Palladium-Catalyzed Intramolecular Migratory Cycloisomerization of 3-Phenoxy Acrylic Acid Ester via C–O Bond Cleavage and C–O/C–C Bonds Formation for 2,3-Disubstituted Benzofurans Synthesis

Abstract

Migratory cycloisomerization using transition metal catalyst is useful for synthesizing substituted heterocyclic compounds. We achieved palladium-catalyzed migratory cycloisomerization of 3-o-alkynylphenoxy acrylic acid ester derivatives to give 2,3-disubstituted benzofurans. Although there are several reports of benzofuran synthesis with palladium-catalyzed migratory cycloisomerization, migratory groups are limited to allyl and propargyl groups. This report is the first example of benzofuran synthesis with palladium-catalyzed cycloisomerization of C(sp²)-O bond cleavage.

Introduction

Benzofuran is a common structure of agrochemical and pharmaceuticals, and its synthetic methods have been studied since the 19th century.^1,2) In recent years, migratory cycloisomerization of o-alkynylphenol ethers and o-alkynylanilines using transition metal catalysts have been reported to synthesize 2,3-disubstituted benzofurans and indoles (Fig. 1, A). Migratory groups on aromatic nitrogen in indole synthesis are carbonyl,^3–7) alkoxyalkyl,^8–11) propargyl,¹²⁾ allyl,¹³⁾ and sulfonyl^13–16) groups. On the other hand, migratory groups on phenol in the benzofurans synthesis are alkoxyalkyl,⁸⁾ allyl,¹⁶⁾ boryl,¹⁷⁾ vinyl¹⁸⁾ propalgyl,¹⁹⁾ and carbonyl²⁰⁾ groups. Transition metals used in the migratory cycloisomerization are Pd, Ni, Ru, Rh, Au, and Pt. The palladium catalyst is only reported to catalyze the allyl or propargyl group transfer in migratory isomerization to give benzofuranes.^16,19) Our group reported Ni-catalyzed migratory cycloisomerization of 3-o-alkynylphenoxy acrylic acid derivatives to give 2,3-disubstituted benzofurans.²¹⁾ This is the first example that an acrylic acid derivative was used as the migratory group (Fig. 1, B). After this report, two groups reported migratory cycloisomerization of an acrylic acid derivative. However, both used Ni catalysts.^20,22) Here, we report unprecedented Pd-catalyzed migratory cycloisomerization of 3-o-alkynylphenoxy acrylic acid derivatives to give 2,3-disubstituted benzofurans (Fig. 1, C).

Fig. 1. Migratory Cycloisomerization for the Synthesis of Benzofuran

Results and Discussion

First, when we stirred a solution of 1a, Pd(dba)₂ (10 mol%), PCy₃ (20 mol%) in N,N-dimethylformamide (DMF) (0.1 M) at 110 °C for 7 h, we found that the migratory cycloisomerization product 2a was isolated in 38% yield (Table 1, entry 1). Because we observed the complete consumption of 1a, we continued our experiments by changing the concentration of DMF solution (entries 2–4). As a result, 2a was obtained in 95% yield at 0.01 M (entry 4). At lower temperatures or using other solvents (such as toluene and tetrahydrofuran (THF)), the reaction did not proceed at all (entries 5–8). Other ligands or Pd catalysts did not work well (entries 9–13). Finally, the yields were examined when the amounts of Pd(dba)₂ and PCy₃ were reduced. The results showed that at 5 and 10 mol% of Pd and ligand, the target product was obtained in 79% (entry 14). Therefore, we decided to investigate the substrate scope using entry 4 as the optimum conditions based on the above.

Table 1. Optimization of Reaction Conditions

Entry	Pd catalyst (mol%)	Ligand (mol%)	Solv. (M)	Temp. (°C)	Result (%)
1	Pd(dba)2 (10)	PCy3 (20)	DMF (0.1)	110	38
2	Pd(dba)2 (10)	PCy3 (20)	DMF (0.5)	110	47
3	Pd(dba)2 (10)	PCy3 (20)	DMF (0.02)	110	39
4	Pd(dba)2 (10)	PCy3 (20)	DMF (0.01)	110	95
5	Pd(dba)2 (10)	PCy3 (20)	DMF (0.01)	70	Trace
6	Pd(dba)2 (10)	PCy3 (20)	DMF (0.01)	r.t.	N.R.a)
7	Pd(dba)2 (10)	PCy3 (20)	Toluene (0.01)	110	N.R.a)
8	Pd(dba)2 (10)	PCy3 (20)	THF (0.01)	110	N.R.a)
9	Pd(dba)2 (10)	PPh3 (20)	DMF (0.01)	110	N.R.a)
10	Pd(dba)2 (10)	P(o-tol)3 (20)	DMF (0.01)	110	N.R.a)
11	Pd(dba)2 (10)	P(n-Bu)3 (20)	DMF (0.01)	110	55
12	Pd(OAc)2 (10)	PCy3 (20)	DMF (0.01)	110	81
13	PdCl2(PPh3)2 (10)	PCy3 (20)	DMF (0.01)	110	Trace
14	Pd(dba)2 (5.0)	PCy3 (10)	DMF (0.01)	110	79

a) No reaction.

Using the optimal conditions, we next examined the effect of alkene substituents (Table 2). In the cases of ethyl ester derivative 1b, t-Bu ester derivative 1c, and benzyl ester derivative 1d, we succeeded in obtaining the desired products in good yields. On the other hand, the phenyl ester derivative was not converted to the corresponding benzofuran 2e at all. We decided to change the ester group to another substituent and continue the study. The reaction did not proceed with substrates where the amide derivative 1f, propenyloxy derivative 1g, or vinyloxy derivative 1h were functionalized to the alkene. Next, we examined the effect of the substituents on the alkynes. The substrate with p-anisyl derivative 1i gave the desired products in 43%. The reaction proceeded quantitatively for both p-nitrobenzene derivative 1j, which has an electron-withdrawing group, and p-n-butylbenzene derivative 1k, which has an alkyl chain, which is known as a weak electron-donating group. In the case of the methylalkyne derivative 1l, the desired product was not obtained. Even in the case of (triethylsilyl)alkyne derivative 1m, terminal alkyne derivative 1n, and n-butylalkyne derivative 1o, there was no progress in the reaction, and the corresponding benzofuran derivatives were not obtained. Finally, the effect of substituents on the aromatic ring was investigated. Compounds 1q, 1r, 1u, and 1v, which have a substituent at the 4- or 5-position, were converted to the corresponding cyclized product in 72, 65, 64, and 75%. However, the reaction did not proceed for substrates 1p, 1s, and 1w with substituents at the 3- and 6-positions, but the target product was obtained in 65% of cases only for substrate 1t with a methyl group at the 3-position.

Table 2. Substrate Scope

Finally, to uncover the reaction mechanism, we conducted a crossover experiment (Fig. 2). This reaction was investigated by mixing substrates 1j and 1d with different acrylic acid esters and substituents on the aromatic ring. As a result, no compound in which the acrylic acid ester of the substrate intersected with another was observed. Therefore, it was found that this reaction is an intramolecular cycloisomerization reaction. The plausible mechanism of this reaction is shown in Fig. 3.²⁸⁾ In this reaction mechanism, Pd catalyst could be coordinated by the substrate to undergo oxidative cyclization forming a five-membered palladacylce. Subsequently, β-oxygen elimination leads to the corresponding six-membered palladacycle intermediate, and the following reductive elimination could give the final product, the benzofuran derivative.

Fig. 2. Crossover Reaction

Fig. 3. Plausible Reaction Mechanism

In conclusion, we have achieved the synthesis of benzofurans via a palladium-catalyzed cyclization isomerization involving the transfer of salicylate derivatives.

Experimental

General Methods

Melting points were measured by BÜCHI B-545 and all melting points were uncorrected. ¹H- and ¹³C-NMR spectra were measured by JEOL JNM-ECS 400, JEOL ECS 300 or JEOL JNM-LA 500 spectrometers. ¹H-NMR spectra are reported as follows: chemical shift in ppm relative to the chemical shift of CDCl₃ at 7.26 ppm, integration, multiplicities (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), and coupling constants (Hz). ¹³C-NMR spectra reported in ppm relative to the central line of triplet for CDCl₃ at 77 ppm as an internal standard. High resolution mass spectra and elemental analysis were performed by the Elemental Analysis Section of Osaka University. Column chromatography was performed with SiO₂ (Merck Silica Gel 60, 230–400 mesh or Kanto Chemical Silicagel 60, spherical neutral, 63–210 µm) unless otherwise stated. Commercially available organic and inorganic compounds were used without further purification.

Procedure and Experimental Data for Derivatives

(E)-1-(Phenylethynyl)-2-(prop-1-en-1-yloxy)benzene (1g)

1g was prepared according to the literature.²³⁾ 2-Iodophenol (550 mg, 2.5 mmol) was converted to 1g (260 mg, 47%). Colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.57–7.50 (m, 3H), 7.38–7.27 (m, 4H), 7.05–6.97 (m, 2H), 6.47 (qd, J = 3.1, 1.7 Hz, 1H), 4.94 (qd, J = 6.9, 6.9 Hz, 1H), 1.80 (dd, J = 6.9, 1.7 Hz, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 157.8, 140.8, 133.4, 131.6, 129.6, 128.3, 128.2, 123.5, 122.2, 114.8, 113.6, 107.8, 93.8, 85.2, 9.5.

1-(Phenylethynyl)-2-(vinyloxy)benzene (1h)

1h was prepared according to the literature.²⁴⁾ 2-Iodophenol (550 mg, 2.50 mmol) was converted to 1h (240 mg, 41%). Colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ: 7.58–7.51 (m, 3H), 7.38–7.27 (m, 4H), 7.09 (ddd, J = 7.5, 7.5, 1.0 Hz, 1H), 7.04 (dd, J = 8.3, 1.0 Hz, 1H), 6.70 (dd, J = 13.8, 6.2 Hz, 1H), 4.80 (dd, J = 13.8, 2.1 Hz, 1H), 4.48 (dd, J = 6.2, 1.7 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 157.0, 148.6, 133.5, 131.6, 129.6, 128.5, 128.3, 123.3, 117.2, 114.6, 95.0, 94.1, 84.9.

Typical Procedure A for Preparation of Compounds 1a–1f, 1i–1o, 1q, 1u–1w

To a round-bottom flask containing 2-iodophenol (1.0 equivalent (equiv.)) and mono-substituted acetylene (1.1 equiv.) and triethylamine (15 equiv.) in THF (0.4 M) under nitrogen were added copper iodide (2 mol%) and bis(triphenylphosphine) palladium(II) dichloride (1 mol%). The mixture was stirred at ambient temperature for 4 h. The mixture was diluted with AcOEt and filtered by celite pad. The filtrate was concentrated, and the residue was purified by short column chromatography (n-hexane/AcOEt = 15 : 1) to give 2-substituted-ethynylphenol. To a stirred solution of the above obtained crude substituted 2-ethynylphenol in CH₂Cl₂ (0.2 M) was added DABCO (0.1 equiv.) and propiolic acid derivative (1.05 equiv.) at 0 °C. The mixture was stirred at ambient temperature for 2 h. After addition of water to the mixture, the organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂. The combined organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to give compounds.

Methyl (E)-3-(2-(Phenylethynyl)phenoxy)acrylate (1a)²⁵⁾

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1a (598 mg, 86%). Yellow oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.86 (d, J = 12.5 Hz, 1H), 7.57 (dd, J = 7.4, 1.7 Hz, 1H), 7.53–7.50 (m, 2H), 7.37–7.33 (m, 4H), 7.23–7.19 (m, 1H), 7.12–7.09 (m, 1H), 5.57 (d, J = 12.5 Hz, 1H), 3.72 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.5, 159.8, 155.8, 133.5, 131.5, 129.7, 128.5, 128.3, 125.2, 122.7, 118.8, 115.4, 101.4, 95.0, 83.8, 51.2.

Ethyl (E)-3-(2-(Phenylethynyl)phenoxy)acrylate (1b)²⁵⁾

Following the typical procedure A, 2-Iodophenol (550 mg, 2.50 mmol) was converted to 1b (618 mg, 84%). Colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.85 (d, J = 12.4 Hz, 1H), 7.59–7.49 (m, 3H), 7.38–7.31 (m, 4H), 7.20 (dd, J = 7.5, 7.5 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 5.56 (d, J = 12.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.2, 159.7, 155.9, 133.6, 131.6, 129.8, 128.6, 128.3, 125.2, 122.8, 119.0, 115.5, 101.9, 95.1, 83.9, 60.1, 14.3.

tert-Butyl (E)-3-(2-(Phenylethynyl)phenoxy)acrylate (1c)

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1c (640 mg, 80%). Colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.77 (d, J = 12.0 Hz, 1H), 7.58–7.50 (m, 3H), 7.38–7.32 (m, 4H), 7.19 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 7.10 (dd, J = 8.3, 1.0 Hz, 1H), 5.50 (d, J = 12.0 Hz, 1H), 1.47 (s, 9H); ¹³C-NMR (100 MHz, CDCl₃) δ: 166.5, 159.0, 156.1, 133.6, 131.6, 129.8, 128.6, 128.3, 125.0, 122.8, 118.9, 115.4, 103.5, 95.0, 84.0, 80.1, 28.2 high resolution (HR)MS (matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF)) Calcd for C₂₁H₂₀O₃Na [M + Na]⁺: 343.1305, Found 343.1285.

Benzyl (E)-3-(2-(Phenylethynyl)phenoxy)acrylate (1d)

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1d (710 mg, 80%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.89 (d, J = 12.5 Hz, 1H), 7.56 (dd, J = 7.8, 1.3 Hz, 1H), 7.51–7.49 (m, 2H), 7.37–7.31 (m, 9H), 7.22–7.18 (m, 1H), 7.12–7.08 (m, 1H), 5.59 (d, J = 12.0 Hz, 1H), 5.17 (s, 2H); ¹³C-NMR (75 MHz, CDCl₃) δ: 167.0, 160.2, 155.8, 136.1, 133.6, 131.6, 129.8, 128.6, 128.5, 128.3, 128.1, 125.3, 122.8, 119.0, 115.5, 101.5, 95.1, 83.8, 65.9; HRMS (MALDI-TOF) Calcd for C₂₄H₁₈O₃Na [M + Na]⁺: 377.1148, Found 377.1169.

Phenyl (E)-3-(2-(Phenylethynyl)phenoxy)acrylate (1e)

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1e (710 mg, 84%). Colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ: 8.06 (d, J = 12.4 Hz, 1H), 7.61–7.55 (m, 3H), 7.41–7.35 (m, 6H), 7.24–7.16 (m, 3H), 7.09–7.06 (m, 2H), 5.75 (d, J = 11.9 Hz, 1H); ¹³C-NMR (100 MHz, CDCl₃) δ: 165.6, 161.5, 155.8, 150.6, 133.7, 131.6, 129.9, 129.3, 128.7, 128.4, 125.6, 125.5, 122.7, 121.7, 119.2, 115.5, 100.9, 95.3, 83.8; HRMS (MALDI-TOF) Calcd for C₂₃H₁₆O₃ [M]⁺: 363.0992, Found 363.0998.

(E)-N,N-Dimethyl-3-(2-(phenylethynyl)phenoxy)acrylamide (1f)

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1f (624 mg, 86%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.81 (d, J = 11.5 Hz, 1H), 7.56–7.51 (m, 3H), 7.35–7.31 (m, 4H), 7.17–7.11 (m, 1H), 7.11–7.08 (m, 1H), 6.10 (d, J = 11.5 Hz, 1H), 3.00 (s, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 166.5, 157.5, 156.3, 133.5, 131.6, 129.7, 128.4, 128.2, 124.5, 122.9, 117.8, 114.8, 101.6, 94.5, 84.2, 37.2, 35.5; HRMS (MALDI-TOF) Calcd for C₁₉H₁₈NO₂Na [M + Na]⁺: 292.1332, Found 292.1327.

Methyl (E)-3-(2-((4-Methoxyphenyl)ethynyl)phenoxy)acrylate (1i)²⁵⁾

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1i (458 mg, 59%). Colorless powder. M.p. 86–88 °C (CHCl₃) ¹H-NMR (300 MHz, CDCl₃) δ: 7.85 (d, J = 12.4 Hz, 1H), 7.54 (dd, J = 7.6, 1.7 Hz, 1H), 7.45 (ddd, J = 9.4, 2.4, 2.4 Hz, 2H), 7.33 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.19 (J = 7.6, 7.6, 1.4 Hz, 1H), 7.09 (dd, J = 7.9, 1.0 Hz, 1H), 6.87 (d, J = 8.9 Hz, 2H), 5.56 (d, J = 12.4 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.6, 160.0, 159.9, 155.7, 133.4, 133.1, 129.4, 125.2, 118.9, 115.8, 114.9, 114.0, 101.3, 95.2, 82.6, 55.3, 51.3.

Methyl (E)-3-(2-((4-Nitrophenyl)ethynyl)phenoxy)acrylate (1j)

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1j (458 mg, 59%). Yellow powder. M.p. 102–104 °C (CHCl₃) ¹H-NMR (500 MHz, CDCl₃) δ: 8.21 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 12.0 Hz, 1H), 7.64 (d, J = 8.6 Hz, 2H), 7.59 (dd, J = 7.4, 1.7 Hz, 1H), 7.42 (ddd, J = 7.9, 7.9, 1.5 Hz, 1H), 7.25–7.22 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 5.59 (d, J = 12.6 Hz, 1H), 3.73 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.4, 159.4, 156.1, 147.1, 133.8, 132.3, 130.9, 129.7, 125.3, 123.6, 118.8, 114.2, 102.0, 92.8, 89.1, 51.4; HRMS (MALDI-TOF) Calcd for C₁₈H₁₃NO₅Na [M + Na]⁺: 323.0788, Found 323.0781.

Methyl (E)-3-(2-((4-Butylphenyl)ethynyl)phenoxy)acrylate (1k)

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1k (458 mg, 59%). Colorless needle. M.p. 42–44 °C (n-hexane) ¹H-NMR (300 MHz, CDCl₃) δ: 7.86 (d, J = 12.0 Hz, 1H), 7.55 (dd, J = 7.6, 1.7 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.33 (dd, J = 8.1, 1.5 Hz, 1H), 7.22–7.08 (m, 4H), 5.56 (d, J = 12.0 Hz, 1H), 3.72 (s, 3H), 2.62 (t, J = 7.7 Hz, 2H), 1.62–1.57 (m, 2H), 1.35 (q, J = 7.3 Hz, 2H), 0.93 (t, J = 7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.6, 160.0, 155.8, 143.8, 133.6, 131.5, 129.6, 128.5, 125.2, 119.9, 118.9, 115.7, 101.4, 95.4, 83.2, 51.3, 35.6, 33.4, 22.3, 13.9; HRMS (MALDI-TOF) Calcd for C₂₂H₂₃O₃Na [M + Na]⁺: 335.1642, Found 335.1639.

Methyl (E)-3-(2-(Prop-1-yn-1-yl)phenoxy)acrylate (1l)²⁶⁾

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1l (450 mg, 83%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.77 (d, J = 12.4 Hz, 1H), 7.42 (dd, J = 7.6, 1.6 Hz, 1H), 7.28 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H), 7.13 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.03 (dd, J = 8.2, 0.9 Hz, 1H), 5.49 (d, J = 12.4 Hz, 1H), 3.72 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.6, 160.0, 155.8, 133.8, 129.0, 125.1, 118.8, 116.1, 101.2, 92.0, 74.2, 51.3, 4.6.

Methyl (E)-3-(2-((Triethylsilyl)ethynyl)phenoxy)acrylate (1m)²¹⁾

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1m (684 mg, 87%). Yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.77 (d, J = 12.0 Hz, 1H), 7.49 (dd, J = 7.9, 1.7 Hz, 1H), 7.32 (ddd, J = 7.7, 7.7, 1.7 Hz, 1H), 7.14 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H), 7.05 (dd, J = 8.3, 1.0 Hz, 1H), 5.48 (d, J = 12.0 Hz, 1H), 3.71 (s, 3H), 1.02 (t, J = 7.7 Hz, 9H), 0.69–0.61 (m, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.5, 159.8, 156.4, 134.1, 129.9, 125.1, 118.8, 115.6, 101.3, 100.2, 98.5, 51.2, 7.4, 4.2.

Methyl (E)-3-(2-Ethynylphenoxy)acrylate (1n)²¹⁾

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1n (341 mg, 67%). Colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.77 (d, J = 12.5 Hz, 1H), 7.52 (dd, J = 7.5, 1.5 Hz, 1H), 7.37 (ddd, J = 7.8, 7.8, 1.5 Hz, 1H), 7.17 (ddd, J = 7.6, 7.6, 1.4 Hz, 1H), 7.06 (dd, J = 8.3, 1.0 Hz, 1H), 5.52 (d, J = 12.5 Hz, 1H), 3.72 (s, 3H), 3.29 (s, 1H); ¹³C-NMR (75 MHz, CDCl₃) δ: 167.5, 159.3, 156.4, 134.3, 130.4, 125.1, 118.6, 114.2, 101.9, 82.8, 78.1, 51.4.

Methyl (E)-3-(2-(Hex-1-yn-1-yl)phenoxy)acrylate (1o)²⁵⁾

Following the typical procedure A, 2-iodophenol (550 mg, 2.50 mmol) was converted to 1o (525 mg, 81%). Yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.77 (d, J = 12.0 Hz, 1H), 7.42 (dd, J = 7.6, 1.7 Hz, 1H), 7.30–7.23 (m, 1H), 7.12 (ddd, J = 7.5, 7.5, 1.1 Hz, 1H), 7.03 (dd, J = 8.1, 1.2 Hz, 1H), 5.47 (d, J = 12.0 Hz, 1H), 3.71 (s, 3H), 2.41 (t, J = 6.9 Hz, 2H), 1.60–1.41 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 167.7, 160.2, 155.9, 133.7, 128.9, 125.2, 118.9, 116.2, 101.0, 96.6, 75.0, 51.2, 30.5, 21.9, 19.2, 13.6.

Methyl (E)-3-(4-Chloro-2-(phenylethynyl)phenoxy)acrylate (1q)²⁵⁾

Following the typical procedure A, 4-chloro-2-iodophenol (255 mg, 1.00 mmol) was converted to 1q (244 mg, 78%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.80 (d, J = 12.5 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.51–7.49 (m, 2H), 7.37–7.35 (m, 3H), 7.31 (dd, J = 9.0, 2.5 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 5.57 (d, J = 12.5 Hz, 1H), 3.72 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 167.0, 159.1, 154.2, 132.8, 131.5, 130.2, 129.5, 128.8, 128.2, 122.1, 119.8, 116.8, 101.8, 96.1, 82.6, 51.1.

Methyl (E)-3-(4-Methyl-2-(phenylethynyl)phenoxy)acrylate (1u)

Following the typical procedure A, 4-methyl-2-iodophenol (234 mg, 1.00 mmol) was converted to 1u (203 mg, 69%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.83 (d, J = 12.0 Hz, 1H), 7.51–7.49 (m, 1H), 7.39–7.32 (m, 3H), 7.14 (dd, J = 8.3, 1.8 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 5.52 (d, J = 12.0 Hz, 1H), 3.71 (s, 3H), 2.34 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.6, 160.3, 153.7, 135.0, 133.8, 131.5, 130.4, 128.5, 128.3, 122.8, 118.8, 115.0, 100.9, 94.6, 84.0, 51.2, 20.5; HRMS (MALDI-TOF) Calcd for C₁₉H₁₇O₃Na [M + Na]⁺: 293.1172, Found 293.1176.

Methyl (E)-3-(5-Methyl-2-(phenylethynyl)phenoxy)acrylate (1v)

Following the typical procedure A, 5-methyl-2-iodophenol (234 mg, 1.00 mmol) was converted to 1v (185 mg, 63%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.85 (d, J = 12.0 Hz, 1H), 7.51–7.49 (m, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.36–7.32 (m, 3H), 7.01 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 5.57 (d, J = 12.0 Hz, 1H), 3.72 (s, 3H), 2.38 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.6, 160.0, 155.7, 140.7, 133.3, 131.5, 128.4, 128.3, 126.1, 123.0, 119.5, 112.3, 101.3, 94.3, 84.0, 51.3, 21.4; HRMS (MALDI-TOF) Calcd for C₁₉H₁₇O₃Na [M + Na]⁺: 293.1172, Found 293.1171.

Methyl (E)-3-(2-Methyl-6-(phenylethynyl)phenoxy)acrylate (1w)

Following the typical procedure A, 6-methyl-2-iodophenol (234 mg, 1.00 mmol) was converted to 1w (458 mg, 59%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.77 (d, J = 13.0 Hz, 1H), 7.53–7.51 (m, 2H), 7.42–7.32 (m, 5H), 6.96 (d, J = 8.5 Hz, 1H), 5.46 (d, J = 12.0 Hz, 1H), 3.73 (s, 3H), 2.24 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.5, 159.2, 153.6, 134.7, 131.5, 130.7, 129.0, 128.3, 128.3, 123.1, 120.2, 118.0, 101.5, 89.3, 88.5, 51.3, 15.7; HRMS (MALDI-TOF) Calcd for C₁₉H₁₆O₃Na [M + Na]⁺: 292.1094, Found 292.1101.

Typical Procedure B for Preparation of Compounds 1p, 1s

Chloromethyl methyl ether (1.5 equiv.) was added to a solution of substituted iodophenol (1.0 equiv.) and diisopropylethylamine (2.0 equiv.) in dichloromethane (0.4 M) at 0 °C under nitrogen, and the mixture was stirred 1 h at ambient temperature. The resulting solution was quenched with water and extracted with CH₂Cl₂. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by short column chromatography (n-hexane/AcOEt = 20 : 1) to give a MOM ether. To a round-bottom flask containing the above obtained MOM ether (1.0 equiv.) and phenylacetylene (1.1 equiv.) and triethylamine (15 equiv.) in THF (0.4 M) under nitrogen were added copper iodide (2 mol%) and bis(triphenylphosphine) palladium(II) dichloride (1 mol%). The mixture was stirred at ambient temperature for 4 h. The mixture was diluted with AcOEt and filtered by celite pad. The filtrate was concentrated, and the residue was purified by short column chromatography (n-hexane/AcOEt = 15 : 1) to give 1-(methoxymethoxy)-2-(phenylethynyl)benzene derivative. 6 M HCl (6.0 equiv.) was added dropwise to a solution of 1-chloro-2-iodo-3-(methox-ymethoxy)benzene (1 equiv.) in methanol (0.2 M). After stirring for 12 h at ambient temperature, water was added followed by AcOEt. The layers were separated and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (n-hexane/AcOEt = 10 : 1) to afford 2-(phenylethynyl)phenol derivative. To a stirred solution of the above obtained crude 2-substituted-ethynylohenol in CH₂Cl₂ (0.2 M) was added DABCO (0.1 equiv.) and methyl propiolate (1.05 equiv.) at 0 °C. The mixture was stirred at ambient temperature for 2 h. After addition of water to the mixture, the organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂. The combined organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to give compounds.

Methyl (E)-3-(3-Chloro-2-(phenylethynyl)phenoxy)acrylate (1p)

Following the typical procedure B, 3-chloro-2-iodophenol (255 mg, 1.00 mmol) was converted to 1p (188 mg, 60%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.83 (d, J = 12.0 Hz, 1H), 7.57 (dd, J = 6.6, 2.6 Hz, 2H), 7.38 (dd, J = 5.2, 1.7 Hz, 3H), 7.33–7.31 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.05–7.03 (m, 1H), 5.62 (d, J = 12.6 Hz, 1H), 3.74 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 167.3, 159.1, 156.7, 137.4, 131.7, 129.4, 129.0, 128.3, 126.1, 122.5, 116.9, 116.1, 102.2, 100.4, 80.9, 51.4; HRMS (MALDI-TOF) Calcd for C₁₈H₁₂O₃ClNa [M + Na]⁺: 311.0469, Found 311.0462.

Methyl (E)-3-(2-Chloro-6-(phenylethynyl)phenoxy)acrylate (1s)

Following the typical procedure B, 6-chloro-2-iodophenol (255 mg, 1.00 mmol) was converted to 1s (266 mg, 85%). Colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ: 7.79 (d, J = 12.4 Hz, 1H), 7.50–7.46 (m, 3H), 7.42 (dd, J = 8.2, 1.4 Hz, 1H), 7.37–7.33 (m, 3H), 7.17 (t, J = 7.8 Hz, 1H), 5.37 (d, J = 11.9 Hz, 1H), 3.70 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.3, 160.1, 151.2, 131.7, 131.6, 130.6, 129.0, 128.4, 127.1, 126.5, 122.3, 118.8, 100.6, 96.1, 83.0, 51.3; HRMS (MALDI-TOF) Calcd for C₁₈H₁₄O₃ClNa [M + Na]⁺: 313.0626, Found 311.0623.

Typical Procedure C for Preparation of Compounds 1r, 1t

To a flame dried round-bottom flask containing triphenylphosphine (4.0 equiv.) and CH₂Cl₂ (0.3 M) at 0 °C was added carbon tetrabromide (4.0 equiv.) and triehylamine (8.0 equiv.). After stirring at 0 °C for 10 min, the salicylaldehyde (1.0 equiv.) in CH₂Cl₂ (2 M) was added to this solution. The mixture was stirred at 0 °C for 10 min, then warmed ambient temperature and stirred until TLC showed complete consumption of the starting material. The filtrate was concentrated, and the residue was purified by short column chromatography to give 2-(2,2-dibromovinyl)phenol. To a stirred solution of the above obtained 2-(2,2-dibromovinyl)phenol in anhydrous THF (0.2 M) under nitrogen at −78 °C was added n-butyllithium (3.0 equiv., 1.60 M in n-hexane). The mixture was stirred at −78 °C for 3 h, and allowed to warm to ambient temperature. The mixture was quenched with 1 M HClaq., and the organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by short column chromatography to give 2-ethynylpheol. To a round-bottom flask containing 2-ethynylpheol derivative (1.0 equiv.) and iodobenzene (1.1 equiv.) and triethylamine (15 equiv.) in THF (0.4 M) under nitrogen were added copper iodide (2 mol%) and bis(triphenylphosphine) palladium(II) dichloride (1 mol%). The mixture was stirred at ambient temperature for 4 h. The mixture was diluted with AcOEt and filtered by celite pad. The filtrate was concentrated, and the residue was purified by short column chromatography (n-hexane/AcOEt = 15 : 1) to give 2-(phenylethynyl)phenol. To a stirred solution of the above obtained crude substituted 2-ethynylphenol in CH₂Cl₂ (0.2 M) was added DABCO (0.1 equiv.) and methyl propiolate (1.05 equiv.) at 0 °C. The mixture was stirred at ambient temperature for 2 h. After addition of water to the mixture, the organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂. The combined organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to give compounds.

Methyl (E)-3-(5-Chloro-2-(phenylethynyl)phenoxy)acrylate (1r)

Following the typical procedure C, 5-chloro-2-iodophenol (255 mg, 1.00 mmol) was converted to 1r (224 mg, 72%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.81 (d, J = 12.0 Hz, 1H), 7.51–7.47 (m, 3H), 7.36–7.34 (m, 3H), 7.19 (dd, J = 8.3, 2.3 Hz, 1H), 7.12 (d, J = 1.5 Hz, 1H), 5.62 (d, J = 12.0 Hz, 1H), 3.73 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.2, 158.9, 156.1, 135.0, 134.2, 131.6, 128.8, 128.4, 125.5, 122.5, 119.3, 114.0, 102.5, 96.0, 82.9, 51.4; HRMS (MALDI-TOF) Calcd for C₁₈H₁₄O₃ClNa [M + Na]⁺: 313.0626, Found 313.0619.

Methyl (E)-3-(3-Methyl-2-(phenylethynyl)phenoxy)acrylate (1t)

Following the typical procedure C, 3-methyl-iodophenol (255 mg, 1.00 mmol) was converted to 1t (241 mg, 77%). Colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.77 (d, J = 12.0 Hz, 1H), 7.46–7.42 (m, 2H), 7.30–7.24 (m, 3H), 7.15 (dd, J = 8.1, 8.1 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 5.47 (d, J = 12.0 Hz, 1H), 3.64 (s, 3H), 2.46 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.6, 160.1, 156.0, 142.7, 131.4, 128.9, 128.5, 128.3, 126.3, 123.0, 116.0, 115.4, 101.1, 99.2, 82.7, 51.2, 20.7; HRMS (MALDI-TOF) Calcd for C₁₉H₁₇O₃Na [M + Na]⁺: 293.1172, Found 293.1169.

Typical Procedure D for Palladium Catalyzed Benzofuran Synthesis with Acrylicacid Ester Migration of Compound 2a–2d, 2i–2k, 2q, 2s, 2t–2v

In glove box, to a round-bottom flask containing compound 1 (1.0 equiv.) in DMF was added Pd(dba)₂ (10 mol%) and PCy₃ (20 mol%). The mixture was stirred for 7 h at 110 °C before it was quenched with water. The aqueous layer was extracted with AcOEt × 3 and the combined organic layer was washed sequentially with water and brine, dried over anhydrous Na₂SO₄. The solvent was evaporated and the residue was purified by flash column chromatography (n-hexane/EtOAc = 10/1) to give benzofuran.

Methyl (E)-3-(2-Phenylbenzofuran-3-yl)acrylate (2a)²¹⁾

Following the typical procedure D, 1a (13.9 mg, 0.050 mmol) was converted to 2a (13.2 mg, 95%). Colorless oil. ¹H-NMR (300 MHz, CDCl₃) δ: 8.03 (d, J = 16.2 Hz, 1H), 7.90–7.86 (m, 1H), 7.85–7.80 (m, 2H), 7.59–7.46 (m, 4H), 7.42–7.32 (m, 2H), 6.69 (d, J = 15.8 Hz, 1H), 3.84 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.8, 157.7, 154.5, 136.2, 129.8, 129.6, 128.9, 128.6, 126.7, 125.3, 123.8, 121.0, 118.7, 112.6, 111.6, 51.7.

Ethyl (E)-3-(2-Phenylbenzofuran-3-yl)acrylate (2b)²¹⁾

Following the typical procedure D, 1b (14.6 mg, 0.050 mmol) was converted to 2b (13.9 mg, 95%). Colorless needle. M.p. 81–83 °C (CHCl₃) ¹H-NMR (500 MHz, CDCl₃) δ: 8.04 (d, J = 16.0 Hz, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.78 (d, J = 7.4 Hz, 2H), 7.58–7.52 (m, 3H), 7.51–7.47 (m, 1H), 7.41–7.33 (m, 2H), 6.69 (d, J = 16.0 Hz, 1H), 4.30 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.3, 157.6, 154.5, 135.9, 129.7, 129.7, 128.9, 128.6, 126.8, 125.3, 123.7, 121.0, 119.2, 112.6, 111.6, 60.5, 14.4.

tert-Butyl (E)-3-(2-Phenylbenzofuran-3-yl)acrylate (2c)²⁷⁾

Following the typical procedure D, 1c (16.0 mg, 0.050 mmol) was converted to 2c (13.1 mg, 82%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.97 (d, J = 16.0 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.79 (d, J = 7.4 Hz, 2H), 7.57–7.51 (m, 3H), 7.49–7.45 (m, 1H), 7.40–7.32 (m, 2H), 6.62 (d, J = 16.0 Hz, 1H), 1.56 (s, 9H); ¹³C-NMR (125 MHz, CDCl₃) δ: 166.7, 157.3, 154.5, 134.9, 129.8, 129.6, 128.9, 128.5, 126.9, 125.2, 123.6, 121.1, 121.0, 112.7, 111.5, 80.5, 28.2.

Benzyl (E)-3-(2-Phenylbenzofuran-3-yl)acrylate (2d)

Following the typical procedure D, 1d (17.8 mg, 0.050 mmol) was converted to 2d (16.2 mg, 91%). colorless needle. M.p. 50–52 °C (CHCl₃) ¹H-NMR (500 MHz, CDCl₃) δ: 8.10 (dd, J = 16.0, 2.3 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.79–7.77 (m, 2H), 7.59–7.32 (m, 11H), 6.74 (dd, J = 16.0, 2.3 Hz, 1H), 5.29 (s, 2H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.1, 157.8, 154.5, 136.5, 136.1, 129.8, 129.6, 128.9, 128.6, 128.4, 128.2, 126.7, 125.3, 123.8, 121.0, 118.7, 112.6, 111.6, 66.3; HRMS (MALDI-TOF) Calcd for C₂₄H₁₈O₃Na [M + Na]⁺: 354.1250, Found 354.1260.

Methyl (E)-3-(2-(4-Methoxyphenyl)benzofuran-3-yl)acrylate (2i)²¹⁾

Following the typical procedure D, 1i (15.4 mg, 0.050 mmol) was converted to 2i (6.6 mg, 43%). Yellow oil. ¹H-NMR (500 MHz, CDCl₃) δ: 7.84–7.87 (m, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 9.2 Hz, 2H), 7.33 (t, J = 7.7 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.6 Hz, 2H), 5.56 (d, J = 12.6 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 167.6, 160.1, 159.9, 155.7, 133.5, 133.3, 133.1, 129.4, 125.2, 118.9, 115.8, 114.9, 114.0, 101.3, 95.2, 82.6, 55.3, 51.3.

Methyl (E)-3-(2-(4-Nitrophenyl)benzofuran-3-yl)acrylate (1j)

Following the typical procedure D, 1j (16.2 mg, 0.050 mmol) was converted to 2j (15.9 mg, 98%). Yellow plate. M.p. 81–82 °C (CHCl₃) ¹H-NMR (500 MHz, CDCl₃) δ: 8.39 (d, J = 8.6 Hz, 2H), 8.00–7.89 (m, 4H), 7.60 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 7.7, 7.7 Hz, 1H), 7.40 (dd, J = 7.7, 7.7 Hz, 1H), 6.75 (d, J = 16.0 Hz, 1H), 3.86 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.2, 154.8, 153.8, 147.9, 135.6, 134.6, 128.8, 126.5, 126.5, 124.3, 124.2, 121.3, 121.3, 115.3, 111.9, 52.0; HRMS (MALDI-TOF) Calcd for C₁₈H₁₃NO₅Na [M + Na]⁺: 323.0788, Found 323.0792.

Methyl (E)-3-(2-(4-Butylphenyl)benzofuran-3-yl)acrylate (2k)

Following the typical procedure D, 1k (16.7 mg, 0.050 mmol) was converted to 2k (16.0 mg, 96%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 8.05 (d, J = 16.0 Hz, 1H), 7.87 (dd, J = 7.2, 2.0 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.55 (dd, J = 7.2, 2.0 Hz, 1H), 7.39–7.33 (m, 4H), 6.68 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 2.70 (t, J = 8.0 Hz, 2H), 1.63–1.70 (m, 2H), 1.41 (q, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 167.8, 158.1, 154.4, 145.0, 136.4, 129.0, 128.5, 127.0, 126.8, 125.1, 123.7, 120.8, 118.3, 112.1, 111.5, 51.6, 35.5, 33.4, 22.3, 13.9; HRMS (MALDI-TOF) Calcd for C₂₂H₂₂O₃Na [M + Na]⁺: 334.1563, Found 334.1567.

Methyl (E)-3-(5-Chloro-2-phenylbenzofuran-3-yl)acrylate (2q)

Following the typical procedure D, 1q (15.6 mg, 0.050 mmol) was converted to 2q (11.2 mg, 72%). Pale yellow needle. M.p. 89–91 °C (CHCl₃) ¹H-NMR (300 MHz, CDCl₃) δ: 7.98 (d, J = 16.2 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.75 (dd, J = 7.9, 1.7 Hz, 2H), 7.56–7.43 (m, 4H), 7.34 (dd, J = 8.8, 1.9 Hz, 1H), 6.61 (d, J = 16.2 Hz, 1H), 3.84 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ: 167.5, 158.7, 152.8, 135.4, 130.1, 129.5, 129.2, 129.0, 128.5, 128.1, 125.5, 120.6, 119.2, 112.5, 112.1, 51.8; HRMS (MALDI-TOF) Calcd for C₁₈H₁₃O₃ClNa [M + Na]⁺: 312.0548, Found 312.0540.

Methyl (E)-3-(6-Chloro-2-phenylbenzofuran-3-yl)acrylate (2r)

Following the typical procedure D, 1r (15.6 mg, 0.050 mmol) was converted to 2s (10.1 mg, 65%). Pale yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ: 7.98 (d, J = 16.0 Hz, 1H), 7.79–7.73 (m, 3H), 7.58–7.49 (m, 4H), 7.33 (dd, J = 8.4, 1.9 Hz, 1H), 6.63 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ: 167.5, 158.1, 154.6, 135.6, 131.1, 130.0, 129.2, 129.0, 128.5, 125.5, 124.5, 121.5, 119.3, 112.4, 112.2, 51.8; HRMS (MALDI-TOF) Calcd for C₁₈H₁₃O₃ClNa [M + Na]⁺: 312.0548, Found 312.0542.

Methyl (E)-3-(4-Methyl-2-phenylbenzofuran-3-yl)acrylate (2t)

Following the typical procedure D, 1t (15.6 mg, 0.050 mmol) was converted to 2t (10.1 mg, 65%). Colorless oil. ¹H-NMR (500 MHz, CDCl₃) δ: 8.12 (d, J = 16.0 Hz, 1H), 7.80–7.76 (m, 2H), 7.47 (t, J = 7.4 Hz, 2H), 7.44–7.41 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 7.7, 7.7 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.27 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H), 2.66 (s, 3H); ¹³C-NMR (125 MHz, CDCl₃) δ. ¹³C-NMR (100 MHz, CDCl₃) δ: 167.0, 154.3, 153.6, 137.2, 131.8, 130.3, 129.2, 128.8, 128.0, 126.7, 125.2, 124.9, 123.1, 113.4, 109.1, 51.7, 20.8. HRMS (MALDI-TOF) Calcd for C₁₉H₁₆O₃Na [M + Na]⁺: 292.1094, Found 292.1093.

Methyl (E)-3-(5-Methyl-2-phenylbenzofuran-3-yl)acrylate (2u)

Following the typical procedure D, 1u (14.7 mg, 0.050 mmol) was converted to 2u (9.4 mg, 64%). Colorless needle. M.p. 95–97 °C (CHCl₃) ¹H-NMR (500 MHz, CDCl₃) δ: 8.02 (d, J = 16.0 Hz, 1H), 7.76 (dd, J = 8.3, 1.4 Hz, 2H), 7.66 (s, 1H), 7.55–7.52 (m, 2H), 7.49–7.48 (m, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.19 (dd, J = 8.3, 1.4 Hz, 1H), 6.68 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H), 2.51 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.8, 157.9, 152.9, 136.4, 133.4, 129.8, 129.7, 128.9, 128.5, 126.8, 126.5, 120.9, 118.5, 112.4, 111.1, 51.7, 21.5; HRMS (MALDI-TOF) Calcd for C₁₉H₁₆O₃Na [M + Na]⁺: 292.1094, Found 292.1080.

Methyl (E)-3-(6-Methyl-2-phenylbenzofuran-3-yl)acrylate (2v)

Following the typical procedure D, 1v (14.7 mg, 0.050 mmol) was converted to 2v (11.0 mg, 75%). Colorless needle. M.p. 95–97 °C (CHCl₃) ¹H-NMR (400 MHz, CDCl₃) δ: 8.02 (d, J = 16.0 Hz, 1H), 7.74 (dd, J = 7.1, 7.1 Hz, 3H), 7.56–7.45 (m, 3H), 7.36 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.66 (d, J = 16.0 Hz, 1H), 3.83 (s, 3H), 2.51 (s, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 167.8, 157.2, 154.9, 136.3, 135.8, 129.8, 129.5, 128.9, 128.5, 125.1, 124.2, 120.5, 118.5, 112.6, 111.8, 51.7, 21.6; HRMS (MALDI-TOF) Calcd for C₁₉H₁₆O₃Na [M + Na]⁺: 292.1094, Found 292.1092.

Acknowledgments

This study was partially supported by JST, CREST Grant Number JP JPMJCR20R1, Japan, by a Grant-in-Aid from JSPS KAKENHI (Grant No. JP 15KT0063), by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP22ama121054, by Cooperative Research Program of “Network Joint Research Center for Materials and Devices” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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