Pd(II)-Catalyzed Fujiwara–Moritani Reactions for the Synthesis and Functionalization of Substituted Coumarins

Abstract

Highly substituted coumarins, privileged and versatile scaffolds for bioactive natural products and fluorescence imaging, are obtained via a Pd(II)-catalyzed direct C–H alkenylation reaction (Fujiwara–Moritani reaction), which has emerged as a powerful tool for the construction and functionalization of heterocyclic compounds because of its chemical versatility and its environmental advantages. Thus, a selective 6-endo cyclization led to 4-substituted coumarins in moderate yields. Selected examples have been further functionalized in C3 through a second intermolecular C–H alkenylation reaction to give coumarin-acrylate hybrids, whose fluorescence spectra have been measured.

Introduction

Coumarins (2H-chromen-2-nes or benzo-α-pyrones) are privileged scaffolds of a large variety of natural products^1,2 (e.g., pestalasins A-E^3,4 and lamellarins^5,6) and/or synthetic molecules, as exemplified by the antioxidant umbelliferone,⁷ choleretic and antispasmodic hymecromone (4-methylumbelliferone),⁸ anti-inflammatory toddaculin,⁹ or anti-HIV agent 4-propylcoumarins¹⁰ (Figure 1). Owing to their outstanding optical properties, these coumarin fluorophores have found applications as fluorescent probes and tracers in biology, laser dyes, solar energy collectors, etc.¹¹⁻¹³ Additionally, coumarins are widely used as additives in food and cosmetics,^14,15 as well as agrochemicals,¹⁶ and pharmaceuticals.¹⁷ In particular, 4-arylcoumarins, a subgroup of flavonoids, have received great attention because they exhibit important biological activities, such as anti-HIV,¹⁸ antibacterial,¹⁹ antiprotozoal,²⁰ and cytotoxic properties.²¹ For example, 5,7,4′-trimethoxy and 5,7-dimethoxy-4-phenylcoumarins have been tested for their anti-inflammatory activity, specifically as COX inhibitors, which opens the door to future developments as these enzymes are also associated with cancer and neuropsychiatric diseases such as schizophrenia.²² The introduction of a fused heterocyclic moiety into the coumarin core usually leads to compounds with promising or even unprecedented properties.²³ For example, furo[3,2-g]coumarins (e.g., psoralen, xanthoxin, or bergapten) are used in treatment of several skin disorders (psoriasis and vitiligo).²⁴ Therefore, the development of synthetic methods to construct and functionalize the coumarin core has attracted much attention over the past decades. Classical approaches for the preparation of coumarin derivatives usually involve the acid- or base-catalyzed condensation reactions of phenol derivatives with esters of acrylic acids (the Pechmann reaction) or with carbonyl compounds (Perkin, Wittig reaction, or Knoevenagel-type reactions).²⁵⁻²⁷ Some milder methods that do not use phenol precursors have also been developed, such as the PIDA/I₂-mediated reactions of substituted phenyl acrylic acids²⁸ and visible-light induced synthesis of functionalized coumarins.²⁹

Figure 1.

Selected bioactive compounds with the coumarin core.

Transition-metal-catalyzed, particularly palladium–catalyzed, inter- or intramolecular heteroannulation reactions^30,31 represent an excellent alternative for the construction of the coumarin framework.³² Representative examples include the intramolecular Mizoroki–Heck reaction of o-halophenyl 3-alkenoates,³³ the tandem intermolecular Heck/cyclization between aryl halides and acrylates,³⁴⁻³⁶ or the Suzuki cross-coupling/cyclization of 2-(pinacolboronate)phenol and β-brominated dehydroaminoacids.³⁷ In addition, palladium-catalyzed intermolecular carbonylative cyclization of o-halophenols with alkynes^38,39 or salicylic aldehydes with benzyl chlorides⁴⁰ has been reported. More recently, Gilmour et al.⁴¹ has reported a Pd(0)-catalyzed cascade annulation of 2-halophenols with β-borylacrylates as ambiphilic C3-synthons to generate C3 and C4-substituted coumarins. However, the transition-metal-catalyzed oxidative coupling reactions⁴² are even more attractive strategies for the synthesis of heterocyclic scaffolds as coumarins, as they avoid the use of preactivated coupling partners (halides, triflates, boronates, etc.). In this context, the oxidative cyclocarbonylation⁴³ or carboxylation⁴⁴ of 2-vinylphenols are efficient procedures for the synthesis of 4-substituted coumarins. The inter- or intramolecular hydroarylation of alkynes provides a direct and simple route to these heterocycles from phenols and propiolates or aryl propiolates, respectively.⁴⁵ The formation of coumarins by addition of phenols and alkynoates via palladium(II)-catalyzed C–H insertion is an excellent example to illustrate the potential of this methodology.⁴⁶ The palladium(II)-catalyzed intermolecular C–H alkenylation reaction of phenols and acrylates followed by intramolecular C–O formation, first reported by Kitamara et al.⁴⁷ in 2005 and later developed by Maiti et al.⁴⁸ and Shi et al,⁴⁹ has given good results mainly for the synthesis of coumarins with no substituents at the pyrane ring. A related tandem dehydrogenation/oxidative Heck reaction starting from 4-phenylcyclohexanone to generate the intermediate phenol has also been reported.⁵⁰ Therefore, we decided to investigate the intramolecular C–H alkenylation variant^51,52 of aryl alkenoates and cinnamates to prepare 4-alkyl and 4-aryl-substituted coumarins with alkoxy groups at the aromatic ring, a structural feature common to biologically active coumarins (Scheme 1). The strategy involves a 6-endo-trig cyclization, which could be accomplished by controlling the positional selectivity of C–H activation, as we have previously demonstrated in the Pd(II)-catalyzed intramolecular 6-endo C–H alkenylation of N-arylacrylamides⁵³ and N-substituted N-allylanilines⁵⁴ for the construction of quinolone and dihydroquinoline cores, respectively. The effect of the substitution patterns of the benzene ring and the alkene on the reactivity and regioselectivity would be investigated. In addition, as conjugation of coumarin nucleus with an unsaturated moiety at the C-3 position can play a pivotal role in the anticancer activity of these heterocycles,⁵⁵ we decided to carry out an intermolecular alkenylation reaction on the coumarin ring with α,β-unsaturated esters to generate new coumarin-acrylate hybrids.

Scheme 1. Synthesis of Coumarins via C–H Alkenylation.

Results and Discussion

We started the study of the reaction conditions (palladium catalyst and oxidant) using cinnamate 1a as the model substrate (Table 1). We selected the reaction conditions that had been previously employed for the 6-endo cyclization of N-aryl acrylamides to quinolones⁵³ as a starting point, carrying out the reactions at room temperature in acetic acid and in the presence of p-TsOH (1 equiv) as an additive. The presence of this acid has been shown to be a determinant to increase the reactivity in this type of reaction.^53,54,56,57 However, when palladium acetate was used as the catalyst using copper acetate or p-benzoquinone as oxidants, no conversion at all was observed after 30 h at rt, recovering unreacted 1a (Table 1, entries 1 and 2). The use of t-butyl perbenzoate in combination with copper acetate as an oxidant was required to obtain some reactivity, although low yields of the corresponding coumarin 2a were isolated, observing also the formation of decomposition products (Table 1, entries 3 and 4). A change in the palladium catalyst to bis(acetonitrile)dichloropalladium(II) resulted in a low conversion of the substrate (69% of 1a was recovered) after 8 h, but with a low isolated yield of 2a (Table 1, entry 5). A longer reaction time or higher reaction temperature was detrimental due to decomposition of the substrate (Table 1, entries 6 and 7). The use of a pyridine ligand (L1), a higher catalyst loading (10 mol %), or the use of an aqueous medium for the reaction resulted in increased but still low isolated yields (Table 1, entries 8–10). In no case, open-ring or decarboxylated products could be observed in isolable quantities. It was necessary to use a stronger oxidant such as N-fluoro-2,4,6-trimethylpyridinium triflate (F⁺) to obtain a complete conversion after 24 h, affording coumarin 2a in good isolated yield (Table 1, entry 11). This oxidant has been successfully employed in related intermolecular C–H alkenylation reactions in which the use of weaker oxidants gave low reactivity.⁵⁸⁻⁶⁰ It is noteworthy that the reaction was completely regioselective toward the formation of the 6-endo cyclization product (coumarin 2a), not observing the formation of the corresponding 5-exo cyclization product, benzofuran-2(3H)-one. Finally, a control experiment was carried out and in the absence of palladium, the reaction did not take place and unreacted 1a was recovered after 24 h at rt.

Table 1. Optimization of 6-Endo Cyclization of 1a.

entry	[Pd]	[O]	L	t (h)	2a (%)
1	Pd(OAc)2a	Cu(OAc)2b	-	30	-c
2	Pd(OAc)2a	p-BQb	-	30	-c
3	Pd(OAc)2a	PhCO3tBud	-	24	9
4	Pd(dba)2a	PhCO3tBud	-	24	5
5	PdCl2(CH3CN)2a	PhCO3tBud	-	8	10e
6	PdCl2(CH3CN)2a	PhCO3tBud	-	24	-f
7	PdCl2(CH3CN)2a	PhCO3tBud	-	4g	-f
8	PdCl2(CH3CN)2a	PhCO3tBud	L1a	24	23
9	PdCl2(CH3CN)2h	PhCO3tBud	-	24	25
10	PdCl2(CH3CN)2a	PhCO3tBud	-	24i	25
11	PdCl2(CH3CN)2a	F+d,j	-	24	74

^a5 mol %.

^b1 equiv.

^cStarting material was recovered.

^dCu(OAc)₂ (5 mol %) was used as a co-oxidant.

^eConversion: 31%.

^fDecomposition.

^gThe reaction was carried out under reflux.

^h10 mol %.

ⁱ2% wt. PT aqueous solution was used as solvent instead of HOAc.

^jN-Fluoro-2,4,6-trimethylpyridinium triflate (1.2 equiv) was used as the oxidant

These reaction conditions were applied to a series of cinnamates and enoates 1b–1k. The results are summarized in Table 2.

Table 2. Synthesis of 4-Substituted Coumarins 2a–g.

^aYield (%) of the pure isolated compound (rt, 6–24 h).

^b10 mol % of the catalyst was used; 79% conversion.

^c75% conversion.

^dYield (%) of the pure isolated compound (70 °C, 24 h).

^eDecomposition.

As shown, the results obtained were highly dependent on the substrate employed. Different substitution patterns on the aromatic ring at C4 are tolerated, and coumarins 2b–d were obtained in good isolated yields (Table 2). Nevertheless, the obtention of 2e required the use of a higher catalyst loading (10 mol %). A heteroaromatic ring, such as furan, could also be introduced at C4, although in a lower yield (2f, 21%). When an electron-deficient aryl group was introduced, 2g was obtained in a much lower yield (28%). Interestingly, when the reaction temperature was increased to 70 °C, the regioselectivity of the reaction was lost, isolating both the 6-endo and 5-exo cyclization products (2g and 3g, respectively) in low yields, together with decomposition products. Under these reaction conditions, unsubstituted or 4-alkyl substituted coumarins 2h–k were obtained only in moderate to low yields (Table 2), though no starting material could be recovered. An increase of the reaction temperature to 70 °C did not improve the results. It was also shown that the reaction conditions are not compatible with the presence of acyl groups on the alkene (1l R¹ = CO₂Et; 1m R¹ = COAr) or with the substitution on the α-position of the alkene (1n and 1o R = Ph and CH₃, respectively). In these cases, complex mixtures of products were obtained, not isolating coumarins 2l–2o. These results show that it is possible to access the coumarin framework via 6-endo cyclization, but this procedure is not as efficient as it was shown for the synthesis of quinolones from the corresponding amides.⁵³ This difference in reactivity could be attributed to the instability of the esters in acidic media, leading to decomposition when long reaction times are required. Consequently, the reaction conditions were re-evaluated to use an alternative solvent to acetic acid, using in this case pent-5-enoate 1j as the model substrate (Table 3).

Table 3. Cyclization Reaction Conditions for 1j.

entry	solvent	T (°C)	t (h)	2j (%)
1a	CH2Cl2	rt	24	8b
2c	mesitylene/HOAc 4:1	rt	96	37
3c	mesitylene/HOAc 4:1	40	24	33
4c	mesitylene	rt	96	-d
5c	mesitylene	70	24	49

^a5 mol% of catalyst.

^bConversion: 17%.

^c10 mol% of catalyst.

^dNo p-TsOH was added; no reaction.

The change of acetic acid for a non-protic solvent, such as dichloromethane, led to a low conversion at room temperature (Table 3, entry 1). The use of an apolar solvent, such as mesitylene, in combination with a smaller proportion of acetic acid⁶¹ led to an increase of the isolated yield of 2j, although in a longer reaction time (Table 3, entry 2). The reactivity could be recovered at 40 °C, with slight erosion of the yield (Table 3, entry 3). When the reaction was carried out in mesitylene, the presence of p-TsOH was essential, as no reactivity was observed even after 96 h at rt in its absence (Table 3, entry 4). Finally, a moderate yield of 2j could be obtained at 70 °C (Table 3, entry 5). The use of these reaction conditions (mesitylene, 70 °C) resulted in a significant increase in the yield of coumarin 2h (69% vs 20%) and 4-alkyl substituted coumarins 2i–2k (Table 4). The yield of 4-aryl substituted coumarin 2g could not be improved under these conditions, although in this case, the formation of the 5-exo product 3g was not observed by NMR. Finally, the extension to different substitution patterns in the aromatic ring was also studied (Table 4). It was clear that an electron-rich aromatic ring is a determinant to obtain reactivity under these conditions.

Table 4. Synthesis of 4-Substituted Coumarins in Mesitylene.

^aYield (%) of the pure isolated compound.

^b5 mol% of catalyst.

Two mechanistic pathways could be proposed for this type of oxidative alkenylation reaction. On one hand, arene metalation with an electrophilic Pd(II) species would give an aryl-Pd(II) species I, followed by syn-migratory insertion onto the alkene to give II, and syn elimination, after isomerization to III, to afford coumarin 2.⁵³ Alternatively, the alkene could be first activated by the palladium catalyst (IV), followed by anti-addition of the aromatic ring to give also III, and syn elimination would lead to 2 (Scheme 2). In both cases, an electron-rich aromatic ring would be more reactive. As shown on Table 4, 6,7-dialkoxycoumarins 2p, 2q, and 2s could be obtained regioselectively, although in lower yields, as the 5,6,7-trimethoxy-substituted coumarin 2r, but no unreacted substrate was recovered. Although other aromatic substitution patterns were tested, no reactivity was observed with 3,5-dimethylphenyl, 3-methoxyphenyl, and 3-methoxy-5-methyl cinnamates, while complex mixtures of products were formed when using the corresponding (E)-but-2-enoates (see the Supporting Information for the substrates tested, 1t–1y).

Scheme 2. Mechanistic Pproposals for the 6-Endo Cyclization: Arene Metalation vs Alkene Activation.

The selective functionalization of the coumarin skeleton is also an important issue as, in addition to the biological properties, the extension of the conjugation could affect, for instance, their photophysical properties.^62,63 Thus, several procedures have been developed for the C3 alkenylation of coumarins. For instance, palladium-catalyzed decarboxylative couplings have been described for the functionalization of coumarins with cinnamic acids⁶⁴ and for the reaction of coumarin-3-carboxylic acid with acrylates.⁶⁵ In addition, the selective C3 alkenylation of non-substituted coumarins has also been efficiently accomplished through the oxidative Heck reaction.⁶⁶ Thus, we decided to study the derivatization of selected 4-substituted coumarins through a second intermolecular C–H alkenylation reaction.

First, we tested the conditions used for the 6-endo-cyclization, but no intermolecular alkenylation reaction with t-butyl acrylate was observed. After some experimentation, we found that the best results were obtained using the reaction conditions previously developed for the alkenylation of quinolones.⁵³ However, in most cases, conversions were low and 30–40% of the starting material was recovered (Table 5). When longer reaction times or higher temperatures were used, complex mixtures of products were isolated. We tried to optimize the reaction conditions by changing the oxidant or the palladium source, but the results could not be improved (see the Supporting Information). As shown in Table 5, C4 aryl- and methyl-substituted coumarins 2a,d,e,i could be alkenylated with methyl or t-butyl acrylate using palladium acetate in the presence of silver acetate and pivalic acid obtaining alkenylated coumarins 4a–f in moderate yields (Table 5, entries 1–6). Substitution on the β-position of the alkene is also possible, obtaining 4g in moderate yield (Table 5, entry 7).

Table 5. Intermolecular C–H Alkenylation of Coumarins 2.

entry	2	R1	R2	R3	4	yield (%)a
1	2a	Ph	CH3	H	4a	31
2	2a	Ph	t-Bu	H	4b	31
3	2d	4(tBu)C6H4	CH3	H	4c	52
4	2e	3,4(OMe)C6H4	CH3	H	4d	28
5	2i	CH3	CH3	H	4e	45
6	2i	CH3	t-Bu	H	4f	53
7	2i	CH3	CH3	CH3	4 g	44

^aYield (%) of the pure isolated compound; in all cases, 30–40% of the unreacted starting material was also recovered.

As 3-vinyl and 3-styryl coumarins^62,63 can be interesting fluorophores, the absorption and emission properties of selected coumarins 2a,d,e and 4a–d were also studied (see Table 6, Figure 2, and the Supporting Information). All coumarins showed UV–vis absorption, only one absorption band around λ_max. = 375 nm for 4-aryl coumarins 2a,d,e and around λ_abs. = 300 nm for their C3 alkenylated derivatives 4a–d. This shift to a lower wavelength upon introduction of the acrylate moiety reflects the loss of coplanarity of the aromatic ring and the coumarin nucleus, thus decreasing delocalization. C3 alkenylation in the coumarin core leads to considerable changes in the fluorescence properties of coumarins 4a–d, whose maximum emission were more blue-shifted than those of coumarins 2 (λ_em. = 452–480 nm vs λ_em. = 435–446 nm) and presented higher Stoke shifts (up to 180) (Table 6). Fluorescent organic dyes with large Stoke shift are essential for biological applications.⁶⁷⁻⁶⁹

Table 6. Absorption and Emission Maxima of Selected Coumarins 2 and 4.

entry	compd	λabsa (nm)	λemb (nm)	ΔStokec (nm)
1	2a	375	435	60
2	2d	377	441	64
3	2e	376	446	70
4	4a	301	453	152
5	4b	302	452	150
6	4c	300	480	180
7	4d	300	455	155

^aThe maximum absorption wavelength in acetonitrile (2.3 mM).

^bExcited at the maximum absorption wavelength in acetonitrile (2.3 mM).

^cStoke shift = λ_em – λ_abs.

Figure 2.

Excitation and emission spectra of coumarins 4a–d at 2.3 mM in acetonitrile.

In conclusion, it has been shown that 4-aryl-substituted coumarins can be obtained in moderate to good yields via palladium(II)-catalyzed C–H alkenylation reactions. 4-Aryl-substituted derivatives can be obtained in acetic acid at room temperature, while mesitylene at 70 °C is required to obtain moderate yields of 4-alkyl-substituted coumarins, avoiding decomposition in an acidic medium. However, the procedure is limited to an electron-rich aromatic ring for the cyclization to proceed efficiently. The coumarin skeleton can be further functionalized via C3 intermolecular alkenylation. Additionally, the fluorescence spectra of selected coumarins have been measured to provide perspective for potential applications.

Experimental Section

General Experimental Methods

Melting points were measured in unsealed capillary tubes. The NMR spectra were obtained at 300 MHz for ¹H and 75.5 MHz for ¹³C or at 500 MHz for ¹H and 125.7 MHz for ¹³C using CDCl₃ as solvent and internal standard at 20–25 °C. Distortionless enhancement by polarization transfer (DEPT) experiments and 2D correlation experiments (COSY, heteronuclear single-quantum coherence (HSQCed), or heteronuclear multiple bond correlation (HMBC)) were used when necessary for the assignments of individual ¹³C and ¹H resonances. Electron impact (EI, 70 eV), chemical ionization (CI, 230 eV), or electrospray ionization (ESI⁺) sources were used for obtaining the mass spectra. A TOF detector was employed for the obtention of exact mass. The IR spectra were obtained using an ATR instrument. The fluorescence spectra were measured using a Jasco FP-6500 spectrofluorimeter using acetonitrile as solvent at 2.3 mM. The emission spectra were acquired by irradiating the sample at its maximum absorbance. Both excitation and emission spectra were collected with a 3 nm slit bandwidth and were recorded at 25 °C. TLC was carried out with 0.2 mm-thick silica gel plates. Visualization was accomplished by UV light. Flash column chromatography was carried out on silica gel (230–400 mesh). All solvents used in reactions were purified according to standard procedures. Palladium catalysts were purchased from Aldrich and were used without further purification: Pd(OAc)₂, 98% purity, and PdCl₂(CH₃CN)₂, 99% purity.

Intramolecular Alkenylation of Enoates 1 and Synthesis of Coumarins 2: General Procedure

1-Fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (1.2 mmol), Cu(OAc)₂ (0.05 mmol), p-TsOH (1 mmol), and PdCl₂(CH₃CN)₂ (0.05 or 0.1 mmol) were added sequentially over a solution of the corresponding enoate 1 (1 mmol) in HOAc or mesitylene (4 mL). The mixture was stirred at room temperature or at 70 °C for 4–24 h. The solvent was removed under vacuum and the residue was dissolved in EtOAc (5 mL). The solution was washed with a 2 M aqueous solution of Na₂CO₃ (2 × 15 mL) and brine (2 × 15 mL). The aqueous phase was re-extracted with EtOAc (10 mL) and the combined organic extracts were dried (Na₂SO₄) and concentrated in vacuo. Flash column chromatography (silica gel, hexane/EtOAc) afforded coumarins 2.

5,7-Dimethoxy-4-phenyl-2H-chromen-2-one (2a)

Coumarin 2a was prepared from 1a (101.7 mg, 0.36 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (130.7 mg, 0.43 mmol), Cu(OAc)₂ (3.3 mg, 0.018 mmol), p-TsOH (69.1 mg, 0.36 mmol), and PdCl₂(CH₃CN)₂ (4.7 mg, 0.018 mmol) in HOAc (1.4 mL). The mixture was stirred at room temperature for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 8/2) afforded 2a (75 mg, 74%) as a solid, whose data are coincidental with those reported:⁴⁶ mp (CH₂Cl₂): 164–166 °C [lit.⁴⁶ mp (CH₂Cl₂/hexanes) 164–165 °C]; IR (ATR) 1713 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.42 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 6.01 (s, 1H, H₃), 6.23 (d, J = 2.3 Hz, 1H, H₆), 6.53 (d, J = 2.3 Hz, 1H, H₈), 7.22–7.30 (m, 2H, H_3′, H_5′), 7.32–7.41 (m, 3H, H_2′, H_4′, H_6′); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 55.4 (OCH₃), 55.8 (OCH₃), 93.6 (C₈), 95.8 (C₆), 103.6 (C_4a), 112.7 (C₃), 127.1 (C_2′, C_6′), 127.3 (C_3′, C_5′), 127.9 (C_4′), 139.8 (C_1′), 155.7 (C₄), 157.2 (C_8a), 158.2, 163.4 (C₅, C₇), 160.9 (CO); MS (CI) m/z (rel intensity) 284 (MH⁺ + 1, 18), 283 (MH⁺, 100), 282 (34), 254 (7); HRMS (CI) Calcd. for C₁₇H₁₅O₄ [MH⁺]: 283.0965; found, 283.0958.

5,7-Dimethoxy-4-(4-methoxyphenyl)-2H-chromen-2-one (2b)

Coumarin 2b was prepared from 1b (117.6 mg, 0.37 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (131.2 mg, 0.45 mmol), Cu(OAc)₂ (3.5 mg, 0.019 mmol), p-TsOH (72.2 mg, 0.37 mmol), and PdCl₂(CH₃CN)₂ (4.9 mg, 0.019 mmol) in HOAc (1.5 mL). The mixture was stirred at room temperature for 6 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 2b (85.5 mg, 73%) as a solid, whose data are coincidental with those reported:⁷⁰ mp (CH₂Cl₂): 153–155 °C [lit.⁷⁰ mp (methanol) 151–152 °C]; IR (ATR) 1716 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.46 (s, 3H, OCH₃), 3.84 (s, 6H, 2 × OCH₃), 5.95 (s, 1H, H₃), 6.22 (d, J = 2.4 Hz, 1H, H₆), 6.48 (d, J = 2.4 Hz, 1H, H₈), 6.88 (d, J = 8.8 Hz, 2H, H_3′, H_5′), 7.19 (d, J = 8.8 Hz, 2H, H_2′, H_6′); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 55.3 (OCH₃), 55.4 (OCH₃), 55.7 (OCH₃), 93.6 (C₈), 95.7 (C₆), 103.6 (C_4a), 112.5 (C₃), 112.7 (C_3′, C_5′), 128.7 (C_2′, C_6′), 132.0 (C_1′), 155.5 (C₄), 157.2 (C_8a), 158.3 (C_4′), 159.6, 163.3 (C₅, C₇), 160.9 (CO); MS (CI) m/z (rel intensity) 314 (MH⁺ + 1, 20), 313 (MH⁺, 100), 312 (60), 284 (18); HRMS (CI) Calcd. for C₁₈H₁₇O₅ [MH⁺]: 313.1071; found, 313.1061.

5,7-Dimethoxy-4-(p-tolyl)-2H-chromen-2-one (2c)

Coumarin 2c was prepared from 1c (105.9 mg, 0.36 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (123.2 mg, 0.43 mmol), Cu(OAc)₂ (3.2 mg, 0.018 mmol), p-TsOH (67.5 mg, 0.36 mmol), and PdCl₂(CH₃CN)₂ (4.6 mg, 0.018 mmol) in HOAc (1.4 mL). The mixture was stirred at room temperature for 24 h, and after the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc t 8/2) afforded 2c (75.9 mg, 72%) as a solid, whose data are coincidental with those reported:⁷⁰ mp (CH₂Cl₂): 131–133 °C [lit.⁷⁰ mp (ethanol/water) 131–133 °C]; IR (ATR) 1712 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 2.42 (s, 3H, CH₃), 3.47 (s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 6.00 (s, 1H, H₃), 6.25 (d, J = 2.4 Hz, 1H, H₆), 6.53 (d, J = 2.4 Hz, 1H, H₈), 7.15–7.21 (m, 4H, H_2′, H_3′, H_5′, H_6′); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 21.3 (CH₃), 55.4 (OCH₃), 55.8 (OCH₃), 93.6 (C₈), 95.8 (C₆), 103.6 (C_4a), 112.7 (C₃), 127.2 (C_2′, C_6′), 128.0 (C_3′, C_5′), 136.9 (C_4′), 137.8 (C_1′), 155.8 (C₄), 157.2 (C_8a), 158.3, 161.0 (C₅, C₇), 163.3 (CO); MS (ESI⁺) m/z (rel intensity) (MH⁺ + 1, 15), 297 (MH⁺, 100); HRMS (ESI⁺) Calcd. for C₁₈H₁₇O₄ [MH⁺]: 297.1127; found, 297.1132.

4-[4-(tert-Butyl)phenyl]-5,7-dimethoxy-2H-chromen-2-one (2d)

Coumarin 2d was prepared from 1d (122.0 mg, 0.36 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (124.4 mg, 0.43 mmol), Cu(OAc)₂ (3.3 mg, 0.018 mmol), p-TsOH (68.2 mg, 0.36 mmol), and PdCl₂(CH₃CN)₂ (4.7 mg, 0.018 mmol) in HOAc (1.4 mL). The mixture was stirred at room temperature for 24 h, and after the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded 2d (101.0 mg, 83%) as a solid: mp (CH₂Cl₂): 176–178 °C; IR (ATR) 1718 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 1.38 (s, 9H, C(CH₃)₃), 3.43 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 6.02 (s, 1H, H₃), 6.25 (d, J = 2.4 Hz, 1H, H₆), 6.53 (d, J = 2.4 Hz, 1H, H₈), 7.19–7.22 (m, 2H, H_3′, H_5′), 7.39–7.42 (m, 2H, H_2′, H_6′); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 31.3 (C(CH₃)₃), 34.7 (C(CH₃)₃), 55.5 (OCH₃), 55.8 (OCH₃), 93.6 (C₈), 95.8 (C₆), 103.7 (C_4a), 112.5 (C₃), 124.2 (C_2′, C_6′), 127.0 (C_3′, C_5′), 136.8 (C_4′), 151.1 (C_1′), 155.8 (C₄), 157.2 (C_8a), 158.3, 161.0 (C₅, C₇), 163.3 (CO); MS (ESI⁺) m/z (rel intensity) 340 (MH⁺ + 1, 17), 339 (MH⁺, 100); HRMS (ESI⁺) Calcd. for C₂₁H₂₃O₄ [MH⁺]: 339.1596; found, 339.1600.

4-(3,5-Dimethoxyphenyl)-5,7-dimethoxy-2H-chromen-2-one (2e)

Coumarin 2e was prepared from 1e (115.6 mg, 0.34 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (116.5 mg, 0.40 mmol), Cu(OAc)₂ (3.0 mg, 0.017 mmol), p-TsOH (63.9 mg, 0.34 mmol), and PdCl₂(CH₃CN)₂ (8.6 mg, 0.034 mmol) in HOAc (1.4 mL). The mixture was stirred at room temperature for 24 h, and after the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded 2e (63.9 mg, 55%, 79% conversion) as a solid: mp (CH₂Cl₂): 126–128 °C; IR (ATR) 1718 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.49 (s, 3H, OCH₃), 3.81 (s, 6H, 2 × OCH₃), 3.87 (s, 3H, OCH₃), 6.02 (s, 1H, H₃), 6.25 (d, J = 2.4 Hz, 1H, H₆), 6.41 (d, J = 2.3 Hz, 2H, H_2′, H_6′), 6.49 (t, J = 2.3 Hz, 1H, H_4′), 6.52 (d, J = 2.4 Hz, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 55.5 (2 × OCH₃), 55.6 (OCH₃), 55.8 (OCH₃), 93.6 (C₈), 95.9 (C₆), 100.0 (C_4′), 103.5 (C_4a), 105.4 (C_2′, C_6′), 112.4 (C₃), 141.7 (C_1′), 155.5 (C₄), 157.1 (C_8a), 158.2 (C₇), 160.0 (C_3′, C_5′), 160.9 (C₅), 163.4 (CO); MS (ESI⁺) m/z (rel intensity) 344 (MH⁺ + 1, 16), 343 (MH⁺, 100); HRMS (ESI⁺) Calcd. for C₁₉H₁₉O₆ [MH⁺]: 343.1182; found, 343.1180.

4-(Furan-3-yl)-5,7-dimethoxy-2H-chromen-2-one (2f)

Coumarin 2f was prepared from 1f (98.1 mg, 0.36 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (124.1 mg, 0.43 mmol), Cu(OAc)₂ (3.2 mg, 0.018 mmol), p-TsOH (68.0 mg, 0.36 mmol), and PdCl₂(CH₃CN)₂ (4.6 mg, 0.018 mmol) in HOAc (1.4 mL). The mixture was stirred at room temperature for 24 h, and after the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded 2f (20.6 mg, 21%, 75% conversion) as a solid: mp (CH₂Cl₂): 153–155 °C; IR (ATR) 1714 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.67 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 6.09 (s, 1H, H₃), 6.30 (d, J = 2.4 Hz, 1H, H₆), 6.49–6.52 (m, 2H, H₈, H_4′), 7.45 (t, J = 1.8 Hz, 1H, H_5′), 7.56–7.57 (m, 1H, H_2′); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 55.3 (OCH₃), 55.8 (OCH₃), 93.6 (C₈), 95.7 (C₆), 103.4 (C_4a), 112.1 (C_4′), 112.5 (C₃), 125.0 (C_3′), 140.3 (C_2′), 142.0 (C_5′), 146.7 (C₄), 157.3, 158.2, 160.8 (C_8a, C₅, C₇), 163.3 (CO); MS (ESI⁺) m/z (rel intensity) 274 (MH⁺ + 1, 12), 273 (MH⁺, 100); HRMS (ESI⁺) Calcd. for C₁₅H₁₃O₅ [MH⁺]: 273.0763; found, 273.0769.

4-(3,5-Difluorophenyl)-5,7-dimethoxy-2H-chromen-2-one (2g)

Coumarin 2g was prepared from 1g (87.5 mg, 0.27 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (94.9 mg, 0.33 mmol), Cu(OAc)₂ (3.0 mg, 0.016 mmol), p-TsOH (79.3 mg, 0.27 mmol), and PdCl₂(CH₃CN)₂ (8.5 mg, 0.032 mmol) in mesitylene (1.1 mL). The mixture was stirred at 70 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 8/2) afforded 2g (25.8 mg, 30%) as a solid: mp (CH₂Cl₂): 170–172 °C; IR (ATR) 1724 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.48 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 5.97 (s, 1H, H₃), 6.23 (d, J = 2.4 Hz, 1H, H₆), 6.51 (d, J = 2.4 Hz, 1H, H₈), 6.72–6.91 (m, 3H, H_2′, H_4′, H_6′); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 55.6 (OCH₃), 55.8 (OCH₃), 93.7 (C₈), 95.8 (C₆), 102.8 (C_4a), 103.2 (t, J = 25.2 Hz, C_4′), 110.9–112.7 (m, C_2′, C_6′), 112.7 (C₃), 142.8 (t, J = 10.1 Hz, C_1′), 153.0 (C₄), 157.1 (C_8a), 157.9 (C₅), 160.3 (C₇), 162.2 (dd, J = 248.1, 13.2 Hz, C_3′, C_5′), 163.8 (CO); MS (EI) m/z (rel intensity) 319.1 (M⁺ + 1, 19), 318.1 (M⁺, 100), 291.1 (16), 290.1 (93), 275.1 (39), 247 (12), 188 (14), 175 (15), 69 (10); HRMS (CI) Calcd. for C₁₇H₁₃ F₂O₄ [MH⁺]: 319.0776; found, 319.0770.

5,7-Dimethoxy-2H-chromen-2-one (2h)

Coumarin 2h was prepared from 1h (94.4 mg, 0.45 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (157.4 mg, 0.54 mmol), Cu(OAc)₂ (4.1 mg, 0.023 mmol), p-TsOH (131.6 mg, 0.45 mmol), and PdCl₂(CH₃CN)₂ (5.9 mg, 0.023 mmol) in mesitylene (1.8 mL). The mixture was stirred at 70 °C for 4 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 2h (64.9 mg, 69%) as a white solid, whose data are coincidental with those reported:⁴⁶ mp (CH₂Cl₂): 144–146 °C [lit.⁴⁶ mp (CH₂Cl₂/pentanes) 143–145 °C]; IR (ATR) 1724 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.82 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 6.15 (d, J = 9.7 Hz, 1H, H₃), 6.28 (d, J = 2.1 Hz, 1H, H₆), 6.41 (d, J = 2.1 Hz, 1H, H₈), 7.96 (d, J = 9.7 Hz, 1H, H₄); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 55.8 (OCH₃), 55.9 (OCH₃), 92.8 (C₈), 94.8 (C₆), 104.0 (C_4a), 110.9 (C₃), 138.7 (C₄), 156.8 (C_8a), 157.0, 163.7 (C₅, C₇), 161.5 (CO); MS (EI) m/z (rel intensity) 207 (M⁺ + 1, 12), 206 (M⁺, 100), 178 (79), 163 (48), 135 (22); HRMS (CI) Calcd. for C₁₁H₁₁O₄ [MH⁺]: 207.0652; found, 207.0658.

5,7-Dimethoxy-4-methyl-2H-chromen-2-one (2i)

Coumarin 2i was prepared from 1i (84.2 mg, 0.38 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (131.5 mg, 0.45 mmol), Cu(OAc)₂ (3.4 mg, 0.018 mmol), p-TsOH (72.1 mg, 0.38 mmol), and PdCl₂(CH₃CN)₂ (9.8 mg, 0.036 mmol) in mesitylene (1.5 mL). The mixture was stirred at 70 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 2i (50.3 mg, 60%) as a white solid, whose data are coincidental with those reported:⁴⁶ mp (CH₂Cl₂): 166–168 °C [lit.⁴⁶ mp (methanol): 168–170 °C; IR (ATR) 1740 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 2.50 (d, J = 1.2 Hz, 3H, CH₃), 3.82 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 5.91 (br s, 1H, H₃), 6.26 (d, J = 2.4 Hz, 1H, H₆), 6.39 (d, J = 2.4 Hz, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 24.2 (CH₃), 55.6 (OCH₃), 55.7 (OCH₃), 93.4 (C₈), 95.4 (C₆), 104.8 (C_4a), 111.3 (C₃), 154.5 (C_8a), 156.9 (C₄), 159.1, 162.8 (C₅, C₇), 161.0 (CO); MS (EI) m/z (rel intensity) 221 (M⁺ + 1, 13), 220 (M⁺, 100), 193 (11), 192 (91), 178 (10), 177 (73), 149 (13); HRMS (CI) Calcd. for C₁₂H₁₃O₄ [MH⁺]: 221.0808; found, 221.0811.

4-Ethyl-5,7-dimethoxy-2H-chromen-2-one (2j)

Coumarin 2j was prepared from 1j (61.0 mg, 0.26 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (94.3 mg, 0.31 mmol), Cu(OAc)₂ (2.4 mg, 0.013 mmol), p-TsOH (49.9 mg, 0.26 mmol), and PdCl₂(CH₃CN)₂ (6.8 mg, 0.026 mmol) in mesitylene (1 mL). The mixture was stirred at 70 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 2j (29.8 mg, 49%) as a solid, whose data are coincidental with those reported:⁷¹ mp (CH₂Cl₂): 141–143 °C [lit.⁷¹ mp (EtOH:H₂O) 146–148 °C]; IR (ATR) 1710 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 1.21 (t, J = 7.3 Hz, 3H, CH₃), 2.94 (q, J = 7.3 Hz, 2H, CH₂), 3.84 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 6.00 (s, 1H, H₃), 6.30 (d, J = 2.4 Hz, 1H, H₆), 6.45 (d, J = 2.4 Hz, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 13.5 (CH₃), 29.4 (CH₂), 55.7 (OCH₃), 55.8 (OCH₃), 93.6 (C₈), 95.6 (C₆), 104.3 (C_4a), 109.7 (C₃), 157.2 (C_8a), 158.8 (C₄), 159.9, 162.6 (C₅, C₇), 161.4 (CO); MS (EI) m/z (rel intensity) 235 (M⁺ + 1, 15), 234 (M⁺, 100), 207 (12), 206 (86), 205 (16), 191 (52), 161 (12), 103 (11); HRMS (CI) Calcd. for C₁₃H₁₅O₄ [MH⁺]: 235.0965; found, 235.0966.

5,7-Dimethoxy-4-propyl-2H-chromen-2-one (2k)

Coumarin 2k was prepared from 1k (77.0 mg, 0.31 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (112.4 mg, 0.37 mmol), Cu(OAc)₂ (2.9 mg, 0.015 mmol), p-TsOH (59.4 mg, 0.31 mmol), and PdCl₂(CH₃CN)₂ (8.0 mg, 0.030 mmol) in mesitylene (1.2 mL). The mixture was stirred at 70 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 2k (37.9 mg, 50%) as a solid, whose data are coincidental with those reported:⁷² mp (CH₂Cl₂): 109–111 °C [lit.⁷² mp (CHCl₃) 113.5–115 °C]; IR (ATR) 1713 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 1.00 (t, J = 7.3 Hz, 3H, CH₂–CH₂–CH₃), 1.52–1.69 (m, 2H, CH₂–CH₂–CH₃), 2.82–2.88 (m, 2H, CH₂–CH₂–CH₃), 3.84 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 5.96 (s, 1H, H₃), 6.30 (d, J = 2.4 Hz, 1H, H₆), 6.45 (d, J = 2.4 Hz, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 14.0 (CH₂–CH₂–CH₃), 22.8 (CH₂–CH₂–CH₃), 38.5 (CH₂–CH₂–CH₃), 55.7 (OCH₃), 55.8 (OCH₃), 93.6 (C₈), 95.6 (C₆), 104.3 (C_4a), 110.7 (C₃), 157.3 (C_8a), 158.2 (C₄), 158.7, 162.6 (C₅, C₇), 161.3 (CO); MS (EI) m/z (rel intensity) 249.1 (M⁺ + 1, 15), 248.1 (M⁺, 100), 233.1 (36), 220.1 (63), 205.1 (41), 192.1 (56), 191.1 (28), 178 (15), 177.1 (25), 161.1 (22), 146 (15), 91 (10), 77.1 (12), 69 (14); HRMS (CI) Calcd. for C₁₄H₁₇O₄ [MH⁺]: 249.1121; found, 249.1123.

6,7-Dimethoxy-4-phenyl-2H-chromen-2-one (2p)

Coumarin 2p was prepared from 1p (60 mg, 0.21 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (75.9 mg, 0.25 mmol), Cu(OAc)₂ (2.2 mg, 0.010 mmol), p-TsOH (40.2 mg, 0.21 mmol), and PdCl₂(CH₃CN)₂ (5.6 mg, 0.021 mmol) in mesitylene (1.0 mL). The mixture was stirred at 70 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 2p (17.8 mg, 30%) as an oil, whose data are coincidental with those reported:⁷³ IR (ATR): 1715 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.77 (s, 3H, OCH₃), 3.99 (s, 3H, OCH₃), 6.26 (s, 1H, H₃), 6.88 (s, 1H, H₈), 6.94 (s, 1H, H₅), 7.46–7.56 (m, 5H, Ph); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 56.3 (OCH₃), 56.4 (OCH₃), 100.3 (C₈), 107.5 (C₅), 111.4 (C_4a), 112.4 (C₃), 128.3, 128.9, 129.7 (C_2′, C_3′, C_4′, C_5′, C_6′), 135.8 (C_1′), 146.1 (C₄), 150.2 (C_8a), 152.9, 155.6 (C₆, C₇), 161.4 (CO); MS (EI) m/z (rel intensity): 282 (M⁺, 100), 254 (23), 239 (16), 207 (27), 168 (10), 155 (12), 139 (15), 127 (17); HRMS (ESI⁺) Calcd. for C₁₇H₁₅O₄ [MH⁺]: 283.0965; found, 283.0957.

6,7-Dimethoxy-4-methyl-2H-chromen-2-one (2q)

Coumarin 2q was prepared from 1q (60.1 mg, 0.27 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (98.9 mg, 0.33 mmol), Cu(OAc)₂ (5.1 mg, 0.027 mmol), p-TsOH (52.2 mg, 0.27 mmol), and PdCl₂(CH₃CN)₂ (7.1 mg, 0.027 mmol) in mesitylene (1.3 mL). The mixture was stirred at 70 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 2q (20.3 mg, 34%) as a solid, whose data are coincidental with those reported:⁷¹ mp (CH₂Cl₂): 128–129 °C [lit.⁷¹ mp (EtOH:H₂O) 128–129 °C]; IR (ATR): 1715 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 2.41 (d, J = 1.0 Hz, 3H, CH₃), 3.94 (s, 6H, 2 × OCH₃), 6.17 (d, J = 1.0 Hz, 1H, H₃), 6.85 (s, 1H, H₅), 6.94 (s, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 18.9 (CH₃), 56.3 (OCH₃), 56.4 (OCH₃), 100.1 (C₈), 105.2 (C₅), 112.4 (C_4a), 112.5 (C₃), 146.2 (C₄), 149.2 (C_8a), 152.3, 159.1 (C₆, C₇), 161.5 (CO); MS (EI) m/z (rel intensity): 220 (M⁺, 100), 192 (10), 149 (14), 1201 (10); HRMS (ESI⁺) Calcd. for C₁₂H₁₃O₄ [MH⁺]: 221.0808; found, 221.0820.

5,6,7-Trimethoxy-4-methyl-2H-chromen-2-one (2r)

Coumarin 2r was prepared from 1r (674 mg, 0.24 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (88.3 mg, 0.31 mmol), Cu(OAc)₂ (4.4 mg, 0.024 mmol), p-TsOH (48.8 mg, 0.24 mmol), and PdCl₂(CH₃CN)₂ (6.2 mg, 0.024 mmol) in mesitylene (1.0 mL). The mixture was stirred at 70 °C for 72 h, and after the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded 2r (13.0 mg, 18%) as an oil, whose data are coincidental with those reported:⁷⁴ IR (ATR): 1735 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 2.56 (d, J = 1.1 Hz, 3H, CH₃), 3.85 (s, 3H, OCH₃), 3.91 (s, 3H, OCH₃), 3.96 (s, 3H, OCH₃), 6.04 (d, J = 1.1 Hz, 1H, H₃), 6.64 (s, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 23.0 (CH₃), 56.2 (OCH₃), 61.0 (OCH₃), 61.3 (OCH₃), 96.2 (C₈), 108.1 (C_4a), 113.0 (C₃), 139.2 (C₆), 151.3 (C_8a), 151.6 (C₄), 153.6, 156.3 (C₅, C₇), 160.1 (CO); MS (EI) m/z (rel intensity): 250 (M⁺, 90), 235 (100), 207 (75), 163 (39), 149 (14), 69 (17), 53 (14), 51 (13); HRMS (ESI⁺) Calcd. for C₁₃H₁₅O₅ [MH⁺]: 251.0914; found, 251.0939.

4-Methyl-6,7-methylenedioxy-2H-chromen-6-one (2s)

Coumarin 2s was prepared from 1s (61.5 mg, 0.30 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (101.1 mg, 0.35 mmol), Cu(OAc)₂ (5.1 mg, 0.015 mmol), p-TsOH (57.7 mg, 0.30 mmol), and PdCl₂(CH₃CN)₂ (8.0 mg, 0.027 mmol) in mesitylene (1.5 mL). The mixture was stirred at 70 °C for 96 h, and after the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc 7/3) afforded 2s (13.0 mg, 20%) as a solid, whose data are coincidental with those reported:⁷⁵ mp (CH₂Cl₂): 120–122 °C; IR (ATR): 1735 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 2.37 (s, 3H, CH₃), 6.07 (s, 2H, OCH₂O), 6.17 (s, 1H, H₃), 6.83 (s, 1H, H₅), 6.96 (s, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 19.1 (CH₃), 98.4 (OCH₂O), 102.1 (C₈), 102.3 (C₅), 112.2 (C_4a), 113.8 (C₃), 144.9 (C₄), 150.6 (C_8a), 150.9, 152.4 (C₆, C₇), 161.2 (CO); MS (EI) m/z (rel intensity): 204 (M⁺, 100), 176 (72), 96 (15); HRMS (ESI⁺) Calcd. for C₁₁H₉O₄ [MH⁺]: 205.0495; found, 205.0523.

(Z)-3-(3,5-Difluorobenzylidene)-4,6-dimethoxybenzofuran-2(3H)-ne (3g)

Compound 3g was obtained from 1g (123.8 mg, 0.39 mmol), 1-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate (135.5 mg, 0.46 mmol), Cu(OAc)₂ (3.6 mg, 0.019 mmol), p-TsOH (74.6 mg, 0.39 mmol), and PdCl₂(CH₃CN)₂ (5.1 mg, 0.019 mmol) in HOAc (1.5 mL). The mixture was stirred at 70 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 8/2) afforded 2g (9.8 mg, 8%) and 3g (18.3 mg, 15%) as a solid: mp (CH₂Cl₂): 202–204 °C; IR (ATR): 1774 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.85 (s, 3H, OCH₃), 3.97 (s, 3H, OCH₃), 6.26 (d, J = 2.0 Hz, 1H, H₅), 6.32 (d, J = 2.0 Hz, 1H, H₇), 6.79–6.88 (m, 1H, H_4′), 7.49–7.63 (m, 1H, H_2′, H_6′), 7.80 (s, 1H, C=CH–Ar); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 55.8 (OCH₃), 55.9 (OCH₃), 89.3 (C₇), 94.3 (C₅), 104.7–105.8 (m, C_3a, C_4′), 113.5–113.9 (m, C_2′, C_6′), 122.6 (C₃), 136.4 (C=CH–Ar), 136.9 (t, J = 10.0 Hz, C_1′), 155.1 (C_7a), 157.0 (C₄), 162.6 (dd, J = 247.5, 13.0 Hz, C_3′, C_5′), 163.1 (C₆), 165.8 (CO); MS (EI) m/z (rel intensity) 319 (M⁺ + 1, 19), 318 (M⁺, 100), 275 (28), 188 (12), 175 (11), 69 (10); HRMS (ESI⁺) Calcd. for C₁₇H₁₃F₂O₄ [MH⁺]: 319.0776; found, 319.0783.

C3 Intermolecular C–H Alkenylation of Coumarins 2: General Procedure

Over a solution of coumarins 2 (1 mmol) in 1,4-dioxane (5 mL), AgOAc (3 mmol), PivOH (10 mmol), and Pd(OAc)₂ (0.1 or 0.2 mmol) were added. The mixture was stirred vigorously for 5 min, and then the corresponding acrylate (2 or 4 mmol) was added. The reaction was heated at 120 °C for 24–48 h, and then the reaction was allowed to cool down to room temperature. The mixture was filtered through diatomaceus earth and the filtrate was concentrated in vacuo. Flash column chromatography (silica gel, hexane/EtOAc) afforded coumarins 4.

Methyl (E)-3-(5,7-Dimethoxy-2-oxo-4-phenyl-2H-chromen-3-yl)acrylate (4a)

Coumarin 4a was prepared from 2a (83.2 mg, 0.29 mmol), AgOAc (0.15 g, 0.88 mmol), PivOH (0.30 g, 2.95 mmol), methylacrylate (0.06 mL, 0.59 mmol), and Pd(OAc)₂ (6.6 mg, 0.029 mmol). The reaction was heated at 120 °C for 24 h, and after this, additional amounts of methyl acrylate (0.06 mL, 0.59 mmol) and Pd(OAc)₂ (6.6 mg, 0.029 mmol) were added, and it was heated again at 120 °C for 24 h. After the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 4a (33.4 mg, 31%) as a solid: mp (CH₂Cl₂) 194–196 °C; IR (ATR): 1710 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.29 (s, 3H, CH=CH–COOCH₃), 3.65 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 6.15 (d, J = 2,4 Hz, 1H, H₆), 6.49 (d, J = 2,4 Hz, 1H, H₈), 7.06–7.15 (m, 4H, H_2′, H_4′, H_6′, CH=CH–COOCH₃), 7.34–7.47 (m, 3H, H_3′, H_5′, CH=CH–COOCH₃); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 51.4 (CH=CH–COOCH₃), 55.7 (OCH₃), 55.9 (OCH₃), 93.1 (C₈), 96.0 (C₆), 104.7 (C_4a), 115.7 (C₃), 121.9 (CH=CH–COOCH₃), 127.1 (C_2′, C_6′), 127.8 (C_3′, C_5′), 127.9 (C_4′), 137.2 (CH=CH–COOCH₃), 137.7 (C_1′), 155.8 (C₄), 156.0 (C_8a), 159.1, 164.4 (C₅, C₇) 159.2 (CO), 168.4 (COOCH₃); MS (CI) m/z (rel intensity) 368 (MH⁺ + 1, 19), 367 (MH⁺, 100), 336 (7), 335 (41); HRMS (ESI⁺) Calcd. for C₂₁H₁₉O₆ [MH⁺]: 367.1176; found, 367.1180.

tert-Butyl (E)-3-(5,7-Dimethoxy-2-oxo-4-phenyl-2H-chromen-3-yl)acrylate (4b)

Coumarin 4b was prepared from 2a (82.4 mg, 0.29 mmol), AgOAc (0.15 g, 0.88 mmol), PivOH (0.30 g, 2.92 mmol), tert-butyl acrylate (85 μL, 0.58 mmol), and Pd(OAc)₂ (6.6 mg, 0.029 mmol). The reaction was heated at 120 °C for 24 h, and after the work-up, flash column chromatography (silica gel, CH₂Cl₂) afforded 4b (37.3 mg, 31%, 44% conversion) as a solid: mp (CH₂Cl₂) 148–150 °C; IR (ATR): 1732 (COO), 1706 (COOtBu) cm^–1; ¹H NMR (CDCl₃, 300 MHz): δ 1.41 (s, 9H, C(CH₃)₃), 3.31 (s, 3H, OCH₃), 3.89 (OCH₃), 6.17 (d, J = 2.4 Hz, 1H, H₆), 6.52 (d, J = 2.4 Hz, 1H, H₈), 7.02–7.15 (m, 4H, H_2′, H_4′, H_6′, CH=CH–COOtBu), 7.35–7.47 (m, 3H, H_3′, H_5′, CH=CH–COOtBu); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 28.1 (C(CH₃)₃), 55.7 (OCH₃), 55.9 (OCH₃), 79.9 (C(CH₃)₃), 93.1 (C₈), 96.0 (C₆), 104.8 (C_4a), 115.9 (C₃), 124.4 (CH=CH–COOtBu), 127.1 (C_3′, C_5′), 127.7 (C_4′), 127.9 (C_2′, C_6′), 135.9 (CH=CH–COOtBu), 137.8 (C_1′), 155.4, 155.9 (C₄, C_8a), 159.1, 159.2 (C₅, C₇), 164.2 (CO), 166.9 (COOtBu); MS (ESI⁺) m/z (rel intensity) 410 (MH⁺ + 1, 9), 409 (MH⁺, 45), 354 (16), 353 (100); HRMS (ESI⁺) Calcd. for C₂₅H₂₅O₆ [MH⁺]: 409.1651; found, 409.1653.

Methyl (E)-3-{4-[4-(tert-Butyl)phenyl]-5,7-dimethoxy-2-oxo-2H-chromen-3-ylacrylate (4c)

Coumarin 4c was prepared from 2d (85.0 mg, 0.25 mmol), AgOAc (0.13 g, 0.75 mmol), PivOH (0.26 g, 2.51 mmol), methyl acrylate (45 μL, 0.50 mmol), and Pd(OAc)₂ (5.6 mg, 0.025 mmol). The reaction was heated at 120 °C for 24 h, and after this, additional amounts of methyl acrylate (45 μL, 0.50 mmol) and Pd(OAc)₂ (5.6 mg, 0.025 mmol) were added, and it was heated again at 120 °C for 24 h. After the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded 4c (55.4 mg, 52%, 63% conversion) as a solid: mp (CH₂Cl₂): 159–162 °C; IR (ATR): 1726 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 1.40 (s, 9H, C(CH₃)₃), 3.28 (s, 3H, COOCH₃), 3.67 (s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 6.16 (d, J = 2.4 Hz, 1H, H₆), 6.50 (d, J = 2.4 Hz, 1H, H₈), 7.04–7.06 (m, 2H, H_3′, H_5′), 7.16 (d, J = 15.8 Hz, 1H, CH=CH–COOCH₃), 7.24 (d, J = 15.8 Hz, 1H, CH=CH–COOCH₃), 7.44–7.47 (m, 2H, H_2′, H_6′); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 31.3 (C(CH₃)₃), 34.7 (C(CH₃)₃), 51.4 (COOCH₃), 55.8 (OCH₃), 55.8 (OCH₃), 93.1 (C₈), 96.1 (C₆), 105.0 (C_4a), 115.7 (C₃), 121.8 (CH=CH–COOCH₃), 124.7 (C_3′, C_5′), 126.9 (C_2′, C_6′), 134.6 (C_1′), 137.4 (CH=CH–COOCH₃), 150.8 (C_4′), 156.0 (C₄, C_8a), 156.3, 159.2 (C₅, C₇), 164.3 (CO), 168.3 (COOCH₃); MS (ESI⁺) m/z (rel intensity) 424 (MH⁺ + 1, 24), 423 (MH⁺, 100), 391 (20), 318 (11); HRMS (ESI⁺) Calcd. for C₂₅H₂₇O₆ [MH⁺]: 423.1808; found, 423.1801.

Methyl (E)-3-[4-(3,5-Dimethoxyphenyl)-5,7-dimethoxy-2-oxo-2H-chromen-3-yl]acrylate (4d)

Coumarin 4d was prepared from 2e (69.2 mg, 0.20 mmol), AgOAc (0.10 g, 0.61 mmol), PivOH (0.21 g, 2.02 mmol), methyl acrylate (36 μL, 0.40 mmol), and Pd(OAc)₂ (4.5 mg, 0.020 mmol). The reaction was heated at 120 °C for 24 h, and after this, additional amounts of methyl acrylate (36 μL, 0.40 mmol) and Pd(OAc)₂ (4.5 mg, 0.020 mmol) were added, and it was heated again at 120 °C for 24 h. After the work-up, flash column chromatography (silica gel, petroleum ether/EtOAc 6/4) afforded 4d (24.2 mg, 28%, 57% conversion) as a solid: mp (CH₂Cl₂) 207–209 °C; IR (ATR): 1722 cm^–1 (C=O); ¹H NMR (CDCl₃, 300 MHz): δ 3.40 (s, 3H, COOCH₃), 3.69 (s, 3H, OCH₃), 3.81 (s, 6H, 2 × OCH₃), 3.88 (s, 3H, OCH₃), 6.19 (d, J = 2.4 Hz, 1H, H₆), 6.28–6.29 (m, 2H, H_2′, H_6′), 6.49–6.51 (m, 2H, H₈, H_4′), 7.15–7.27 (m, 2H, CH=CH–COOCH₃); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 51.5 (COOCH₃), 55.5 (2 × OCH₃), 55.9 (OCH₃), 56.0 (OCH₃), 93.1 (C₈), 96.1 (C₆), 99.8 (C_4′), 104.6 (C_4a), 105.5 (C_2′, C_6′), 115.5 (C₃), 122.0 (CH=CH–COOCH₃), 137.2 (CH=CH–COOCH₃), 139.5 (C_1′), 155.5 (C₄), 156.0 (C_8a), 159.2, 160.6 (C₅, C₇), 164.4 (CO), 168.2 (COOCH₃); MS (ESI⁺) m/z (rel intensity) 428 (MH⁺ + 1, 19), 427 (MH⁺, 100), 396 (10), 395 (56), 353 (24); HRMS (ESI⁺) Calcd. for C₂₃H₂₃O₈ [MH⁺]: 427.1393; found, 427.1393.

Methyl (E)-3-(5,7-Dimethoxy-4-methyl-2-oxo-2H-chromen-3-yl)acrylate (4e)

Coumarin 4e was prepared from 2i (81.3 mg, 0.37 mmol), AgOAc (0.19 g, 1.11 mmol), PivOH (0.38 g, 3.69 mmol), methyl acrylate (0.07 mL, 0.74 mmol), and Pd(OAc)₂ (8.5 mg, 0.04 mmol). The reaction was heated at 120 °C for 48 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 6/4) afforded 4e (50.7 mg, 45%) as a solid: mp (CH₂Cl₂) 199–201 °C; IR (ATR): 1713 cm^–1 (COO, COOCH₃); ¹H NMR (CDCl₃, 300 MHz): δ 2.72 (s, 3H, CH₃), 3.79 (s, 3H, COOCH₃), 3.85 (s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 6.30 (d, J = 2,4 Hz, 1H, H₆), 6.40 (d, J = 2,4 Hz, 1H, H₈), 7.07 (d, J = 15,7 Hz, 1H, CH=CH–COOCH₃), 7.82 (d, J = 15,7 Hz, 1H, CH=CH–COOCH₃); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 19.7 (CH₃), 51.7 (CH=CH–COOCH₃), 55.8 (OCH₃), 55.9 (OCH₃), 93.1 (C₈), 96.0 (C₆), 106.5 (C_4a), 115.5 (C₃), 123.1 (CH=CH–COOCH₃), 136.3 (CH=CH–COOCH₃), 154.5 (C₄), 155.8 (C_8a), 159.0, 163.5 (C₅, C₇), 159.8 (CO), 168.4 (COOCH₃); MS (CI) m/z (rel intensity) 306 (MH⁺ + 1, 14), 305 (MH⁺, 100), 274 (10), 273 (85); HRMS (CI) Calcd. for C₁₆H₁₇O₆ [MH⁺]: 305.1020; found, 305.1021.

tert-Butyl (E)-3-(5,7-Dimethoxy-4-methyl-2-oxo-2H-chromen-3-yl)acrylate (4f)

Coumarin 4f was prepared from 2i (60 mg, 0.27 mmol), AgOAc (0.14 g, 0.82 mmol), PivOH (0.28 g, 2.72 mmol), tert-butyl acrylate (0.08 mL, 0.54 mmol), and Pd(OAc)₂ (6.2 mg, 0.03 mmol). The reaction was heated at 120 °C for 24 h, and after the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 4f (49.8 mg, 53%) as a solid: mp (CH₂Cl₂): 159–161 °C; IR (ATR): 1716 (COO), 1695 (COOtBu) cm^–1; ¹H NMR (CDCl₃, 300 MHz): δ 1.51 (s, 9H, C(CH₃)₃), 2.69 (s, 3H, CH₃), 3.83 (s, 3H, OCH₃), 3.87 (s, 3H, OCH₃), 6.28 (d, J = 2.4 Hz, 1H, H₆), 6.38 (d, J = 2.4 Hz, 1H, H₈), 6.97 (d, J = 15.7 Hz, 1H, CH=CH–COOtBu), 7.71 (d, J = 15.7 Hz, 1H, CH=CH–COOtBu); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 19.6 (CH₃), 28.2 (C(CH₃)₃), 55.7 (OCH₃), 55.9 (OCH₃), 80.3 (C(CH₃)₃), 93.1 (C₈), 95.9 (C₆), 105.5 (C_4a), 115.6 (C₃), 125.4 (CH=CH–COOtBu), 135.0 (CH=CH–COOtBu), 154.0 (C_8a), 155.7 (C₄), 159.1, 159.7 (C_5, C₇), 163.4 (COO), 167.3 (COOtBu); MS (CI) m/z (rel intensity) 347.1 (MH⁺, 6), 346.1 (20), 292.1 (10), 291 (52), 290.1 (100), 274.1 (10), 273.1 (63), 262.1 (12), 245.1 (72); HRMS (CI) Calcd. for C₁₉H₂₃O₆ [MH⁺]: 347.1489; found, 347.1507.

Methyl (E)-3-(5,7-Dimethoxy-4-methyl-2-oxo-2H-chromen-3-yl)but-2-enoate (4g)

Coumarin 4g was prepared from 2i (52.1 mg, 0.24 mmol), AgOAc (0.12 g, 0.71 mmol), PivOH (0.24 g, 2.37 mmol), methyl crotonate (0.05 mL, 0.47 mmol), and Pd(OAc)₂ (5.4 mg, 0.024 mmol). The reaction was heated at 120 °C for 48 h. After the work-up, flash column chromatography (silica gel, hexane/EtOAc 7/3) afforded 4g (33.5 mg, 44%) as a solid: mp (CH₂Cl₂): 153–155 °C; IR (ATR): 1706 cm^–1 (COO, COOCH₃); ¹H NMR (CDCl₃, 300 MHz): δ 2.39 (d, J = 1.3 Hz, 3H, C(CH₃)=CH(COOCH₃)), 2.48 (s, 3H, C–CH₃), 3.73 (s, 3H, C(CH₃)=CH(COOCH₃)), 3.85 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 5.76–5.79 (m, 1H, C(CH₃)=CH(COOCH₃)), 6.31 (d, J = 2,4 Hz, 1H, H₆), 6.43 (d, J = 2,4 Hz, 1H, H₈); ¹³C{¹H} NMR (CDCl₃, 75.5 MHz): δ 19.4 (C(CH₃)=CH(COOCH₃)), 20.7 (C–CH₃), 51.1 (C(CH₃)=CH(COOCH₃)), 55.7 (OCH₃), 55.8 (OCH₃), 93.2 (C₈), 95.8 (C₆), 104.8 (C_4a), 111.4 (C₃), 121.6 (C(CH₃)=CH(COOCH₃)), 148.8 (C(CH₃)=CH(COOCH₃)), 152.6 (C₄), 155.8 (C_8a), 159.4, 159.5 (C₅, C₇), 162.6 (CO), 166.5 (C(CH₃)=CH(COOCH₃)); MS (ESI⁺) m/z (rel intensity) 319 (MH⁺, 100), 288 (17), 287 (71); HRMS (ESI⁺) Calcd. for C₁₇H₁₉O₆ [MH⁺]: 319.1176, found, 319.1171.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c03469.

• Preparation procedures for the substrates 1, additional substrates tested in the cyclization, additional essays for the intermolecular alkenylation reaction of 2i, copies of the ¹H and ¹³C NMR spectra of compounds 2–4, and the fluorescence spectra for selected compounds 2 and 4 (PDF)

The authors declare no competing financial interest.