 2.5 5 DCE 77%
6 -- 5 5 DCE 0%
7 10 -- 5 DCE 20%
8 10 5 5 DCE 0%b
9 10 5 5 DCE 19%c
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a

Yields determined by 1H NMR spectroscopy.

b

No light.

c

Reaction was not sparged with an O2 balloon before light irradiation (conducted under ambient air).

Note: All reagents were handled on the benchtop without exclusion of air or moisture.

We next investigated the nitrogen nucleophile scope for this transformation. As shown in Scheme 1, pyrazole, triazole, and pyridine derivatives react to afford N-aryl azole and N-arylpyridinium products24,25 2–10 in moderate to good yields. The reactions tolerate a range of functional groups and substitution patterns on the nitrogen nucleophiles. The N-arylpyridinium products26 are particularly versatile, as they are readily transformed into anilines (via reactions with amine bases)6d,26b or piperidine derivatives (via hydrogenation).27,28 In addition, cationic pyridinium substituents are highly electron-withdrawing, which minimizes overoxidation of the C–N coupled products.6d Imidazole (IM) is not an effective nucleophile for this transformation, likely because it disrupts formation of the photocatalyst.29

Scheme 1.

Scheme 1.

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Scope of Nitrogen Nucleophilesa

aReactions were conducted under blue light irradiation for 24 h in either DCE or MeCN, see Supporting Information. All yields are isolated. Ratios represent ratio of crude products, as determined by 1H NMR spectroscopy. bRatio refers to p:o selectivity. cRatio refers to p:m selectivity. d10 equiv of nitrogen nucleophile. e105 mol % Sc(OTf)3 utilized to balance the charge of the pyridinium product.

The arene scope was explored with the goal of establishing the range of Eox values that can be accessed with catalyst A. As expected, electron-rich (hetero)arenes (with Eox ≤ +2.0 V vs SCE) show good reactivity. For instance, anisole and diphenyl ether, afford 11 and 12 in 54% and 82% isolated yield, respectively, as mixtures of para and ortho isomers (Scheme 2). The observed regioselectivity (4.5 : 1 and 7 : 1, respectively) is similar to that reported in other photocatalytic C(sp2)–H amination methods with these arenes.3 Chloro- and bromo-substituted anisoles as well as quinoline and benzothiazole derivatives are also compatible, affording aminated products 13-16. Similarly, bioactive molecules containing electron-rich aromatic rings, including napropamide, metaxalone, and hyamine, afford C(sp2)–H amination products 28-30 under the standard conditions in modest to good yields.

Scheme 2.

Scheme 2.

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Arene Scope for Photocatalytic C(sp2)–H Aminationa

aReactions were conducted under blue light (440 nm Kessil LED) irradiation for 24 h in either DCE or MeCN, see Supporting Information for more detail. All yields are isolated. Ratios represent ratio of crude products, as determined by 1H NMR spectroscopy, between major (pictured) and minor (*) isomers. bRatio refers to p : m : o selectivity. cReaction run under an atmosphere of N2 with 1 equiv of TEMPO.3 dRatio represents ratio of the isolated mixture, as determined by 1H NMR spectroscopy. A ratio of crude products could not be obtained.

We also explored more challenging substrates with Eox ≥ +2.0 V vs SCE. A series of alkyl substituted arenes (17-20), including mesitylene, m-xylene, t-butylbenzene, and toluene, afforded high yield under our standard conditions (1 equiv of arene, 5 equiv of pyrazole). The 68% isolated yield with toluene (17) (Eox = +2.36 V vs SCE)18a at this stoichiometry is particularly noteworthy. Most common visible light photocatalysts are incapable of promoting the C(sp2)–H amination of toluene,3,4 and even among those that do, large excesses of toluene relative to amine are typically required to achieve synthetically useful yields.5d,8–10,30 Anisole derivatives bearing electron-withdrawing ester, amide, and trifluoromethyl substituents also react to form aminated products 23–25. Amide (21), triflate (22), acetate (26), lactone (27), and protonated amine (31) functional groups are all well tolerated (Scheme 2).31,32

Subjecting 1 equiv of benzene (Eox = +2.48 V vs SCE)18b to our standard conditions with pyrazole as a nucleophile afforded <1% of the C(sp2)–N coupled product 32. Preliminary results indicate that both product inhibition and product decomposition can occur with 32.33 In an effort to limit these competing processes, we next evaluated the use of an excess of benzene with pyrazole as the limiting reagent. This modification led to a significantly increased yield of 32 (62%; Scheme 3).8–10 Under these conditions, benzene also undergoes photocatalytic C(sp2)–H amination with a range of other nitrogen nucleophiles.34 Pyrazoles bearing various electron-withdrawing groups, including halogen (33), aldehyde (34), ketone (35), carboxylic acid (36), trifluoromethyl (37), cyano (38), and nitro (39) afford moderate to good yields. Both urea and tert-butyl carbamate, proved effective as nucleophiles, affording 40 and 41 in 41% and 31% yield, respectively (Scheme 3). 3-Nitropyridine also reacts to form 42 in 56% yield.35,36 Finally, arenes bearing electron-withdrawing chloro, bromo, and trifluoromethoxy substituents also show good reactivity with 4-cyanopyrazole under these conditions (43–47 in Scheme 3).37

Scheme 3.

Scheme 3.

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Photocatalytic C(sp2)–H Amination of Arenes with Eox ≥ +2.4 V vs SCEa

aReactions were conducted using 0.2 mmol of nitrogen nucleophile, 5 mL of arene. Ratio of arene to MeCN is 1:1. All yields are isolated. bReaction time 48 h. c105 mol % Sc(OTf)3 utilized to balance the charge of the pyridinium product.

Both the Lewis acid and acridine components of the in situ- photocatalyst can be varied independently, making the system highly modular. This offers the potential for rapid combinatorial screening for catalyst optimization. To demonstrate the utility of this approach, we focused on a challenging substrate, benzene, with the ultimate goal of identifying a photocatalyst that enables C(sp2)–H amination with benzene as the limiting reagent.38

A first set of studies evaluated different Lewis acids and acridine derivatives for the photocatalytic reaction of benzene (in excess) with three nitrogen nucleophiles: 1H-pyrazole-4-carbonitrile, tert-butyl carbamate, and 3-nitropyridine (Scheme 4A). Lewis acids were selected to encompass diverse metal cations (Al, Zn, K, and Li) and anions (triflate, perchlorate, and hexafluorophosphate). Acridine derivatives (Acr, Acr-Cl, and Acr-Py+)39 were chosen based on the hypothesis that the incorporation of electron-withdrawing substituents would increase E*red of the photocatalyst and thus enhance reactivity.

Scheme 4.

Scheme 4.

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Screens of Different Lewis Acid and Acridine Derivatives for the C–H Amination of Benzene

Yields are crude and were determined by 1H NMR spectroscopy. All reagents were handled on the benchtop without exclusion of air or moisture. aConditions: 0.2 mmol of nitrogen nucleophile and 5 mL of benzene. Ratio of benzene to MeCN is 1:1. bConditions: 0.05 mmol of 3-nitropyridine, 1.25 mL of benzene, and 105 mol % of Lewis acid to balance the charge of the pyridinium product. Ratio of benzene to MeCN is 1:1. cConditions: 0.05 mmol of benzene and 105 mol % of Lewis acid to balance the charge of the pyridinium product. dConditions: piperidine (0.5 mmol, 10 equiv) added to the crude reaction mixture. Yield is over 2 steps, based on benzene.

The acridine/Lewis acid combinations in Scheme 4A generated photocatalysts with a wide range of reactivity towards the amination of benzene. There are several key takeaways from these data. First, the yield varies dramatically (<1–99%) upon changing the Lewis acid, the acridine, and the amine nucleophile, highlighting the value of a combinatorial screening approach. Second, Acr-based photocatalysts derived from Sc(OTf)3, Al(OTf)3, or Zn(OTf)2 afforded comparable yields with all three nucleophiles. Fukuzumi’s original report only explored Sc(OTf)3,13 and, as such, the Al and Zn derivatives represent novel photocatalyst structures. The Al version is particularly noteworthy because Al is approximately three orders of magnitude more earth abundant than Sc.40 Third, Acr-Cl and Acr-Py+ afford similar yields to Acr with 1H-pyrazole-4-carbonitrile and 3-nitropyridine, but significantly lower yields with tert-butyl carbamate. We hypothesize that the higher E*red values of photocatalysts with electron-deficient acridines (vide infra) makes them particularly susceptible to either product/substrate inhibition and/or product overoxidation with this nucleophile.

Encouraged by the learnings from the screen in Scheme 4A, we next sought leverage the modular catalyst design to address a key limitation of the first-generation catalyst A: poor performance in C(sp2)–H amination reactions when using benzene as the limiting reagent. 3-Nitropyridine was selected as the nucleophile, because the highly electron-deficient N-phenyl pyridinium product 42 should be inert towards overoxidation,6d a frequent issue at this stoichiometry. The three top performing Lewis acids from Scheme 4A (Sc(OTf)3, Al(OTf)3, and Zn(OTf)2) were evaluated in combination with the three acridine derivatives (Acr, Acr-Cl, and Acr-Py+). As expected, the first-generation Acr/Sc(OTf)3 catalyst afforded low (4%) yield of 42 (Scheme 4B). However, remarkably, the yield increased to ≥55% upon changing either the Lewis acid (to Al(OTf)3) or the acridine ligand (to Acr-Py+) (Scheme 4B).30,41,42

To gain further insight into the improved performance of Acr/Al(OTf)3 (second generation photocatalyst B) and Acr-Py+/Sc(OTf)3 (second generation photocatalyst C) we experimentally determined E*red for each using the procedure detailed above. These experiments estimate an E*red of +2.44 V for B and +2.65 V for C (vs SCE in MeCN, Figure 4). These results confirm our hypothesis that electron-deficient acridines lead to in situ photocatalysts that are more oxidizing than A. However, interestingly, the effectiveness of catalyst B, which has essentially the same E*red value as A, shows that this is not the only parameter impacting performance in benzene C–H pyridination. Other factors, such as differing rates of back electron transfer and/or E* lifetimes, may be responsible for the enhanced performance of B, and future work will follow up with detailed photophysical comparisons between these three catalysts.

Figure 4.

Figure 4.

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Experimentally determined E*red for in situ photocatalysts A, B, and C.

In conclusion, this manuscript describes the development of in situ-generated acridine–Lewis acid adducts as simple, cost-effective, and modular visible light photocatalysts for C(sp2)–H amination reactions. We first show that the combination of Acr and Sc(OTf)3 generates a potent photooxidant (A) that catalyzes the amination of diverse arene substrates with Eox values of ≤ 2.5 V vs SCE. A broad range of nitrogen nucleophiles with pKaH less than that of acridine are compatible, including pyrazole, pyridine, triazole, urea, and carbamate derivatives. We further demonstrate that the in situ photocatalyst is highly modular and can be optimized for challenging transformations by varying either the Lewis acid or acridine component. Specifically, screening different pairings unveiled two second-generation photocatalysts (Al(OTf)3/Acr (B) and Sc(OTf)3/Acr-Py+ (C)) that promote visible light photocatalytic C–H pyridination with benzene as the limiting reagent. Moving forward, we anticipate that these acridine–Lewis acid systems will find much broader application to diverse photocatalytic transformations and that their modularity will facilitate new reaction discovery and optimization.

Supplementary Material

Supporting Information

ACKNOWLEDGMENT

This project was initiated with funding from Dow through the University Partnership Initiative. This work was completed and is currently supported by funding from the NIH (NIGMS R35GM1361332). We thank Dr. Ryan Walser-Kuntz for assisting in electrochemical measurements.

ABBREVIATIONS

PC

photocatalyst

Acr

acridine

SCE

standard calomel electrode

Footnotes

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

Procedure details and NMR spectra (PDF)

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  • (15). Both the excitation and emission spectrum of A are analogous to those reported by Fukuzumi, see ref. 13. Complete details can be found in the Supporting Information.
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  • (21).The crude reaction mixture of 1 (97% crude) affords a 12 : 1 ratio of the para : ortho isomers, as determined by 1H NMR spectroscopy. However, 1 was isolated as a single (para) isomer.
  • (22). Fukuzumi also reported a pyrene-Sc(OTf)3 catalyst in ref. 13. However, under our conditions with (10 mol % pyrene, 5 mol % Sc(OTf)3, 5 equiv pyrazole, MeCN, 440 nm, room temperature, O2) this catalyst afforded just 15% yield of 1 with biphenyl and <1% yield of 17 with toluene.
  • (23). The quenching rate constants, kq, for biphenyl (kq = 5.1 × 109 M−1s−1) and pyrazole (kq = 2.1 × 109 M−1s−1) in DCE were determined via Stern-Volmer quenching experiments. Due to the high excited state potential of A (E*red = 2.38 V vs SCE in DCE), fluorescence quenching of A with both biphenyl (Eox = 1.96 V vs SCE) and pyrazole (Eox = 2.27 V vs SCE) is consistent with known redox potentials for each respective substrate (see ref. 18). These data indicate that the excited state of A is quenched most efficiently by biphenyl, consistent with a mechanism proceeding through an aryl radical cation intermediate. However, the quenching data do not completely rule out an alternative mechanism in which pyrazole is oxidized by A*, followed by addition to biphenyl. That said, other data are inconsistent with such a mechanism. For example, amination with pyrazole is only effective for arenes that are within the potential range of the photocatalyst, which would not be expected if pyrazole oxidation were the predominant mechanism (Table S9). The compatibility with pyridine nucleophiles (Scheme 1) further supports an aryl radical cation mechanism, since the oxidation potential of pyridine (>+2.7 V vs SCE) is higher than the excited state reduction potential of A (E*red = +2.38 V vs SCE in DCE).
  • (24).105 mol % of Sc(OTf)3 was utilized to balance the charge of the pyridinium product.
  • (25). The observed regioselectivity of pyridinium products (5–10) is similar to that observed in our previously reported method of C(sp2)–H pyridination, see ref. 12c.
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  • (29). Utilizing tert-butyl carbamate with anisole under our standard conditions (10 mol % acridine, 5 mol % Sc(OTf)3, DCE, 440 nm, room temperature, O2) affords modest (20%) yield of the C(sp2)–H amination product. See Table S9 for details.
  • (30).The effectiveness of our in situ acridine–Lewis acid systems relative to literature photo(electro)catalysts with toluene or benzene as limiting reagent could be due to different E* lifetimes, rates of back electron-transfer, and/or rates of over-oxidation.
  • (31). See Supporting Information (Table S9) for low yielding and incompatible arene substrates and nitrogen nucleophiles.
  • (32).The reaction with Prozac was conducted with the HBF4 salt of the amine, and the product was subsequently converted to the pivaloyl amide to facilitate isolation. This isolation procedure was adopted from: Lee M; Sanford MS Platinum-Catalyzed, Terminal-Selective C(sp3)–H Oxidation of Aliphatic Amines. J. Am. Chem. Soc 2015, 137, 12796–12799. [DOI] [PMC free article] [PubMed] [Google Scholar]
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  • (34). Stern-Volmer fluorescence quenching of A with benzene revealed a quenching rate constant of kq = 8.0 × 108 M−1s−1. Complete details can be found in the Supporting Information.
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  • (37). Substrates with stronger electron-withdrawing groups (e.g. trifluorotoluene and acetophenone) showed no reactivity, likely because their Eox values are higher than the E*red of A. See Supporting Information for low yielding and incompatible arene substrates and nitrogen nucleophiles (Table S10).
  • (38).Being able to use a high potential arene as the limiting reagent is of broad utility, as it would allow the use of either the nitrogen source or arene as the limiting reagent, depending on which is more synthetically valuable.
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  • (42).Utilizing second generation photocatalyst C with 1 equiv of benzene and 2 equiv of 3-nitropyridine, under otherwise analogous conditions, affords 42 in 43% yield, as determined by 1H NMR spectroscopy.

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Supporting Information
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