Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 3582−3589
External Oxidant-Free Dehydrogenative Lactonization of 2‑Arylbenzoic Acids via Visible-Light Photocatalysis Ailong Shao,† Jirui Zhan,† Na Li,† Chien-Wei Chiang,*,† and Aiwen Lei*,†,‡ †
Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, Hubei, People’s Republic of China ‡ National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, People’s Republic of China S Supporting Information *
ABSTRACT: An external oxidant-free C−H functionalization/ C−O bond formation reaction for constructing benzo-3,4coumarins accompanied by quantitative H2 evolution has been developed. High functional group tolerance and excellent reaction efficiency are shown in this transformation. Meanwhile, the substrates containing heterocyclic substituents such as thienyl-, pyridinyl-, and pyrrolylbenzoic acids displayed good performance. Importantly, this reaction can be performed with good efficiency on a gram scale. A cyclic voltammetry study and density functional theory calculations could provide insight into the mechanism of this reaction.
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INTRODUCTION Intramolecular cyclization of tethered carbon atoms or heteroatoms onto proximate C−H bonds is one of the most straightforward and efficient method for numerous ring formations.1 However, these reactions mainly utilized the traditional metal catalysis strategy or excess of oxidants to perform the reaction under high temperature, which would limit the practical application of these reactions. Recently, photocatalysis has emerged as the new generation method to perform C−H bond functionalization.2 The combination of a photoredox catalyst and a cobaloxime catalyst could achieve oxidative cross-coupling reactions under the oxidant-free conditions, which could satisfy the demand of green chemistry.3 This dual catalytic system provided a great opportunity for the synthesis of various ring formations through the oxidative intramolecular cyclization reaction without the requirement of stoichiometric oxidants, in which the unexpected chemical waste can be avoided and the H2 serves as the only byproduct. Benzo-3,4-coumarins make up the privileged structural cores in natural products and pharmaceuticals such as cell proliferation inhibitors,4a alternariol,4b,c and graphislactones4d,e (Scheme 1a). In view of the important synthetic applications of benzo-3,4-coumarins, tremendous efforts have been made to develop methods through the intramolecular C−H lactonization of 2-arylbenzoic acids. Early on, the synthesis of benzo-3,4coumarins usually required harsh reaction conditions, such as a chromic acid oxidant and ultraviolet irradiation.5 Recently, transition-metal-catalyzed oxidative C−H lactonization has been developed to realize this C−O bond formation.6 In addition, Martin and his co-workers developed a metal-free C− H lactonization process in which the in situ generated hypervalent iodine species was an important intermediate.7 © 2018 American Chemical Society
Scheme 1. (a) Natural and Pharmaceutical Molecules and (b) External Oxidant-Free Dehydrogenative Lactonization of 2-Arylbenzoic Acids via Visible-Light Photocatalysis
Besides, the photoredox catalysis also provided an alternative approach for this oxidative intramolecular cyclization reaction. In 2013, Wei et al. reported oxidative lactonization of 2arylbenzoic acids mediated by NIS for the synthesis of dibenzopyranones.8 In 2015, Gonzalez-Gomez et al. also described a visible-light photocatalytic oxidative C−O coupling of 2-arylbenzoic acids using NH4S2O8 as the stoichiometric oxidant,9 and Gilmour et al. reported direct synthesis of coumarins from (E)-cinnamic acids by using (−)-riboflavin as the photocatalyst and oxygen as the terminal oxidant.10 More Received: December 18, 2017 Published: March 5, 2018 3582
DOI: 10.1021/acs.joc.7b03195 J. Org. Chem. 2018, 83, 3582−3589
Article
The Journal of Organic Chemistry
Meanwhile, the investigation of the proton-reduction catalyst showed that the cobalt catalyst C emerged as the best catalyst for this reaction (Table 1, entries 1, 5, and 6). Since the redox potentials of catalysts A (E°(Co(II/I)) = −1.13 V vs SCE) and B (E°(Co(II/I)) = −1.13 V vs SCE) are significantly lower than that of catalyst C (E°(Co(II/I)) = −0.81 V vs SCE),15a catalyst A or B would show a lower oxidative efficiency than catalyst C to oxidize the radical intermediate. In addition, the reaction was drastically inhibited when the additive was introduced into this reaction (Table 1, entries 7−9). We propose two explanations: (1) To some degree, we thought that because of the special structure of the acridinium catalyst, the alkaline additives would gradually deactivate it and then interrupt the reaction. Meanwhile, according to the investigation of the reaction conditions of ref 11, this reaction could be carried out smoothly with a moderate yield without adding any alkaline additives. In addition, the use of 2,6-lutidine or PhCO2Na as a promoter was a good option just to improve the reaction efficiency. However, in our protocol, we just carried out a strict deoxygenation process of the reaction system. (2) Different types of bases might lead to differences in the efficiency of the reaction. For example, trimethylamine was more basic than 2,6-lutidine11a and could react with the substrate to generate a stable ammonium salt to stop the reaction. Meanwhile, it also had a strong reducing ability to destroy the structure of the acridinium catalyst. Moreover, chlorine atoms on the cobalt catalyst C might be replaced by triethylamine to form a new cobalt catalyst, with a reduced reactivity compared to that of the original cobalt catalyst. Finally, control experiments showed that the photocatalyst, cobaloxime catalyst, and visible light were indispensable in this transformation (Table 1, entries 10−12). With the optimized conditions in hand, we turned to explore the functional group tolerances for the construction of benzo3,4-coumarins (Table 2). The effect of Ar1 will be first investigated. For instance, both electron-rich and electron-poor 4′-substituted arenecarboxylic acids could furnish the corresponding products in moderate to excellent yields (Table 2, 2a, 2b, 2c, 2f, 2g). Notably, this reaction could tolerate an unprotected OH group (Table 2, 2h) and halogen groups, such as fluoro and chloro (Table 2, 2d, 2e). Meanwhile, the corresponding benzocoumarins (Table 2, 2i, 2j) were obtained in moderate yields and with good regioselectivities. A naphthalene ring and a dibenzofuran ring could also be tolerated in this reaction (Table 2, 2k, 2l). Distinct from the prior reports in ref 11, we found that thiofuran and pyridyl heterocyclic motifs could be incorporated and with complete regiocontrol (Table 2, 2m, 2n). Interestingly, none of the other regioisomers of 2k, 2m, and 2n were observed. Benzoic acid with a pyrrolyl heterocyclic motif could also be transformed into the corresponding product in good yield (Table 2, 2o). In addition, Ar2, which is bound to the carboxylate group directly, with either electron-rich or electron-poor substituents could provide good reactivity to build benzo-3,4-coumarins (Table 2, 2p−2v). The yields of substrates with electron-deficient substituents showed a slight decrease (Table 2, 2s and 2t vs 2q and 2r). In the meantime, substrates with halogen groups, such as fluoro and chloro, could be transformed into the target products in good yield (Table 2, 2u, 2v). Naphthalene was also tolerated in this transformation and gave 75% isolated yield (Table 2, 2p). However, when the ortho position of Ar1 was substituted, the reaction was significantly inhibited (Scheme 2),
recently, Luo et al. and Zhu et al. demonstrated a photoredox− cobalt-cocatalyzed system to perform the dehydrogenative lactonization of 2-arylbenzoic acids, accompanied by hydrogen evolution.11a,b We also envisioned that the merging of a photoredox catalyst and a cobaloxime catalyst should have the capacity of realizing the dehydrogenative lactonization with hydrogen evolution, which could provide an alternative avenue to build the C−O bond (Scheme 1b).
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RESULTS AND DISCUSSION We began our studies by using 2-phenylbenzoic acid (1a) as the model substrate to examine the suitable conditions for this photoredox−cobaloxime-catalyzed C−H lactonization reaction. To our delight, the desired product can be isolated in 75% yield, and quantitative H2 can be detected by GC-TCD in the presence of Fukuzumi’s acridium photosensitizer and a protonreduction catalyst, Co(dmgH)2(4-(Me2N)C5H4N)Cl after 10 h of irradiation of blue light. Further investigation of the photocatalysts demonstrated that only Acr+MesClO4− enabled the coumarin product formation, while Ru(bpy)3Cl2, Ru(bpz)3(PF6)2, and Ir(ppy)3 were not effective (Table 1, entries 1−4). Table 1. Optimization of the Reaction Conditionsa
a
Conditions: 1 (0.20 mmol), photocatalyst (1.5 mol %), and Co catalyst (2 mol %) were mixed in CH3CN (1 mL) under a nitrogen atmosphere and irradiated with 3 W blue LEDs at room temperature for 10 h. H2 was detected by gas chromatography. bIsolated yields are shown. cThrough a strict deoxygenation process (for details, see the Experimental Section). dWithout light. 3583
DOI: 10.1021/acs.joc.7b03195 J. Org. Chem. 2018, 83, 3582−3589
Article
The Journal of Organic Chemistry
Scheme 3. Scope of Arylcinnamic Acids and o-Enylbenzoic Acids
Table 2. Substrate Scope of the Synthesis of Substituted Benzo-3,4-coumarinsa
obtained. When CF3CH2OH was used as the solvent, the newly generated alkyl radical would undergo a hydrogen atom transfer with CF3CH2OH to give an anti-Markovnikov hydrocarboxylation product. However, in our study, CH3CN was considered as a nonprotic solvent with a higher BDE, which made it difficult to accomplish the hydrogen atom transfer process with the newly generated alkyl radical. Consequently, the generated alkyl radical was transferred to a cation intermediate after undergoing a single electron transfer (SET) process with a Co(II) intermediate and quickly lost a proton to produce the desired product. Furthermore, a gram-scale synthesis of this oxidant-free dehydrogenative lactonization was performed (Scheme 4). A 6
Conditions: 1 (0.20 mmol), Acr+MesClO4− (1.5 mol %), and Co(dmgH)2Cl2 (2 mol %) were mixed in CH3CN (1 mL) under a nitrogen atmosphere and irradiated with 3 W blue LEDs at room temperature for 10 h. H2 was detected by gas chromatography. Isolated yields are shown. An asterisk indicates the minor regioisomer (NOESY spectra of 2d; see the Supporting Information (Figure S2). a
Scheme 4. Gram-Scale Synthesis
indicating that the steric effect on the ortho position would influence the coupling efficiency. Scheme 2. Reactivity of Different 2′-Substituted Acids mmol portion of 1a could be cyclized to 2a in 85% yield (1.01 g) and undergo the dehydrogenation. This result indicated that the photoredox−cobalt-cocatalyzed dehydrogenation crosscoupling had great potential in a practical synthesis. To gain more insight into the reaction mechanism, we experimentally explored the presence of radical intermediates. First, radical trapping reagents such as BHT and triethyl phosphite have been introduced into the reaction mixture. As the results show, the reaction could be completely quenched by the above reagents (Scheme 5a). Thus, we proposed that this transformation might proceed through a radical pathway. In addition, the competitive intermolecular kinetic isotopic effect has been determined (kH/kD = 1.10). This result suggested that the C−H bond cleavage might not be the rate-determining step in this process (Scheme 5b). Moreover, cyclic voltammetry (CV) experiments of a series of substrates and their deprotonated salts have been performed (Figure 1). In the CV experiments, electron-poor and electronneutral substrates 1 showed a relatively higher redox potential (E1/2,red = +2.20−2.55 V vs SCE) compared to an excited state of acridinium (E*1/2,red = +2.08 V vs SCE)12 (Figure 1a), indicating that these substrates could not be oxidized directly by the photocatalyst. In contrast, the redox potentials of sodium aryl benzoates Na(1−) (E1/2,red = +1.58−1.71 V vs SCE) were apparently lower than that of the photocatalyst (Figure 1b).
To explore the synthetic potential of this oxidant-free lactonization, some arylcinnamic acids such as 1w and 1x, were synthesized and tested under standard conditions (Scheme 3). 2w and 2x could be successfully obtained as the corresponding coumarins in good yield. Interestingly, oenylbenzoic acids such as 1y and 1z, could react to form isocoumarins, which is different from the results of the recent work that Luo and his co-workers have published.11a A possible explanation is that CF3CH2OH is a protic solvent and is probably used as a H atom donor, yet CH3CN is considered as a nonprotic solvent, which leads to the difference in the results of the two transformations. According to the proposed mechanism, we suggested that, after the radical addition of a carboxyl radical to the CC bond, the alkyl radical could be 3584
DOI: 10.1021/acs.joc.7b03195 J. Org. Chem. 2018, 83, 3582−3589
Article
The Journal of Organic Chemistry Scheme 5. Mechanistic Study
Figure 1. Cyclic voltammetry of (a) a series of arylbenzoic acids 1 and (b) a series of sodium arylbenzoates Na(1−) in CH3CN with n-Bu4NBF4 (0.2 M) as the electrolyte under nitrogen at a platinum-disk electrode at a scan rate of 100 mV s−1.
Therefore, aryl benzoate (1−) would be an intermediate in the catalytic process. In addition, DFT calculation was performed to explain the generation of oxidative species. The spin density map of the oxidative species is shown in Figure 2. According to the result,
were limited (Table 3). One possible explanation is due to the existence of lone pair electrons on the nitrogen atom of Table 3. Solvent Effecta
Figure 2. Spin density plot of the 1a radical. Blue and green represent the spin-up and spin-down spin densities, respectively.
entry
solvent
yieldb (%)
1 2 3 4 5
CH3CN DCE THF DMF DMSO
99 10
