Hydroxy-Assisted Regio- and Stereoselective Synthesis of

Nov 3, 2017 - In this work, we present a new strategy for the chemo-, regio-, and stereoselective synthesis of functionalized pyrrolidine derivatives ...
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Hydroxy-Assisted Regio- and Stereoselective Synthesis of Functionalized 4‑Methylenepyrrolidine Derivatives via PhosphineCatalyzed [3 + 2] Cycloaddition of Allenoates with o‑Hydroxyaryl Azomethine Ylides Zhusheng Huang, Yishu Bao, Yu Zhang, Fulai Yang, Tao Lu, and Qingfa Zhou* State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P. R. China S Supporting Information *

ABSTRACT: In this work, we present a new strategy for the chemo-, regio-, and stereoselective synthesis of functionalized pyrrolidine derivatives via a hydroxy-assisted phosphinecatalyzed reaction of allenoates or substituted allenoates with o-hydroxyaryl azomethine ylides that offers a wide variety of 4methylenepyrrolidine derivatives in synthetically useful yields with high stereoselctivities under mild conditions. Remarkably, it is the first example of highly regio- and stereoselective phosphine-catalyzed [3 + 2] cycloaddition of allenoates with o-hydroxyaryl azomethine ylides.

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functionalized pyrrolidine derivative A. The possibility of forming pyrrolidine derivative B could not be excluded.5 However, a novel 4-methylenepyrrolidine derivative 3aa was formed as the only product when o-hydroxyaryl azomethine ylide 1a was used as reactant with allenoate 2a under phosphine conditions. This transformation appears to be not only a practical and operationally simple method for preparing 4methyleneprrolidine derivatives under extremely mild conditions but also the first example of unactivated imine used as an electrophile partner, although N-sulfonylimines have been widely researched in the nucleophilic phosphine-catalyzed system. This inspired us to exploit the potential of constructing diverse pyrrolidine derivatives using phosphine-catalyzed [3 + 2] reaction of azomethine ylides with allenoates. To our surprise, no product was found when azomethine ylide (X = H) was used as the reactant in place of 1a under the same conditions, which suggested that the hydroxy group located at the 2-position of azomethine ylide might play a determinate role for the present cyclization. To further understand the role of a hydroxy group on the aromatic ring, 3-hydroxy azomethine ylide (X = 3-OH) and 4-hydroxy azomethine ylide (X = 4-OH) were synthesized and tested in the reaction in place of ohydroxyaryl azomethine ylide 1a. No product was found in the presence of 3- or 4-hydroxy azomethine ylide. It should be noted that the hydroxy-assisted reaction has been an important substrate-assisted reaction and provides useful synthetic tools for the construction of organic molecules.16 However, a hydroxy-assisted phosphine-catalyzed reaction has never been reported as far as we know. Herein we report an unexpected hydroxy-assisted phosphine-catalyzed reaction, leading to a

he development of efficient methodologies to synthesize the functionalized pyrrolidines is very important because of their occurrence in a wide range of pharmaceuticals, natural products, organocatalysts, and useful synthetic intermediates.1 The reaction of azomethine ylides with various dipolarophiles has been proved to be a useful and practicable method for the synthesis of diverse pyrrolidines, which was first reported by Grigg in 1978.2 However, the substrates applied in the dipolar cycloaddition of azomethine ylides are limited to various electron-deficient alkenes3 and alkynes4 using either metal or organocatalysts; the allenoate derivatives as a unique kind of unsaturated compound have seldom been employed as reactants in the cycloaddition of azomethine ylides.5 There are only three reports on the reaction of azomethine ylides with allenoate derivatives, which supplied an effective method for the synthesis of 3-methylenepyrrolidine derivatives or spiro[indoline-3,2′-pyrrole] derivatives in the present of bisphosphoric acid5a,c or Ag(I)/TF-BiphamPos catalyst.5b To our best knowledge, the phosphine-catalyzed reaction of azomethine ylides with allenoate derivatives has never been achieved. The phosphine-catalyzed reaction of allenoates has been one of the most powerful tools for the construction of various important cyclic compounds in organic chemistry.6 Generally, phosphine-catalyzed annulations of allenoates proceed via the zwitterion that could be formed via the nucleophilic attack of the phosphine catalyst on allenoate.7 The zwitterion then react with a series of electrophiles,8 such as activated carbon−carbon double bonds9 and carbonyl derivatives10 and imines,11 to construct various important carbocycles and heterocycles. According to previous studies 12 and our work, 13 we hypothesized that o-hydroxyaryl azomethine ylide would undergo a cascade oxygen umpolung addition14 and intramolecular [3 + 2] cyclization15 with the zwitterion to yield © 2017 American Chemical Society

Received: October 9, 2017 Published: November 3, 2017 12726

DOI: 10.1021/acs.joc.7b02560 J. Org. Chem. 2017, 82, 12726−12734

Article

The Journal of Organic Chemistry Scheme 1. Reaction of Allenoates with Azomethine Ylides

in the yields of 89% and 92%, respectively. In comparison, the yield of 3aa was obviously lower with the use of PBu3 as promoter. The effect of the solvent was also examined. Compared with CH2Cl2, THF gave a comparative yield, while toluene, Et2O, CH3NO2, and MeCN led to decreased yields (entries 8−12). Additionally, the reaction temperature could be lowered to 0 °C without impacting the product yield, although a slightly longer reaction time was needed. The starting materials were quickly consumed and offered a lower yield when the reaction was performed in CH2Cl2 at reflux (entries 13 and 14). The structure and relative configuration of compound 3 were confirmed by the data of NMR spectroscopy, high-resolution mass spectrometry (HRMS), and singlecrystal X-ray diffraction.17 Under the optimized conditions for the synthesis of functional 4-methylenepyrrolidine derivatives, a lot of allenoates were first examined coupling with o-hydroxyaryl azomethine ylide 1a, and the results are outlined in Scheme 2. In general, various straight-chain ester units, such as methyl, ethyl, n-propyl, n-butyl, phenethyl, and 3-MeO-propyl, gave the corresponding products in good yields. The bulky ester groups in 2, such as benzhydryl and phenyl, were also tolerant, despite that they gave the target products in moderate yields. It is noteworthy here that, under the above conditions, γ-substituted allenoate, such as benzyl penta-2,3-dienoate, could also react with 1a to furnish the corresponding product in 45% yield. However, no target product was formed when α-substituted allenoate, such as ethyl 2-benzylbuta-2,3-dienoate, was applied in the reaction. Ethyl but-2-ynoate, which reacts in a fashion similar to that of allenoates when subjected to phosphine catalysis, was also examined under the optimized conditions. Happily, the 4-methylenepyrrolidine derivative 3ac was also smoothly formed in 76% yield, although a very long reaction time, 3 days, was needed to consume the reactants (Scheme 3). We next investigated the scope of o-hydroxyaryl azomethine ylides. As shown in Scheme 4, a wide range of substituted ohydroxyaryl azomethine ylides containing functional groups with different electron natures on the benzene ring worked well with allenoate 2a, giving the corresponding 4-methylenepyrrolidine derivatives in good yields with excellent stereoselectivities. For example, for substrates with an ethoxy or diethylamino group attached on the benzene ring, the corresponding pyrrolidine derivatives 3ba and 3ea were obtained in yields of 90% and 88%, respectively. Substrates with a strong-electron-withdrawing group, such as a nitro group, on the benzene ring also gave the target product 3ka in

wide variety of functionalized 4-methylenepyrrolidine derivatives with excellent stereoselectivity (Scheme 1). At the outset of our study, o-hydroxyaryl azomethine ylide 1a and allenoate 2a were selected for the initial reaction in the presence of 5 mol % PPh3 in CH2Cl2 at room temperature (Table 1, entry 1). The 4-methylenepyrrolidine derivative 3aa Table 1. Survey on the Conditions for Formation of 3aaa

entry

base

equiv

solvent

t (h)

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13c 14d 15e

PPh3 PPh3 PPh3 PPh3 PPh2Et PPhEt2 PBu3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3 PPh3

0.05 0.10 0.20 0.50 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.20

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene MeCN CH3NO2 THF Et2O CH2Cl2 CH2Cl2 CH2Cl2

12 6 2 2 2 2 2 6 6 6 6 6 6 1 6

68 77 96 90 89 92 47 67 26 47 88 68 94 76 89

a

Typical conditions: under an Ar atmosphere and at room temperature, to a stirred solution of 1a (0.1 mmol) and 2a (0.12 mmol) in solvent (2.0 mL) was added phosphine reagent. bIsolated yield based on 1a. cThe reaction was performed at 0 °C. dThe reaction was performed at reflux. eUsing 0.1 mmol of 2a.

was obtained with a synthetically useful level of efficiency (entry 1). To increase the reaction rate and improve the yield of 3aa, the loading of PPh3 was first screened (entries 2−4). The amount of PPh3 has a great effect both on the reaction rate and the yield of 3aa. The product 3aa was obtained in almost quantitative yield in 2 h when 20 mol % PPh3 was used. However, a slightly lower yield was given when the loading of catalyst was increased to 100 mol %. Subsequently, several other phosphine reagents were examined (entries 5−7). PPh2Et and PPhEt2 are usable catalysts and they afforded the product 12727

DOI: 10.1021/acs.joc.7b02560 J. Org. Chem. 2017, 82, 12726−12734

Article

The Journal of Organic Chemistry Scheme 2. Scope of Allenoatesa,b

a

Typical conditions: under an Ar atmosphere and at room temperature, to a stirred solution of 1a (0.1 mmol) and 2 (0.12 mmol) in solvent (2.0 mL) was added phosphine reagent. bIsolated yield based on 1.

good yield. The various halogen substituents still remained active and effectively gave the corresponding pyrrolidines under the reaction conditions, which provides a potential handle for subsequent coupling operation. To our delight, naphthylcontaining substrate is also compatible, efficiently giving 4methylenepyrrolidine derivative 3la. Additionally, the present protocol could also be readily extended to the challenging diethyl 2-((1-(2-hydroxyphenyl)ethylidene)amino)malonate (1m), and the corresponding product 3ma was formed in 62% yield. To our disappointment, only a trace of target product was formed when ethyl 2-((2-hydroxybenzylidene)amino)acetate (1n) was applied in the reaction. Happily, 1n could give the target product 3na in a moderate yield when PBu3 was used as catalyst in place of PPh3. To show the practical utility of the present catalytic system, the gram-scale synthesis of functionalized 4-methylenepyrrolidine derivative 3aa was examined. The reaction of 1.12 g of 1a with 0.84 g of 2a proceeded smoothly and supplied the corresponding product 3aa in 76% yield without a significant loss of efficiency (small scale, 96%). The 4-methylenepyrrolidine derivatives can be readily transformed into other interesting compounds due to the presence of a free hydroxyl group. Treatment of 3aa with a formaldehyde aqueous solution in THF afforded the novel derivative 4 in 86% yield. The derivative 5 could be effectively formed when 3aa was treated with triphosgene in CH2Cl2, while derivative 6 was given when 3aa was treated with SO2Cl2 and Et3N in CH2Cl2. These Nfused dihydropyrroles are popular because of their potential applications in drug syntheses. Interestingly, only O-Michael addition product 7 was released when 3aa was coupled with ethyl propiolate using PPh3 as catalyst (Scheme 5) . On the basis of the above results and previous literature, a plausible mechanism accounting for the formation of 4methylenepyrrolidine derivative 3ac is proposed in Scheme 6.

Scheme 3. Reaction of Ethyl But-2-ynoate and 1a

Scheme 4. Scope of o-Hydroxyaryl Azomethine Ylidesa,b

a

Typical conditions: under an Ar atmosphere and at room temperature, to a stirred solution of 1 (0.1 mmol) and 2a (0.12 mmol) in solvent (2.0 mL) was added phosphine reagent. bIsolated yield based on 1. 12728

DOI: 10.1021/acs.joc.7b02560 J. Org. Chem. 2017, 82, 12726−12734

Article

The Journal of Organic Chemistry Scheme 5. Gram-Scale and Synthetic Transformations

■

Scheme 6. Proposed Mechanism for the Formation of 3ac

EXPERIMENTAL SECTION

General Information. All reactions were performed in dry solvents under an argon atmosphere and anhydrous conditions. DCM, THF, MeCN, etc. were freshly distilled over CaH2 prior to use. All other reagents were used as received from commercial sources. Reactions were monitored through thin-layer chromatography (TLC) on 0.30 mm SiliCycle silica gel plates and visualized under UV light. NMR spectra of the new products were recorded using Bruker Avance300 and Bruker Avance-500 instruments, calibrated to CD(H)Cl3 as the internal reference (7.26 and 77.0 ppm for 1H and 13C NMR spectra, respectively). 1H NMR spectral data are reported in terms of chemical shift (δ, ppm), multiplicity, coupling constant (Hz), and integration. 13C NMR spectral data are reported in terms of chemical shift (δ, ppm) and multiplicity. The following abbreviations indicate the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. High-resolution mass spectrometry (HRMS) was obtained on a Q-TOF micro spectrometer. IR spectra were recorded on a Bruker Optics Tensor 37 spectrometer by the KBr pellet method. Xray crystallographic data were collected using a Enraf Nonius CAD4SDP44 four-circle X-ray diffractometer operated at 25 °C. General Procedure for Synthesis of Allenoates. The detailed procedure is available free of charge on the ACS Publications website within the Supporting Information for DOI: 10.1021/acs.orglett.7b01482. General Procedure for Synthesis of 1. To a stirred solution of diethyl aminomalonate hydrochloride (3 g, 14.2 mmol) and H2O (30 mL) in a 50 mL round-bottomed flask was added NaHCO3 (1.31 g, 15.6 mmol). After stirring for 15 min, the solution was extracted with AcOEt three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford diethyl aminomalonate (2.3 g, 13.1 mmol), which was used without further purification. Substituted salicylaldehyde (13.1 mmol) was added to a mixture of diethyl aminomalonate (2.3 g, 13.1 mmol) and MgSO4 (7.86 g, 65.5 mmol) in CH2Cl2 (30 mL). After stirring for 48 h, MgSO4 was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product can be purified by flash chromatography on Al2O3 or recrystallization with petroleum ether/ethyl acetate (PE/ EA) to afford products 1a−1l.18 Diethyl (E)-2-((2-Hydroxybenzylidene)amino)malonate (1a). Yellow solid, purified by freezing from PE and then washed three times with PE. Yield: 56% (2.05 g). Mp: 45−46 °C. 1H NMR (300 MHz, chloroform-d): δ 12.60 (s, 1H), 8.41 (s, 1H), 7.33−7.18 (m, 2H), 6.95−6.88 (m, 1H), 6.83 (td, J = 7.5, 1.1 Hz, 1H), 4.79 (d, J = 0.7 Hz, 1H), 4.22 (qd, J = 7.1, 0.8 Hz, 4H), 1.24 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((3-Ethoxy-2-hydroxybenzylidene)amino)malonate (1b). Yellow solid, purified by flash chromatography (PE/EA 8:1). Yield: 62% (2.62 g). Mp: 49−50 °C. 1H NMR (300 MHz, chloroformd): δ 12.93 (s, 1H), 8.40 (s, 1H), 6.89 (ddd, J = 13.3, 7.9, 1.6 Hz, 2H),

Initially, phosphine reacts with allenoate to produce the zwitterionic intermediate I, which could also be formed from the nucleophilic attack of the phosphine catalyst on ethyl but-2ynoate. The zwitterionic intermediate I then deprotonates ohydroxy azomethine ylide 1a and generates intermediates II and III. The hydroxy group located at the 2-position of azomethine ylide might activate the carbonyl group and stabilize the azomethine ylide via an intramolecular hydrogen bond. Intermediate III then undergoes nucleophilic attack on the γ-position of intermediate II to give IV. Intermediate IV might then undergo a Mannich cyclization pathway to form intermediate V. The intermediate V then proceeds to subsequent proton transfer and elimination of phosphine to produce the desired product 3ac. In conclusion, an unprecedented chemo-, regio-, and stereoselective hydroxy-assisted phosphine-catalyzed cycloaddition of allenoates or substituted allenoates with o-hydroxyaryl azomethine ylides has been developed. This novel process, carried out under extremely mild conditions, provides access to functionalized 4-methylenepyrrolidine derivatives. Moreover, the reaction could be scaled up without significant loss of yield, and the synthesized 4-methylenepyrrolidine derivatives could be further transformed into other interesting N-fused dihydropyrroles. 12729

DOI: 10.1021/acs.joc.7b02560 J. Org. Chem. 2017, 82, 12726−12734

Article

The Journal of Organic Chemistry

Diethyl (E)-2-((1-(2-Hydroxyphenyl)ethylidene)amino)malonate (1m). Yellow oil, purified by flash chromatography (PE/EA 8:1). Yield: 48% (1.84 g). 1H NMR (500 MHz, chloroform-d): δ 14.81 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.86 (t, J = 8.1 Hz, 1H), 5.20 (s, 1H), 4.37−4.29 (m, 4H), 2.40 (s, 3H), 1.35 (t, J = 7.1 Hz, 6H). General Procedure for the Synthesis of 1n. To a stirred solution of glycine ethyl ester hydrochloride (3 g, 21.5 mmol) and H2O (30 mL) in a 50 mL round-bottomed flask was added NaHCO3 (2.0 g, 24 mmol). After stirring for 30 min, the solution was extracted with AcOEt three times. The combined organic layers were dried over Na2SO4 and concentrated under vacuum to afford diethyl aminomalonate (2.1 g, 20.0 mmol), which was used without further purification. Salicylaldehyde (2.4 g, 20.0 mmol) was added to a mixture of diethyl aminomalonate (2.1 g, 20.0 mmol) and MgSO4 (12.0 g, 100 mmol) in CH2Cl2 (50 mL). After stirring for 48 h, MgSO4 was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product can be purified by flash chromatography on Al2O3 (PE/EA = 8/1) to afford product 1n in 65% yield. Ethyl (E)-2-((2-Hydroxybenzylidene)amino)acetate (1n). Yellow oil, purified by flash chromatography (PE/EA 8:1). Yield: 65% (2.69 g). 1H NMR (500 MHz, chloroform-d): δ 12.96 (s, 1H), 8.42 (s, 1H), 7.41−7.34 (m, 1H), 7.32−7.29 (m, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 4.42 (d, J = 1.3 Hz, 2H), 4.29 (d, J = 7.2 Hz, 2H), 1.35 (td, J = 7.1, 1.2 Hz, 3H). General Procedure for the Synthesis of 3. To a mixture of diethyl (E)-2-((2-hydroxybenzylidene)amino)malonate derivatives 1 (0.1 mmol) and allenoates 2 (0.12 mmol) in anhydrous CH2Cl2 (2.0 mL) was added PPh3 (0.02 mmol, 5.3 mg). The resulting solution was stirred at room temperature under an argon atmosphere for 2−12 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/AcOEt) to give the desired products 3. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(2hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3aa). Following the general procedure, after reacting for 2 h, 3aa was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 96% yield (43.5 mg) as a white solid. Mp: 69−70 °C. 1H NMR (500 MHz, chloroform-d): δ 9.85 (s, 1H), 7.41−7.33 (m, 5H), 7.28−7.22 (m, 1H), 7.01 (dd, J = 7.4, 1.6 Hz, 1H), 6.88 (qd, J = 7.8, 1.2 Hz, 2H), 5.49 (q, J = 2.6 Hz, 1H), 5.18 (d, J = 12.3 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 4.98 (d, J = 2.5 Hz, 1H), 4.40−4.28 (m, 4H), 3.90 (ddd, J = 20.3, 2.6, 1.2 Hz, 1H), 3.82 (dt, J = 20.4, 2.7 Hz, 1H), 1.36 (td, J = 7.1, 3.6 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.6, 168.7, 165.7, 160.3, 156.9, 135.8, 130.0, 129.5, 128.6 (2C), 128.4 (2C), 128.3, 122.2, 119.5, 117.9, 114.5, 70.6, 66.8, 66.2, 62.8, 62.6, 38.3, 14.0, 13.96. HRMS (ESITOF): calcd for C25H28NO7(M + H+) 454.1866, found 454.1869. IR (KBr) ν (neat, cm−1): 3459, 2993, 1734, 1722, 1638, 1502. Diethyl (E)-5-(2-Hydroxyphenyl)-4-(2-methoxy-2-oxoethylidene)pyrrolidine-2,2-dicarboxylate (3ab). Following the general procedure, after reacting 6 h, 3ab was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 79% yield (29.8 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.94 (s, 1H), 7.26 (ddd, J = 8.9, 7.4, 1.7 Hz, 1H), 7.02 (dd, J = 7.4, 1.6 Hz, 1H), 6.93−6.84 (m, 2H), 5.43 (q, J = 2.6 Hz, 1H), 4.98 (q, J = 2.0 Hz, 1H), 4.40−4.28 (m, 4H), 3.86 (ddd, J = 20.3, 2.6, 1.3 Hz, 1H), 3.78 (dt, J = 20.3, 2.7 Hz, 1H), 3.70 (s, 3H), 1.35 (td, J = 7.1, 5.1 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.5, 168.7, 166.3, 159.8, 156.9, 129.9, 129.4, 122.3, 119.5, 117.9, 114.6, 70.6, 66.7, 62.8, 62.6, 51.3, 38.2, 14.0, 13.95. HRMS (ESI-TOF): calcd for C19H24NO7 (M + H+) 378.1523, found 378.1522. IR (KBr) ν (neat, cm−1): 3460, 2989, 1733, 1722, 1635, 1504. Diethyl (E)-4-(2-ethoxy-2-oxoethylidene)-5-(2-hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3ac). Following the general procedure, after reacting 6 h, 3ac was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 92% yield (36.0 mg) as a colorless oil. 1H NMR (300 MHz, chloroform-d): δ 9.75 (s, 1H), 7.21−7.12 (m, 1H), 6.91 (dd, J = 7.7, 1.7 Hz, 1H), 6.77 (t, J = 7.3 Hz, 2H), 5.31 (q, J = 2.6 Hz, 1H), 4.86 (q, J = 2.1 Hz, 1H), 4.34−4.14 (m, 4H), 4.04 (t, J

6.76 (t, J = 7.8 Hz, 1H), 4.77 (s, 1H), 4.21 (q, J = 7.1 Hz, 4H), 4.06 (q, J = 7.0 Hz, 2H), 1.40 (t, J = 7.0 Hz, 3H), 1.23 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((2-Hydroxy-5-methylbenzylidene)amino)malonate (1c). Yellow oil, purified by flash chromatography (PE/EA 8:1). Yield: 56% (2.15 g). 1H NMR (500 MHz, chloroform-d): δ 12.46 (s, 1H), 8.46 (s, 1H), 7.20 (dd, J = 8.4, 2.2 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 4.88 (s, 1H), 4.32 (qd, J = 7.1, 2.1 Hz, 4H), 2.32 (s, 3H), 1.34 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((3,5-Di-tert-butyl-2-hydroxybenzylidene)amino)malonate (1d). Yellow oil, purified by flash chromatography (PE/ EA 8:1). Yield: 42% (2.15 g). 1H NMR (500 MHz, chloroform-d): δ 13.08 (s, 1H), 8.54 (s, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 4.90 (s, 1H), 4.34 (tq, J = 7.1, 3.5 Hz, 4H), 1.49 (d, J = 1.9 Hz, 9H), 1.35 (t, J = 7.1 Hz, 15H). Diethyl (E)-2-((4-(Diethylamino)-2-hydroxybenzylidene)amino)malonate (1e). Yellow oil, purified by flash chromatography (PE/ EA 8:1). Yield: 30% (1.37 g). 1H NMR (500 MHz, chloroform-d): δ 13.10 (s, 1H), 8.26 (s, 1H), 7.10 (d, J = 8.7 Hz, 1H), 6.24 (dd, J = 8.8, 2.5 Hz, 1H), 6.20 (d, J = 2.4 Hz, 1H), 4.77 (s, 1H), 4.30 (qd, J = 7.1, 2.0 Hz, 4H), 3.41 (q, J = 7.1 Hz, 4H), 1.33 (t, J = 7.1 Hz, 6H), 1.22 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((5-Chloro-2-hydroxybenzylidene)amino)malonate (1f). Yellow solid, purified by recrystallization (EA). Yield: 63% (2.58 g). Mp: 59−60 °C. 1H NMR (300 MHz, chloroform-d): δ 12.59 (s, 1H), 8.35 (s, 1H), 7.22 (s, 2H), 6.91−6.84 (m, 1H), 4.81 (d, J = 0.7 Hz, 1H), 4.23 (qd, J = 7.1, 1.0 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((5-Bromo-2-hydroxybenzylidene)amino)malonate (1g). Yellow solid, purified by recrystallization (EA). Yield: 66% (3.09 g). Mp: 79−80 °C. 1H NMR (300 MHz, chloroform-d): δ 12.62 (s, 1H), 8.35 (s, 1H), 7.36 (dd, J = 4.7, 2.4 Hz, 2H), 6.82 (d, J = 9.5 Hz, 1H), 4.81 (d, J = 0.8 Hz, 1H), 4.23 (qd, J = 7.1, 1.1 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((3,5-Dichloro-2-hydroxybenzylidene)amino)malonate (1h). Yellow solid, purified by recrystallization (EA). Yield: 63% (2.87 g). Mp: 68−69 °C. 1H NMR (300 MHz, chloroformd): δ 13.43 (s, 1H), 8.37 (s, 1H), 7.38 (dd, J = 2.5, 0.7 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 4.85 (s, 1H), 4.23 (q, J = 7.1 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((3,5-Dibromo-2-hydroxybenzylidene)amino)malonate (1i). Yellow solid, purified by recrystallization (EA). Yield: 60% (3.43 g). Mp: 87−88 °C. 1H NMR (300 MHz, chloroform-d): δ 13.57 (s, 1H), 8.37−8.31 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 4.85 (d, J = 0.7 Hz, 1H), 4.23 (q, J = 7.1 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((3-Bromo-5-chloro-2-hydroxybenzylidene)amino)malonate (1j). Yellow solid, purified by recrystallization (EA). Yield: 58% (2.98 g). Mp: 78−79 °C. 1H NMR (300 MHz, chloroform-d): δ 13.54 (s, 1H), 8.34 (d, J = 0.7 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.22 (d, J = 2.5 Hz, 1H), 4.85 (d, J = 0.8 Hz, 1H), 4.23 (q, J = 7.1 Hz, 4H), 1.25 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-((2-Hydroxy-5-nitrobenzylidene)amino)malonate (1k). Yellow solid, purified by recrystallization (EA). Yield: 59% (2.50 g). Mp: 77−78 °C. 1H NMR (300 MHz, chloroform-d): δ 13.62 (s, 1H), 8.52 (s, 1H), 8.26 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 9.2, 2.8 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 4.89 (d, J = 0.7 Hz, 1H), 4.29−4.21 (m, 4H), 1.26 (t, J = 7.1 Hz, 6H). Diethyl (E)-2-(((2-Hydroxynaphthalen-1-yl)methylene)amino)malonate (1l). Yellow solid, purified by recrystallization (EA). Yield: 59% (2.54 g). Mp: 66−67 °C. 1H NMR (300 MHz, chloroform-d): δ 14.50 (s, 1H), 9.13 (s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.64−7.56 (m, 1H), 7.39 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.22 (ddd, J = 8.0, 7.0, 1.0 Hz, 1H), 7.02 (d, J = 9.1 Hz, 1H), 4.90 (s, 1H), 4.24 (qt, J = 7.1, 1.0 Hz, 4H), 1.24 (td, J = 7.1, 0.9 Hz, 6H). General Procedure for the Synthesis of 1m. 1-(2Hydroxyphenyl)ethan-1-one (1.78 g, 13.1 mmol) was added to a mixture of diethyl aminomalonate (2.3 g, 13.1 mmol) and MgSO4 (7.85 g, 65.5 mmol) in toluene (50 mL) and the solution reflux for 48 h. After stirring for 48 h, MgSO4 was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product can be purified by flash chromatography on Al2O3 (PE/EA = 8/1) to afford product 1m in 48% yield. 12730

DOI: 10.1021/acs.joc.7b02560 J. Org. Chem. 2017, 82, 12726−12734

Article

The Journal of Organic Chemistry

1H), 7.37−7.28 (m, 11H), 7.05 (dd, J = 7.7, 1.7 Hz, 1H), 6.96−6.85 (m, 3H), 5.58 (q, J = 2.6 Hz, 1H), 4.99 (d, J = 2.7 Hz, 1H), 4.40−4.27 (m, 4H), 3.89 (ddd, J = 20.4, 2.6, 1.2 Hz, 1H), 3.80 (dt, J = 20.4, 2.8 Hz, 1H), 1.34 (t, J = 7.1 Hz, 6H). 13C NMR (126 MHz, chloroformd): δ 170.5, 168.6, 164.9, 160.9, 157.0, 130.0, 129.5, 128.5 (3C), 127.9, 127.9 (2C), 127.3 (3C), 127.1 (3C), 122.1, 119.5, 118.0, 114.4, 70.6, 66.9, 62.8, 62.6, 38.4 (2C), 13.98, 13.95. HRMS (ESI-TOF): calcd for C31H32NO7 (M + H+) 530.2179, found 530.2183. IR (KBr) ν (neat, cm−1): 3473, 2998, 1737, 1721, 1638, 1503. Diethyl (E)-5-(2-Hydroxyphenyl)-4-(2-oxo-2-phenoxyethylidene)pyrrolidine-2,2-dicarboxylate (3ai). Following the general procedure, after reacting for 12 h, 3ai was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 56% yield (24.6 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.93 (s, 1H), 7.43−7.38 (m, 2H), 7.31 (d, J = 2.3 Hz, 1H), 7.25 (td, J = 7.3, 1.2 Hz, 1H), 7.10 (ddd, J = 7.3, 4.6, 1.5 Hz, 3H), 6.98−6.92 (m, 2H), 5.67 (q, J = 2.6 Hz, 1H), 5.07 (s, 1H), 4.39−4.30 (m, 4H), 3.93 (ddd, J = 20.5, 2.6, 1.2 Hz, 1H), 3.88−3.82 (m, 1H), 1.38−1.33 (m, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.5, 168.6, 164.2, 162.4, 157.0, 150.4, 130.1, 129.5, 129.4, 125.8, 122.1, 121.5, 119.6, 118.0, 114.1, 70.6, 67.0, 62.9, 62.7, 38.5, 14.01, 13.95. HRMS (ESI-TOF): calcd for C24H26NO7 (M + H+) 440.1709, found 440.1706. IR (KBr) ν (neat, cm−1): 3466, 2996, 1737, 1722, 1638, 1509. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(2-hydroxyphenyl)-3-methylpyrrolidine-2,2-dicarboxylate (3aj). Following the general procedure, after reacting for 12 h, 3aj was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 45% yield (21.0 mg) as a colorless oil. 1H NMR (300 MHz, chloroform-d): δ 10.26 (s, 1H), 7.20 (dh, J = 3.8, 2.1 Hz, 3H), 7.13−7.06 (m, 1H), 7.05−6.96 (m, 2H), 6.93 (dd, J = 7.7, 1.7 Hz, 1H), 6.79−6.67 (m, 2H), 6.22 (qd, J = 7.1, 1.7 Hz, 1H), 4.85−4.76 (m, 2H), 4.74−4.68 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.06 (qd, J = 7.1, 1.3 Hz, 2H), 3.89 (ddd, J = 7.3, 1.8, 1.0 Hz, 1H), 1.66 (dd, J = 7.0, 0.9 Hz, 3H), 1.26−1.15 (m, 6H). 13C NMR (75 MHz, chloroform-d): δ 169.9, 169.5, 167.5, 157.6, 135.4, 133.0, 129.3 (2C), 128.8, 128.3 (2C), 128.2, 128.1, 128.0, 119.7, 119.1, 117.5, 73.9, 66.8, 64.5, 62.9, 62.3, 52.5, 15.6, 13.97, 13.91. HRMS (ESITOF): calcd for C26H30NO7 (M + H+) 468.2022, found 468.2021. IR (KBr) ν (neat, cm−1): 3458, 2997, 1731, 1724, 1638, 1504. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(3-ethoxy-2hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3ba). Following the general procedure, after reacting for 4 h, 3ba was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 90% yield (44.8 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.03 (s, 1H), 7.37 (d, J = 6.1 Hz, 5H), 6.87 (dd, J = 8.1, 1.6 Hz, 1H), 6.82 (t, J = 7.8 Hz, 1H), 6.73 (dd, J = 7.6, 1.6 Hz, 1H), 5.54 (q, J = 2.6 Hz, 1H), 5.17 (d, J = 12.4 Hz, 1H), 5.13 (s, 1H), 5.11 (d, J = 2.6 Hz, 1H), 4.38−4.26 (m, 4H), 4.11 (qd, J = 7.0, 4.6 Hz, 2H), 3.85 (dd, J = 2.6, 1.3 Hz, 1H), 3.83−3.77 (m, 1H), 1.49 (t, J = 7.0 Hz, 3H), 1.34 (td, J = 7.1, 4.4 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.9, 168.6, 165.8, 161.1, 147.7, 145.8, 135.9, 128.5 (2C), 128.4 (2C), 128.2, 123.7, 121.2, 119.3, 114.2, 112.8, 70.9, 66.0, 65.3, 64.3, 62.6, 62.5, 38.4, 14.9, 14.01, 13.98. HRMS (ESI-TOF): calcd for C27H32NO8 (M + H+) 498.2128, found 498.2133. IR (KBr) ν (neat, cm−1): 3465, 2990, 1733, 1721, 1632, 1506. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(2-hydroxy-5methylphenyl)pyrrolidine-2,2-dicarboxylate (3ca). Following the general procedure, after reacting for 4 h, 3ca was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 92% yield (43.0 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.60 (s, 1H), 7.40−7.35 (m, 5H), 7.05 (dd, J = 8.3, 2.2 Hz, 1H), 6.83−6.75 (m, 2H), 5.51 (d, J = 2.6 Hz, 1H), 5.18 (d, J = 12.4 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 4.92 (d, J = 2.5 Hz, 1H), 4.39−4.30 (m, 4H), 3.96− 3.86 (m, 1H), 3.83 (s, 1H), 2.30 (s, 3H), 1.36 (td, J = 7.2, 3.9 Hz, 6H). 13 C NMR (126 MHz, chloroform-d): δ 170.6, 168.7, 165.7, 160.6, 154.5, 135.8, 130.4, 129.9, 128.6 (2C), 128.4 (2C), 128.3 (2C), 121.9, 117.6, 114.4, 70.6, 66.8, 66.2, 62.8, 62.6, 38.4, 20.4, 14.02, 13.97. HRMS (ESI-TOF): calcd for C26H30NO7 (M + H+) 468.2022, found 468.2026. IR (KBr) ν (neat, cm−1): 3462, 2984, 1734, 1721, 1635, 1505.

= 7.1 Hz, 2H), 3.85−3.64 (m, 2H), 1.24 (td, J = 7.1, 2.8 Hz, 6H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, chloroform-d): δ 165.8, 159.4, 156.9, 129.9 (2C), 129.4 (2C), 122.3, 119.4, 117.8, 114.8, 70.6, 66.7, 62.8, 62.6, 60.1, 38.2, 14.2, 14.0 13.9. HRMS (ESI-TOF): calcd for C20H26NO7 (M + H+) 392.1709, found 392.1710. IR (KBr) ν (neat, cm−1): 3463, 2996, 1736, 1724, 1638, 1506. Diethyl (E)-5-(2-Hydroxyphenyl)-4-(2-oxo-2-propoxyethylidene)pyrrolidine-2,2-dicarboxylate (3ad). Following the general procedure, after reacting for 6 h, 3ad was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 88% yield (35.7 mg) as a colorless oil. 1H NMR (300 MHz, chloroform-d): δ 9.83 (s, 1H), 7.15 (td, J = 7.7, 1.7 Hz, 1H), 6.97−6.89 (m, 1H), 6.78 (t, J = 7.0 Hz, 2H), 5.32 (q, J = 2.6 Hz, 1H), 4.87 (q, J = 2.0 Hz, 1H), 4.35−4.14 (m, 4H), 3.95 (td, J = 6.8, 2.2 Hz, 2H), 3.78−3.58 (m, 2H), 1.55 (q, J = 7.1 Hz, 2H), 1.24 (td, J = 7.1, 2.6 Hz, 6H), 0.84 (t, J = 7.4 Hz, 3H). 13 C NMR (75 MHz, chloroform-d): δ 170.5, 168.7, 165.9, 159.4, 156.9, 129.9, 129.4, 122.3, 119.4, 117.8, 114.9, 70.6, 66.7, 65.9, 62.8, 62.6, 38.2, 21.9, 14.00, 13.9, 10.4. HRMS (ESI-TOF): calcd for C21H28NO7 (M + H+) 406.1866, found 406.1866. IR (KBr) ν (neat, cm−1): 3463, 2996, 1736, 1724, 1638, 1504. Diethyl (E)-4-(2-Butoxy-2-oxoethylidene)-5-(2-hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3ae). Following the general procedure, after reacting for 6 h, 3ae was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 77% yield (32.3 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.94 (s, 1H), 7.27 (ddd, J = 8.9, 7.5, 1.7 Hz, 1H), 7.03 (dd, J = 7.4, 1.7 Hz, 1H), 6.92−6.87 (m, 2H), 5.42 (q, J = 2.6 Hz, 1H), 4.98 (q, J = 2.1 Hz, 1H), 4.39−4.30 (m, 4H), 4.14−4.07 (m, 2H), 3.87 (ddd, J = 20.3, 2.6, 1.2 Hz, 1H), 3.78 (dt, J = 20.2, 2.7 Hz, 1H), 1.66−1.60 (m, 2H), 1.44−1.37 (m, 2H), 1.35 (td, J = 7.1, 4.8 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, chloroform-d): δ 170.6, 168.7, 166.0, 159.3, 157.0, 129.9, 129.5, 122.3, 119.5, 117.9, 114.9, 70.6, 66.7, 64.1, 62.8, 62.6, 38.3, 30.6, 19.1, 14.0, 13.95, 13.6. HRMS (ESI-TOF): calcd for C22H30NO7 (M + H+) 420.2022, found 420.2022. IR (KBr) ν (neat, cm−1): 3464, 2997, 1732, 1722, 1635, 1502. Diethyl (E)-5-(2-Hydroxyphenyl)-4-(2-oxo-2phenethoxyethylidene)pyrrolidine-2,2-dicarboxylate (3af). Following the general procedure, after reacting for 6 h, 3af was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 82% yield (38.3 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.88 (s, 1H), 7.33 (dd, J = 8.1, 6.7 Hz, 2H), 7.28−7.21 (m, 4H), 7.03 (dd, J = 7.5, 1.7 Hz, 1H), 6.93−6.87 (m, 2H), 5.43 (q, J = 2.6 Hz, 1H), 4.98 (q, J = 2.0 Hz, 1H), 4.39−4.30 (m, 6H), 3.82 (ddd, J = 20.3, 2.6, 1.3 Hz, 1H), 3.75 (dt, J = 20.3, 2.7 Hz, 1H), 2.96 (t, J = 7.2 Hz, 2H), 1.36 (td, J = 7.1, 3.0 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.5, 168.7, 165.8, 159.7, 157.0, 137.7, 129.9, 129.5, 128.8, 128.5 (2C), 126.5, 122.3, 119.5, 117.9, 117.3, 114.8, 70.6, 66.8, 64.8, 62.8, 62.6, 38.3, 35.1, 14.0, 13.97. HRMS (ESI-TOF): calcd for C26H30NO7 (M + H+) 468.2022, found 468.2023. IR (KBr) ν (neat, cm−1): 3469, 2993, 1736, 1724, 1635, 1509. Diethyl (E)-5-(2-Hydroxyphenyl)-4-(2-(3-methoxypropoxy)-2oxoethylidene)pyrrolidine-2,2-dicarboxylate (3ag). Following the general procedure, after reacting for 6 h, 3ag was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 82% yield (35.7 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.95 (s, 1H), 7.26 (d, J = 1.6 Hz, 1H), 7.02 (dd, J = 7.4, 1.6 Hz, 1H), 6.89 (d, J = 7.8 Hz, 2H), 5.42 (d, J = 2.6 Hz, 1H), 4.97 (d, J = 2.7 Hz, 1H), 4.40−4.27 (m, 4H), 4.19 (td, J = 6.4, 3.7 Hz, 2H), 3.84 (dd, J = 2.6, 1.2 Hz, 1H), 3.80 (t, J = 2.8 Hz, 1H), 3.44 (t, J = 6.3 Hz, 2H), 3.34 (s, 3H), 1.90 (p, J = 6.4 Hz, 2H), 1.35 (td, J = 7.1, 4.7 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.5, 168.7, 165.8, 159.6, 157.0, 129.9, 129.5, 122.3, 119.5, 117.8, 114.7, 70.6, 69.1, 66.7, 62.8, 62.6, 61.5, 58.6, 38.3, 28.9, 14.0, 13.95. HRMS (ESI-TOF): calcd for C22H30NO8 (M + H+) 436.1971, found 436.1972. IR (KBr) ν (neat, cm−1): 3460, 2993, 1732, 1722, 1636, 1501. Diethyl (E)-5-(2-Hydroxyphenyl)-4-(2-oxo-3,3diphenylpropylidene)pyrrolidine-2,2-dicarboxylate (3ah). Following the general procedure, after reacting for 12 h, 3ah was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 58% yield (30.7 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.89 (s, 12731

DOI: 10.1021/acs.joc.7b02560 J. Org. Chem. 2017, 82, 12726−12734

Article

The Journal of Organic Chemistry Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(3,5-di-tert-butyl2-hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3da). Following the general procedure, after reacting for 12 h, 3da was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 68% yield (38.4 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.77 (s, 1H), 7.38 (d, J = 3.9 Hz, 5H), 7.32 (d, J = 2.4 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 5.47 (d, J = 2.6 Hz, 1H), 5.20 (d, J = 12.3 Hz, 1H), 5.14 (d, J = 12.3 Hz, 1H), 4.96 (s, 1H), 4.39−4.30 (m, 4H), 3.88 (dd, J = 2.6, 1.3 Hz, 1H), 3.85 (t, J = 2.7 Hz, 1H), 1.43 (s, 9H), 1.38−1.35 (m, 6H), 1.34 (d, J = 1.3 Hz, 9H). 13C NMR (126 MHz, chloroform-d): δ 170.6, 168.7, 165.9, 161.0, 153.5, 140.9, 137.4, 135.9, 128.6 (2C), 128.5, 128.4, 128.3, 124.5, 124.2, 121.4, 113.9, 70.5, 67.8, 66.1, 62.7, 62.5, 38.4, 35.1, 34.2, 31.6 (3C), 29.7 (3C), 14.02, 13.95. HRMS (ESITOF): calcd for C33H44NO7 (M + H+) 566.3118, found 566.3120. IR (KBr) ν (neat, cm−1): 3465, 2988, 1732, 1720, 1633, 1502. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(4-(diethylamino)-2-hydroxy-phenyl)pyrrolidine-2,2-dicarboxylate (3ea). Following the general procedure, after reacting for 6 h, 3ea was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 88% yield (46.2 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.67 (s, 1H), 7.38 (d, J = 3.8 Hz, 5H), 6.83 (d, J = 8.3 Hz, 1H), 6.24− 6.17 (m, 2H), 5.56 (q, J = 2.6 Hz, 1H), 5.18 (d, J = 12.3 Hz, 1H), 5.12 (d, J = 12.3 Hz, 1H), 4.88 (s, 1H), 4.37−4.28 (m, 4H), 3.90−3.84 (m, 1H), 3.80 (dt, J = 20.3, 2.7 Hz, 1H), 3.35 (t, J = 7.1 Hz, 4H), 1.34 (dt, J = 7.1, 3.6 Hz, 6H), 1.19 (t, J = 7.0 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.7, 168.9, 165.9, 161.4, 157.9, 149.5, 135.9, 130.2, 128.5 (2C), 128.4 (2C), 128.2, 114.0, 109.2, 103.2, 100.6, 70.3, 66.6, 66.0, 62.7, 62.5, 62.2, 44.3, 38.3, 14.02, 13.97, 12.7. HRMS (ESITOF): calcd for C29H37N2O7 (M + H+) 525.2601, found 525.2602. IR (KBr) ν (neat, cm−1): 3463, 2994, 1734, 1721, 1635, 1504. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(5-chloro-2hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3fa). Following the general procedure, after reacting for 4 h, 3fa was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 78% yield (38.1 mg) as a yellow oil. 1H NMR (500 MHz, chloroform-d): δ 9.91 (s, 1H), 7.37 (d, J = 5.5 Hz, 5H), 7.21 (dd, J = 8.7, 2.6 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 5.51 (q, J = 2.6 Hz, 1H), 5.18 (d, J = 12.3 Hz, 1H), 5.12 (d, J = 12.4 Hz, 1H), 4.92 (d, J = 2.5 Hz, 1H), 4.39−4.30 (m, 4H), 3.90 (ddd, J = 20.3, 2.6, 1.2 Hz, 1H), 3.79 (dt, J = 20.4, 2.8 Hz, 1H), 1.35 (td, J = 7.1, 4.7 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.3, 168.6, 165.5, 159.5, 155.6, 135.7, 129.8, 129.0, 128.6 (2C), 128.4 (2C), 128.3, 124.1, 123.7, 119.3, 114.8, 70.6, 66.3, 66.2, 62.9, 62.7, 38.3, 14.00, 13.95. HRMS (ESI-TOF): calcd for C25H27ClNO7 (M + H+) 488.1476, found 488.1475. IR (KBr) ν (neat, cm−1): 3465, 2996, 1733, 1720, 1638, 1506. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(5-bromo-2hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3ga). Following the general procedure, after reacting for 4 h, 3ga was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 81% yield (43.1 mg) as a yellow oil. 1H NMR (500 MHz, chloroform-d): δ 9.96 (s, 1H), 7.39−7.32 (m, 6H), 7.14 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.6 Hz, 1H), 5.51 (q, J = 2.6 Hz, 1H), 5.19 (d, J = 12.3 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 4.95−4.89 (m, 1H), 4.38−4.28 (m, 4H), 3.87 (dd, J = 2.6, 1.2 Hz, 1H), 3.81 (d, J = 2.8 Hz, 1H), 1.35 (td, J = 7.1, 4.4 Hz, 6H). 13 C NMR (126 MHz, chloroform-d): δ 170.3, 168.6, 165.5, 159.5, 156.2, 135.7, 132.7, 131.8, 128.6 (2C), 128.4 (2C), 128.4, 124.2, 119.8, 114.8, 111.2, 70.6, 66.3, 66.1, 62.9, 62.7, 38.3, 14.00, 13.95. HRMS (ESI-TOF): calcd for C25H27BrNO7 (M + H+) 532.0971, found 532.0968. IR (KBr) ν (neat, cm−1): 3469, 2999, 1736, 1723, 1639, 1504. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(3,5-dichloro-2hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3ha). Following the general procedure, after reacting for 6 h, 3ha was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 62% yield (32.4 mg) as a yellow oil. 1H NMR (500 MHz, chloroform-d): δ 9.96 (s, 1H), 7.38 (d, J = 5.3 Hz, 6H), 6.95 (d, J = 2.5 Hz, 1H), 5.50 (t, J = 2.6 Hz, 1H), 5.19 (d, J = 12.3 Hz, 1H), 5.15 (d, J = 2.3 Hz, 1H), 4.98 (d, J = 2.6 Hz, 1H), 4.38−4.31 (m, 4H), 3.87 (dd, J = 2.6, 1.2 Hz, 1H), 3.84− 3.75 (m, 1H), 1.37−1.34 (m, 6H). 13C NMR (126 MHz, chloroformd): δ 170.3, 168.2, 165.3, 158.8, 151.6, 135.6, 129.9, 128.7, 128.6,

128.5, 128.5, 128.4, 127.5, 124.7, 124.1, 123.2, 115.2, 70.7, 66.4, 65.9, 63.0, 62.9, 38.2, 13.97, 13.96. HRMS (ESI-TOF): calcd for C25H26Cl2NO7 (M + H+) 522.1086, found 522.1087. IR (KBr) ν (neat, cm−1): 3473, 2997, 1736, 1724, 1635, 1507. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(3,5-dibromo-2hydroxyphenyl)pyrrolidine-2,2-dicarboxylate (3ia). Following the general procedure, after reacting for 6 h, 3ia was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 70% yield (42.8 mg) as a yellow oil. 1H NMR (500 MHz, chloroform-d): δ 9.98 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.40−7.37 (m, 5H), 7.12 (d, J = 2.4 Hz, 1H), 5.50 (q, J = 2.7 Hz, 1H), 5.19 (d, J = 12.2 Hz, 1H), 5.15 (s, 1H), 4.96 (d, J = 2.5 Hz, 1H), 4.37−4.31 (m, 4H), 3.86 (dd, J = 2.6, 1.2 Hz, 1H), 3.82 (d, J = 2.8 Hz, 1H), 1.35 (d, J = 7.2 Hz, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.3, 168.2, 165.3, 158.8, 153.0, 135.6, 135.4, 131.1, 128.7, 128.7, 128.6, 128.5, 128.4, 125.1, 115.2, 112.7, 111.2, 70.6, 66.4, 65.9, 63.0, 62.9, 38.2, 13.99, 13.96. HRMS (ESI-TOF): calcd for C25H26Br2NO7 (M + H+) 612.0066, found 612.0064. IR (KBr) ν (neat, cm−1): 3479, 2999, 1738, 1723, 1636, 1505. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(3-bromo-5chloro-2-hydroxy-phenyl)pyrrolidine-2,2-dicarboxylate (3ja). Following the general procedure, after reacting for 6 h, 3ja was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 76% yield (43.1 mg) as a yellow oil. 1H NMR (500 MHz, chloroform-d): δ 9.98 (s, 1H), 7.52 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 5.6 Hz, 5H), 6.99 (d, J = 2.5 Hz, 1H), 5.50 (q, J = 2.6 Hz, 1H), 5.19 (d, J = 12.3 Hz, 1H), 5.14 (d, J = 9.9 Hz, 1H), 4.97 (d, J = 2.7 Hz, 1H), 4.35−4.30 (m, 4H), 3.88 (ddd, J = 20.4, 2.7, 1.2 Hz, 1H), 3.80 (dt, J = 20.4, 2.8 Hz, 1H), 1.35 (s, 6H). 13C NMR (126 MHz, chloroform-d): δ 170.3, 168.2, 165.3, 158.8, 152.5, 139.0, 135.6, 132.7, 128.6, 128.5, 128.4, 128.3, 124.5, 124.4, 124.3, 115.2, 112.2, 70.7, 68.8, 66.4, 66.0, 62.8, 38.2, 14.01, 13.96. HRMS (ESI-TOF): calcd for C25H26ClBrNO7 (M + H+) 566.0581, found 566.0581. IR (KBr) ν (neat, cm−1): 3476, 2994, 1734, 1720, 1634, 1503. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(2-hydroxy-5nitrophenyl)pyrrolidine-2,2-dicarboxylate (3ka). Following the general procedure, after reacting for 6 h, 3ka was isolated by silica gel chromatography (petroleum ether/AcOEt 3:1) in 79% yield (39.4 mg) as a yellow oil. 1H NMR (300 MHz, chloroform-d): δ 11.03 (s, 1H), 8.09−8.02 (m, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.25 (d, J = 2.9 Hz, 5H), 6.83 (d, J = 9.0 Hz, 1H), 5.36 (d, J = 2.6 Hz, 1H), 5.04 (d, J = 4.6 Hz, 2H), 4.99 (d, J = 3.0 Hz, 1H), 4.24 (dt, J = 8.7, 7.1 Hz, 4H), 3.80 (s, 1H), 3.70 (s, 1H), 1.28−1.22 (m, 6H). 13C NMR (75 MHz, chloroform-d): δ 170.0, 168.5, 165.2, 163.3, 158.6, 140.3, 135.5, 128.6 (2C), 128.4 (2C), 126.1 (2C), 125.3, 122.4, 118.3, 115.2, 70.6, 66.4, 65.9, 63.1, 62.9, 38.2, 13.97, 13.92. HRMS (ESI-TOF): calcd for C25H27N2O9 (M + H+) 499.1717, found 499.1720. IR (KBr) ν (neat, cm−1): 3481, 2998, 1736, 1721, 1635, 1507. Diethyl 4-(2-(Benzyloxy)-2-oxoethyl)-5-(2-hydroxynaphthalen-1yl)-1,3-dihydro-2H-pyrrole-2,2-dicarboxylate (3la). Following the general procedure, after reacting for 12 h, 3la was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 52% yield (26.2 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 10.38 (s, 1H), 7.83 (t, J = 8.0 Hz, 2H), 7.75 (d, J = 8.9 Hz, 1H), 7.54 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.38 (ddd, J = 8.2, 6.8, 1.3 Hz, 2H), 7.32 (d, J = 2.8 Hz, 2H), 7.26 (dd, J = 6.8, 2.9 Hz, 2H), 7.04 (d, J = 8.8 Hz, 1H), 5.37 (s, 1H), 5.12 (d, J = 12.3 Hz, 1H), 5.08 (d, J = 12.2 Hz, 1H), 4.26 (qd, J = 7.1, 1.3 Hz, 2H), 3.86 (dq, J = 10.8, 7.1 Hz, 1H), 3.67 (dq, J = 10.7, 7.1 Hz, 1H), 3.33 (d, J = 14.6 Hz, 1H), 2.91 (d, J = 14.6 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.83 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, chloroform-d): δ 170.0, 169.9, 169.2, 156.7, 135.4, 131.1, 130.5, 129.7, 128.9, 128.5 (2C), 128.2 (2C), 128.2 (2C), 127.4, 123.3, 122.1, 119.5, 112.1, 95.9, 73.2, 68.4, 66.7, 62.3, 44.7, 42.2, 13.9, 13.4. HRMS (ESITOF): calcd for C29H30NO7 (M + H+) 504.2022, found 504.2028. IR (KBr) ν (neat, cm−1): 3477, 2995, 1732, 1722, 1631, 1505. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(2-hydroxyphenyl)-5-methylpyrrolidine-2,2-dicarboxylate (3ma). Following the general procedure, after reacting for 12 h, 3ma was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 62% yield (29.0 mg) as a colorless oil. 1H NMR (300 MHz, chloroform-d): δ 14.80 (s, 1H), 12.19 (s, 1H), 7.47 (dd, J = 8.1, 1.6 Hz, 1H), 7.31−7.24 (m, 5H), 12732

DOI: 10.1021/acs.joc.7b02560 J. Org. Chem. 2017, 82, 12726−12734

Article

The Journal of Organic Chemistry 6.95−6.81 (m, 2H), 6.76 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 5.89 (dd, J = 15.6, 1.4 Hz, 1H), 5.09 (s, 2H), 4.22 (qd, J = 7.1, 1.8 Hz, 4H), 3.09 (dd, J = 7.5, 1.5 Hz, 2H), 2.24 (s, 3H), 1.23−1.18 (m, 6H). 13C NMR (126 MHz, chloroform-d): δ 173.7, 168.8, 165.3, 162.3, 141.6, 136.0, 133.2, 132.8, 128.5, 128.4, 128.4, 128.2, 128.1, 125.5, 120.1, 118.7, 117.7, 72.7, 66.2, 62.7 (2C), 62.7, 39.7, 18.9, 14.0 (2C). HRMS (ESITOF): calcd for C26H30NO7 (M + H+) 468.2022, found 468.2021. IR (KBr) ν (neat, cm−1): 3457, 2998, 1733, 1722, 1637, 1502. 4-Benzyl 2-Ethyl 5-(2-Hydroxyphenyl)-3-methyl-2,5-dihydro-1Hpyrrole-2,4-dicarboxylate (3na). Following the general procedure, after reacting for 12 h, 3na was isolated by silica gel chromatography (petroleum ether/AcOEt 5:1) in 38% yield (14.5 mg) as a colorless oil. 1H NMR (500 MHz, chloroform-d): δ 9.66 (s, 1H), 7.40 (d, J = 3.8 Hz, 5H), 7.26 (s, 1H), 7.00 (d, J = 1.7 Hz, 1H), 6.91 (dd, J = 8.2, 1.2 Hz, 1H), 6.86 (d, J = 1.3 Hz, 1H), 5.31 (d, J = 12.3 Hz, 1H), 5.20− 5.13 (m, 2H), 4.98−4.89 (m, 1H), 4.12 (qd, J = 7.2, 3.0 Hz, 2H), 1.96 (t, J = 1.5 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, chloroform-d): δ 172.1, 163.0, 157.7, 156.3, 135.5, 129.9, 129.4, 128.6 (2C), 128.4 (2C), 128.3, 124.1, 121.9, 119.1, 117.9, 73.3, 66.4, 65.8, 61.7, 13.9, 13.7. HRMS (ESI-TOF): calcd for C22H24NO5 (M + H+) 382.1654, found 382.1656. IR (KBr) ν (neat, cm−1): 3453, 2994, 1732, 1724, 1636, 1501. General Procedure for the Synthesis of 4. A mixture of 3aa (0.15 mmol, 68.0 mg) and a formaldehyde solution (37%) (stabilized with methanol) (0.30 mmol, 25.0 mg) in THF (2.0 mL) was prepared. The resulting solution was stirred at room temperature under an argon atmosphere for 12 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/AcOEt 5:1) to give the colorless oil 4 in 86% (60.0 mg) yield.19 Diethyl 1-(2-(Benzyloxy)-2-oxoethyl)-5H-benzo[e]pyrrolo[1,2-c][1,3]oxazine-3,3(2H)-dicarboxylate (4). 1H NMR (300 MHz, chloroform-d): δ 7.40−7.21 (m, 5H), 7.14−7.00 (m, 2H), 6.84 (td, J = 7.5, 1.3 Hz, 1H), 6.64 (dd, J = 8.1, 1.3 Hz, 1H), 6.18 (td, J = 2.7, 1.5 Hz, 1H), 5.36−5.29 (m, 2H), 5.13 (s, 2H), 5.04 (d, J = 11.2 Hz, 1H), 4.28−4.14 (m, 2H), 4.04−3.99 (m, 1H), 4.00−3.82 (m, 2H), 3.32 (dd, J = 20.0, 2.8 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). 13 C NMR (75 MHz, chloroform-d): δ 170.30, 170.27, 165.6, 159.7, 154.2, 135.9, 128.6, 128.4 (2C), 128.30, 128.28, 125.4, 121.3, 121.2, 117.2, 114.6, 114.4, 76.1, 71.5, 66.2, 62.9, 62.5, 61.9, 39.6, 14.0, 13.4. HRMS (ESI-TOF): calcd for C26H28NO7 (M + H+) 466.1866, found 466.1861. IR (KBr) ν (neat, cm−1): 3020, 2995, 1737, 1733, 1630, 1503. General Procedure for the Synthesis of 5. A mixture of 3aa (0.15 mmol, 68.0 mg) and bis(trichlormethyl)carbonate (0.30 mmol, 89.1 mg) in anhydrous CH2Cl2 (2.0 mL) was prepared. The resulting solution was stirred at room temperature under an argon atmosphere for 12 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/AcOEt 5:1) to give the colorless oil 5 in 78% (56.1 mg) yield.20 Diethyl 1-(2-(Benzyloxy)-2-oxoethyl)-5-oxo-5H-benzo[e]pyrrolo[1,2-c][1,3]oxazine-3,3(2H)-dicarboxylate (5). 1H NMR (300 MHz, chloroform-d): δ 7.59 (dd, J = 8.1, 1.5 Hz, 1H), 7.41−7.17 (m, 6H), 7.13−7.01 (m, 2H), 5.09 (s, 2H), 4.23 (q, J = 7.1 Hz, 4H), 3.42 (s, 2H), 3.36 (s, 2H), 1.23 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, chloroform-d): δ 169.3, 167.6 (2C), 150.6, 135.3, 131.0 (2C), 129.8, 128.6, 128.4, 128.2, 124.8 (2C), 124.7, 117.2 (2C), 114.0, 105.5, 71.2, 67.1, 62.8 (2C), 44.2, 33.7, 13.9. HRMS (ESI-TOF): calcd for C26H26NO8 (M + H+) 480.1658, found 480.1652. IR (KBr) ν (neat, cm−1): 3024, 2997, 1736, 1732, 1713, 1629, 1506. General Procedure for the Synthesis of 6. To a mixture of 3aa (0.15 mmol, 68.0 mg) and Et3N (0.30 mmol, 30.3 mg) in anhydrous CH2Cl2 (2.0 mL) was added slowly thionyl chloride (0.3 mmol, 35.7 mg). The resulting solution was stirred at room temperature under an argon atmosphere for 12 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/ AcOEt 5:1) to give the colorless oil 6 in 66% (49.5 mg) yield.21 Diethyl 1-(2-(Benzyloxy)-2-oxoethyl)benzo[e]pyrrolo[1,2-c][1,2,3]oxathiazine-3,3(2H)-dicarboxylate 5-Oxide (6). 1H NMR (300 MHz, chloroform-d): δ 7.55 (dd, J = 7.9, 1.7 Hz, 1H), 7.39− 7.23 (m, 6H), 7.20 (s, 1H), 7.02 (dd, J = 8.4, 1.2 Hz, 1H), 6.85 (ddd, J

= 8.4, 7.3, 1.2 Hz, 1H), 6.53 (t, J = 2.7 Hz, 1H), 5.18 (s, 2H), 4.22 (qd, J = 7.1, 0.8 Hz, 4H), 3.71 (d, J = 2.7 Hz, 2H), 1.27−1.22 (m, 6H). 13C NMR (75 MHz, chloroform-d): δ 174.1, 167.9, 165.7, 159.7, 153.8, 133.3 (2C), 129.0 (2C), 128.6, 128.5, 128.5, 120.0 (2C), 118.9 (2C), 118.1, 66.9, 62.6 (2C), 37.4 (2C), 13.9 (2C). HRMS (ESI-TOF): calcd for C25H26NO8S (M + H+) 500.1379, found 500.1381. IR (KBr) ν (neat, cm−1): 3028, 2995, 1733, 1727, 1630, 1505. General Procedure for the Synthesis of 7. To a mixture of 3aa (0.15 mmol, 68.0 mg) and ethyl propiolate (0.18 mmol, 18.0 mg) in anhydrous CH2Cl2 (2.0 mL) was added PPh3 (0.03 mmol, 8.0 mg). The resulting solution was stirred at room temperature under an argon atmosphere for 2 h. After removal of the solvent, the product was purified through silica gel chromatography (petroleum ether/AcOEt 5:1) to give the colorless oil 7 in 62% (51.3 mg) yield. Diethyl (E)-4-(2-(Benzyloxy)-2-oxoethylidene)-5-(2-(((E)-3-ethoxy3-oxoprop-1-en-1-yl)oxy)phenyl)pyrrolidine-2,2-dicarboxylate (7). 1 H NMR (500 MHz, chloroform-d): δ 10.07 (s, 1H), 7.77 (d, J = 12.2 Hz, 1H), 7.52 (dd, J = 7.7, 1.6 Hz, 1H), 7.36 (d, J = 7.5 Hz, 6H), 7.22 (td, J = 7.6, 1.1 Hz, 1H), 7.07 (dd, J = 8.2, 1.1 Hz, 1H), 5.57 (d, J = 12.3 Hz, 1H), 5.52 (q, J = 2.6 Hz, 1H), 5.34 (q, J = 1.9 Hz, 1H), 5.20−5.13 (m, 2H), 4.34−4.25 (m, 4H), 4.25−4.19 (m, 2H), 3.79 (t, J = 2.3 Hz, 2H), 1.32 (dt, J = 7.2, 3.5 Hz, 9H). 13C NMR (126 MHz, chloroform-d): δ 171.7, 169.1, 167.0, 165.9, 163.0, 158.9, 153.6, 136.0 131.8, 130.1, 129.5, 128.5 (2C), 128.3 (2C), 128.2, 125.6, 118.1, 113.7, 102.7, 71.5, 66.0, 62.3, 62.1, 61.0, 60.1, 38.6, 14.3, 14.0, 13.99. HRMS (ESI-TOF): calcd for C30H34NO9 (M + H+) 552.2234, found 552.2235. IR (KBr) ν (neat, cm−1): 3474, 2989, 1734, 1721, 1720, 1630, 1504.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02560. Crystallographic data for compound 3aa in CIF format (CIF) ORTEP drawing of 3aa and 1H and 13C NMR spectra of key substrates and final products (PDF)

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AUTHOR INFORMATION

Corresponding Author

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

Qingfa Zhou: 0000-0001-6360-2285 Notes

The authors declare no competing financial interest. CCDC 1570006 contains the supplementary crystallographic data for compound 3aa. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grant No. 21102179 and 21572271), Qing Lan Project of Jiangsu Province, National Found for Fostering Talents of Basic Science (Grant no. J1030830).

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REFERENCES

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