Visible-Light-Induced Regioselective Alkylation of Coumarins via

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Visible-Light-Induced Regioselective Alkylation of Coumarins via Decarboxylative Coupling with N‑Hydroxyphthalimide Esters Can Jin,*,† Zhiyang Yan,† Bin Sun,*,‡ and Jin Yang† †

College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. China Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, P. R. China

‡

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S Supporting Information *

ABSTRACT: An efficient photocatalytic decarboxylative 3position alkylation of coumarins by using alkyl N-hydroxyphthalimide esters as alkylation reagents has been developed. A variety of NHP esters derived from aliphatic carboxylic acids (primary, secondary, and tertiary) has been proved to be tolerated for this decarboxylation process, affording a broad scope of 3-alkylated coumarin derivatives in moderate to excellent yields. This protocol was highlighted by its mild conditions, readily available starting materials, operational simplicity, and wide functional group tolerance.

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coumarins with a variety of nucleophilic reagents was regarded as a traditional method for synthesis of coumarin derivatives (Scheme 1a).3 In recent decades, the direct C−H functionalizations through oxidative cross-coupling reactions have served as a powerful strategy for construction of C−C or C−X bonds.4 By employing this strategy, extensive progress has been made in the synthesis of various 3-substituted coumarin derivatives.5−9 Hong’s group developed a regioselective palladium-catalyzed C−H olefination of coumarin, affording a variety of 3-vinyl or 3-styryl coumarin compounds.5a Subsequently, other inexpensive and abundant metals, such as Cu,6 Fe,7 and Co,8 also have received considerable attention in C−H functionalization of coumarin. For example, Ge and co-workers reported iron-catalyzed oxidative cross-coupling reactions of coumarin with ethers, leading to the construction of various 3-ether substituted coumarin scaffolds.7a Recently, Jafarpour’s group developed a metal-free method for the etherification9a or aroylation9b of coumarins employing tert-butyl hydroperoxide exclusively. Although it is true that impressive progress has been achieved in preparing corresponding substituted coumarin compounds, some drawbacks such as the use of excess amounts of oxidants, harsh reaction conditions, and low conversions or yields are still the issues limiting further application. Moreover, the more difficult task of alkylation of coumarin to synthesize chainalkylated coumarin derivatives via oxidative coupling reaction is still a formidable challenge. To the best of our knowledge, thus far there is no report on chain alkylation of coumarin except for Zou’s research,6d which could only provide the 3methylated coumarins by using DTBP as the methylation reagent. Therefore, developing novel highly efficient methods to prepare chain-alkylated coumarins is of great interest.

oumarin derivatives, a major class of naturally occurring compounds and medicinal scaffolds, exhibit a broad range of notable activities such as antimicrobial, antiinflammatory, anticancer, or anti-HIV (Scheme 1),1 and also have been widely used in organic materials for their competent optical properties.2 The Michael conjugate addition to Scheme 1. Strategies for the Synthesis of Coumarin Derivatives and Examples of Coumarin-Type Pharmaceuticals

Received: January 26, 2019

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.9b00327 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 1. Optimization of the Reaction Conditionsa

In the past decade, with the growing demand for developing environmentally benign synthetic approaches, visible-lightinduced catalysis has gained significant interest in organic synthesis due to its environment-friendliness, mild conditions, and low-energy irradiation.10 Meanwhile, the alkyl Nhydroxyphthalimide (NHP) ester derived from alkyl carboxylic acid and NHPI were demonstrated to be effective alkyl sources because it can be easily reduced by photocatalysts to generate extensive kinds of alkyl radicals while eliminating CO2.11 With this in mind, a radical type decarboxylative alkylation of coumarin by employing alkyl NHP esters may solve the problem of a lack of effective methods for preparation of 3chain alkylated coumarins. Herein, we uncover a concise assembly of C(sp2)−C(sp3) bonds between coumarins and alkyl NHP esters via a visible-light-mediated decarboxylative process. This protocol features good yields and excellent regioselectivities, which provides another avenue to achieve the regioselective functionalization of coumarins under mild conditions. To begin our study, we chose coumarin (1a) and alkyl NHP esters (2a) as model reactants to explore and optimize the decarboxylation coupling reaction. Initially, an extension screen of various photocatalysts, such as Ru(bpy)3Cl2, EosinY, Ir(ppy) 3 , Rose Bengal, Methylene Blue and MesAcr+ClO4−were investigated for this transformation at room temperature with irradiation by blue LEDs under N 2 atmosphere. The experimental results revealed that only Ir(ppy)3 could give the corresponding product in 29% yield, and no desired coupling product was observed when other photocatalysts were employed (Table 1, entries 1−6). To further enhance the reaction efficiency, several additives were then examined. To our delight, a significant improvement could be obtained when the reaction was conducted in the presence of 0.5 equiv of TFA and gave the desired product in 67% yield (Table 1, entry 7). Other two screened acids, TfOH and AcOH, seem to be less effective than TFA and could only give the 3aa in 61% and 46% yield (Table 1, entries 8−9). Several base additives were also studied for this transformation but proved to be completely ineffective (Table 1, entries 10− 11). Increasing the amount of TFA to 1.0 equiv. or decreasing to 0.2 equiv. both led to a diminished yield (Table 1, entries 12−13). Subsequently, various commonly used solvents including MeCN, DCE, EtOAc, DMF, were examined. No product was found with MeCN, DCE or EtOAc as solvent, and only 45% yield was obtained when DMF was employed, where DMSO still turned out to be the most appropriate (Table 1, entries 14−17). We then employed 3W white LEDs as light source and surprisingly found that the yield of 3aa was enhanced from 67% to 81%, but no improvement could be obtained as the reaction time was prolonged to 48 h (Table 1, entries 18−19). Contrast experiments revealed that both photocatalyst and visible lights were essential for this decarboxylative coupling reaction, and of note, only trace yield was obtained when this transformation was carried out under air (Table 1, entries 20−22). On the basis of the screening of the reaction conditions, it was concluded that this decarboxylative coupling reaction should be performed at room temperature in DMSO with irradiation by white LEDs under a N2 atmosphere for 24 h. Initially, the scope of coumarins was examined via the decarboxylative coupling with tert-butyl NHP esters. As given in Scheme 2, this method was found to be applicable to a wide range of coumarins 1a−1m, which were all able to undergo

entry

photocatalyst

solvent

additive

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12c 13d 14 15 16 17 18e 19f 20g 21 22h

Ru(bpy)3Cl2 EosinY Ir(ppy)3 Rose Bengal Methylene Blue Acr-Mes+ClO4− Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 Ir(ppy)3 − Ir(ppy)3

DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO MeCN DCE EtOAc DMF DMSO DMSO DMSO DMSO DMSO

− − − − − − TFA TfOH AcOH Et3N DIEPA TFA TFA TFA TFA TFA TFA TFA TFA TFA TFA TFA

N.D. N.D. 29% N.D. N.D. N.D. 67% 61% 46% N.D. N.D. 50% 34% N.D. N.D. N.D. 45% 81% 77% N.D. N.D. Trace

a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (0.01 mmol), additive (0.25 mmol), solvent (1 mL), rt, blue lights, 24 h. b Isolated yield. cTFA (0.5 mmol). dTFA (0.1 mmol). e3 W white LEDs for entries 18, 19, 21, and 22. f48 h. gWithout light. hUnder air.

Scheme 2. Substrate Scope of Coumarinsa

a

All reactions were performed with 1 (0.5 mmol), 2a (1.0 mmol), Ir(ppy)3 (0.01 mmol), and TFA (0.25 mmol) in DMSO (1 mL) at room temperature with irradiation by white LEDs under a N2 atmosphere for 24 h.

this decarboxylative-coupling reaction smoothly to give the corresponding product 3aa−3ma in 30% to 90% yields. Coumarins bearing electron-donating groups at the 6-position of aromatic ring such as methyl 1b or methoxy 1c provided the desired products 3ba, 3ca in 75% and 85% yields, respectively. B

DOI: 10.1021/acs.orglett.9b00327 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

primary alkyl NHP esters bearing methyl, n-propyl, 3-butene-1yl, n-octyl, and 4-bromobutyl all showed good tolerance for this reaction, affording the corresponding products 3ab−3af in 47% to 75% yields. Benzyl and aryl propyl NHP esters 2g−2h were then tested for this transformation, and the desired products 3ag−3ah could be obtained in satisfactory yields. Substrates with an ester group also exhibited tolerance in this procedure, delivering the product 3ai in 58% yield. Subsequently, we explored whether the secondary alkyl NHP esters could adapt to this reaction. Satisfactorily, isopropyl NHP esters 2j, isobutyl NHP esters 2k, and cyclohexyl NHP esters 2l all could be well tolerated, and the corresponding products 3aj, 3ak, and 3al were obtained in 92%, 88%, and 69% yields, respectively. In addition, secondary alkyl NHP esters containing a heteroatom (N or O) on the aliphatic ring also performed well to provide the products 3am−3an in good yields. To our delight, natural amino acid derived NHP esters were also suitable substrates, furnishing the aminoalkylated product 3ao in 58% yield. To gain the insight into this reaction mechanism, several control experiments were carried out as shown in Scheme 4. A

The electron-withdrawing substituents at the 6-position of the benzene ring, such as fluoro, chloro, or bromo, seem to disfavor this transformation, as the yield of 3da−3fa was reduced to 42%, 51%, and 45%. Subsequently, coumarins with substituents at different positions of the benzene ring were also investigated. The screening revealed that the substituted position did not affect the efficiency of the reaction, and the coumarins bearing either an electron-donating or -withdrawing group at the 7- or 8-position of the aromatic ring were all suitable for the reaction and gave the desired product 3ga−3ka in 53% to 90% yields. It was noted that the disubstituted coumarins containing two electron-withdrawing groups in the 6- and 8-positions, such as 6,8-diCl 1l and 6,8-diBr 1m, also could undergo this decarboxylative coupling process well and furnished the target products 3la and 3ma, however, in relatively low yields. After the scope of coumarins was examined, a variety of alkyl NHP esters were then investigated in the decarboxylative coupling reaction with coumarin 1a under the standard conditions. This method was found to be applicable to a variety of alkyl NHP esters, which were able to undergo the decarboxylative coupling process with coumarin 1a smoothly, affording the desired C-3 alkylated coumarin derivatives 3ab− 3ao in moderate to excellent yields (Scheme 3). Initially,

Scheme 4. Control Experiments

Scheme 3. Substrate Scope of Alkyl NHP Estersa

radical scavenger, TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) (3.0 equiv), was first applied into the model reaction system, and the transformation was totally suppressed (Scheme 4, eq 1). Subsequently, the similar result was obtained when another radical scavenger 2,6-di-tert-butyl-4-methyphenol (BHT) was employed in the same reaction system (Scheme 4, eq 2). These results suggested that the reaction might proceed via a radical mechanism. To confirm the formation of an alkyl radical, 1,1-diphenylethylene was then added into the decarboxylative coupling reaction between coumarin 1a and aryl propyl NHP ester 2h under the standard conditions. It was observed that no desired product 3ah was found, while the only product isolated was the adduct 4 of the 3-phenylpropyl radical and 1,1-diphenylethylene (Scheme 4, eq 3). In addition, the Stern−Volmer experiment was performed and the results indicated that Ir(ppy)3* could be quenched by alkyl NHP esters, suggesting that the reaction might proceed through an oxidative quenching pathway (for details, see Supporting Information). According to the above-mentioned observations and previous literature reports, a plausible mechanism for this decarboxylative coupling reaction was proposed in Scheme 5. Initially, the photocatalyst Ir(ppy)3 was irradiated to the activated species Ir(ppy)3*, from which the protonated alkyl NHP ester 2a′ abstracted an electron to form a radical A, accompanied by the oxidation of Ir(ppy)3* to IrIV. The radical

a Unless otherwise noted, all reactions were performed with 1a (0.5 mmol), 2 (1.0 mmol), Ir(ppy)3 (0.01 mmol), and TFA (0.25 mmol) in DMSO (1 mL) at room temperature with irradiation by white LEDs under a N2 atmosphere for 24 h.

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DOI: 10.1021/acs.orglett.9b00327 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

College of Pharmaceutical Sciences, Zhejiang University of Technology and Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals for the financial help.

Scheme 5. Proposed Mechanism

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A could provide a tert-butyl radical via elimination of phthalimide and release of carbon dioxide. Subsequently, the addition of the tert-butyl radical to coumarin 1a generated the key intermediate B, which was further oxidized to the carbocation intermediate C by IrIV. After a deprotonation process, C could be immediately transformed into the desired product 3aa. In summary, we have succeeded in developing a novel and synthetically valuable method for the construction of C(sp2)−C(sp3) bonds via a decarboxylative coupling reaction between various coumarins and alkyl NHP esters by employing a photocatalytic system promoted by white light. This transformation has been proven to be compatible with a wide range of linear alkyl NHP esters, especially the primary substituted esters, and a variety of coumarins bearing various functional groups also exhibited good tolerance for this transformation. Furthermore, this protocol featured mild conditions, excellent regioselectivity, and simple operation, which provided a novel avenue to synthesize C-3 alkylated coumarin derivatives.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00327. Experimental procedures, characterization data, and 1H NMR, 13C NMR spectra for compounds (3aa−3la, 3ab−3ao) (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Can Jin: 0000-0003-1997-6209 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21606202). We are also grateful to the D

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DOI: 10.1021/acs.orglett.9b00327 Org. Lett. XXXX, XXX, XXX−XXX