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Article Cite This: J. Org. Chem. 2018, 83, 2592−2600

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Vinylogous Elimination/Heck Coupling/Allylation Domino Reactions: Access to 2‑Substituted 2,3-Dihydrobenzofurans and Indolines Jianguo Yang,*,† Hanjie Mo,† Xiuxiu Jin,† Dongdong Cao,† Haijian Wu,‡ Di Chen,† and Zhiming Wang*,†,‡ †

School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou, Zhejiang 317000, People’s Republic of China College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311400, People’s Republic of China

‡

S Supporting Information *

ABSTRACT: A highly regio- and stereoselctive palladium-catalyzed domino reaction of functionalized aryl allyl ethers has been developed. Various aryl allyl ethers derived from the phosphine-catalyzed addition of electron-deficient allenes with phenol are found to be efficient substrates for the synthesis of 2-substituted 2,3-dihydrobenzofurans and indolines. It is the first example of aryl allyl ether used as an ideal and practical precursor of hard to get functionalized 1,3-butadiene for the heterocyclic compound synthesis.

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INTRODUCTION Dihydrobenzofuran- and indoline-containing molecules are very important heterocyclic compounds that are found in numerous bioactive natural products and pharmaceuticals.1 In particular, the 2-substituted 2,3-dihydrobenzofuran and indoline derivatives play a significant role in drug discovery and organic synthesis. For example, annullations A/B can be used as cannabinoid receptor ligands,2 (−)-tremetone displays insecticidal properties,3 and (R)-indolinyglycinamide is identified as a dopamine D2/D4 receptor antagonist.4 Moreover, (S)-indoline2-carboxylic acid is used as an intermediate in the synthesis of perindopril (Figure 1).5 Because of their importance, the

optically active chiral 2-substituted indolines has also been reported by Han’s group.11 However, the reaction scope of such palladium-catalyzed annulations is relatively limited to structurally simple 1,3-dienes, and methods for extension to other complex starting materials (such as the functionalized 1,3dienes and their precursors) by using the domino strategy are highly desirable.12 On the other hand, aryl allyl ethers are important precursors in organic synthesis and have been found to be widely used in natural product total synthesis13 and aromatic Claisen rearrangement.14 However, aryl allyl ethers are not commonly used in transition-metal-catalyzed domino reactions because of their high stabilities.15 Herein, we report a general method for both 2-substituted 2,3-dihydrobenzofurans and indolines synthesis from the functionalized aryl allyl ethers through an unexpected vinylogous elimination/intermolecular Heck coupling/intramolecular allylation domino reaction sequence (Scheme 1). To our knowledge, this is the first attempt to use aryl allyl ethers as the precursors of hard to get Scheme 1. Synthesis of 2-Substituted 2,3Dihydrobenzofurans and Indolines from 1,3-Dienes and Aryl Allyl Ethers

Figure 1. Selected examples of 2-substituted 2,3-dihydrobenzofurans and indolines.

development of methods for the construction of these privileged structures has received much attention,6,7 and the new, more efficient protocols still continue to be vigorously pursued in recent years.8,9 Given the structural similarity between 2-substituted 2,3-dihydrobenzofurans and indolines, a general method to prepare them from a common precursor is particularly desired. A highly valuable approach to accessing the 2-substituted 2,3-dihydrobenzofurans or indolines is palladiumcatalyzed [3 + 2] annulation of 1,3-dienes with o-iodophenols or o-iodoanilines.10 Very recently, palladium-catalyzed heteroannulation of 1,3-dienes by o-iodoanilines for the synthesis of © 2018 American Chemical Society

Received: November 26, 2017 Published: February 8, 2018 2592

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

Article

The Journal of Organic Chemistry

We then examined the reaction scope of substrates 1 and 2 under the optimized reaction conditions. As shown in Table 2,

functionalized 1,3-dienes in palladium-catalyzed domino reactions for the construction of heterocyclic frameworks. Furthermore, unlike the other vinylogous elimination methods with strong Lewis acid or base,16 our vinylogous elimination with aryl allyl ethers can take place smoothly under mild reaction conditions, which are quite compatible with the palladium-catalyzed annulation reaction system.

Table 2. Vinylogous Elimination/Heck Coupling/Allylation Domino Reactions for the Synthesis of 2-Substituted 2,3Dihydrobenzofuransa,b

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RESULTS AND DISCUSSION To begin our study, we chose o-iodophenol 1a and ethyl (Z)-2(phenoxy(phenyl)methyl)but-2-enoate 2a, which was readily synthesized by the phosphine-catalyzed β′-addition reaction of ethyl 2-benzylbuta-2,3-dienoate and phenol,17 as reaction partners to optimize the reaction conditions by varying the catalyst, solvent, and base. The results are summarized in Table 1. Initially, 1a and 2a were stirred under typical Heck coupling Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

solvent

base

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Pd(OAc)2 PdCl2 Pd(MeCN)Cl2 Pd(PPh3)2Cl2 Pd(dppf)Cl2 Pd(dppp)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2 Pd(dppe)Cl2

DMF DMF DMF DMF DMF DMF DMF DMSO CHCl3 MeCN benzene toluene DMF DMF DMF DMF

NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 NaHCO3 Na2CO3 K2CO3 NaHCO3 NaHCO3

83 78 79 68 81 88 90 83 75 64 61 66 82 72 82c 80d

a A 0.5 mmol amount of 1 and 2, 0.025 mmol of Pd(dppe)Cl2, 1.0 mmol of NaHCO3, 0.5 mmol of n-Bu4NCl, and 2 mL of DMF at 90 °C under N2 for 8h. bIsolated yield. cReaction performed on a 4 mmol scale.

the aryl allyl ethers with either electron-rich or electrondeficient substituents on the phenyl group at the allylic position all functioned well in the domino reactions, affording the unexpected 2-substituted 2,3-dihydrobenzofurans 3a−3j in 68− 90% yields. In general, a substituent on the ortho position of the benzene ring in aryl allyl ethers exhibited better reactivity than on the para and meta positions (3b−3g and 3i−3j). The aryl allyl ether with 2-naphthyl on the allylic position also provided its desired product 3k in excellent yield. The domino reaction for the 2,3-dihydrobenzofuran synthesis tolerated methyl, ethyl, 2-methoxyethyl, chloro, bromo, trifluoromethyl, and ethoxycarbonyl groups on o-iodophenols, achieving the corresponding products in 70−94% yields. In addition, the aryl allyl ethers with methoxylcarbonyl, phenoxylcarbonyl, and nitro groups were suitable for the domino reaction with slightly lower reaction yields (3s−3u). To our delight, the palladiumcatalyzed domino cyclization could be readily carried out on 4 mmol scale, giving the desired product 3a in 86% yield. To probe the possible reaction mechanism of the vinylogous elimination/Heck coupling/allylation domino reaction, two more experiments were performed (Scheme 2). Only the vinylogous elimination product of 1,3-diene 4 could be isolated in 85% yield when the reaction mixture was stirred under the optimized reaction conditions without the palladium catalyst Pd(dppe)Cl2. The Z-stereochemistry of compound 4 was identified by NOESY. However, when 1,3-diene intermediate 4 and o-iodophenol 1a were subjuected to the optimized reaction conditions, the palladium-catalyzed [3 + 2] annulation product 3a was obtained in 92% yield.

a

A 0.5 mmol amount of 1a and 2a, 0.025 mmol of catalyst, 1.0 mmol of base, 0.5 mmol of n-Bu4NCl, and 2 mL of solvent at 90 °C under N2 for 8 h. bIsolated yield. cA 0.05 mmol amount of Pd(dppe)Cl2 was used. dA 0.6 mmol amount of 1a was used.

condition [5 mol % Pd(OAc)2, NaHCO3, and n-Bu4NCl in DMF under N2 at 90 °C], affording the unexpected domino reaction product 3a in 83% yield with E stereoselectivity (entry 1). The structure of compound 3a was unequivocally confirmed by X-ray crystallographic analysis.18 Further studies demonstrated that Pd(dppe)Cl2 was the optimal catalyst for this domino process (entries 1−7). Subsequently, we examined the effect of solvents. The slightly lower yields of 3a were obtained when using DMSO, CHCl3, MeCN, benzene, or toluene as the solvent (cf. entry 7 vs entries 8−12). When Na2CO3 and K2CO3 were applied as the base, 82−72% yields of 3a were achieved (entries 13 and 14). Moreover, increasing the catalyst loading or amount of 1a did not improve the reaction outcome (entries 15 and 16). Thus, the combination of 1a (1.0 equiv), 2a (1.0 equiv), Pd(dppe)Cl2 (5 mol %), n-Bu4NCl (1.0 equiv), and NaHCO3 (2.0 equiv) in DMF at 90 °C was chosen as the optimal reaction conditions, providing 3a in 90% yield (entry 7). 2593

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

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The Journal of Organic Chemistry

stereoselectivity of the C−C double bond in the product 3a is probably due to the steric clash between the phenyl and the ester groups.23 Encouraged by the results described above, we decided to apply this new domino reaction for the synthesis of 2substituted indolines (Table 3). Gratifyingly, various function-

Scheme 2. Mechanistic Studies

Table 3. Vinylogous Elimination/Heck Coupling/Allylation Domino Reactions for the Synthesis of 2-Substituted Indolinesa,b

Significantly, 1,3-butadienes are common structure units, and they can be prepared in a lot of different ways. However, the only reported practical preparation of the functionalized 1,3diene 4 and its analogs is the condensation of crotonic anhydride with the corresponding aromatic aldehydes followed by esterification in low reaction yields (two steps, 10−28% overall yields).19 Similarly, the 1-phenyl-2-cyano-1,3-butadiene (the intermediate of 3u) can be obtained through a five-step process from 3-cyanopropyltrimethylammonium chloride and benzaldehyde in the presence of 3.0 equiv of tert-butoxide and 3.0 equiv of methyl iodide in 42% yield.20 In sharp contrast, our aryl allyl ethers (2) seem to be ideal and practical precursors of the hard to get functionalized 1,3-butadienes, such as ethyl 1phenyl-1,3-butadiene-2-carboxylate (4) and its derivatives. Because with using the aryl allyl ether 2a as an intermediate, the hard to get functionalized 1,3-butadiene 4 can be easily prepared from the readily available ethyl 2-benzybuta-2,3dienoate21 and phenol through a phosphine-catalyzed addition followed by vinylogous elimination reaction (two steps, 82% overall yield). Thus, our vinylogous elimination/intermolecular Heck coupling/intramolecular allylation domino reaction based on the aryl allyl ethers (2) turns out to be an efficient synthetic strategy for the construction of the functionalized 2,3dihydrobenzofurans with the electro-deficient alkene substituents on the 2 position (3). According to these insights and the reported literature,10,22 a possible mechanism is proposed in Scheme 3. It was initiated

a

A 0.5 mmol amount of 2 and 5, 0.025 mmol of Pd(dppe)Cl2, 1.0 mmol of NaHCO3, 0.5 mmol of n-Bu4NCl, and 2 mL of DMF at 90 °C under N2 for 8h. bIsolated yield.

Scheme 3. Possible Mechanism for the Vinylogous Elimination/Heck Coupling/Allylation Domino Reaction of Functionalized Aryl Allyl Ethers

alized aryl allyl ethers with different substituents reacted well with tosyl-protected o-iodoaniline under optimized reaction conditions (6a−6o). All of the products were performed in moderate to good yields (65−86%). The aryl allyl ethers bearing electron-withdrawing groups on the benzene ring at the allylic position showed slightly better reaction efficiency than those having electron-donating groups. The aryl allyl ethers with methoxylcarbonyl, phenoxylcarbonyl, and cyano groups were suitable for the vinylogous elimination/Heck coupling/ allylation domino reaction (6m-6o). To expand the reaction scope, different kinds of o-iodoanilines were further examined (6p−6z). When o-iodoanilines with methyl, ethyl, tert-butyl, chloro, bromo, trifluoromethyl, ethoxylcarbonyl, and acetyl groups were used, the corresponding products were achieved in 69−90% yields. In addition, o-iodoanilines with mesyl, benzyl, and methyl protecting groups all functioned well in the domino reaction, albeit with slightly lower reaction yields. Furthermore, the structures of compounds 6t and 6w were unequivocally confirmed by X-ray crystallographic analysis.18

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by palladium(0) oxidative addition of 1a to generate the intermediate I, which was then captured by the vinylogous elimination intermediate 4 to lead to allyl palladium complex II. The isomerization of II gave the π-allylpalladium intermediates IIIa and IIIb, which would undergo nucleophilic attack and reductive elimination to afford the final product 3a. The E-

CONCLUSIONS In conclusion, a new vinylogous elimination/Heck coupling/ allylation domino reaction based on functionalized aryl allyl ethers has been developed. It is the first attempt to use the functionalized aryl allyl ethers as ideal and practical precursors 2594

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

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The Journal of Organic Chemistry

NMR (100 MHz, CDCl3) δ 166.4, 157.8, 138.7, 138.2, 133.8, 132.8, 129.5, 128.8, 128.7, 121.4, 116.0, 78.4, 60.6, 15.6, 14.2. Ethyl (IZ)-2-((3-Chlorophenyl)(phenoxy)methyl)but-2-enoate (2f). 90% yield, 302 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.30−7.20 (m, 5H), 6.91−6.89 (m, 3H), 6.25 (qd, J = 7.2, 0.8 Hz, 1H), 6.07 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 2.03 (dd, J = 7.2, 0.8 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 157.7, 141.8, 139.1, 134.4, 132.6, 129.8, 129.5, 128.1, 127.4, 125.5, 121.4, 116.0, 78.3, 60.6, 15.6, 14.2. Ethyl (IZ)-2-((2-Chlorophenyl)(phenoxy)methyl)but-2-enoate (2g). 93% yield, 310 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.51−7.49 (m, 1H), 7.40−7.37 (m, 1H), 7.26−7.21 (m, 4H), 6.92− 6.87 (m, 3H), 6.51 (s, 1H), 5.95 (q, J = 7.2 Hz, 1H), 4.26−4.16 (m, 2H), 2.03 (d, J = 7.63 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 157.9, 139.8, 136.5, 133.3, 131.8, 129.6, 129.4, 129.3, 129.0, 127.1, 121.1, 115.7, 76.0, 60.6, 15.6, 14.1. Ethyl (IZ)-2-((4-Bromophenyl)(phenoxy)methyl)but-2-enoate (2h). 89% yield, 331 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7. 46 (d, J = 6.8 Hz, 2H), 7.28 (d, J = 6.8 Hz, 2H), 7.23−7.19 (m, 2H), 6.93−6.88 (m, 3H), 6.25 (qd, J = 7.2, 1.2 Hz, 1H), 6.06 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.02 (dd, J = 7.2, 1.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 157.7, 138.8, 138.7, 132.7, 131.6, 129.4, 129.1, 121.9, 121.4, 116.0, 78.4, 60.6, 15.6, 14.2. Ethyl (iZ)-2-((4-Fluorophenyl)(phenoxy)methyl)but-2-enoate (2i). 92% yield, 292 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.39−7.35 (m, 2H), 7.24−7.20 (m, 2H), 7.04−6.99 (m, 2H), 6.93− 6.89 (m, 3H), 6.25 (q, J = 7.2 Hz, 1H), 6.08 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.02 (d, J = 7.2 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 162.4 (d, J = 245.0 Hz), 157.8, 138.3, 135.3 (d, J = 3.1 Hz), 132.9, 129.4, 129.2 (d, J = 8.1 Hz), 121.3, 116.0, 115.4 (d, J = 21.4 Hz), 78.4, 60.5, 15.5, 14.2. Ethyl (Z)-2-((2-Fluorophenyl)(phenoxy)methyl)but-2-enoate (2j). 90% yield, 280 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.44 (td, J = 7.6, 1.6 Hz, 1H), 7.24−7.18 (m, 3H), 7.11−7.08 (m, 1H), 7.05−7.00 (m, 1H), 6.94−6.88 (m, 3H), 6.45 (s, 1H), 6.23 (q, J = 7.2 Hz, 1H), 4.21−4.14 (m, 2H), 2.04 (dd, J = 7.2, 1.2 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 160.3 (d, J = 246.0 Hz), 157.8, 138.9, 131.9, 129.8 (d, J = 8.2 Hz), 129.4, 129.0 (d, J = 3.6 Hz), 126.5 (d, J = 13.5 Hz), 124.3 (d, J = 3.5 Hz), 121.3, 115.8, 115.4 (d, J = 21.7 Hz), 72.7 (d, J = 2.9 Hz), 60.5, 15.5, 14.1. Ethyl (Z)-2-(Naphthalen-2-yl(phenoxy)methyl)but-2-enoate (2k). 93% yield, 321 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.82−7.77 (m, 3H), 7.51 (dd, J = 8.4, 1.6 Hz, 1H), 7.46−7.41 (m, 2H), 7.22−7.18 (m, 2H), 6.96 (d, J = 8.0 Hz, 2H), 6.88 (t, J = 7.6 Hz, 1H), 6.29 (s, 1H), 6.24 (q, J = 7.2 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.01 (dd, J = 7.2, 0.8 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 158.1, 138.8, 136.9, 133.3, 133.2, 129.4, 128.4, 128.2, 127.8, 126.5, 126.2, 126.1, 125.2, 121.2, 116.1, 79.3, 60.6, 15.6, 14.2. Methyl (Z)-2-(Phenoxy(phenyl)methyl)but-2-enoate (2l). 90% yield, 250 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.41− 7.38 (m, 2H), 7.35−7.32 (m, 2H), 7.29−7.27 (m, 1H), 7.23−7.19 (m, 2H), 6.92−6.90 (m, 3H), 6.26 (qd, J = 7.2, 0.8 Hz, 1H), 6.11 (s, 1H), 3.74 (s, 3H), 2.01 (dd, J = 7.6, 0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 157.9, 139.4, 138.8, 132.9, 129.4, 128.5, 128.0, 127.3, 121.1, 116.0, 78.9, 51.4, 15.6. (E)-2-(Phenoxy(phenyl)methyl)but-2-enenitrile (2m). 85% yield, 211 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.2 Hz, 2H), 7.39−7.29 (m, 3H), 7.24−7.20 (m, 2H), 6.96−6.90 (m, 3H), 6.51 (q, J = 7.2 Hz, 1H), 5.66 (s, 1H), 1.99 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.1, 144.6, 137.6, 129.6, 129.0, 128.8, 126.7, 122.0, 117.9, 116.5, 115.7, 79.9, 17.0. Benzyl (Z)-2-(Phenoxy(phenyl)methyl)but-2-enoate (2n). 85% yield, 300 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.32−7.16 (m, 10H), 6.90−6.87 (m, 3H), 6.23 (q, J = 7.2 Hz, 1H), 6.13 (s, 1H), 5.17 (s, 2H), 2.01 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 158.0, 139.4, 139.3, 135.8, 132.9, 129.4, 128.6, 128.5, 128.2, 128.1, 128.0, 127.5, 121.2, 116.0, 79.0, 66.4, 15.7.

of hard to get functionalized 1,3-butadienes for the heterocyclic compound formation. A myriad of aryl allyl ethers readily obtained from the nucleophilic phosphine-catalyzed β′-addition of electron-deficient allenes with phenol are found to be efficient starting materials for producing the 2-substituted 2,3dihydrobenzofurans and indolines in good to excellent yields. The facile and efficient methodology appears to be a useful tool for the synthesis of biologically important 2,3-dihydrobenzofuran and indoline derivatives.

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EXPERIMENTAL SECTION

General Information. All reactions were performed under a N2 atmosphere in oven-dried glassware with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Toluene and benzene were freshly distilled from CaH2. 1H and 13C NMR spectra were recorded in CDCl3 using a Bruker Avance 400 MHz NMR spectrometer (referenced internally to Me4Si). Accurate mass measurements were performed using a Varian instrument with the TOF EI-MS technique. Melting points were determined using a X-4 digital micromelting point apparatus. X-ray crystallographic data were collected using a Bruker Smart Apex CCD apparatus. Aryl allyl ethers 2 were prepared following reported methods.17 General Procedure for the Synthesis of Substrates 2. An oven-dried Schlenk tube was charged with phenol (1.0 mmol) and PPh3 (0.2 mmol) under N2. Distilled benzene (2 mL) was added via syringe. The mixture was stirred at 80 °C. Finally, the corresponding allene (1.2 mmol) was weighed in a syringe, mixed with distilled benzene (1 mL), and added dropwise to the reaction mixture over 3 h. The reaction was left to proceed until the phenol was consumed, typically 12 h (TLC, 40:1 petroleum ether/EtOAc). The crude reaction mixture was concentrated and loaded onto a silica gel column and separated chromatographically (Petroleum ether/EtOAc, 40:1) to give the desired substrate (2). Ethyl (Z)-2-(Phenoxy(phenyl)methyl)but-2-enoate (2a). 94% yield, 282 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.41− 7.38 (m, 2H), 7.34−7.30 (m, 2H), 7.28−7.24 (m, 1H), 7.22−7.18 (m, 2H), 6.92−6.87 (m, 3H), 6.21 (qd, J = 7.2, 1.2 Hz, 1H), 6.11 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.00 (dd, J = 7.2, 1.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 158.0, 139.5, 138.4, 133.2, 129.4, 128.5, 128.0, 127.4, 121.1, 116.0, 79.1, 60.5, 15.6, 14.2. Ethyl (Z)-2-(Phenoxy(p-tolyl)methyl)but-2-enoate (2b). 96% yield, 301 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J = 8.0 Hz, 2H), 7.21−7.17 (m, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.92−6.86 (m, 3H), 6.20 (qd, J = 7.2, 0.8 Hz, 1H), 6.08 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.00 (dd, J = 7.2, 0.8 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 158.1, 138.1, 137.7, 136.4, 133.3, 129.4, 129.2, 127.4, 121.0, 116.0, 78.9, 60.5, 21.2, 15.5, 14.2. Ethyl (Z)-2-(Phenoxy(m-tolyl)methyl)but-2-enoate (2c). 92% yield, 282 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.16− 7.11 (m, 5H), 7.00 (d, J = 6.8 Hz, 1H), 6.84−6.80 (m, 3H), 6.12 (q, J = 7.2 Hz, 1H), 6.00 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 2.25 (s, 3H), 1.93 (d, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 157.0, 138.3, 137.2, 137.0, 132.2, 128.3, 127.7, 127.3, 127.0, 123.4, 120.0, 114.9, 78.0, 59.4, 20.4, 14.5, 13.1. Ethyl (Z)-2-(Phenoxy(o-tolyl)methyl)but-2-enoate (2d). 94% yield, 291 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.31−7.29 (m, 1H), 7.10−7.05 (m, 5H), 6.79−6.75 (m, 3H), 6.19 (s, 1H), 5.86 (q, J = 7.2 Hz, 1H), 4.14−4.04 (m, 2H), 2.21 (s, 3H), 1.89 (d, J = 7.2 Hz, 3H), 1.07 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 158.4, 138.8, 136.9, 136.0, 132.2, 130.6, 129.4, 128.0, 127.3, 126.3, 121.1, 115.8, 76.7, 60.5, 19.2, 15.5, 14.2. Ethyl (Z)-2-((4-Chlorophenyl)(phenoxy)methyl)but-2-enoate (2e). 95% yield, 310 mg; colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.02 Hz, 2H), 7.21−7.17 (m, 2H), 6.90−6.87 (m, 3H), 6.25 (q, J = 7.2 Hz, 1H), 6.09 (s, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.01 (d, J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); 13C 2595

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

Article

The Journal of Organic Chemistry General Procedure for the Synthesis of 2,3-Dihydrobenzofuran or Indoline Products 3 or 6 from Substrates 1, 2, and 5. An oven-dried Schlenk tube was charged with 1 or 5 (0.5 mmol), 2 (0.5 mmol), Pd(dppe)Cl2 (0.025 mmol), n-Bu4NCl (0.5 mmol), NaHCO3 (1.0 mmol), and dry DMF (5 mL) under N2. The mixture was stirred at 90 °C for 8 h and monitored by TLC. Finally, EtOAc (5 mL) and H2O (5 mL) were added, and the solution was partitioned. The aqueous layer was washed with EtOAc, and EtOAc extracts were washed sequentially with water and saturated NaCl solution. The combined extracts were dried (Na2SO4), and the crude reaction mixture was concentrated and loaded onto a silica gel column and separated chromatographically (petroleum ether/EtOAc, 20:1) to give the desired product (3 or 6). (E)-Ethyl-2-(2,3-dihydrobenzofuran-2-yl)-3-phenyl acrylate (3a). 90% yield, 132 mg; white solid; mp 75−76 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.41−7.35 (m, 5H), 7.15 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.81 (dd, J = 10.4, 8.8 Hz, 1H), 4.17−4.09 (m, 2H), 3.52 (dd, J = 15.2, 8.8 Hz, 1H), 3.42 (dd, J = 15.2, 10.4 Hz, 1H), 0.97 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 159.8, 142.5, 134.4, 131.9, 129.2, 129.0, 128.6, 127.8, 127.3, 124.4, 120.2, 109.0, 77.6, 60.8, 35.9, 13.6; IR (neat) 3019, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C19H18O3+ (M+) 294.1250, found 294.1254. (E)-Ethyl-2-(2,3-dihydrobenzofuran-2-yl)-3-(p-tolyl)acrylate (3b). 82% yield, 126 mg; white solid; mp 77−78 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 5.84 (dd, J = 10.4, 8.4 Hz, 1H), 4.16−4.08 (m, 2H), 3.51 (dd, J = 15.2, 8.4 Hz, 1H), 3.40 (dd, J = 15.2, 10.4 Hz, 1H), 2.37 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 159.8, 142.7, 139.3, 131.5, 131.1, 129.3, 129.2, 127.8, 127.4, 124.4, 120.2, 109.0, 77.6, 60.7, 35.9, 21.3, 13.6; IR (neat) 3019, 1705, 1481, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C20H20O3 (M+) 308.1407, found 308.1415. (E)-Ethyl-2-(2,3-dihydrobenzofuran-2-yl)-3-(m-tolyl)acrylate (3c). 84% yield, 129 mg; white solid; mp 85−86 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.19−7.15 (m, 4H), 7.10 (t, J = 8.0 Hz, 1H), 6.83 (td, J = 7.2, 0.8 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.83 (dd, J = 10.4, 8.4 Hz, 1H), 4.16−4.10 (m, 2H), 3.51 (dd, J = 15.2, 8.4 Hz, 1H), 3.42 (dd, J = 15.2, 10.4 Hz, 1H), 2.36 (s, 3H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 159.8, 142.8, 138.2, 134.4, 131.6, 129.9, 129.8, 128.4, 127.8, 127.4, 126.3, 124.4, 120.2, 109.0, 77.6, 60.8, 35.9, 21.4, 13.56; IR (neat) 3019, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C20H20O3+ (M+): 308.1407, found 308.1408. (E)-ethyl-2-(2,3-dihydrobenzofuran-2-yl)-3-(o-tolyl)acrylate (3d). 87% yield, 134 mg; white solid; mp 86−87 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.29−7.06 (m, 6H), 6.81 (td, J = 7.6, 0.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.64 (dd, J = 10.4, 8.4 Hz, 1H), 4.19− 4.08 (m, 2H), 3.50 (dd, J = 15.2, 8.4 Hz, 1H), 3.37 (dd, J = 15.2, 10.4 Hz, 1H), 2.35 (s, 3H), 0.96 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 159.8, 142.3, 137.0, 133.8, 132.2, 130.2, 129.0, 128.9, 127.8, 127.4, 125.8, 124.4, 120.2, 109.0, 77.8, 60.8, 35.9, 20.1, 13.5; IR (neat) 3019, 2399, 1701, 1470, 760 cm−1. HRMS (TOF EI): m/z calcd for C20H20O3+ (M+): 308.1407, found 308.1413. (E)-Ethyl-3-(4-chlorophenyl)-2-(2,3-dihydrobenzofuran-2-yl)acrylate (3e). 72% yield, 118 mg; white solid; mp 88−89 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.37 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.16−7.08 (m, 2H), 6.84 (t, J = 7.2 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.74 (t, J = 9.6 Hz, 1H), 4.16−4.11 (m, 2H), 3.49 (dd, J = 15.2, 9.6 Hz, 1H), 3.41 (dd, J = 15.2, 9.6 Hz, 1H), 0.99 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 159.7, 141.1, 135.1, 132.9, 132.5, 130.5, 128.8, 127.9, 127.1, 124.4, 120.4, 109.1, 77.4, 60.9, 35.9, 13.6; IR (neat) 3019, 1717, 1481, 1215, 1015, 758 cm−1. HRMS (TOF EI): m/z calcd for C19H17ClO3+ (M+) 328.0861, found 328.0869. (E)-Ethyl-3-(3-chlorophenyl)-2-(2,3-dihydrobenzofuran-2-yl)acrylate (3f). 82% yield, 134 mg; white solid; mp 91−92 °C; 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.33−7.32 (m, 3H), 7.24−7.21 (m, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.83 (t, J = 7.2

Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.73 (dd, J = 10.4, 8.4 Hz, 1H), 4.18−4.10 (m, 2H), 3.50 (dd, J = 15.2, 8.4 Hz, 1H), 3.42 (dd, J = 15.2, 10.4 Hz, 1H), 0.99 (t, J = 7 0.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 159.7, 140.6, 136.2, 134.6, 133.3, 129.8, 129.1, 129.0, 127.9, 127.2, 127.1, 124.5, 120.4, 109.1, 77.4, 61.0, 36.0, 13.6; IR (neat) 3019, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C19H17ClO3+ (M+) 328.0861, found 328.0870. (E)-Ethyl-3-(2-chlorophenyl)-2-(2,3-dihydrobenzofuran-2-yl)acrylate (3g). 90% yield, 148 mg; white solid; mp 76−77 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.32−7.24 (m, 3H), 7.13 (d, J = 7.2 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.62 (dd, J = 10.4, 8.4 Hz, 1H), 4.19−4.13 (m, 2H), 3.49 (dd, J = 15.2, 8.4 Hz, 1H), 3.34 (dd, J = 15.2, 10.4 Hz, 1H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 159.7, 139.8, 134.1, 133.3, 133.2, 130.4, 130.1, 129.7, 127.8, 127.2, 126.6, 124.4, 120.3, 109.0, 77.9, 61.0, 35.8, 13.6; IR (neat) 3019, 1215, 756, 669 cm−1. HRMS (TOF EI): m/z calcd for C19H17ClO3+ (M+) 328.0861, found 328.0866. (iE)-Ethyl-3-(4-bromophenyl)-2-(2,3-dihydrobenzofuran-2-yl)acrylate (3h). 68% yield, 126 mg; white solid. mp 90−91 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 7.2 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.84 (td, J = 7.6, 0.8 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.74 (dd, J = 8.4 Hz, 1H), 4.16−4.10 (m, 2H), 3.49 (dd, J = 15.2, 8.4 Hz, 1H), 3.41 (dd, J = 15.2, 10.4 Hz, 1H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 159.6, 141.2, 133.3, 132.5, 131.8, 130.8, 127.9, 127.1, 124.5, 123.4, 120.4, 109.1, 77.4, 61.0, 35.9, 13.6; IR (neat) 3019, 1715, 1636, 1481, 1215, 1011, 758 cm−1. HRMS (TOF EI): m/z calcd for C19H17BrO3+ (M+) 372.0356, found 372.0359. (E)-Ethyl-2-(2,3-dihydrobenzofuran-2-yl)-3-(4-fluorophenyl)acrylate (3i). 78% yield, 122 mg; white solid; mp 76−77 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.37−7.33 (m, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.11−7.07 (m, 3H), 6.84 (t, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.77 (dd, J = 10.4, 8.4 Hz, 1H), 4.16−4.10 (m, 2H), 3.50 (dd, J = 15.2, 8.4 Hz, 1H), 3.41 (dd, J = 15.2, 10.4 Hz, 1H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 163.0 (d, J = 248.9 Hz), 159.7, 141.4, 131.8, 131.3 (d, J = 8.2 Hz), 130.5 (d, J = 3.6 Hz), 127.9, 127.2, 124.5, 120.3, 115.7 (d, J = 22.4 Hz), 109.1, 77.4, 60.9, 35.8, 13.6; IR (neat) 3019, 2357, 1506, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C19H17FO3+ (M+) 312.1156, found 312.1161. (E)-Ethyl-2-(2,3-dihydrobenzofuran-2-yl)-3-(2-fluorophenyl)acrylate (3j). 87% yield, 136 mg; white solid; mp 67−68 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.38−7.31 (m, 2H), 7.19−7.07 (m, 4H), 6.83 (td, J = 7.2, 0.8 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 5.68 (t, J = 9.4 Hz, 1H), 4.18−4.12 (m, 2H), 3.52 (dd, J = 15.2, 9.4 Hz, 1H), 3.44 (dd, J = 15.2, 9.4 Hz, 1H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 160.2 (d, J = 248.5 Hz), 159.7, 135.6 (d, J = 2.9 Hz), 133.73, 131.0 (d, J = 8.7 Hz), 130.7 (d, J = 3.9 Hz), 127.8, 127.3, 124.4, 124.1 (d, J = 3.0 Hz), 122.4 (d, J = 14.5 Hz), 120.3, 115.8 (d, J = 21.5 Hz), 109.0, 78.0, 61.0, 35.6, 13.6; IR (neat) 3019, 1717, 1481, 1215, 758 cm−1. HRMS (TOF EI): m/z calcd for C19H17FO3+ (M+): 312.1156, found 312.1162. (iE)-Ethyl-2-(2,3-dihydrobenzofuran-2-yl)-3-(naphthalen-2-yl)acrylate (3k). 90% yield, 155 mg; white solid; mp 124−125 °C; 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.88−7.84 (m, 4H), 7.54− 7.46 (m, 3H), 7.17 (d, J = 6.8 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.84 (td, J = 7.6, 0.8 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.93 (dd, J = 10.4, 8.4 Hz, 1H), 4.20−4.14 (m, 2H), 3.56 (dd, J = 15.2, 8.4 Hz, 1H), 3.47 (dd, J = 15.2, 10.4 Hz, 1H),1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 159.8, 142.7, 133.2, 132.9, 131.9, 131.8, 129.1, 128.4, 128.2, 127.8, 127.7, 127.3, 127.0, 126.7, 126.5, 124.4, 120.2, 109.1, 77.7, 60.9, 35.9, 13.6; IR (neat) 3019, 1215, 756, 669 cm−1. HRMS (EI): m/z calcd for C23H20O3+ (M+) 344.1407, found 344.1409. (E)-Ethyl-2-(5-methyl-2,3-dihydrobenzofuran-2-yl)-3-phenyl acrylate (3l). 79% yield, 122 mg; white solid; mp 101−102 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.42−7.34 (m, 5H), 6.96 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.78 (dd, J = 10.4, 8.8 Hz, 1H), 4.20−4.09 (m, 2H), 3.49 (dd, J = 15.2, 8.8 Hz, 1H), 2596

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

Article

The Journal of Organic Chemistry

MHz, CDCl3) δ 7.92 (s, 1H), 7.43−7.35 (m, 5H), 7.16 (dd, J = 6.8, 0.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.84 (td, J = 7.6, 0.4 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.79 (dd, J = 10.0, 9.0 Hz, 1H), 3.71 (s, 3H), 3.56 (dd, J = 15.2, 9.0 Hz, 1H), 3.38 (dd, J = 15.2, 10.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.6, 159.6, 143.0, 134.3, 131.2, 129.2, 129.1, 128.6, 127.8, 127.2, 124.5, 120.3, 109.1, 77.8, 51.9, 35.7; IR (neat) 3019, 1717, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C18H16O3+ (M+) 280.1094, found 280.1098. (E)-Phenyl-2-(2,3-dihydrobenzofuran-2-yl)-3-phenyl acrylate (3t). 69% yield, 118 mg; white solid; mp 149−150 °C ; 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.46−7.40 (m, 5H), 7.34−7.30 (m, 2H), 7.21−7.15 (m, 2H), 7.09 (t, J = 8.0 Hz, 1H), 7.01−6.99 (m, 2H), 6.84−6.76 (m, 2H), 5.90 (dd, J = 10.4, 8.8 Hz, 1H), 3.69 (dd, J = 15.2, 8.8 Hz, 1H), 3.49 (dd, J = 15.2, 10.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.7, 159.6, 150.6, 144.2, 134.1, 131.1, 129.4, 129.3, 129.3, 128.7, 127.9, 127.1, 125.7, 124.6, 121.4, 120.4, 109.1, 77.6, 35.8; IR (neat) 3019, 1215, 756, 669 cm−1. HRMS (TOF EI): m/z calcd for C23H18O3+ (M+) 342.1250, found 342.1259. (Z)-2-(2,3-Dihydrobenzofuran-2-yl)-3-phenylacrylonitrile (3u). 70% yield, 86 mg; white solid; mp 93−94 °C; 1H NMR (400 MHz, CDCl3) δ 7.79−7.77 (m, 2H), 7.43−7.42 (m, 3H), 7.28 (s, 1H), 7.20−7.15 (m, 2H), 6.93−6.87 (m, 2H), 5.41 (t, J = 9.2 Hz, 1H), 3.56 (dd, J = 15.4, 9.2 Hz, 1H), 3.38 (dd, J = 15.4, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 158.8, 144.2, 132.7, 130.9, 129.2, 129.0, 128.5, 125.3, 125.0, 121.5, 116.6, 111.3, 109.6, 82.5, 35.7; IR (neat) 3019, 1478, 1215, 758, 690, 669 cm−1. HRMS (TOF EI): m/z calcd for C17H13NO+ (M+) 247.0992, found 247.1001. (E)-Ethyl 3-Phenyl-2-(1-tosylindolin-2-yl)acrylate (6a). 86% yield, 192 mg; white solid; mp 144−145 °C; 1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.46−7.45 (m, 3H), 7.34−7.32 (m, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.04−6.91 (m, 6H), 5.06 (t, J = 8.0 Hz, 1H), 4.16−4.01 (m, 2H), 3.24 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H), 0.92 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 143.6, 142.7, 141.2, 135.2, 133.4, 133.3, 131.1, 129.3, 128.9, 128.5, 128.4, 127.5, 127.3, 124.4, 123.8, 115.6, 60.7, 57.6, 35.8, 21.5, 13.4; IR (neat) 3050, 2980, 1708, 1635, 1309, 1244, 1112, 754 cm−1. HRMS (TOF EI): m/z calcd for C26H25NO4S (M+): 447.1499. Found, 447.1516. (E)-Ethyl 3-(p-Tolyl)-2-(1-tosylindolin-2-yl)acrylate (6b). 75% yield, 173 mg; white solid; mp 171−172 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.67 (d, J = 12.0 Hz, 1H), 7.24−7.16 (m, 5H), 7.05−6.92 (m, 6H), 5.11 (dd, J = 12.0, 8.0 Hz, 1H), 4.14−4.00 (m, 2H), 3.23 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.30 (s, 3H), 0.92 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 143.5, 142.7, 141.3, 138.6, 133.7, 132.7, 132.3, 131.1, 129.2, 129.1, 129.0, 127.5, 127.3, 124.3, 123.7, 115.5, 60.6, 57.6, 35.7, 21.4, 21.3, 13.4; IR (neat) 3050, 2987, 1712, 1635, 1355, 1296, 1165, 759 cm−1.. HRMS (TOF EI): m/z calcd for C27H27NO4S (M+): 461.1655. Found, 461.1665. (E)-Ethyl 3-(m-Tolyl)-2-(1-tosylindolin-2-yl)acrylate (6c). 65% yield, 150 mg; white solid; mp 113−114 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.19−7.10 (m, 3H), 7.04−6.93 (m, 6H), 5.11 (t, J = 8.0 Hz, 1H), 4.15−4.01 (m, 2H), 3.22 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H), 2.29 (s, 3H), 0.92 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 143.6, 142.7, 141.3, 138.1, 135.1, 133.5, 133.2, 131.1, 129.6, 129.28, 129.24, 128.3, 127.5, 127.3, 126.0, 124.4, 123.8, 115.6, 60.7, 57.6, 35.8, 21.4, 13.4; IR (neat) 3050, 2978, 1720, 1479, 1352, 1207, 1172, 752 cm−1. HRMS (TOF EI): m/z calcd for C27H27NO4S (M+): 461.1655. Found, 461.1669. (E)-Ethyl 3-(o-Tolyl)-2-(1-tosylindolin-2-yl)acrylate (6d). 68% yield, 157 mg; white solid; mp 138−139 °C; 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.37−7.34 (m, 2H), 7.20−7.15 (m, 2H), 7.02−6.95 (m, 3H), 6.91−6.86 (m, 4H), 4.94 (t, J = 8.0 Hz, 1H), 4.16−4.01 (m, 2H), 3.17 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H), 2.27 (s, 3H), 0.89 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9, 143.5, 142.7, 141.5, 138.0, 134.6, 133.4, 131.3, 130.2, 129.2, 128.6, 128.5, 127.4, 127.2, 125.3, 124.3, 123.8, 115.9, 60.7, 57.7, 35.7, 21.4, 19.9, 13.3; IR (neat) 3061, 2983, 1718, 1481, 1359, 1257, 1170, 758 cm−1. HRMS (TOF EI): m/z calcd for C27H27NO4S (M+): 461.1655. Found, 461.1638.

3.36 (dd, J = 15.2, 10.4 Hz, 1H), 2.27 (s, 3H), 1.02 (t, J = 6.8 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 166.4, 157.7, 142.3, 134.5, 132.0, 129.4, 129.2, 128.9, 128.5, 128.1, 127.3, 125.0, 108.5, 77.7, 60.8, 36.0, 20.8, 13.7; IR (neat) 3019, 1709, 1493, 1263, 758 cm−1. HRMS (TOF EI): m/z calcd for C20H20O3+ (M+) 308.1407, found 308.1408. (E)-Ethyl-2-(5-ethyl-2,3-dihydrobenzofuran-2-yl)-3-phenyl acrylate (3m). 90% yield, 145 mg; white solid; mp 38−39 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.43−7.35 (m, 5H), 6.99 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.79 (dd, J = 10.4, 8.4 Hz, 1H), 4.18−4.10 (m, 2H), 3.50 (dd, J = 15.2, 8.4 Hz, 1H), 3.38 (dd, J = 15.2, 10.4 Hz, 1H), 2.57(q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 157.8, 142.4, 136.2, 134.4, 131.9, 129.2, 129.0, 128.5, 127.3, 127.0, 123.9, 108.6, 77.6, 60.8, 36.0, 28.4, 16.3, 13.6; IR (neat) 3053, 2986, 2305, 1711, 1491, 1206, 895, 739 cm−1. HRMS (TOF EI): m/z calcd for C21H22O3+ (M+) 322.1563, found 322.1566. (E)-Ethyl-2-(5-(2-methoxyethyl)-2,3-dihydrobenzofuran-2-yl)-3phenyl acrylate (3n). 76% yield, 134 mg; white solid; mp 62−63 °C; 1 H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.43−7.35 (m, 5H), 7.02 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 5.80 (dd, J = 10.4, 8.8 Hz, 1H), 4.18−4.10 (m, 2H), 3.56−3.47 (m, 3H), 3.38 (dd, J = 15.2, 10.4 Hz, 1H), 3.35 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 0.98 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 158.4, 142.5, 134.4, 131.8, 130.6, 129.2, 129.0, 128.6, 128.2, 127.5, 124.9, 108.7, 77.7, 74.3, 60.8, 58.6, 35.9, 35.7, 13.6; IR (neat) 3019, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C22H24O4 +(M+) 352.1669, found 352.1671. (E)-Ethyl-2-(5-chloro-2,3-dihydrobenzofuran-2-yl)-3-phenyl acrylate (3o). 70% yield, 115 mg; white solid; mp 111−112 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.44−7.33 (m, 5H), 7.11 (t, J = 0.8 Hz, 1H), 7.06 (dd, J = 8.4. 2.0 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 5.83 (dd, J = 10.4, 8.4 Hz, 1H), 4.18−4.12 (m, 2H), 3.50 (dd, J = 15.2, 8.4 Hz, 1H), 3.40 (dd, J = 15.2, 10.4 Hz, 1H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 158.6, 143.0, 134.2, 131.3, 129.4, 129.2, 129.1, 128.6, 127.7, 124.8, 124.6, 109.8, 78.3, 60.9, 35.8, 13.7; IR (neat) 3019, 1215, 758, 669 cm−1. HRMS (TOF EI): m/z calcd for C19H17ClO3+ (M+) 328.0861, found 328.0864. (E)-Ethyl-2-(5-bromo-2,3-dihydrobenzofuran-2-yl)-3-phenyl acrylate (3p). 75% yield, 140 mg; white solid; mp 109−110 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.42−7.33 (m, 5H), 7.25 (s, 1H), 7.19 (dd, J = 8.4, 1.6 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 5.83 (dd, J = 10.4, 8.4 Hz, 1H), 4.18−4.11 (m, 2H), 3.51 (dd, J = 15.2, 8.4 Hz, 1H), 3.40 (dd, J = 15.2, 10.4 Hz, 1H), 1.03 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 159.1, 143.0, 134.2, 131.3, 130.6, 130.0, 129.2, 129.1, 128.6, 127.4, 111.9, 110.5, 78.2, 60.9, 35.7, 13.7; IR (neat) 3019, 1707, 1477, 1215, 756 cm−1. HRMS (TOF EI): m/z calcd for C19H17BrO3+ (M+): 372.0356, found 372.0361. (E)-Ethyl-3-phenyl-2-(5-(trifluoromethyl)-2,3-dihydrobenzofuran2-yl)acrylate (3q). 94% yield, 169 mg; white solid; mp 91−92 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.45−7.25 (m, 7H), 6.78 (d, J = 8.0 Hz, 1H), 5.90 (dd, J = 10.4, 8.4 Hz, 1H), 4.20−4.08 (m, 2H), 3.54 (dd, J = 15.6, 8.4 Hz, 1H), 3.46 (dd, J = 15.6, 8.4 Hz, 1H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 162.5, 143.4, 134.2, 131.1, 129.2, 129.1, 128.7, 128.4, 125.9 (q, J = 3.8 Hz), 125.0 (q, J = 300.0 Hz), 123.0 (q, J = 32.0 Hz), 121.8 (q, J = 3.5 Hz), 108.9, 78.6, 61.0, 35.4, 13.6; IR (neat) 3019, 2359, 1717, 1327, 1163, 758 cm−1. HRMS (TOF EI): m/z calcd for C20H17F3O3+ (M+): 362.1124, found 362.1129. (E)-Ethyl-2-(3-ethoxy-3-oxo-1-phenylprop-1-en-2-yl)-2,3-dihydrobenzofuran-5-carboxylate (3r). 77% yield, 141 mg; white solid; mp 82−83 °C; 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.89−7.87 (m, 2H), 7.45−7.31 (m, 5H), 6.74 (d, J = 8.8 Hz, 1H), 5.91 (dd, J = 10.4, 8.4 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 4.17−4.08 (m, 2H), 3.55− 3.42 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 166.1, 163.9, 143.2, 134.2, 131.2, 131.0, 129.2, 128.7, 128.0, 126.2, 122.8, 108.6, 78.8, 60.9, 60.6, 35.2, 14.4, 13.6; IR (neat) 3019, 1705, 1275, 1215, 758 cm−1. HRMS (TOF EI): m/z calcd for C22H22O5+ (M+) 366.1462, found 366.1465. (E)-Methyl-2-(2,3-dihydrobenzofuran-2-yl)-3-phenyl acrylate (3s). 89% yield, 125 mg; white solid; mp 91−92 °C; 1H NMR (400 2597

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

Article

The Journal of Organic Chemistry (E)-Ethyl 3-(4-Chlorophenyl)-2-(1-tosylindolin-2-yl)acrylate (6e). 85% yield, 204 mg; white solid; mp 173−174 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.21−7.20 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.04−6.98 (m, 6H), 4.99 (t, J = 8.0 Hz, 1H), 4.14−4.03 (m, 2H), 3.22 (d, J = 8.0 Hz, 2H), 2.31 (s, 3H), 0.93 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 143.9, 142.6, 139.8, 134.5, 134.0, 133.7, 133.3, 130.8, 130.2, 129.3, 128.6, 127.6, 127.2, 124.4, 123.9, 115.6, 60.9, 57.5, 35.6, 21.5, 13.4; IR (neat) 3050, 2983, 1710, 1458, 1257, 1166, 1089, 754 cm−1. HRMS (TOF EI): m/z calcd for C26H24ClNO4S (M+): 481.1109. Found, 481.1117. (E)-Ethyl 3-(3-Chlorophenyl)-2-(1-tosylindolin-2-yl)acrylate (6f). 79% yield, 190 mg; white solid; mp 160−161 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.43−7.36 (m, 2H), 7.30 (s, 1H), 7.25−7.17 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.04− 6.97 (m, 4H), 5.03 (dd, J = 12.0, 4.0 Hz, 1H), 4.14−4.04 (m, 2H), 3.26−3.13 (m, 2H), 2.31 (s, 3H), 0.93 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 143.8, 142.6, 139.2, 137.0, 134.7, 134.4, 133.5, 130.9, 139.8, 129.4, 128.6, 128.4, 127.6, 127.2, 127.1, 124.4, 123.9, 115.7, 60.9, 57.5, 35.7, 21.4, 13.4; IR (neat) 3070, 2976, 1714, 1483, 1359, 1284, 1166, 761 cm−1. HRMS (TOF EI): m/z calcd for C26H24ClNO4S (M+): 481.1109. Found, 481.1125. (E)-Ethyl 3-(2-Chlorophenyl)-2-(1-tosylindolin-2-yl)acrylate (6g). 75% yield, 180 mg; white solid; mp 136−137 °C; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39−7.28 (m, 3H), 7.14 (m, 3H), 6.99−6.94 (m, 4H), 4.95 (dd, J = 12.0, 4.0 Hz, 1H), 4.12−4.02 (m, 2H), 3.26−3.09 (m, 2H), 2.29 (s, 3H), 0.92 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 143.7, 142.5, 138.4, 134.0, 133.9, 131.3, 130.4, 129.6, 129.5, 129.3, 127.4, 127.1, 126.3, 124.3, 123.8, 115.6, 60.9, 58.0, 35.5, 21.4, 13.4; IR (neat) 3050, 2981, 1712, 1479, 1240, 1172, 1111, 754 cm−1. HRMS (TOF EI): m/z calcd for C26H24ClNO4S (M+): 481.1109. Found, 481.1119. (E)-Ethyl 3-(4-Bromophenyl)-2-(1-tosylindolin-2-yl)acrylate (6h). 83% yield, 219 mg; white solid; mp 171−172 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.20−7.18 (m, 3H), 7.04−6.98 (m, 6H), 4.97 (dd, J = 12.0, 8.0 Hz, 1H), 4.16−4.02 (m, 2H), 3.21 (d, J = 8.0 Hz, 2H), 2.32 (s, 3H), 0.93 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 143.9, 142.6, 139.8, 134.2, 134.1, 133.3, 131.6, 130.8, 130.5, 129.3, 127.6, 127.2, 124.4, 123.9, 122.7, 115.6, 60.9, 57.5, 35.6, 21.5, 13.4; IR (neat) 3050, 2980, 1710, 1631, 1359, 1255, 1166, 755 cm−1. HRMS (TOF EI): m/z calcd for C26H24BrNO4S (M+): 527.0583. Found, 527.0561. (E)-Ethyl 3-(4-Fluorophenyl)-2-(1-tosylindolin-2-yl)acrylate (6i). 81% yield, 188 mg; white solid; mp 185−186 °C; 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.32−7.29 (m, 2H), 7.20−7.11 (m, 3H), 7.08−6.97 (m, 6H), 5.03 (dd, J = 12.0, 8.0 Hz, 1H), 4.13−4.02 (m, 2H), 3.27−3.16 (m, 2H), 2.30 (s, 3H), 0.92 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9, 162.8, 143.8, 142.6, 139.9, 133.7, 133.6, 131.2 (d, J = 4.0 Hz), 130.9, 130.8 (d, J = 7.0 Hz), 129.3, 127.6, 127.2, 124.4, 123.9, 115.6, 115.5 (d, J = 21.0 Hz), 60.8, 57.5, 35.7, 21.4, 13.4; IR (neat) 3070, 2983, 1710, 1506, 1357, 1257, 1166, 756 cm−1. HRMS (TOF EI): m/z calcd for C26H24FNO4S (M+): 465.1405. Found, 465.1429. (E)-Ethyl 3-(2-Fluorophenyl)-2-(1-tosylindolin-2-yl)acrylate (6j). 75% yield, 174 mg; white solid; mp 162−163 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.47−7.36 (m, 2H), 7.24−7.13 (m, 3H), 7.04−6.95 (m, 6H), 4.93−4.89 (m, 1H), 4.11−4.02 (m, 2H), 3.31−3.24 (m, 1H), 3.18−3.13 (m, 1H), 2.29 (s, 3H), 0.91 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 159.9 (d, J = 247.0 Hz), 143.7, 142.6, 135.5, 134.6, 133.8, 131.5, 130.9 (d, J = 2.7 Hz), 130.4 (d, J = 8.1 Hz), 129.3, 127.4, 127.2, 124.4, 124.1 (d, J = 3.6 Hz), 123.8, 123.1 (d, J = 15.1 Hz), 115.8, 115.6, 60.9, 58.3, 34.9, 21.4, 13.3; IR (neat) 3070, 2985, 1710, 1479, 1350, 1240, 1107, 752 cm−1. HRMS (TOF EI): m/z calcd for C26H24FNO4S (M+): 465.1405. Found, 465.1428. (E)-Ethyl 3-(4-(tert-Butyl)phenyl)-2-(1-tosylindolin-2-yl)acrylate (6k). 70% yield, 176 mg; white solid; mp 171−172 °C; 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.46 (d, J

= 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), 7.05−7.03 (m, 3H), 6.98 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H), 5.10 (t, J = 8.0 Hz, 1H), 4.13−4.02 (m, 2H), 3.24 (d, J = 12.0 Hz, 2H), 2.27 (s, 3H), 1.41 (s, 9H), 0.93 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 151.8, 143.5, 142.7, 141.2, 133.5, 132.8, 132.3, 131.0, 129.2, 128.8, 127.5, 127.3, 125.3, 124.4, 123.7, 115.5, 60.6, 57.7, 35.8, 34.8, 31.3, 21.4, 13.4; IR (neat) 3050, 2968, 1716, 1355, 1238, 1168, 1109, 756 cm−1. HRMS (TOF EI): m/z calcd for C30H33NO4S (M+): 503.2125. Found, 503.2116. (E)-Ethyl 3-(Naphthalen-2-yl)-2-(1-tosylindolin-2-yl)acrylate (6l). 69% yield, 172 mg; white solid; mp 177−178 °C; 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.94−7.92 (m, 2H), 7.79 (d, J = 8.0 Hz, 1H), 7.71−7.66 (m, 2H), 7.60−7.47 (m, 3H), 7.17 (t, J = 8.0 Hz, 1H), 7.06−6.97 (m, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.0 Hz, 2H), 5.15 (t, J = 8.0 Hz, 1H), 4.19−4.05 (m, 2H), 3.29 (d, J = 8.0 Hz, 2H), 2.12 (s, 3H), 0.96 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 143.5, 142.8, 141.2, 133.7, 133.2, 133.1, 133.0, 132.8, 131.0, 129.1, 128.3, 128.2, 128.1, 127.8, 127.6, 127.2, 126.9, 126.6, 126.5, 124.4, 123.9, 115.8, 60.8, 57.6, 35.7, 21.2, 13.4; IR (neat) 3050, 2978, 1712, 1631, 1481, 1244, 1168, 576 cm−1. HRMS (TOF EI): m/z calcd for C30H27NO4S (M+): 497.1655. Found, 497.1647. (E)-Methyl 3-Phenyl-2-(1-tosylindolin-2-yl)acrylate (6m). 84% yield, 182 mg; white solid; mp 171−172 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.46−7.43 (m, 3H), 7.33−7.31 (m, 2H), 7.19 (t, J = 8.0 Hz, 1H), 7.04−6.97 (m, 4H), 6.92 (d, J = 8.0 Hz, 2H), 5.04 (dd, J = 10.8, 7.2 Hz, 1H), 3.67 (s, 3H), 3.30−3.18 (m, 2H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.2, 143.6, 142.5, 141.1, 135.1, 133.3, 133.2, 130.7, 129.2, 128.9, 128.4, 127.5, 127.3, 124.4, 123.8, 115.5, 57.8, 51.8, 35.7, 21.4; IR (neat) 3070, 2951, 1707, 1481, 1357, 1251, 1172, 1112, 680 cm−1. HRMS (TOF EI): m/z calcd for C25H23NO4S (M+): 433.1342. Found, 433.1334. (E)-Benzyl 3-Penyl-2-(1-tosylindolin-2-yl)acrylate (6n). 79% yield, 201 mg; white solid; mp 129−130 °C; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.45−7.43 (m, 3H), 7.32−7.29 (m, 2H), 7.26−7.24 (m, 2H), 7.16−7.14 (m, 4H), 6.97−6.95 (m, 4H), 6.89 (d, J = 8.0 Hz, 2H), 5.15−5.02 (m, 3H), 3.29−3.17 (m, 2H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.8, 143.7, 142.5, 141.8, 135.6, 135.2, 133.1, 133.0, 130.7, 129.3, 128.9, 128.6, 128.5, 128.4, 128.2, 128.0, 127.6, 127.4, 124.5, 123.9, 115.7, 66.7, 57.7, 35.7, 21.4; IR (neat) 3032, 2974, 1718, 1707, 1654, 1458, 1354, 752 cm−1. HRMS (TOF EI): m/z calcd for C31H27NO4S (M+): 509.1655. Found, 509.1676. (E)-3-Phenyl-2-(1-tosylindolin-2-yl)acrylonitrile (6o). 65% yield, 130 mg; white solid; mp 165−166 °C; 1H NMR (400 MHz, CDCl3) δ 7.73−7.71 (m, 3H), 7.60 (d, J = 8.0 Hz, 2H), 7.40 (br, 4H), 7.29−7.26 (m, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.09−7.05 (m, 2H), 5.02 (dd, J = 12.0, 2.0 Hz, 1H), 3.18−3.01 (m, 2H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.5, 144.4, 141.1, 134.8, 132.7, 130.6, 130.2, 129.8, 129.2, 128.8, 128.2, 127.1, 125.3, 125.2, 117.1, 116.9, 111.2, 64.0, 35.0, 21.5; IR (neat) 3050, 2906, 1718, 1458, 1355, 1166, 964, 756 cm−1. HRMS (TOF EI): m/z calcd for C24H20N2O2S (M+): 400.1240. Found, 400.1266. (E)-Ethyl 2-(5-Methyl-1-tosylindolin-2-yl)-3-phenyl acrylate (6p). 88% yield, 203 mg; white solid; mp 148−149 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.45−7.43 (m, 3H), 7.32−7.30 (m, 2H), 6.98−6.96 (m, 3H), 6.91 (d, J = 8.0 Hz, 2H), 6.83 (s,1H), 5.03 (dd, J = 12.0, 8.0 Hz, 1H), 4.17−4.02 (m, 2H), 3.18 (d, J = 8.0 Hz, 2H), 2.27 (s, 3H), 2.26 (s, 3H), 0.97 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.0, 143.5, 140.9, 140.3, 135.3, 133.5, 133.4, 133.3, 131.1, 129.2, 128.9, 128.5, 128.4, 128.1, 127.3, 125.0, 115.4, 60.7, 57.8, 35.7, 21.4, 20.8, 13.5; IR (neat) 3022, 2985, 1712, 1485, 1350, 1255, 1091, 675 cm−1. HRMS (TOF EI): m/z calcd for C27H27NO4S (M+): 461.1655. Found, 461.1647. (E)-Ethyl 2-(5-Ethyl-1-tosylindolin-2-yl)-3-phenyl acrylate (6q). 89% yield, 211 mg; white solid; mp 140−141 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.45−7.43 (m, 3H), 7.32 (d, J = 4.0 Hz, 2H), 7.00−6.86 (m, 6H), 5.04 (t, J = 8.0 Hz, 1H), 4.14−4.04 (m, 2H), 3.20 (d, J = 8.0 Hz, 2H), 2.56 (q, J = 8.0 Hz, 2H), 2.27 (s, 3H), 1.18 (t, J = 8.0 Hz, 3H), 0.93 (t, J = 8.0 Hz, 3H); 2598

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

Article

The Journal of Organic Chemistry C NMR (100 MHz, CDCl3) δ 166.0, 143.4, 140.9, 140.4, 140.0, 135.3, 133.5, 133.4, 131.1, 129.3, 129.0, 128.5, 128.4, 127.3, 127.0, 123.8, 115.4, 60.7, 57.8, 35.8, 28.3, 21.4, 15.7, 13.4; IR (neat) 3025, 2976, 1712, 1489, 1249, 1170, 954, 763 cm−1. HRMS (TOF EI): m/z calcd for C28H29NO4S (M+): 475.1812. Found, 475.1811. (E)-Ethyl 2-(5-(tert-Butyl)-1-tosylindolin-2-yl)-3-phenyl acrylate (6r). 90% yield, 212 mg; white solid; mp 173−174 °C; 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45− 7.43 (m, 3H), 7.32 (t, J = 4.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.04− 6.99 (m, 3H), 6.92 (d, J = 8.0 Hz, 2H), 5.05 (t, J = 8.0 Hz, 1H), 4.12− 4.04 (m, 2H), 3.23 (d, J = 8.0 Hz, 2H), 2.28 (s, 3H), 1.27 (s, 9H), 0.89 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.1, 146.9, 143.4, 141.0, 140.1, 135.3, 133.6, 133.5, 130.5, 129.2, 128.9, 128.5, 128.4, 127.3, 124.4, 121.3, 114.9, 60.7, 57.8, 36.0, 34.3, 31.5, 21.4, 13.2; IR (neat) 3051, 2962, 1712, 1490, 1255, 1168, 956, 759 cm−1. HRMS (TOF EI): m/z calcd for C30H33NO4S (M+): 503.2125. Found, 503.2133. (E)-Ethyl 2-(5-Chloro-1-tosylindolin-2-yl)-3-phenyl acrylate (6s). 83% yield, 200 mg; white solid; mp 158−159 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.48−7.46 (m, 3H), 7.31 (d, J = 4.0 Hz, 2H), 7.16 (d, J = 4.0 Hz, 1H), 7.01 (s, 1H), 6.95 (br, 4H), 5.06 (t, J = 8.0 Hz, 1H), 4.19−4.04 (m, 2H), 3.21 (d, J = 12.0 Hz, 2H), 2.30 (s, 3H), 1.00 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 143.9, 141.6, 141.4, 135.0, 133.1, 133.0, 132.9, 129.4, 129.0, 128.8, 128.6, 128.5, 127.4, 127.2, 124.5, 116.5, 60.8, 57.9, 35.3, 21.4, 13.5; IR (neat) 3050, 2985, 1714, 1471, 1251, 1168, 912, 748 cm−1. HRMS (TOF EI): m/z calcd for C26H24ClNO4S (M+): 481.1109. Found, 481.1127. (E)-Ethyl 2-(5-Bromo-1-tosylindolin-2-yl)-3-phenyl acrylate (6t). 77% yield, 203 mg; white solid; mp 170−171 °C; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.47−7.45 (m, 3H), 7.36−7.29 (m, 3H), 7.15 (s, 1H), 6.95 (br, 4H), 5.06 (dd, J = 12.0, 8.0 Hz, 1H), 4.17−4.06 (m, 2H), 3.21 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H), 1.01 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 143.9, 142.0, 141.6, 135.0, 133.4, 130.0, 132.9, 130.4, 129.4, 128.8, 128.6, 128.5, 127.5, 127.2, 116.9, 116.5, 60.8, 57.8, 35.3, 21.4, 13.5; IR (neat) 3100, 2985, 1712, 1467, 1352, 1251, 1168, 700 cm−1. HRMS (TOF EI): m/z calcd for C26H24BrNO4S (M+): 525.0609. Found, 525.0611. (E)-Ethyl 3-Phenyl-2-(1-tosyl-5-(trifluoromethyl)indolin-2-yl)acrylate (6u). 69% yield, 178 mg; white solid; mp 147−148 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.47 (br, 4H), 7.33−7.28 (m, 3H), 7.01−6.96 (m, 4H), 5.16 (t, J = 8.0 Hz, 1H), 4.14−4.04 (m, 2H), 3.30 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H), 0.96 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 145.8, 144.2, 142.0, 135.0, 133.4, 132.7, 131.7, 129.6, 128.9, 128.7, 128.6, 127.2, 125.8 (q, J = 32.2 Hz), 125.2 (q, J = 3.9 Hz), 124.3 (q, J = 270.0 Hz), 121.6 (q, J = 3.7 Hz), 114.9, 60.9, 58.0, 35.4, 21.4, 13.4; IR (neat) 3030, 2987, 1718, 1440, 1255, 1168, 1112, 659 cm−1. HRMS (TOF EI): m/z calcd for C27H24F3NO4S (M+): 515.1373. Found, 515.1368. (E)-Ethyl 2-(3-Ethoxy-3-oxo-1-phenylprop-1-en-2-yl)-1-tosylindoline-5-carboxylate (6v). 78% yield, 202 mg; white solid; mp 155−156 °C; 1H NMR (400 MHz, CDCl3) δ 7.95−7.91 (m, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.47−7.46 (m, 3H), 7.36−7.33 (m, 2H), 7.02−6.94 (m, 4H), 5.15 (t, J = 8.0 Hz, 1H), 4.34 (q, J = 8.0 Hz, 2H), 4.16−4.00 (m, 2H), 3.28 (d, J = 8.0 Hz, 2H), 2.29 (s, 3H), 1.38 (t, J = 8.0 Hz, 3H), 0.95 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 165.7, 146.8, 144.0, 141.8, 135.0, 133.4, 132.8, 131.2, 129.9, 129.4, 128.8, 128.6, 128.5, 127.1, 125.9, 114.5, 60.87, 60.83, 58.1, 35.2, 21.4, 14.3, 13.5; IR (neat) 3050, 2983, 1712, 1363, 1273, 1168, 1026, 765 cm−1. HRMS (TOF EI): m/z calcd for C29H29NO6S (M+): 519.1710. Found, 519.1698. (E)-Ethyl 2-(5-Acetyl-1-tosylindolin-2-yl)-3-phenyl acrylate (6w). 72% yield, 176 mg; white solid; mp 160−161 °C; 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.83 (dd, J = 8.0, 4.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.48−7.46 (m, 3H), 7.36−7.32 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.0 Hz, 2H), 5.17 (dd, J = 10.0, 8.0 Hz, 1H), 4.15−4.00 (m, 2H), 3.29 (dd, J = 12.0, 4.0 Hz, 2H), 2.55 (s, 3H), 2.30 (s, 3H), 0.97 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 196.9, 165.6, 147.1, 144.2, 141.9, 135.0, 133.5, 133.0, 132.7, 13

131.6, 129.5, 129.3, 128.9, 128. 7, 128.6, 127.1, 124.6, 114.4, 60.8, 58.2, 35.2, 26.5, 21.5, 13.6; IR (neat) 3070, 2980, 1712, 1664, 1361, 1253, 1170, 669 cm−1. HRMS (TOF EI): m/z calcd for C28H27NO5S (M+): 489.1604. Found, 489.1585. (E)-Ethyl 2-(1-(Methylsulfonyl)indolin-2-yl)-3-phenyl acrylate (6x). 78% yield, 145 mg; white solid; mp 158−159 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (s,1H), 7.39−7.33 (m, 6H), 7.19−7.15 (m, 2H), 7.02 (t, J = 8.0 Hz, 1H), 5.40 (dd, J = 11.2, 6.4 Hz, 1H), 4.15− 4.05 (m, 2H), 3.61 (dd, J = 16.0, 11.2 Hz, 1H), 3.35 (dd, J = 16.0, 6.4 Hz, 1H), 2.70 (s, 3H), 0.95 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 142.4, 141.0, 134.8, 133.2, 130.6, 128.7, 128.6, 128.5, 127.7, 124.7, 123.6, 114.0, 60.9, 58.7, 36.2, 36.1, 13.5; IR (neat) 3035, 2854, 1718, 1654, 1157, 1028, 979, 767 cm−1. HRMS (TOF EI): m/z calcd for C20H21NO4S (M+): 371.1186. Found, 371.1194. (E)-Ethyl 2-(1-Benzylindolin-2-yl)-3-phenyl acrylate (6y). 84% yield, 161 mg; Yellow solid; mp 59−60 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H), 7.33−7.31 (m, 3H), 7.22−7.20 (m, 2H), 7.15−7.13 (m, 3H), 7.06−7.05 (m, 3H), 6.96 (t, J = 8.0 Hz, 1H), 6.63 (t, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 4.85 (t, J = 10.0 Hz, 1H), 4.20−4.10 (m, 3H), 3.96 (d, J = 16.0 Hz, 1H), 3.62 (dd, J = 15.6, 10.0 Hz, 1H), 3.35 (dd, J = 15.6, 10.0 Hz, 1H), 1.09 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.6, 152.0, 140.9, 138.4, 134.7, 133.5, 129.0, 128.6, 128.5, 128.3, 128.2, 127.4, 127.2, 126.7, 124.0, 117.5, 107.1, 61.1, 60.6, 51.5, 35.5, 13.8; IR (neat) 3059, 2845, 1718, 1350, 1244, 1109, 933, 754 cm−1. HRMS (TOF EI): m/z calcd for C26H25NO2 (M+): 383.1880. Found, 383.1889. (E)-Ethyl 2-(1-Methylindolin-2-yl)-3-phenyl acrylate (6z). 65% yield, 100 mg; Yellow solid; mp 67−68 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.37−7.29 (m, 5H), 7.07−7.03 (m, 2H), 6.65 (t, J = 8.0 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 4.58 (t, J = 8.0 Hz, 1H), 4.24−4.17 (m, 2H), 3.55 (dd, J = 16.0, 8.0 Hz, 1H), 3.30 (dd, J = 16.0, 8.0 Hz, 1H), 2.49 (s, 3H), 1.16 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 152.7, 140.7, 134.8, 133.7, 129.1, 128.6, 128.4, 128.2, 127.3, 123.9, 117.6, 107.0, 63.9, 60.7, 35.5, 34.1, 14.0; IR (neat) 3050, 2978, 1714, 1487, 1249, 1103, 933, 746 cm−1. HRMS (TOF EI): m/z calcd for C20H21NO2 (M+): 307.1567. Found, 307.1562. Procedure for Transformation of 2a to 4. An oven-dried Schlenk tube was charged with 1a (0.5 mmol), 2a (0.5 mmol), nBu4NCl (0.5 mmol), NaHCO3 (1.0 mmol), and dry DMF (5 mL) under N2. The mixture was stirred at 90 °C for 6 h and monitored by TLC. Finally, EtOAc (5 mL) and H2O (5 mL) were added, and the solution was partitioned. The aqueous layer was washed with EtOAc, and EtOAc extracts were washed sequentially with water and saturated NaCl solution. The combined extracts were dried (Na2SO4), and the crude reaction mixture was concentrated and loaded onto a silica gel column and separated chromatographically (petroleum ether/EtOAc, 20:1) to give the compound (4) in 85%. (Z)-Ethyl 2-benzylidenebut-3-enoate (4). 85% yield, 86 mg; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.43− 7.32 (m, 5H), 6.64 (ddd, J = 18.0, 11.6, 0.8 Hz, 1H), 5.86 (dd, J = 18.0, 1.6 Hz, 1H), 5.44 (dt, J = 11.6, 1.2 Hz, 1H), 4.31 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ 167.4, 139.1, 135.3, 130.4, 130.0, 129.7, 128.7, 128.3, 120.9, 61.0, 14.3. HRMS (TOF EI): m/z calcd for C13H14O2+ (M+): 202.0988, found 202.0992. Z stereochemistry was confirmed by NOESY (δ 7.54 and 6.64). Procedure for Transformation of 1a and 4 to 3a. An ovendried Schlenk tube was charged with 1a (0.5 mmol), 4 (0.5 mmol), Pd(dppe)Cl2 (0.025 mmol), n-Bu4NCl (0.5 mmol), NaHCO3 (1.0 mmol), and dry DMF (5 mL) under N2. The mixture was stirred at 90 °C for 8 h and monitored by TLC. Finally, EtOAc (5 mL) and H2O (5 mL) were added, and the solution was partitioned. The aqueous layer was washed with EtOAc, and EtOAc extracts were washed sequentially with water and saturated NaCl solution. The combined extracts were dried (Na2SO4), and the crude reaction mixture was concentrated and loaded onto a silica gel column and separated chromatographically (petroleum ether/EtOAc, 20:1) to give the desired product (3a) in 92% yield. 2599

DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600

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The Journal of Organic Chemistry

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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.joc.7b02986. NMR (1H, 13C) spectra for compounds 2, 3, 4, and 6 (PDF) X-ray crystallographic data for compounds 3a, 6t, and 6w (CIF)

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AUTHOR INFORMATION

Corresponding Authors

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

Zhiming Wang: 0000-0002-6583-3826 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the Natural Science Foundation of China (no. 21372033) and the Zhejiang Provincial National Science Foundation of China (no. LY18B020002 and LQ15B020001).

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REFERENCES

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DOI: 10.1021/acs.joc.7b02986 J. Org. Chem. 2018, 83, 2592−2600