catalysts Syntheses of 3,3-Disubstituted Dihydrobenzofurans, Indolines, Indolinones and Isochromanes by Palladium-Catalyzed Tandem Reaction Using Pd(PPh 3 ) 2 Cl 2 / ( ± )-BINAP as a Catalytic System

: A general procedure for the tandem arylation reaction of arylbromide with heteroaryl compounds was developed by using Pd(PPh 3 ) 2 Cl 2 / ( ± )-BINAP (1,1 (cid:48) -Binaphthalene-2,2 (cid:48) -diylbis (diphenylphosphane)) as catalytic system. Both sulphur- and oxygen-containing heterocycles were also employed as an e ﬃ cient reagent for arylation, which gave moderate to excellent yields with moderate to good regioselectivities (5:1 to > 20:1 ir (isomer ratio)). Except for dihydrobenzofurans, indolines and indolinones, this type of tandem reaction was also expanded to synthesize isochromanes. The synthesized new compounds were well characterized through di ﬀ erent spectroscopic techniques, such as 1 H and 13 C NMR (nuclear magnetic resonance), and mass spectral analysis.


Results and Discussion
Initially, we also tried to perform the same reaction with palladium salts and chiral P and N,Pligands (for example: (R)-BINAP, (R)-SDP (spiro-di(1,1′-indanyl)bisphosphine), (R)-Segphos and spiro-phosporamidites) and expected to realize an asymmetric synthesis edition in the condition reported by Fagnou's group [62]. Nevertheless, it was unlucky to not obtain satisfying enantioselectivity (0-10% ee). We found the (R)-BINAP and Pd salts catalyzed the reaction to give the desired product in a satisfying yield, although it could not induce chirally in the process of a reaction. As a common phosphine ligand, the price of (±)-BINAP (162 RMB/mmol from Sigma-Aldrich (Shanghai, China) Trading Co., Shanghai, China) is cheaper than the one of X-phos (348 RMB/mmol from Sigma-Aldrich Sigma-Aldrich (Shanghai) Trading Co.) and other phosphine ligands with more efficiency. Furthermore, BINAP has been widely applied in all kinds of catalyzed symmetric or asymmetric syntheses as a ligand. As a necessary and useful supplement of Fagnou's work, we decided to make our efforts in further developing Pd(PPh3)2/(±)-BINAP as an efficient catalyst to be used in the synthesis of 3,3-substituted 5 or 6-membered heterocycles, on the basis of the above experimental results.

Results and Discussion
Initially, we also tried to perform the same reaction with palladium salts and chiral P and N,P-ligands (for example: (R)-BINAP, (R)-SDP (spiro-di(1,1 -indanyl)bisphosphine), (R)-Segphos and spiro-phosporamidites) and expected to realize an asymmetric synthesis edition in the condition reported by Fagnou's group [62]. Nevertheless, it was unlucky to not obtain satisfying enantioselectivity (0-10% ee). We found the (R)-BINAP and Pd salts catalyzed the reaction to give the desired product in a satisfying yield, although it could not induce chirally in the process of a reaction. As a common phosphine ligand, the price of (±)-BINAP (162 RMB/mmol from Sigma-Aldrich (Shanghai, China) Trading Co., Shanghai, China) is cheaper than the one of X-phos (348 RMB/mmol from Sigma-Aldrich Sigma-Aldrich (Shanghai) Trading Co.) and other phosphine ligands with more efficiency. Furthermore, BINAP has been widely applied in all kinds of catalyzed symmetric or asymmetric syntheses as a ligand. As a necessary and useful supplement of Fagnou's work, we decided to make our efforts in further developing Pd(PPh 3 ) 2 /(±)-BINAP as an efficient catalyst to be used in the synthesis of 3,3-substituted 5 or 6-membered heterocycles, on the basis of the above experimental results.
(TEA) and pyridine were distilled from calcium hydride under argon; toluene and dioxane were distilled from Na/benzophenone under argon; and methanol (MeOH) was distilled from Mg/I 2 under argon. Flash chromatography was performed using silica gel (300-400 mesh). Reactions were monitored by TLC (thin-layer chromatography). Visualization was achieved under a UV (Ultraviolet) lamp (254 nm and 365 nm), I 2 and by developing the plates with para-anisaldehyde, phosphomolybdic acid, or potassium permanganate. 1 H and 13 C NMR were recorded on a 400 MHz NMR spectrometer with tetramethylsilane (TMS) as the internal standard and were calibrated using a residual nondeuterated solvent as an internal reference (CDCl 3 : 1 H NMR δ = 7.26, 13 C NMR δ = 77.16; DMSO-d 6 : 1 H NMR δ = 2.54, 13 C NMR δ = 40.45). High-resolution mass spectra were obtained using electrospray ionization (ESI). The following abbreviations were used for the multiplicities: s: singlet, d: doublet, t: triplet, m: multiplet and br s: broad singlet for proton spectra. Coupling constants (J) are reported in Hertz (Hz).

General Procedure A for the Preparation of O or N-methylallyl Arylbromides
All non-aqueous reactions were carried out using flame-dried round-bottomed flasks and Schlenk tubes under an inert atmosphere of argon with dry solvents. All reagents were obtained from commercial suppliers unless otherwise stated. N, N-dimethylformamide (DMF), N, Ndimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile (ACN), benzonitrile, dichloromethane (DCM), triethylamine (TEA) and pyridine were distilled from calcium hydride under argon; toluene and dioxane were distilled from Na/benzophenone under argon; and methanol (MeOH) was distilled from Mg/I2 under argon. Flash chromatography was performed using silica gel (300-400 mesh). Reactions were monitored by TLC (thin-layer chromatography). Visualization was achieved under a UV (Ultraviolet) lamp (254 nm and 365 nm), I2 and by developing the plates with para-anisaldehyde, phosphomolybdic acid, or potassium permanganate. 1 H and 13 C NMR were recorded on a 400 MHz NMR spectrometer with tetramethylsilane (TMS) as the internal standard and were calibrated using a residual nondeuterated solvent as an internal reference (CDCl3: 1 H NMR  = 7.26, 13 C NMR  = 77.16; DMSO-d6: 1 H NMR  = 2.54, 13 C NMR  = 40.45). High-resolution mass spectra were obtained using electrospray ionization (ESI). The following abbreviations were used for the multiplicities: s: singlet, d: doublet, t: triplet, m: multiplet and br s: broad singlet for proton spectra. Coupling constants (J) are reported in Hertz (Hz).

General Procedure A for the Preparation of O or N-methylallyl Arylbromides
To a solution of 2-bromophenol (1.73 g, 10 mmol, 1.0 equiv.) in dry DMF (50 mL), NaH (60%, 440 mg, 11.0 mmol, 1.1 equiv.) was added in three portions at 0 °C , and the mixture was stirred for 30 min. 2-Methallyl chloride (1.08 g, 12.0 mmol, 1.2 equiv.) was added and then the mixture was stirred at rt (room temperature) until the reaction was judged to be completed by TLC analysis. After the completion of the reaction, saturated NH4Cl solution (10 mL) and brine (100 mL) was added, and then extracted with petroleum ether/EtOAc (V/V = 10:1, 3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1a as a colorless oil (1.86 g, 82%) [62]. A solution of 2-bromoaniline (1.72 g, 10 mmol) in Ac2O (5 mL) was stirred at 70 °C for 1 h. The mixture was added dropwise to a saturated NaHCO3 solution (50 mL) at 0 °C and then extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the N-Ac product as a white solid (2.30 g, quantitative yield). The above product (0.85 g, 4.0 mmol, 1 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 °C . The mixture was stirred for 30 min and then 2-methallyl chloride (0.43 mL, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at To a solution of 2-bromophenol (1.73 g, 10 mmol, 1.0 equiv.) in dry DMF (50 mL), NaH (60%, 440 mg, 11.0 mmol, 1.1 equiv.) was added in three portions at 0 • C, and the mixture was stirred for 30 min. 2-Methallyl chloride (1.08 g, 12.0 mmol, 1.2 equiv.) was added and then the mixture was stirred at rt (room temperature) until the reaction was judged to be completed by TLC analysis. After the completion of the reaction, saturated NH 4 Cl solution (10 mL) and brine (100 mL) was added, and then extracted with petroleum ether/EtOAc (V/V = 10:1, 3 × 30 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1a as a colorless oil (1.86 g, 82%) [62]. Schlenk tubes under an inert atmosphere of argon with dry solvents. All reagents were obtained from commercial suppliers unless otherwise stated. N, N-dimethylformamide (DMF), N, Ndimethylacetamide (DMA), dimethyl sulfoxide (DMSO), acetonitrile (ACN), benzonitrile, dichloromethane (DCM), triethylamine (TEA) and pyridine were distilled from calcium hydride under argon; toluene and dioxane were distilled from Na/benzophenone under argon; and methanol (MeOH) was distilled from Mg/I2 under argon. Flash chromatography was performed using silica gel (300-400 mesh). Reactions were monitored by TLC (thin-layer chromatography). Visualization was achieved under a UV (Ultraviolet) lamp (254 nm and 365 nm), I2 and by developing the plates with para-anisaldehyde, phosphomolybdic acid, or potassium permanganate. 1 H and 13 C NMR were recorded on a 400 MHz NMR spectrometer with tetramethylsilane (TMS) as the internal standard and were calibrated using a residual nondeuterated solvent as an internal reference (CDCl3: 1 H NMR  = 7.26, 13 C NMR  = 77.16; DMSO-d6: 1 H NMR  = 2.54, 13 C NMR  = 40.45). High-resolution mass spectra were obtained using electrospray ionization (ESI). The following abbreviations were used for the multiplicities: s: singlet, d: doublet, t: triplet, m: multiplet and br s: broad singlet for proton spectra. Coupling constants (J) are reported in Hertz (Hz).

General Procedure A for the Preparation of O or N-methylallyl Arylbromides
To a solution of 2-bromophenol (1.73 g, 10 mmol, 1.0 equiv.) in dry DMF (50 mL), NaH (60%, 440 mg, 11.0 mmol, 1.1 equiv.) was added in three portions at 0 °C , and the mixture was stirred for 30 min. 2-Methallyl chloride (1.08 g, 12.0 mmol, 1.2 equiv.) was added and then the mixture was stirred at rt (room temperature) until the reaction was judged to be completed by TLC analysis. After the completion of the reaction, saturated NH4Cl solution (10 mL) and brine (100 mL) was added, and then extracted with petroleum ether/EtOAc (V/V = 10:1, 3 × 30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1a as a colorless oil (1.86 g, 82%) [62]. A solution of 2-bromoaniline (1.72 g, 10 mmol) in Ac2O (5 mL) was stirred at 70 °C for 1 h. The mixture was added dropwise to a saturated NaHCO3 solution (50 mL) at 0 °C and then extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the N-Ac product as a white solid (2.30 g, quantitative yield). The above product (0.85 g, 4.0 mmol, 1 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 °C . The mixture was stirred for 30 min and then 2-methallyl chloride (0.43 mL, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at A solution of 2-bromoaniline (1.72 g, 10 mmol) in Ac 2 O (5 mL) was stirred at 70 • C for 1 h. The mixture was added dropwise to a saturated NaHCO 3 solution (50 mL) at 0 • C and then extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the N-Ac product as a white solid (2.30 g, quantitative yield). The above product (0.85 g, 4.0 mmol, 1 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 • C. The mixture was stirred for 30 min and then 2-methallyl chloride (0.43 mL, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at rt overnight, before it was quenched with saturated NH 4 Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 1b (0.83 g, 77%) as a pale yellow solid [70].  To a solution of 2-bromoaniline (1.37 g, 8 mmol, 1 equiv.) in pyridine (20 mL) at 0 °C , MsCl (0.74 mL, 9.6 mmol, 1.2 equiv.) was added dropwise. The mixture was stirred at rt for 48 h, before it was quenched with 10% hydrochloric acid at 0 °C and up to pH = 5. The mixture was extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated To a solution of 2-bromoaniline (1.37 g, 8 mmol, 1 equiv.) in pyridine (20 mL) at 0 • C, MsCl (0.74 mL, 9.6 mmol, 1.2 equiv.) was added dropwise. The mixture was stirred at rt for 48 h, before it was quenched with 10% hydrochloric acid at 0 • C and up to pH = 5. The mixture was extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the N-Ms product as a brown solid (1.80 g, 90%). The above crude product (1.00 g, 4.0 mmol, 1.0 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 • C. The mixture was stirred for 30 min and then 2-methallyl chloride (0.40 g, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at rt for 38 h, before it was quenched with saturated NH 4 Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 1c (0.89 g, 72%) as a pale yellow solid [77]. 1  To a solution of 2-bromoaniline (1.37 g, 8 mmol, 1 equiv.) in pyridine (20 mL) at 0 °C , MsCl (0.74 mL, 9.6 mmol, 1.2 equiv.) was added dropwise. The mixture was stirred at rt for 48 h, before it was quenched with 10% hydrochloric acid at 0 °C and up to pH = 5. The mixture was extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the N-Ms product as a brown solid (1.80 g, 90%). The above crude product (1.00 g, 4.0 mmol, 1.0 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 °C . The mixture was stirred for 30 min and then 2methallyl chloride (0.40 g, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at rt for 38 h, before it was quenched with saturated NH4Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 1c (0.89 g, 72%) as a pale yellow solid [77]. 1  A solution of 2-bromoaniline (1.38 g, 8 mmol, 1 equiv.), TsCl (1.83 g, 9.6 mmol, 1.2 equiv.), and pyridine (1.93 mL, 24 mmol, 3.0 equiv.) in dry DCM (30 mL) was stirred at rt for 24 h. Then it was quenched with 10% hydrochloric acid at 0 °C and up to pH = 5. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the N-Ts product as a white solid (2.56 g, 98%). The above product (1.30 g, 4.0 mmol, 1 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 °C . The mixture was stirred for 30 min and then 2-methallyl chloride (0.43 mL, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at rt overnight, before it was quenched with saturated NH4Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 5:1) to provide 1d (0.85 g, 54%) as a pale yellow solid [78].

(s, 3 H).
A solution of 2-bromoaniline (1.38 g, 8 mmol, 1 equiv.), TsCl (1.83 g, 9.6 mmol, 1.2 equiv.), and pyridine (1.93 mL, 24 mmol, 3.0 equiv.) in dry DCM (30 mL) was stirred at rt for 24 h. Then it was quenched with 10% hydrochloric acid at 0 • C and up to pH = 5. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the N-Ts product as a white solid (2.56 g, 98%). The above product (1.30 g, 4.0 mmol, 1 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 • C. The mixture was stirred for 30 min and then 2-methallyl chloride (0.43 mL, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at rt overnight, before it was quenched with saturated NH 4 Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 5:1) to provide 1d (0.85 g, 54%) as a pale yellow solid [78]. To a solution of 2-bromoaniline (1.37 g, 8 mmol, 1 equiv.) in pyridine (20 mL) at 0 °C , MsCl (0.74 mL, 9.6 mmol, 1.2 equiv.) was added dropwise. The mixture was stirred at rt for 48 h, before it was quenched with 10% hydrochloric acid at 0 °C and up to pH = 5. The mixture was extracted with EtOAc (4 × 30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the N-Ms product as a brown solid (1.80 g, 90%). The above crude product (1.00 g, 4.0 mmol, 1.0 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 °C . The mixture was stirred for 30 min and then 2methallyl chloride (0.40 g, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at rt for 38 h, before it was quenched with saturated NH4Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 1c (0.89 g, 72%) as a pale yellow solid [77]. 1  A solution of 2-bromoaniline (1.38 g, 8 mmol, 1 equiv.), TsCl (1.83 g, 9.6 mmol, 1.2 equiv.), and pyridine (1.93 mL, 24 mmol, 3.0 equiv.) in dry DCM (30 mL) was stirred at rt for 24 h. Then it was quenched with 10% hydrochloric acid at 0 °C and up to pH = 5. The mixture was extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the N-Ts product as a white solid (2.56 g, 98%). The above product (1.30 g, 4.0 mmol, 1 equiv.) was dissolved in dry DMF (25 mL) and NaH (60%, 192 mg, 4.8 mmol, 1.2 equiv.) was added in two portions at 0 °C . The mixture was stirred for 30 min and then 2-methallyl chloride (0.43 mL, 4.4 mmol, 1.1 equiv.) was added. The resulting mixture was stirred at rt overnight, before it was quenched with saturated NH4Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (4 × 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc 5:1) to provide 1d (0.85 g, 54%) as a pale yellow solid [78]. To a solution of 2 -bromobenzyl alcohol (3.74 g, 20 mmol, 1.0 equiv.) in DMF (40 mL), NaH (60%, 960 mg, 24 mmol, 1.2 equiv.) was added in three portions at 0 • C, and the mixture was stirred for 30 min. 2-Methallyl chloride (2.35 mL, 22 mmol, 1.1 equiv.) was added and then the mixture was stirred at rt until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, saturated NH 4 Cl solution and brine was added, and then extracted with EtOAc (ethyl acetate; 4 × 20 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1j as a colorless oil (3.90 g, 75%) [79].

General Procedure B for the Preparation of Starting Materials
reaction, saturated NH4Cl solution and brine was added, and then extracted with EtOAc (ethyl acetate; 4 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1j as a colorless oil (3.90 g, 75%) [79].

General Procedure B for the Preparation of Starting Materials
To a solution of 2-bromoaniline (3.40 g, 20 mmol, 1.0 equiv.) and TEA (3.60 mL, 26 mmol, 1.3 equiv.) in dry DCM (30 mL), methacryloyl chloride (2.52 mL, 26 mmol, 1.3 equiv.) was slowly added. The mixture was stirred at rt for 12 h and extra methacryloyl chloride (0.5 g, 4.78 mmol, 0.24 equiv.) was added. After 18 h, brine (15 mL) was added and the mixture was concentrated, followed by extraction with EtOAc (3 × 30 mL). The organic layer was dried over Mg2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford N-substituted product as a yellow oil (4.42 g, 92%).
To a solution of the above oil (2.40 g, 10 mmol, 1.0 equiv.) in dry THF (50 mL), NaH (60%, 0.50 g, 12.5 mmol, 1.2 equiv.) was added and the mixture was stirred at rt for 30 min. Alkyl iodide (1.2 equiv.) was added slowly and the mixture was stirred until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, brine was added and the mixture was extracted with EtOAc (4 × 30 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the corresponding product 1e-I [80]. To a solution of 2-bromoaniline (3.40 g, 20 mmol, 1.0 equiv.) and TEA (3.60 mL, 26 mmol, 1.3 equiv.) in dry DCM (30 mL), methacryloyl chloride (2.52 mL, 26 mmol, 1.3 equiv.) was slowly added. The mixture was stirred at rt for 12 h and extra methacryloyl chloride (0.5 g, 4.78 mmol, 0.24 equiv.) was added. After 18 h, brine (15 mL) was added and the mixture was concentrated, followed by extraction with EtOAc (3 × 30 mL). The organic layer was dried over Mg 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford N-substituted product as a yellow oil (4.42 g, 92%).
To a solution of the above oil (2.40 g, 10 mmol, 1.0 equiv.) in dry THF (50 mL), NaH (60%, 0.50 g, 12.5 mmol, 1.2 equiv.) was added and the mixture was stirred at rt for 30 min. Alkyl iodide (1.2 equiv.) was added slowly and the mixture was stirred until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, brine was added and the mixture was extracted with EtOAc (4 × 30 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the corresponding product 1e-I [80]. reaction, saturated NH4Cl solution and brine was added, and then extracted with EtOAc (ethyl acetate; 4 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1j as a colorless oil (3.90 g, 75%) [79].

General Procedure B for the Preparation of Starting Materials
To a solution of 2-bromoaniline (3.40 g, 20 mmol, 1.0 equiv.) and TEA (3.60 mL, 26 mmol, 1.3 equiv.) in dry DCM (30 mL), methacryloyl chloride (2.52 mL, 26 mmol, 1.3 equiv.) was slowly added. The mixture was stirred at rt for 12 h and extra methacryloyl chloride (0.5 g, 4.78 mmol, 0.24 equiv.) was added. After 18 h, brine (15 mL) was added and the mixture was concentrated, followed by extraction with EtOAc (3 × 30 mL). The organic layer was dried over Mg2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford N-substituted product as a yellow oil (4.42 g, 92%).
To a solution of the above oil (2.40 g, 10 mmol, 1.0 equiv.) in dry THF (50 mL), NaH (60%, 0.50 g, 12.5 mmol, 1.2 equiv.) was added and the mixture was stirred at rt for 30 min. Alkyl iodide (1.2 equiv.) was added slowly and the mixture was stirred until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, brine was added and the mixture was extracted with EtOAc (4 × 30 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the corresponding product 1e-I [80]. at rt until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, saturated NH4Cl solution and brine was added, and then extracted with EtOAc (ethyl acetate; 4 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1j as a colorless oil (3.90 g, 75%) [79].

General Procedure B for the Preparation of Starting Materials
To a solution of 2-bromoaniline (3.40 g, 20 mmol, 1.0 equiv.) and TEA (3.60 mL, 26 mmol, 1.3 equiv.) in dry DCM (30 mL), methacryloyl chloride (2.52 mL, 26 mmol, 1.3 equiv.) was slowly added. The mixture was stirred at rt for 12 h and extra methacryloyl chloride (0.5 g, 4.78 mmol, 0.24 equiv.) was added. After 18 h, brine (15 mL) was added and the mixture was concentrated, followed by extraction with EtOAc (3 × 30 mL). The organic layer was dried over Mg2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford N-substituted product as a yellow oil (4.42 g, 92%).
To a solution of the above oil (2.40 g, 10 mmol, 1.0 equiv.) in dry THF (50 mL), NaH (60%, 0.50 g, 12.5 mmol, 1.2 equiv.) was added and the mixture was stirred at rt for 30 min. Alkyl iodide (1.2 equiv.) was added slowly and the mixture was stirred until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, brine was added and the mixture was extracted with EtOAc (4 × 30 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the corresponding product 1e-I [80]. min. 2-Methallyl chloride (2.35 mL, 22 mmol, 1.1 equiv.) was added and then the mixture was stirred at rt until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, saturated NH4Cl solution and brine was added, and then extracted with EtOAc (ethyl acetate; 4 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1j as a colorless oil (3.90 g, 75%) [79].

General Procedure B for the Preparation of Starting Materials
To a solution of 2-bromoaniline (3.40 g, 20 mmol, 1.0 equiv.) and TEA (3.60 mL, 26 mmol, 1.3 equiv.) in dry DCM (30 mL), methacryloyl chloride (2.52 mL, 26 mmol, 1.3 equiv.) was slowly added. The mixture was stirred at rt for 12 h and extra methacryloyl chloride (0.5 g, 4.78 mmol, 0.24 equiv.) was added. After 18 h, brine (15 mL) was added and the mixture was concentrated, followed by extraction with EtOAc (3 × 30 mL). The organic layer was dried over Mg2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford N-substituted product as a yellow oil (4.42 g, 92%).
To a solution of the above oil (2.40 g, 10 mmol, 1.0 equiv.) in dry THF (50 mL), NaH (60%, 0.50 g, 12.5 mmol, 1.2 equiv.) was added and the mixture was stirred at rt for 30 min. Alkyl iodide (1.2 equiv.) was added slowly and the mixture was stirred until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, brine was added and the mixture was extracted with EtOAc (4 × 30 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the corresponding product 1e-I [80].  To a solution of 2′-bromobenzyl alcohol (3.74 g, 20 mmol, 1.0 equiv.) in DMF (40 mL), NaH (60%, 960 mg, 24 mmol, 1.2 equiv.) was added in three portions at 0 °C , and the mixture was stirred for 30 min. 2-Methallyl chloride (2.35 mL, 22 mmol, 1.1 equiv.) was added and then the mixture was stirred at rt until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, saturated NH4Cl solution and brine was added, and then extracted with EtOAc (ethyl acetate; 4 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 1j as a colorless oil (3.90 g, 75%) [79]

General Procedure B for the Preparation of Starting Materials
To a solution of 2-bromoaniline (3.40 g, 20 mmol, 1.0 equiv.) and TEA (3.60 mL, 26 mmol, 1.3 equiv.) in dry DCM (30 mL), methacryloyl chloride (2.52 mL, 26 mmol, 1.3 equiv.) was slowly added. The mixture was stirred at rt for 12 h and extra methacryloyl chloride (0.5 g, 4.78 mmol, 0.24 equiv.) was added. After 18 h, brine (15 mL) was added and the mixture was concentrated, followed by extraction with EtOAc (3 × 30 mL). The organic layer was dried over Mg2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford N-substituted product as a yellow oil (4.42 g, 92%).
To a solution of the above oil (2.40 g, 10 mmol, 1.0 equiv.) in dry THF (50 mL), NaH (60%, 0.50 g, 12.5 mmol, 1.2 equiv.) was added and the mixture was stirred at rt for 30 min. Alkyl iodide (1.2 equiv.) was added slowly and the mixture was stirred until the reaction was judged to be completed by the TLC analysis. After the completion of the reaction, brine was added and the mixture was extracted with EtOAc (4 × 30 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford the corresponding product 1e-I [80]. 142.0, 140. 5, 133.8, 131.1, 129.1, 128.1, 123.6, 118.1, 48.4, 29.4, 20.4, 20.2, 13.