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Article

Syntheses of 3,3-Disubstituted Dihydrobenzofurans, Indolines, Indolinones and Isochromanes by Palladium-Catalyzed Tandem Reaction Using Pd(PPh3)2Cl2/(±)-BINAP as a Catalytic System

by
Guizhou Yue
1,*,†,
Sicheng Li
1,†,
Dan Jiang
1,
Gang Ding
2,
Juhua Feng
1,
Huabao Chen
2,
Chunping Yang
2,
Zhongqiong Yin
3,
Xu Song
3,
Xiaoxia Liang
3,
Li Zhang
1,
Xianxiang Wang
1 and
Cuifen Lu
4,*
1
College of Science, Sichuan Agricultural University, Ya’an 625014, China
2
College of Agricultural Sciences, Sichuan Agricultural University, Chengdu 611130, China
3
College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, China
4
Hubei Collaborative Innovation Center for Advanced Organochemical Materials & Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules, Hubei University, Wuhan 430062, China
*
Authors to whom correspondence should be addressed.
†
The authors contributed equally to this work.
Catalysts 2020, 10(9), 1084; https://0-doi-org.brum.beds.ac.uk/10.3390/catal10091084
Submission received: 13 August 2020 / Revised: 7 September 2020 / Accepted: 15 September 2020 / Published: 18 September 2020
(This article belongs to the Special Issue Transition-Metal Catalysts for C–H Bond Functionalization of Heteroarenes)
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Abstract

:
A general procedure for the tandem arylation reaction of arylbromide with heteroaryl compounds was developed by using Pd(PPh3)2Cl2/(±)-BINAP (1,1′-Binaphthalene-2,2′-diylbis (diphenylphosphane)) as catalytic system. Both sulphur- and oxygen-containing heterocycles were also employed as an efficient 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 different spectroscopic techniques, such as 1H and 13C NMR (nuclear magnetic resonance), and mass spectral analysis.

1. Introduction

The benzofuran and indoline scaffold existed extensively in various biologically active molecules, important natural products and also part of different functional materials [1,2,3,4,5,6]. For example, megapodiol (I) is an antileukemic agent [7] and conocarpan (II) is toxic to mosquito larvae [8,9]. Coerulescine (III) is as an inhibitor of MDM2 (Murine Double Minute 2)-p53 [10,11], where compound IV shows antiproliferative activity and may be especially useful for the treatment of cancer [12]. Compound V exhibits selective 5-hydroxytryptamine7 (5-HT7) antagonist activity (Ki = 0.79 nm) [13] and alstonisine (VI) also reveals antiplasmodial activity against Plasmodium falciparum, with an IC50 (half maximal inhibitory concentration) of 7.6 μM [14] (Figure 1). Therefore, organic chemists around the world made extensive efforts to develop the highly efficient methods of constructing these heterocycles [15,16,17,18,19,20,21,22,23,24,25,26,27,28]. Of these molecules, 3,3-disubsitituted five-membered heterocycles, including dihydrobenzofurans, indolines and indolinones, have been extensively studied. The domino reactions of the synthesis of them were summarized mainly as follows: (i) the Pd or Ni-catalyzed cyclocarbopalladation/coupling fractions, in which the process was initiated by Heck cyclization of a starter (halide) and a relay (alkene), followed by intermolecular coupling reactions with a terminator (organometallic reagents, alkenes, alkynes, etc.), including Suzuki, Stille, Heck, Sonogashira, C-H activation, carbonylation and amination and so forth [15,16,17,22,24,25,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44]; (ii) the C-H oxidative radical coupling reactions, in which these transformations were based on tandem radical addition/cyclization in the presence of oxidants with/without metal catalysts [18,19,20,21,23,26,45,46,47,48,49,50,51,52,53,54,55]; and (iii) the other reactions [24,56,57,58,59,60,61], such as C-H activated cyclization/trapping with the Pd (IV) intermediate or O- and N-based nucleophiles, Heck/C-H activated cyclization. Among the variety of new synthetic protocols, transition metal-catalyzed reactions are part of the most attractive methodologies, because they can directly lead to complicated molecules with quickness and high efficiency. In particular, palladium-catalyzed domino reactions provide versatile and efficient methods for the assembly of a wide range of these molecules [8].
In 2009, Fagnou and coworkers [62] reported the X-phos catalytic domino Heck/arylation reaction of arylbromide with sulphur-containing heterocycles (thiazole, thiophene and benzothiophene) to provide 18 products in 41–99% yields (Figure 2). Next, an elegant asymmetric synthesis of 3,3-disubsitituted indolinones via the same domino sequence was presented by Zhu’s group [63]. 2-aryl-1,3,4-oxadiazoles were chosen as substrate for the second step and the reaction obtained 24 desired products in 55–75% yields with 82–99% ee. However only two other heterocyclic examples (benzothiazole and benzoxazole) were reported in 60–61% yields with 92–97% ee. Recently, Xu and Liang also reported an efficient tandem alkylation of electron-deficient polyfluoroarenes with aryl iodides in 51–96% yields [64]. Despite the excellent works mentioned above, the scope of this domino reaction needs to be further expanded with other heterocyclic substrates. Based on our previous studies of reductive Heck cyclization and Suzuki coupling reaction [65,66,67], synthesis of spiropyrrolidine oxindoles [68,69] and ongoing interest in the highly efficient and atom-economic domino reactions for organic synthesis, we demonstrated herein the synthesis of 3,3-disubstituted hydrobenzofurans, indolines, indolinones and isochromanes using Pd(PPh3)2Cl2/(±)-BINAP as a catalytic system and various arylheterocycles as substrates.

2. 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(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.
In the beginning of our study, for the optimization of the reaction conditions, aryl bromide and benzothiophene were chosen as the model substrates. Initially, the reaction was performed in the presence of 5 mol% Pd(OAc)2 as a catalyst, 6 mol% (±)-BINAP as a ligand, 30 mol% PivOH (pivalic acid) as an additive, and 2 equiv. of K2CO3 as a base under DMA (N,N-dimethylacetamide) at 110 °C for 30 h. The desired product was obtained in 61% isolated yield, with 10:1 regioselectivity. The other palladium salts, such as PdCl2, Pd2(dba)3, Pd(dppf)2Cl2, Pd(PPh3)2Cl2 and Pd/C were tested in the reaction. Pd(PPh3)2Cl2 gave the highest yield (80%; Table 1, entry 7), while Pd/C afforded almost no product (Table 1, entry 6). The other palladium salts provided moderate yields (Table 1, entries 2–5). Subsequently, the various bases and solvents were screened by using Pd(PPh3)2Cl2 (5 mol%) as a catalyst and (±)-BINAP (6 mol%) as a ligand. In DMA, performing the reaction in the presence of either weak bases (KOAc, K3PO4, Na2CO3 and Cs2CO3) or strong bases (KOtBu, LiOH·H2O, NaOH and KOH) resulted in low yields (15–65%) and none of the desired product was formed using an organic base (TEA (triethylamine)). In DMF (N,N-dimethylformamide), the reaction gave the light lower yield (76%). The other solvents (e.g., DMSO (dimethyl sulfoxide), 1,4-dioxane, 1,2-DCE (dichloroethane), DME (dimethoxyethane), PhCN (benzonitrile), THF (tetrahydrofuran) and PhH (benzene)) obtained the very lower yields (<10%) or had no predicted product except for toluene and acetonitrile (59% and 44% yields, respectively). The additives were also screened. CsF (cesium fluoride) gave the product in 61% yield, while silver salts (Ag2CO3 and AgNO3) furnished one in <20% yields. Furthermore, the yield dropped to 66% without any additive (Table 1, entry 19). Secondly, some common phosphine ligands (PPh3, PCy3, PtBu3, dppe, dppp and dppb) were used to promote the reaction (Table 2). The result was that most ligands gave the poor reactivities in 36%–65% yields. Furthermore, monophosphine ligands (PPh3, PCy3 and PtBu3) at 12 mol% loading only provided slightly increased yields (50%–71%). Finally, the optimal reaction condition (Table 1, entry 6) for the tandem arylation reaction was established as bromide 1a (1.0 equiv.), benzothiophene (4.0 equiv.), PivOH (0.3 equiv.) and K2CO3 (2.0 equiv.) in DMA at 110 °C under Pd(PPh3)2Cl2 (5 mmol%) as a catalyst and (±)-BINAP (6 mol%) as a ligand.
With the readily obtained optimization conditions in hand, we further investigated the substrate scope for this Pd(PPh3)2Cl2/(±)-BINAP-catalyzed tandem arylation reaction. A range of aromatic heterocycles was first screened. As shown in Scheme 1, outside benzothiophene, benzofuran and thiophene worked well in this reaction, thus affording the corresponding products 2ab and 2ad in 77% and 65% yields, respectively, with 10:1 and >20:1 regioselectivities. Whereas, N-methylindole, substituted thiophenes, thiazole, and furan only obtained moderate yields (35–45%), but with excellent regioselectivities (>20:1 ir). However, no products were observed using other bicyclic substrates, such as benzoxazole, benzothiazole, 2-bromfuran and 3-bromthiophenes. Unfortunately, (2-phenylallyl)arylether, instead of 1a, combined with benzothiophene and gave a complex, which showed that the reaction system was not suitable for that kind of substrate.
To ascertain further the scope of this method, a variety of N- substituted anilines bearing electron-withdrawing groups (Ac, Ms and Ts) were investigated. As summarized in Scheme 2, the reaction is compatible with a wide range of anilines to afford different indoles in moderate to good yields with acceptable to high regioselectivity. N-substituted 1b-d, reacted with benzothiophene smoothly, affording the corresponding α-substituted products 2ba, 2ca and 2da in moderate to high yields (65–82%) with moderate selectivity (5:1–10:1 ir). 1b-d reacted with benzofuran to give similar results (67–72% yields and 6:1–10:1 ir). Compared with benzothiophene and benzofuran, the reaction of N-methylindole with compounds 1b-d led to relatively poor results (52–67% yield and 5:1–10:1 ir). Meanwhile, in the reaction of thiophene, 1b coupled with 2-chlorothiophene to produce excellent yield (92%). Finally, the reaction of 1b with benzothiazole and benzoxazole gave a good result (72% and 90% yields), while 1c-d had unsatisfactory results that only one product 2dd was obtained in a low yield.
A scope of the reaction with respect to N-heteroarylacrylamides is summarized in Scheme 3. N-substituted groups, such as methyl, ethyl, n-butyl and benzyl, were well tolerated, providing the desired adducts 2ea-2ib in moderate to excellent yields (28–84%) with moderate to high regioselectivities (5:1 to >20:1 ir). Acrylamide with benzyl group 1h reacted smoothly with heteroarylenes. Among the four compounds 1e-h, both 1f and 1h smoothly reacted with benzoxazole, respectively, to get high yields (84% for 2fc and 82% for 2hb), if compared to 1e (54% for 1ea) and 1g (41% for 1gb). Overall, 1e-h performed with benzothiazole and gave the similar results (56–76%). Substituted and unsubstituted thiophenes obtained moderate yields (42–73%), but excellent regioselectivities (>20:1 ir) in most cases. However, both benzofuran and N-methylindole led to the worst results (40% yield for 2fb and 37% yield for 2ha). Finally, the N-allyl substrate also proceeded the tandem reaction with benzothiophene and benzothiazole, but in low yields (28% for 2ia and 34% for 2ib).
Recently, domino cyclizations of constructing 3,3-disubstituted six-membered heterocycle skeletons also were developed [70,71,72,73,74,75,76]. On extending the investigations toward the scope of this transformation, we also studied the reaction of benzylallyl ether or allylbenzyl amines with heteroarenes to form 3,3-disubstituted isochromanes or tetrahydroisoquinolines. As outlined in Scheme 4, ether 1j also reacted smoothly with heteroarenes, in which it generated the desired products 2ja-jc in 31–65% yields. However, N-substituted tetrahydroisoquinolines were not obtained in the standard condition, after many trials.

3. Materials and Methods

Please see Supplementary Materials.

3.1. General Methods

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, N-dimethylacetamide (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. 1H and 13C 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: 1H NMR δ = 7.26, 13C NMR δ = 77.16; DMSO-d6: 1H NMR δ = 2.54, 13C 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).

3.2. General Procedure A for the Preparation of O or N-methylallyl Arylbromides

Catalysts 10 01084 i003
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]. (CAS: 10178–53–7); 1H NMR (400 MHz, CDCl3): δ = 7.54 (dd, J = 7.6, 1.6 Hz, 1 H), 7.25–7.21 (m, 1 H), 6.87 (dd, J = 8.0, 1.2 Hz, 1 H), 6.82 (ddd, J = 7.6, 7.6, 1.2 Hz, 1 H), 5.17 (dd, J = 1.6, 0.8 Hz, 1 H), 5.02 (dd, J = 2.8, 1.2 Hz, 1 H), 4.49 (s, 2 H), 1.86 (d, J = 0.4 Hz, 3 H).
Catalysts 10 01084 i004
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 rt overnight, before it was quenched with saturated NH4Cl solution (20 mL) and brine (20 mL) and then extracted with EtOAc (3 × 20 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 1b (0.83 g, 77%) as a pale yellow solid [70]. (CAS: 115802–65–8); 1H NMR (400 MHz, CDCl3): δ = 7.68 (dd, J = 8.0, 1.2 Hz, 1 H), 7.37–7.33 (m, 1 H), 7.27 (d, J = 4.0 Hz, 1 H), 7.24–7.20 (m, 1 H), 4.94 (d, J = 4.8 Hz, 1 H), 4.83 (s, 1 H), 4.67 (s, 1 H), 3.68 (d, J = 15.0 Hz, 1 H), 1.84 (s, 3 H), 1.80 (s, 3 H).
Catalysts 10 01084 i005
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 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 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]. 1H NMR (400 MHz, CDCl3): δ = 7.64 (dd, J = 8.0, 1.6 Hz, 1 H), 7.44 (dd, J = 8.0, 1.6 Hz, 1 H), 7.36–7.32 (m, 1 H), 7.24–7.20 (m, 1 H), 4.82 (s, 1 H), 4.78 (s, 1 H), 4.38 (s, 1 H), 4.15 (s, 1 H), 3.06 (s, 3 H), 1.84 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 139.9, 137.3, 134.0, 134.0, 1333.9, 130.0, 128.3, 123.8, 115.9, 56.6, 40.9, 20.4; HRMS (high resolution mass spectrometer) m/z Calcd for C11H14O2NSBrNa [M+Na]+ 325.9826, found 325.9835.
Catalysts 10 01084 i006
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]. (CAS: 1191913–83–3); 1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 8.4 Hz, 2 H), 7.56 (dd, J = 8.0, 1.6 Hz, 1 H), 7.28–7.24 (m, 3 H), 7.18–7.13 (m, 2 H), 4.74 (s, 1 H), 4.66 (s, 1 H), 4.15 (d, 2 H), 2.43 (s, 3 H), 1.81 (s, 3 H).
Catalysts 10 01084 i007
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]. (CAS: 935742–52–2); 1H NMR (400 MHz, CDCl3): δ = 7.53–7.49 (m, 2 H), 7.30–7.28 (m, 1 H), 7.14–7.10 (m, 1 H), 5.03 (d, J = 0.6 Hz, 1 H), 4.94 (d, J = 0.6 Hz, 1 H), 4.55 (s, 2 H), 4.00 (s, 2 H), 1.78 (s, 3 H).

3.3. General Procedure B for the Preparation of Starting Materials

Catalysts 10 01084 i008
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].
Catalysts 10 01084 i009
(CAS: 102804-50-2); 62% yield; 1H NMR (400 MHz, CDCl3): δ = 7.63–6.61 (m, 1 H), 7.34–7.30 (m, 1 H), 7.20–7.16 (m, 2 H), 5.00 (d, J = 17.2 Hz, 2 H), 3.26 (s, 3 H), 1.82 (s, 3 H).
Catalysts 10 01084 i010
(CAS: 1638143-30-2); 65% yield; 1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.0 Hz, 1 H), 7.26–7.23 (m, 1 H), 7.13–7.07 (m, 2 H), 4.92 (s, 1 H), 4.88 (s, 1 H), 4.08 (m, 1 H), 3.55 (m, 1 H), 1.75 (s, 3 H), 1.07 (t, J = 5.6 Hz, 3 H).
Catalysts 10 01084 i011
54% yield; 1H NMR (400 MHz, CDCl3): δ = 7.64–7.62 (m, 1 H), 7.34–7.29 (m, 1 H), 7.20–7.16 (m, 2 H), 4.95 (d, J = 11.8 Hz, 2 H), 4.15–4.08 (m, 1 H), 3.33–3.26 (m, 1 H), 1.82 (s, 3 H), 1.61–1.56 (m, 1 H), 1.51–1.45 (m, 1 H), 1.36–1.26 (m, 2 H), 0.90 (t, J = 7.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ = 171.4, 142.0, 140.5, 133.8, 131.1, 129.1, 128.1, 123.6, 118.1, 48.4, 29.4, 20.4, 20.2, 13.8; HRMS m/z Calcd for C14H19NOBr [M+H]+ 296.0650, found 296.0602.
Catalysts 10 01084 i012
(CAS: 151502-76-0); 67% yield; 1H NMR (400 MHz, CDCl3): δ = 7.62–7.59 (m, 1 H), 7.26 (d, J = 2.8 Hz, 1 H), 7.24 (d, J = 1.8 Hz, 2 H), 7.21–7.19 (m, 2 H), 7.14–7.10 (m, 2 H), 5.64 (d, J = 14.4 Hz, 1 H), 5.01 (s, 1 H), 4.97 (s, 1 H), 4.18 (d, J = 14.4 Hz, 1 H), 1.83 (s, 1 H).
Catalysts 10 01084 i013
(CAS: 146499-16-3); 70% yield; 1H NMR (400 MHz, CDCl3): δ = 7.62 (dd, J = 8.0, 0.8 Hz, 1 H), 7.31–7.27 (m, 1 H), 7.18 (dd, J = 7.6, 1.6 Hz, 1 H), 7.16–7.12 (m, 1 H), 5.94–5.96 (m, 1 H), 5.13–5.06 (m, 2 H), 5.05–4.98 (m, 2 H), 4.81 (dd, J = 14.4, 4.4 Hz, 1 H), 3.85–3.80 (m, 1 H), 1.83 (s, 3 H).

3.4. General Procedure for Condition Optimization of the Tandem Reaction

In an argon-filled glove bag, base (0.2 mmol, 2.0 equiv.), Pd salt (0.005 mmol, 0.05 equiv.), ligand (0.006 mmol, 0.06 equiv.), additive (0.03 mmol, 0.3 equiv.), 1a (0.1 mmol, 1.0 equiv.), benzothiophene (0.4 mmol, 4.0 equiv.) and solvent (0.5 mL) were successively added to a 10 mL Schlenk tube. The tube was vigorously stirred in an oil bath for 30 h.

3.5. General Procedure for the Typical Procedure for Tandem Reactions

In an argon-filled glove bag, bromides (0.5 mmol, 1.0 equiv.), arylheterocycles (2.0 mmol, 4.0 equiv.), K2CO3 (138.2 mg, 1.0 mmol, 2.0 equiv.), PivOH (15.3 mg, 0.15 mmol, 0.3 equiv.), (±)-BINAP (18.7 mg, 0.03 mmol, 6 mmol%), Pd(PPh3)2Cl (17.5 mg, 0.025 mmol, 5 mmol%) and DMA (2.0 mL) were added successively to a 25 mL Schlenk tube. The tube was vigorously stirred in an oil bath at 110 °C for 30 h. At the end of the reaction, the mixture cooled to room temperature and then was directly purified by silica gel column chromatography to afford the corresponding product.
(±)-3-(benzothiophen-2-ylmethyl)-3-methyl-2,3-dihydrobenzofuran (2aa)
(CAS: 1191913-87-7); 80% yield, an inseparable pale yellow solid, isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.73 (d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.2 Hz, 1 H), 7.33–7.29 (m, 1 H), 7.28–7.24 (m, 1 H), 7.19–7.15 (m, 1 H), 7.11 (dd, J = 7.6, 0.8 Hz, 1 H), 6.93 (s, 1 H), 6.92–6.88 (m, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 4.59 (d, J = 8.8 Hz, A of AB, 1 H), 4.17 (d, J = 8.8 Hz, B of AB, 1 H), 3.22 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 3.17 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 1.47 (s, 3 H); HRMS m/z Calcd for C18H16OS [M+H]+ 281.1000, found 281.0953. Minor isomer: (±)-3-(benzothiophen-3-ylmethyl)-3-methyl-2,3-dihydrobenzofuran.
(±)-2-((3-methyl-2,3-dihydrobenzofuran-3-yl)methyl)benzofuran (2ab)
77% yield, an inseparable colorless oil, isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.49–7.47 (m, 1 H), 7.412 (d, J = 8.4 Hz, 1 H), 7.23–7.20 (m, 1 H), 7.18–7.13 (m, 2 H), 7.08 (dd, J = 7.4, 0.8 Hz, 1 H), 6.89 (td, J = 7.4, 0.8 Hz, 1 H), 6.81 (d, J = 8.0 Hz, 1 H), 6.35 (s, 1 H), 4.67 (d, J = 8.8 Hz, A of AB, 1 H), 4.19 (d, J = 8.8 Hz, B of AB, 1 H), 3.09 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 3.05 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 1.42 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 159.4, 155.6, 154.8, 134.6, 128.6, 128.5, 123.6, 122.9, 122.6, 120.6, 120.5, 110.9, 109.9, 105.0, 82.2, 45.7, 39.1, 24.9; HRMS m/z Calcd for C18H16O2 [M+H]+ 265.1229, found 265.1185. Minor isomer: (±)-3-((3-methyl-2,3-dihydrobenzofuran-3-yl)methyl) benzofuran.
(±)-1-methyl-2-((3-methyl-2,3-dihydrobenzofuran-3-yl)methyl)-1H-indole (2ac)
36% yield, a colorless oil, isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.49 (dd, J = 8.0, 0.8 Hz, 1 H), 7.17–7.01 (m, 4 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.69 (td, J = 7.2, 0.8 Hz, 1 H), 6.59 (d, J = 7.6 Hz, 1 H), 6.25 (s, 1 H), 4.45 (dd, J = 8.8, 1.6 Hz, A of AB, 1 H), 4.12 (d, J = 8.8 Hz, B of AB, 1 H), 3.12 (s, 3 H), 3.03 (d, J = 14.8 Hz, A′ of A′B′, 1 H), 2.93 (d, J = 14.8 Hz, B′ of A′B′, 1 H), 1.41 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 159.6, 137.2, 136.6, 134.3, 128.6, 123.4, 120.9, 120.7, 120.0, 119.6, 109.9, 109.7, 109.3, 101.8, 82.9, 46.2, 36.9, 29.3, 26.0; HRMS m/z Calcd for C19H20NO [M+H]+ 278.1545, found.278.15744.
(±)-3-methyl-3-(thiophen-2-ylmethyl)-2,3-dihydro benzofuran (2ad)
65% yield, a colorless oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.17–7.15 (m, 2 H), 7.06 (d, J = 7.4 H z, 1 H), 6.91–6.87 (m, 2 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.68 (dd, J = 3.2, 0.8 Hz, 1 H), 4.52 (d, J = 8.8 Hz, A of AB, 1 H), 4.12 (d, J = 8.8 Hz, B of AB, 1 H), 3.13 (d, J = 14.8 Hz, A′ of A′B′, 1 H), 3.09 (d, J = 14.8 Hz, B′ of A′B′, 1 H), 1.42 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 159.7, 139.4, 134.4, 128.4, 127.1, 126.6, 124.3, 123.0, 120.5, 109.8, 81.7, 46.2, 40.7, 25.3; HRMS m/z Calcd for C14H14OS [M+H]+ 231.0844, found 231.0809.
(±)-3-((5-chlorothiophen-2-yl)methyl)-3-methyl-2,3-dihydrobenzofuran (2ae)
(CAS: 1191913-90-2); 34% yield, a yellow oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.18–7.14 (m, 1 H), 7.05(d, J = 7.4 Hz, 1 H), 6.90 (t, J = 7.2 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 6.70 (d, J = 3.6 Hz, 1 H), 6.44 (d, J = 3.6 Hz, 1 H), 4.46 (d, J = 8.8 Hz, A of AB, 1 H), 4.14 (d, J = 8.8 Hz, B of AB, 1 H), 3.03 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 2.97 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 1.42 (s, 3 H); HRMS m/z Calcd for C14H14OSCl [M+H]+ 265.0454, found 265.0463.
(±)-5-((3-methyl-2,3-dihydrobenzofuran-3-yl)methyl) thiophene-2-carbaldehyde (2af)
(CAS: 1191913-92-4); 45% yield, a yellow oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 9.79 (s, 1 H), 7.56 (d, J = 3.6 Hz, 1 H), 7.19–7.14 (m, 1 H), 7.04 (d, J = 7.2 Hz, 1 H), 6.90 (t, J = 7.4 Hz, 1 H), 6.76 (t, J = 8.0 Hz, 1 H), 6.70 (d, J = 3.6 Hz, 1 H), 4.48 (d, J = 8.8 Hz, A of AB, 1 H), 4.15 (d, J = 8.8 Hz, B of AB, 1 H), 3.17 (d, J = 15.2 Hz, A′ of A′B′, 1 H), 3.13 (d, J = 15.2 Hz, B′ of A′B′, 1 H), 1.46 (s, 3 H); HRMS m/z Calcd for C15H14O2SNa [M+Na]+ 281.0612, found 281.0578.
(±)-4-methyl-5-((3-methyl-2,3-dihydrobenzofuran-3-yl)methyl)thiazole (2ag)
(CAS: 1191913-85-5); 40% yield, a yellow oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 8.55 (s, 1 H), 7.19–7.14 (m, 1 H), 6.93 (dd, J = 7.4, 1.2 Hz, 1 H), 6.87 (td, J = 7.2, 0.8 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 4.40 (d, J = 8.8 Hz, A of AB, 1 H), 4.15 (d, J = 8.8 Hz, B of AB, 1 H), 3.10 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 3.00 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 2.18 (s, 3 H), 1.45 (s, 3 H); HRMS m/z Calcd for C14H16NOS [M+H]+ 246.0953, found 246.0866.
(±)-5-((3-methyl-2,3-dihydrobenzofuran-3-yl)methyl)furan-2-carbaldehyde (2ah)
31% yield, a yellow oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 9.54 (s, 1 H), 7.18–7.15 (m, 1 H), 7.13 (d, J = 7.6 Hz, 1 H), 7.03 (dd, J = 7.4, 1.2 Hz, 1 H), 6.89 (td, J = 7.2, 0.8 Hz, 1 H), 6.78 (d, J = 8.0 Hz, 1 H), 6.05 (d, J = 3.6 Hz, 1 H), 4.54 (d, J = 9.0 Hz, A of AB, 1 H), 4.17 (d, J = 9.0 Hz, B of AB, 1 H), 3.02 (ψs, 2 H), 1.42 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 177.1, 159.7, 159.4, 152.3, 133.7, 130.9, 128.7, 122.8, 120.7, 111.2, 110.0, 81.9, 45.8, 39.2, 24.9; HRMS m/z Calcd for C15H14O3Na [M+Na]+ 265.0841, found 265.0811.
(±)-1-(3-(benzothiophen-2-ylmethyl)-3-methylindolin-1-yl)ethan-1-one (2ba)
65% yield, an inseparable yellow solid, isomers ratio = 5:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 7.6 Hz, 1 H), 7.66 (d, J = 7.2 Hz, 1 H), 7.33–7.31 (m, 1 H), 7.30–7.27 (m, 2 H), 7.20–7.18 (m, 1 H), 7.12–7.08 (m, 1 H), 6.90 (s, 1 H), 4.10 (d, J = 10.4 Hz, A of AB, 1 H), 3.66 (d, J = 10.4 Hz, B of AB, 1 H), 3.21 (d, J = 10.2 Hz, A′ of A′B′, 1 H), 3.18 (d, J = 10.2 Hz, B′ of A′B′, 1 H), 2.17 (s, 3 H), 1.50 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 168.6, 142.3, 140.2, 139.8, 139.6, 138.2, 128.4, 124.3, 124.0, 123.9, 123.8, 123.0, 122.4, 122.1, 117.2, 60.4, 44.5, 42.1, 26.9, 24.3; HRMS m/z Calcd for C20H19NOS [M+H]+ 322.1266, found 322.1253. Minor isomer: (±)-1-(3-(benzothiophen-3-ylmethyl)-3-methylindolin -1-yl)ethan-1-one.
(±)-1-(3-(benzofuran-2-ylmethyl)-3-methylindolin-1-yl)ethan-1-one (2bb)
72% yield, an inseparable yellow solid, isomers ratio = 6:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 7.2 Hz, 1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.25–7.22 (m, 1 H), 7.21–7.17 (m, 2 H), 7.14 (d, J = 7.2 Hz, 1 H), 7.06 (td, J = 7.2, 0.8 Hz, 1 H), 6.31 (s, 1 H), 4.22 (d, J = 10.6 Hz, A of AB, 1 H), 3.70 (d, J = 10.6 Hz, B of AB, 1 H), 3.05 (ψs, 2 H), 2.23 (s, 3 H), 1.46 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 168.6, 155.2, 154.8, 142.0, 138.5, 128.4, 128.3, 123.9, 123.8, 122.8, 122.2, 120.6, 117.1, 110.0, 105.2, 61.0, 44.3, 39.8, 26.1, 24.2; HRMS m/z Calcd for C20H19NO2 [M+H]+ 306.1494, found 306.1483. Minor isomer: (±)-1-(3-(benzofuran-3-ylmethyl)-3-methylindolin-1-yl)ethan-1-one.
(±)-1-(3-methyl-3-((1-methyl-1H-indol-2-yl)methyl)indolin-1-yl)ethan-1-one (2bc)
56% yield, an inseparable pale yellow solid, isomer ratio = 5:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 8.0 Hz, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.24–7.22 (m, 1 H), 7.20–7.16 (m, 2 H), 7.12–7.08 (m, 1 H), 6.94 (t, J = 7.6 Hz, 1 H), 6.74 (d, J = 7.4 Hz, 1 H), 6.31 (s, 1 H), 4.07 (d, J = 10.4 Hz, A of AB, 1 H), 3.76 (d, J = 10.4 Hz, B of AB, 1 H), 3.16 (s, 3 H), 3.07 (d, J = 14.8 Hz, A′ of A′B′, 1 H), 3.02 (d, J = 14.8 Hz, B′ of A′B′, 1 H), 2.23 (s, 3 H), 1.52 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 168.8, 142.1, 137.9, 136.1, 128.4, 127.5, 123.8, 122.7, 123.8, 122.7, 121.1, 119.9, 119.6, 117.1, 109.3, 101.8, 61.9, 44.3, 37.7, 29.3, 25.0, 24.3; HRMS m/z Calcd for C21H22N2O [M+H]+ 319.1810, found 319.1803. Minor isomer: (±)-1-(3-methyl-3-((1-methyl-1H-indol-3-yl)methyl)indolin-1-yl)ethan-1-one.
(±)-1-(3-(benzo[d]thiazol-2-ylmethyl)-3-methylindolin-1-yl)ethan-1-one (2bd)
72% yield, a yellow solid; 1H NMR (400 MHz, CDCl3): δ = 8.13 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.47–7.43 (m, 1 H), 7.36–7.32 (m, 1 H), 7.27–7.23 (m, 2 H), 7.13–7.09 (m, 1 H), 4.42 (d, J = 10.8 Hz, A of AB, 1 H), 3.73 (d, J = 10.8 Hz, B of AB, 1 H), 3.42 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 3.34 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 2.16 (s, 3 H), 1.54 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 168.6, 166.8. 152.9, 142.4, 137.6, 135.4, 128.6, 126.1, 125.1, 123.9, 122.7, 122.2, 121.5, 117.3, 60.1, 45.1, 44.3, 26.9, 24.2; HRMS m/z Calcd for C19H18N2OSNa [M+Na]+ 345.1038, found 344.1048.
(±)-1-(3-(benzo[d]oxazol-2-ylmethyl)-3-methylindolin-1-yl)ethan-1-one (2be)
90% yield, a yellow solid; 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.0 Hz, 1 H), 7.71–7.69 (m, 1 H), 7.50–7.47 (m, 1 H), 7.33 (dd, J = 5.6, 3.6 Hz, 2 H), 7.25–7.23 (m, 1 H), 7.22–7.20 (m, 1 H), 7.08 (t, J = 7.2 Hz, 1 H), 4.45 (d, J = 10.8 Hz, A of AB, 1 H), 3.81 (d, J = 10.8 Hz, B of AB, 1 H), 3.24 (d, J = 14.8 Hz, A′ of A′B′, 1 H), 3.22 (d, J = 14.8 Hz, B′ of A′B′, 1 H), 2.27 (s, 3 H), 1.50 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 168.8, 163.6, 150.7, 141.8, 141.1, 137.8, 128.6, 125.0, 124.4, 124.0, 122.1, 119.8, 117.2, 110.5, 60.7, 43.6, 39.7, 25.9, 24.3; HRMS m/z Calcd for C19H18N2O2Na [M+Na]+ 329.1266, found 329.1270.
(±)-1-(3-methyl-3-(thiophen-2-ylmethyl)indolin-1-yl)ethan-1-one (2bf)
65% yield, an inseparable yellow oil, isomers ratio = 5:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.0 Hz, 1 H), 7.25–7.21 (m, 1 H), 7.13 (d, J = 7.2 Hz, 1 H), 7.10–7.06 (m, 2 H), 6,87 (dd, J = 4.8, 3.6 Hz, 1 H), 6.60 (d, J = 3.2 Hz, 1 H), 4.03 (d, J = 10.4 Hz, A of AB, 1 H), 3.62 (d, J = 10.4 Hz, B of AB, 1 H), 3.11 (d, J = 14.8, A′ of A′B′, 1 H), 3.06 (d, J = 14.8 Hz, B′ of A′B′, 1 H), 2.14 (s, 3 H), 1.45 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 168.5, 142.4, 138.9, 138.2, 128.3, 127.0, 126.7, 124.4, 123.8, 122.4, 117.1, 60.3, 44.8, 41.6, 26.5, 24.2; HRMS m/z Calcd for C16H17NOSNa [M+Na]+ 294.0929, found 294.0909. Minor isomer: (±)-1-(3-methyl-3-(thiophen-3-ylmethyl)indolin-1-yl)ethan-1-one.
(±)-1-(3-((5-chlorothiophen-2-yl)methyl)-3-methylindolin-1-yl)ethan-1-one (2bg)
92% yield, an inseparable yellow solid, isomers ratio = 5:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 8.0 Hz, 1 H), 7.28–7.23 (m, 1 H), 7.12–7.05 (m, 2 H), 6.90 (d, J = 3.6 Hz, 1 H), 6.39 (d, J = 3.6 Hz, 1 H), 3.98 (d, J = 10.8 Hz, A of AB, 1 H), 3.66 (d, J = 10.8 Hz, B of AB, 1 H), 3.03 (d, J = 14.6 Hz, A′ of A′B′, 1 H), 2.97 (d, J = 14.6 Hz, B′ of A′B′, 1 H), 2.17 (s, 3 H), 1.45 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 168.5, 142.4, 137.9, 137.7, 128.5, 128.3, 126.5, 125.7, 123.8, 122.4, 117.1, 60.3, 44.4, 42.0, 26.6, 24.2; HRMS m/z Calcd for C16H16ClNOS [M+H]+ 306.0719, found 306.0710. Minor isomer: (±)-1-(3-((5-chlorothiophen-3-yl)methyl)-3-methylindolin-1-yl)ethan-1-one.
(±)-3-(benzothiophen-2-ylmethyl)-3-methyl-1-(methylsulfonyl)indoline (2ca)
82% yield, an inseparable pale yellow solid, isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.64 (t, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.26–7.25 (m, 2 H), 7.24–7.20 (m, 2 H), 7.10 (t, J = 7.4 Hz, 1 H), 6.90 (s, 1 H), 4.01 (d, J = 10.4 Hz, A of AB, 1 H), 3.67 (d, J = 10.4 Hz, B of AB, 1 H), 3.25 (d, J = 14.6 Hz, A′ of A′B′, 1 H), 3.16 (d, J = 14.6 Hz, B′ of A′B′, 1 H), 2.44 (s, 3 H), 1.52 (s, 3 H); 13CNMR (100 MHz, CDCl3): δ = 141.6, 140.3, 139.8, 139.4, 137.6, 128.9, 124.4, 124.2, 124.1, 123.7, 123.6, 123.0, 121.9, 113.2, 60.8, 44.5, 41.9, 34.2, 27.4; HRMS m/z Calcd for C19H19NO2S2Na [M+Na]+ 380.0755, found 380.0709. Minor isomer: (±)-3-(benzothiophen-3-ylmethyl)-3-methyl-1-(methylsulfonyl)indoline.
(±)-3-(benzofuran-2-ylmethyl)-3-methyl-1-(methylsulfonyl)indoline (2cb)
69%, yield, an inseparable pale yellow solid, isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.47–7.45 (m, 1 H), 7.41–7.38 (m, 2 H), 7.26–7.20 (m, 2 H), 7.18 (dd, J = 7.6, 0.8 Hz, 1 H), 7.15 (dd, J = 7.2, 0.8 Hz, 1H), 7.06 (td, J = 7.2, 0.8 Hz, 1 H), 6.32 (s, 1 H), 4.13 (d, J = 10.4 Hz, A of AB, 1 H), 3.66 (d, J = 10.4 Hz, A of AB, 1 H), 3.10 (d, J = 14.8 Hz, A′ of A′B′, 1 H), 3.05 (d, J = 14.8 Hz, B′ of A′B′, 1 H), 2.75 (s, 3 H), 1.45 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 155.0, 154.8, 141.1, 138.1, 128.7, 128.4, 123.8, 123.6, 123.4, 122.8, 120.6, 113.2, 111.0, 105.4, 61.8, 44.0, 39.3, 34.5, 26.1; HRMS m/z Calcd for C19H19NO3S [M+H]+ 342.1164, found 342.1104. Minor isomer: (±)-3-(benzofuran-3-ylmethyl)-3-methyl-1-(methylsulfonyl)indoline.
(±)-1-methyl-2-((3-methyl-1-(methylsulfonyl)indolin-3-yl)methyl)-1H-indole (2cc)
52% yield, an inseparable pale yellow solid, isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.53 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.26–7.22 (m, 1 H), 7.19–7.13 (m, 2 H), 7.09–7.06 (m, 1 H), 6.95 (td, J = 7.6, 0.8 Hz, 1 H), 6.78 (dd, J = 7.6, 0.8 Hz, 1 H), 6.25 (s, 1 H), 4.01 (d, J = 10.0 Hz, A of AB, 1 H), 3.55 (d, J = 10.0 Hz, A of AB, 1 H), 3.18 (s, 3 H), 3.11 (d, J = 14.8 Hz, A′ of A′B′, 1 H), 3.02 (d, J = 14.8 Hz, B′ of A′B′, 1 H), 2.72 (s, 3 H), 1.53 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 141.4, 137.6, 137.2, 135.9, 128.7, 127.5, 123.8, 123.6, 121.1, 119.9, 119.6, 113.0, 109.3, 102.1, 62.4, 44.3, 36.8, 34.2, 29.3, 24.7, HRMS m/z Calcd for C20H22N2O2S [M+H]+ 355.1480, found 355.1449. Minor isomer: (±)-1-methyl-3-((3-methyl-1-(methylsulfonyl)indolin-3-yl)methyl)-1H-indole.
(±)-3-methyl-1-(methylsulfonyl)-3-(thiophen-2-ylmethyl)indoline (2cd)
67% yield, a pale yellow oil, isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.34 (d, J = 8.0 Hz, 1 H), 7.27–7.23 (m, 1 H), 7.19 (dd, J = 7.4, 0.8 Hz, 1 H), 7.11–7.07 (m, 1 H), 7.06 (dd, J = 5.2, 0.8 Hz, 1 H), 6.86 (dd, J = 5.2, 3.4 Hz, 1 H), 6.65 (d, 3.2 Hz, 1 H), 3.93 (d, J = 10.4 Hz, A of AB, 1 H), 3.64 (d, J = 10.4 Hz, B of AB, 1 H), 3.19 (d, J = 14.6 Hz, A′ of A′B′, 1 H), 3.10 (d, J = 14.6 Hz, B′ of A′B′, 1 H), 2.49 (s, 3 H), 1.48 (s, 3 H); 13CNMR (100 MHz, CDCl3): δ = 141.7, 139.2, 137.6, 128.8, 127.4, 126.7, 124.8, 123.6, 123.5, 113.1, 60.6, 44.4, 41.2, 34.1, 27.5; HRMS m/z Calcd for C15H17NO2S2 [M+H]+ 308.0779 found 308.0723.
(±)-3-(benzothiophen-2-ylmethyl)-3-methyl-1-tosylindoline (2da)
(CAS: 1191913-95-7); 67% yield, an inseparable white solid, isomer ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.65–7.59 (m, 4 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.33–7.29 (m, 1 H), 7.28–7.23 (m, 1 H), 7.08–7.02 (m, 2 H), 7.01–6.97 (m, 2 H), 6.82 (s, 1 H), 3.98 (d, J = 10.4 Hz, A of AB, 1 H), 3.60 (d, J = 10.4 Hz, B of AB, 1 H), 3.07 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 3.00 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 2.24 (s, 3 H), 1.30 (s, 3H); HRMS m/z Calcd for C25H23NO2S2 [M+H]+ 434.1248, found 434.1192. Minor isomer: (±)-3-(benzothiophen-3-ylmethyl)-3-methyl-1-tosylindoline.
(±)-3-(benzofuran-2-ylmethyl)-3-methyl-1-tosylindoline (2db)
67% yield, an inseparable yellow solid, isomer ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.69 (d, J = 8.0 Hz, 2 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.43 (dd, J = 6.8, 0.8 Hz, 1 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.24–7.20 (m, 2 H), 7.19–7.15 (m, 3 H), 7.02–7.00 (m, 2 H), 6.22 (s, 1 H), 4.10 (d, J = 10.4 Hz, A of AB, 1 H), 3.57 (d, J = 10.4 Hz, B of AB, 1 H), 2.85 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 2.82 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 2.32 (s, 3 H), 1.21 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 155.1, 154.7, 144.1 141.0, 138.6, 134.0, 129.6, 128.5, 128.4, 127.3, 123.1, 122.6, 120.5, 114.5, 111.0, 105.2, 101.3, 61.3, 43.9, 39.1, 26.0, 21.6; HRMS m/z Calcd for C25H23NO3S [M+H]+ 418.1477 found 418.1418. Minor isomer: (±)-3-(benzofuran-3-ylmethyl)-3-methyl-1-tosylindoline
(±)-1-methyl-2-((3-methyl-1-tosylindolin-3-yl)methyl)-1H-indole (2dc)
40% yield, a pale yellow solid; isomer ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.4 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.50 (dd, J = 7.6, 0.8 Hz, 1 H), 7.21–7.19 (d, J = 8.0 Hz, 2 H), 7.17–7.15 (m, 3 H), 7.10–7.08 (m, 1 H), 6.85 (t, J = 7.4 Hz, 1 H), 6.56 (d, J = 7.6 Hz, 1 H), 6.21 (s, 1 H), 4.00 (d, J = 10.0 Hz, A of AB, 1 H), 3.47 (d, J = 10.0 Hz, B of AB, 1 H), 3.04 (s, 3 H), 2.88 (ψs, 2 H), 2.35 (s, 3 H), 1.35 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 144.3, 141.2, 147.9, 137.1, 135.9, 133.7, 129.7, 128.4, 127.5, 127.4, 123.5, 123.4, 121.0, 119.5, 114.1, 109.0, 101.9, 62.1, 44.2, 36.8, 29.1, 24.4, 21.6; HRMS m/z Calcd for C26H26N2O2S [M+H]+ 431.1793, found 431.1740.
(±)-2-((3-methyl-1-tosylindolin-3-yl)methyl)benzo[d]thiazole (2dd)
31% yield, a white solid; 1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 8.0 Hz, 1 H), 7.71(d, J = 8.0 Hz, 1 H), 7.65–7.60 (m, 3 H), 7.47 (td, J = 7.6, 1.2 Hz, 1 H), 7.35(td, J = 7.6, 0.8 Hz, 1 H), 7.28–7.24 (m, 1 H), 7.09 (dd, J = 7.2, 0.8 Hz, 1 H), 7.06–7.01 (m, 3 H), 4.14 (d, J = 10.8 Hz, A of AB, 1 H), 3.68 (d, J = 10.8 Hz, B of AB, 1 H), 3.27 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 3.17 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 2.25 (s, 3 H), 1.33 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 166.7, 153.0, 141.5, 137.2, 135.3, 130.9, 129.7, 129.0, 126.2, 125.2, 123.7, 123.4, 122.8, 121.4, 120.8, 113.4, 60.9, 44.3, 44.2, 27.1, 22.7; HRMS m/z Calcd for C24H22N2O2S2 [M+H]+ 435.1201, found 435.1197.
(±)-3-methyl-3-(thiophen-2-ylmethyl)-1-tosylindoline (2de)
50% yield, a colorless oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.65 (d, J = 8.0 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.25–7.22 (m, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.05–7.04 (m, 1 H), 7.01–6.98 (m, 2 H), 6.84 (dd, J = 5.2, 3.6 Hz, 1 H), 6.57 (d, J = 3.6 Hz, 1 H), 3.93 (d, J = 10.4 Hz, A of AB, 1 H), 3.49 (d, J = 10.4 Hz, B of AB, 1 H), 2.93 (d, J = 14.4 Hz, A′ of A′B′, 1 H), 2.90 (d, J = 14.4 Hz, B′ of A′B′, 1 H), 2.36 (s, 3 H), 1.22 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 144.0, 141.3, 138.9, 138.3, 134.0, 129.7, 128.4, 127.3, 126.6, 124.4, 123.5, 123.3, 114.3, 60.7, 44.4, 40.5, 26.3, 21.6; HRMS m/z Calcd for C21H21NO2S2 [M+H]+ 384.1092, found 384.1088.
(±)-3-(benzo[d]oxazol-2-ylmethyl)-1,3-dimethylindolin-2-one (2ea)
54% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.50 (dd, J = 6.0, 3.2 Hz, 1 H), 7,21–7.28 (m, 1 H), 7.148–7.14 (m, 2 H), 7.13–7.10 (m, 1 H). 7.04 (d, J = 7.2 Hz, 1 H), 6.91–6.87 (m, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 3.35 (d, J = 14.4 Hz, A of AB, 1 H), 3.32 (d, J = 14.4 Hz, B of AB, 1 H), 3.17 (s, 3 H), 1.49 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 178.3, 161.9, 149.6, 142.0, 140.0, 131.1, 127.3, 123.6, 123.1, 122.1, 121.6, 118.8, 109.2, 107.1, 46.1, 35.4, 25.4, 22.5; HRMS m/z Calcd for C18H16N2O2 [M+H]+ 293.1290, found 293.1296 [M+Na]+ 315.1109, found 315.1118.
(±)-3-(benzo[d]thiazol-2-ylmethyl)-1,3-dimethylindolin-2-one (2eb)
56% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.0 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.39–7.35 (m, 1 H), 7.30–7.28 (m, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 7.21–7.19 (m, 1 H), 7.01 (t, J = 7.4 Hz, 1 H), 6.74 (d, J = 7.6 Hz, 1 H), 3.70 (d, J = 14.4 Hz, A of AB, 1 H), 3.60 (d, J = 14.4 Hz, B of AB, 1 H), 3.19 (s, 3 H), 1.56 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.3, 165.8, 152.7, 143.3, 135.4, 132.1, 128.3, 125.8, 124.8, 123.3, 122.9, 122.6, 121.3, 108.2, 48.4, 41.8, 26.4, 24.2; HRMS m/z Calcd for C18H16N2OS [M+H]+ 309.1062, found 309.1081.
(±)-1,3-dimethyl-3-(thiophen-2-ylmethyl)indolin-2-one (2ec)
43% yield yellow solid, isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.24–7.22 (m, 1 H), 7.18 (dd, J = 7.4, 0.8 Hz, 1 H), 7.09–7.05 (m, 1 H), 6.94 (dd, J = 5.2, 1.2 Hz, 1 H), 6.72 (dd, J = 5.2, 3.4 Hz, 1 H), 6.70 (d, J = 7.6 Hz, 1 H), 6.56–6.55 (m, 1 H), 3.39 (d, J = 14.4 Hz, A of AB, 1 H), 3.22 (d, J = 14.4 Hz, B of AB, 1 H), 3.05 (s, 3 H), 1.48 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.7, 143.5, 138.0, 132.9, 128.1, 126.7, 126.1, 124.0, 123.1, 122.3, 107.9, 49.8, 38.5, 26.0, 23.0; HRMS m/z Calcd for C15H15NOS [M+H]+ 258.0953 found 258.0942 [M+Na]+ 280.0772 found 280.0757.
(±)-3-((5-chlorothiophen-2-yl)methyl)-1,3-dimethylindolin-2-one (2ed)
57% yield, yellow solid, isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.41 (dd, J = 7.2, 0.8 Hz, 1 H), 7.28–7.24 (m, 1 H), 7.09–7.05 (m, 1 H), 6.91 (d, J = 7.6 Hz, 1 H), 6.71 (d, J = 3.6 Hz, 1 H), 6.38 (d, J = 3.6 Hz, 1 H), 3.31 (d, J = 14.8 Hz, A of AB, 1 H), 3.21 (d, J = 14.8 Hz, B of AB, 1 H), 3.00 (s, 3 H), 1.35 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.4, 143.6, 137.0, 132.5, 128.4, 127.8, 126.1, 125.2, 122.9, 122.5, 108.2, 49.6, 38.9, 26.1, 23.1; HRMS m/z Calcd for C15H14ClNOSNa [M+Na]+ 314.0382, found 314.0288.
(±)-ethyl 5-((1,3-dimethyl-2-oxoindolin-3-yl)methyl)thiophene-2-carboxylate (2ee)
56% yield, yellow oil, isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 1.2 Hz, 1 H), 7.27–7.23 (m, 1 H), 7.20 (dd, J = 7.2, 0.8 Hz, 1 H), 7.08 (td, J = 7.6, 1.2 Hz, 1 H), 6.99–6.98 (d, J = 1.2 Hz, 1 H), 6.71 (d, J = 7.6 Hz, 1 H), 4.26–4.21 (m, 2 H), 3.38 (d, J = 14.4 Hz, A of AB, 1 H), 3.18 (d, J = 14.4 Hz, B of AB, 1 H), 3.06 (s, 3 H), 1.48 (s, 3 H), 1.30 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.3, 162.7, 143.5, 138.9, 132.8, 132.4, 131.5, 128.3, 127.2, 123.0, 122.6, 108.1, 60.5, 49.6, 38.5, 26.1, 23.1, 14.3; HRMS m/z Calcd for C18H19NO3S [M+H]+ 330.1164, found 330.1165.
(±)-3-(benzothiophen-2-ylmethyl)-1-ethyl-3-methylindolin-2-one (2fa)
46% yield, an inseparable yellow solid; isomers ratio = 9:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.37–7.35 (m, 1 H), 7.29–7.23 (m, 2 H), 7.22–7.18 (m, 1 H), 7.03–6.99 (m, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 3.85–3.80 (m, 1 H), 3.72 (d, J = 14.4 Hz, A of AB, 1 H), 3.67–3.60 (m, 1 H), 3.55 (d, J = 14.4 Hz, B of AB, 1 H), 1.55 (s, 3 H), 1.13 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 178.8, 165.7, 152.8, 142.5, 135.4, 132.3, 128.2, 125.7, 124.7, 123.4, 122.8, 122.3, 121.2, 108.3, 48.3, 41.7, 34.7, 24.3, 12.4; HRMS m/z Calcd for C20H19NOS [M+H]+ 345.1266, found 322.1210. Minor isomer: (±)-3-(benzothiophen-3-ylmethyl)-1-ethyl-3-methylindolin-2-one.
(±)-3-(benzofuran-2-ylmethyl)-1-ethyl-3-methylindolin-2-one (2fb)
37% yield, an inseparable yellow oil; isomers ratio = 6:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.37 (d, J = 7.2 Hz, 1 H), 7.25–7.27 (m, 1 H), 7.21–7.15 (m, 2 H), 7.13–7.09 (m, 2 H), 7.00 (t, J = 7.6 Hz, 1 H), 6.73 (d, J = 7.2 Hz, 1 H), 6.17 (s, 1 H), 3.82 (m, 1 H), 3.59 (m, 1 H), 3.27 (d, J = 14.8 Hz, A of AB, 1 H), 3.24 (d, J = 14.8 Hz, B of AB, 1 H), 1.50 (s, 3 H), 1.10 (t, J = 7.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 176.6, 154.5, 142.7, 131.1, 128.0, 126.7, 123.4, 122.4, 122.2, 121.8, 120.4, 118.4, 110.8, 108.1, 104.5, 48.1, 35.0, 27.1, 19.2, 13.0; HRMS m/z Calcd for C20H19NO2Na [M+Na]+ 328.1313, found 328.1342. Minor isomer: (±)-3-(benzofuran-3-ylmethyl)-1-ethyl-3-methylindolin-2-one.
(±)-3-(benzo[d]oxazol-2-ylmethyl)-1-ethyl-3-methylindolin-2-one (2fc)
84% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.55 (dd, J = 6.0, 3.2 Hz 1H), 7.34 (dd, J = 6.0, 3.2 Hz, 1 H), 7.24–7.19 (m, 2 H), 7.17 (dd, J = 7.6, 4.0 Hz, 2 H), 6.96 (t, J = 7.6 Hz, 1 H), 6.77 (d, J = 8.0 Hz, 1 H), 3.99–3.89 (m, 1 H), 3.71–3.62 (m, 1 H), 3.47 (d, J = 14.8 Hz, A of AB, 1 H), 3.42 (d, J = 14.8 Hz, B of AB, 1 H), 1.56 (s, 3 H), 1.26 (t, J = 7.2 Hz, 3 H); 13CNMR (100 MHz, CDCl3): δ = 178.8, 162.9, 150.6, 142.1, 141.0, 132.3, 128.2, 124.6, 124.0, 123.2, 122.3, 119.8, 110.2, 108.3, 47.1, 36.4, 34.7, 23.9, 12.3; HRMS m/z Calcd for C19H18N2O2 [M+H]+ 307.1447 found 307.1369 [M+Na]+ 329.1266 found 326.1274.
(±)-3-(benzo[d]thiazol-2-ylmethyl)-1-ethyl-3-methylindolin-2-one (2fd)
62% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.0 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.37–7.35 (m, 1 H), 7.29–7.23 (m, 2 H), 7.22–7.18 (m, 1 H), 7.03–6.99 (m, 1 H), 6.74 (d, J = 8.0 Hz, 1 H), 3.85–3.80 (m, 1 H), 3.72 (d, J = 14.4 Hz, A of AB, 1 H), 3.67–3.60 (m, 1 H), 3.55 (d, J = 14.4 Hz, B of AB, 1 H), 1.55 (s, 3 H), 1.13 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 178.8, 165.7, 152.8, 142.5, 135.4, 132.3, 128.2, 125.7, 124.7, 123.4, 122.8, 122.3, 121.2, 108.3, 48.3, 41.7, 34.7, 24.3, 12.4; HRMS m/z Calcd for C19H18N2OS [M+H]+ 323.1218, found 323.1169.
(±)-1-ethyl-3-methyl-3-(thiophen-2-ylmethyl)indolin-2-one (2fe)
42% yield, an inseparable yellow oil; isomers ratio = 5.3:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.24 (d, J = 7.6 Hz, 2 H), 7.08 (t, J = 7.6 Hz, 1 H), 6.92 (d, J = 5.2 Hz, 1 H), 6.72–6.70 (m, 2 H), 6.54 (d, J = 2.8 Hz, 1 H), 3.78–3.70 (m, 1 H), 3.46–3.99 (m, 1 H), 3.42 (d, J = 14.4 Hz, A of AB, 1 H), 3.22 (d, J = 14.4 Hz, B of AB, 1 H), 1.48 (s, 3 H), 0.92 (t, J = 6.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.1, 142.8, 137.9, 133.2, 128.1, 126.7, 124.0, 123.2, 121.8, 118.4, 108.1, 49.7, 38.7, 22.9, 19.2, 12.2; HRMS m/z Calcd for C16H17NOS [M+H]+ 272.1109, found 272.1040. Minor isomer: (±)-1-ethyl-3-methyl-3-(thiophen-3-ylmethyl)indolin-2-one.
(±)-3-((5-chlorothiophen-2-yl)methyl)-1-ethyl-3-methylindolin-2-one (2ff)
63% yield, an inseparable yellow oil; isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.29–7.25 (m, 1 H), 7.24–7.22 (m, 1 H), 7.11–7.07 (m, 1 H), 6.75 (d, J = 7.6 Hz, 1 H), 6.52 (d, J = 3.6 Hz, 1 H), 6.32 (d, J = 3.6 Hz, 1 H), 3.79–3.72 (m, 1 H), 3.52–3.43 (m, 1 H), 3.30 (d, J = 14.4 Hz, A of AB, 1 H), 3.10 (d, J = 14.4 Hz, B of AB, 1 H), 1.45 (s, 3 H), 0.98 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 178.8, 142.8, 136.8, 132.8, 128.6, 127.8, 126.1, 125.1, 123.0, 122.3, 108.3, 49.5, 38.2, 34.4, 22.9, 12.2; HRMS m/z Calcd for C16H16ClNOS [M+H]+ 306.0719 found 306.0741. Minor isomer: (±)-3-((5-chlorothiophen-3-yl)methyl)-1-ethyl-3-methylindolin-2-one.
(±)-5-((1-ethyl-3-methyl-2-oxoindolin-3-yl)methyl)thiophene-2-carbaldehyde (2fg)
30% yield, yellow oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 9.67 (s, 1 H), 7.41 (d, J = 3.8 Hz, 1 H), 7.28–7.24 (m, 1 H), 7.11–7.08 (m, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.70 (d, J = 3.8 Hz, 1 H), 3.78–3.68 (m, 1 H), 3.49–3.42 (m, 1 H), 3.48 (d, J = 14.0 Hz, A of AB, 1 H), 3.24 (d, J = 14.0 Hz, B of AB, 1 H), 1.50 (s, 3 H), 0.94 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 182.6, 178.5, 149.6, 142.5, 135.8, 132.2, 128.3, 123.1, 122.6, 108.4, 49.5, 47.7, 39.3, 34.4, 23.3, 12.2; HRMS m/z Calcd for C17H18NO2S [M+H]+ 300.1058, found 300.1032.
(±)-3-(benzothiophen-2-ylmethyl)-1-butyl-3-methylindolin-2-one (2ga)
56% yield, an inseparable yellow solid; isomers ratio = 6.3:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.59 (ψt, J = 8.4 Hz, 2 H), 7.32 (dd, J = 7.4, 1.0 Hz, 1 H), 7.28–7.16 (m, 3 H), 7.13 (td, J = 7.6, 0.8 Hz, 1 H), 6.87 (s, 1 H), 6.72 (d, J = 7.6 Hz, 1 H), 3.68 (td, J = 14.0, 7.2 Hz, A of AB, 1 H), 3.33 (d, J = 14.0 Hz, B of AB, 1 H), 1.54 (s, 3 H), 1.29–1.21 (m, 2 H), 0.58 (t, J = 7.2 Hz, 3 H); 13CNMR (100 MHz, CDCl3): δ = 179.2, 143.3, 139.8, 139.2, 133.0, 128.2, 123.8, 123.6, 123.5, 123.1, 122.9, 122.2, 121.8, 108.5, 108.3, 46.5, 39.6, 39.4, 29.3, 23.7, 19.9, 13.5; HRMS m/z Calcd for C22H24NOS [M+H]+ 350.1579 found 350.1596. Minor isomer: (±)-3-(benzothiophen-3-ylmethyl)-1-butyl-3-methylindolin-2-one.
(±)-3-(benzo[d]oxazol-2-ylmethyl)-1-butyl-3-methylindolin-2-one (2gb)
41% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.57–7.54 (m, 1 H), 7.37–7.33 (m, 1 H), 7.25–7.19 (m, 2 H), 7.18–7.14 (m, 2 H), 6.98–6.94 (m, 1 H), 6.77 (d, J = 7.8 Hz, 1 H), 3.87–3.80 (m, 1 H), 3.66–3.59 (m, 1 H), 3.46 (d, J = 5.0 Hz, A of AB, 1 H), 3.45 (d, J = 5.0 Hz, B of AB, 1 H), 1.71–1.61 (m, 2 H), 1.56 (s, 3 H), 1.43–1.34 (m, 2 H), 0.95 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 178.1, 161.9, 149.6, 141.5, 140.0, 131.2, 127.2, 123.6, 123.0, 122.2, 121.3, 118.8, 109.2, 107.4, 46.1, 38.8, 35.2, 28.3, 23.0, 19.2, 12.8; HRMS m/z Calcd for C21H22N2O2 [M+H]+ 335.1760, found 335.1726.
(±)-3-(benzo[d]thiazol-2-ylmethyl)-1-butyl-3-methylindolin-2-one (2gc)
76% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.86 (dd, J = 8.0, 0.4 Hz, 1 H), 7.70–7.68 (m, 1 H), 7.38–7.24 (m, 1 H), 7.28–7.24 (m, 2 H), 7.20 (td, J = 7.8, 1.2 Hz, 1 H), 7.02 (td, J = 7.6, 0.8 Hz, 1 H), 6.74 (d, J = 7.8 Hz, 1 H), 3.76–3.69 (m, 1 H), 3.72 (d, J = 14.4 Hz, A of AB, 1 H), 3.60–3.53 (m, 1 H), 3.55 (d, J = 14.4 Hz, B of AB, 1 H), 1.55 (s, 3 H), 1.53–1.44 (m, 2 H), 1.24–1.21 (m, 1 H), 1.19–1.15 (m, 1 H), 0.78 (t, J = 7.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 178.0, 164.7, 151.6, 141.9, 134.3, 131.2, 127.2, 124.7, 123.7, 122.3, 121.8, 121.3, 120.2, 107.4, 47.3, 40.8, 38.8, 28.3, 23.3, 19.0, 12.6; HRMS m/z Calcd for C21H22N2OSNa [M+Na]+ 373.1351, found 373.1340.
(±)-1-butyl-3-methyl-3-((1-methyl-1H-indol-2-yl)methyl)indolin-2-one (2gd)
34% yield, yellow oil; isomers ratio > 20:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.40–7.38 (m, 1 H), 7.25–7.21 (m, 1 H), 7.16 (d, J = 7.8 Hz, 1 H), 7.12–7.08 (m, 1 H), 7.05–6.99 (m, 3 H), 6.73 (d, J = 7.8 Hz, 1 H), 5.86 (s, 1 H), 3.70–3.63 (m, 1 H), 3,48–3.41 (m, 1 H), 3.45 (s, 3 H), 3.26 (d, J = 14.8 Hz, A of AB, 1 H), 3.23 (d, J = 14.8 Hz, B of AB, 1 H), 1.52 (s, 3 H), 1.35–1.27 (m, 2 H), 1.09–1.02 (m, 2 H), 0.69 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.8, 142.9, 137.0, 135.2, 128.1, 126.0, 127.5, 123.3, 122.1, 120.8, 119.9, 119.2, 109.1, 108.4, 101.6, 48.9, 39.6, 34.2, 29.7, 29.3, 23.2, 19.9, 13.6; HRMS m/z Calcd for C23H26N2O [M+H]+347.2123, found 347.2124.
(±)-1-butyl-3-methyl-3-(thiophen-2-ylmethyl)indolin-2-one (2ge)
65% yield, an inseparable yellow solid; isomers ratio = 5:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 7.6 Hz, 2 H), 7.09–7.05 (m, 1 H), 6.91 (dd, J = 5.6, 1.0 Hz, 1 H), 6.73–6.70 (m, 2 H), 6.56 (d, J = 3.2 Hz, 1 H), 3.69–3.62 (m, 1 H), 3.44–3.37 (m, 1 H), 3.40 (d, J = 14.2 Hz, A of AB, 1 H), 3.21 (d, J = 14.2 Hz, B of AB, 1 H), 1.47 (s, 3 H), 1.41–1.31 (m, 2 H), 1.16–1.07 (m, 2 H), 0.86 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.3, 143.3, 137.9, 133.2, 128.0, 126.8, 126.1, 124.0, 123.2, 122.1, 108.2, 49.7, 39.5, 38.5, 29.3. 23.3, 20.0, 13.8; HRMS m/z Calcd for C18H21NOS [M+H]+300.1422, found 300.1429. Minor isomer: (±)-1-butyl-3-methyl-3-(thiophen-3-ylmethyl)indolin-2-one.
(±)-1-butyl-3-((5-chlorothiophen-2-yl)methyl)-3-methylindolin-2-one (2gf)
73% yield, an inseparable yellow oil; isomers ratio = 7:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.28–7.22 (m, 2 H), 7.10–7.06 (m, 1 H), 6.75(d, J = 7.6 Hz, 1 H), 6.52 (d, J = 3.6 Hz, 1 H), 6.33(d, J = 3.6 Hz, 1 H), 3.73–3.66 (m, 1 H), 3.45–3.38 (m, 1 H), 3.30 (d, J = 14.4 Hz, A of AB, 1 H), 3.10 (d, J = 14.4 Hz, B of AB, 1 H), 1.44 (s, 3 H), 1.42–1.32 (m, 2 H), 1.18–1.08 (m, 2 H), 0.86 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.1, 143.3, 136.9, 132.9, 128.4, 127.8, 126.2, 125.1, 123.0, 122.3, 108.5, 49.5, 39.6, 39.1, 29.4, 23.3, 20.0, 13.8; HRMS m/z Calcd for C18H20ClNOSNa [M+Na]+ 357.1579, found 357.1545. Minor isomer: (±)-1-butyl-3-((5-chlorothiophen-3-yl)methyl)-3-methylindolin-2-one.
(±)-5-((1-butyl-3-methyl-2-oxoindolin-3-yl)methyl)thiophene-2-carbaldehyde (2gg)
48% yield, yellow oil; isomers ratio >20:1; 1H NMR (400 MHz, CDCl3): δ = 9.67 (s, 1 H), 7.41 (d, J = 3.6 Hz, 1 H), 7.28–7.25 (m, 2 H), 7.10 (td, J = 7.2, 0.8 Hz, 1H), 6.73–6.72 (m, 1 H), 6.70 (d, J = 3.8 Hz, 1 H), 3.68–3.61 (m, 1 H), 3.48 (d, J = 14.0 Hz, A of AB, 1 H), 3.46–3.39 (m, 1 H), 3.24 (d, J = 14.0 Hz, B of AB, 1 H), 1.50 (s, 3 H), 1.40–1.30 (m, 2 H), 1.13–1.07 (m, 2 H), 0.82 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 181.5, 177.7, 148.6, 142.0, 141.5, 134.8, 131.1, 127.6, 127.4, 122.0, 121.5, 107.6, 48.5, 38.6, 38.1, 28.3, 22.6, 18.9, 12.7; HRMS m/z Calcd for C19H21NO2S [M+H]+ 328.1371, found 328.1360.
(±)-3-(benzofuran-2-ylmethyl)-1-benzyl-3-methylindolin-2-one (2ha)
37% yield, yellow solid; isomer rate >20:1, 1H NMR (400 MHz, CDCl3): δ = 7.40 (d, J = 7.2 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.24 (d, J = 7.2 Hz, 1 H), 7.21–7.11 (m, 3 H), 3.07–6.96 (m, 5 H), 6.59 (d, J = 7.6 Hz, 1 H), 6.19 (s, 1 H), 5.11 (d, J = 16.0 Hz, 1 H), 4.68 (d, J = 16.0 Hz, 1 H), 3.42 (d, J = 14.6 Hz, A of AB, 1 H), 3.36 (d, J = 14.6 Hz, B of AB, 1 H), 1.60 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.6, 154.5, 154.3, 142.2, 135.5, 132.9, 128.6, 128.5, 128.0, 127.3, 126.9, 123.6, 123.2, 122.5 (2 C), 120.6, 111.0, 109.2, 104.8, 48.4, 43.7, 36.6, 24.1, 19.5; HRMS m/z Calcd for C25H22NO2 [M+H]+ 368.1651, found 368.1660.
(±)-3-(benzo[d]oxazol-2-ylmethyl)-1-benzyl-3-methylindolin-2-one (2hb)
82% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.59–7.56 (m, 1 H), 7.33–7.31 (m, 1 H), 7.25–7.22 (m, 2 H), 7.16 (d, J = 7.2 Hz, 1 H), 7.09–7.04 (m, 1 H), 6.96–6.92 (m, 1 H), 6.62 (d, J = 7.6 Hz, 1 H), 5.09 (d, J = 15.6 Hz, 1 H), 4.81 (d, J = 15.6 Hz, 1 H), 3.55 (d, J = 15.0 Hz, A of AB, 1 H), 3.50 (d, J = 15.0 Hz, B of AB, 1 H), 1.62 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.3, 162.8, 150.6, 142.2, 141.0, 135.8, 132.1, 128.7, 128.2, 127.5, 127.2, 124.7, 124.1, 123.1, 122.6, 119.9, 110.4, 109.3, 47.3, 44.0, 36.1, 24.7; HRMS m/z Calcd for C24H20N2O2 [M+H]+ 369.1603, found 369.1604.
(±)-3-(benzo[d]thiazol-2-ylmethyl)-1-benzyl-3-methylindolin-2-one (2hc)
62% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 8.0 Hz, 1 H). 7.66 (d, J = 8.0 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.32–7.28 (m, 1 H), 7.13–7.08 (m, 2 H), 7.07–7.02 (m, 1 H), 6.58 (d, J = 7.6 Hz, 1 H), 5.03 (d, J = 15.6 Hz, 1 H), 4.67 (d, J = 15.6 Hz, A of AB, 1 H), 3.83 (d, J = 14.4 Hz, B of AB, 1 H), 3.61 (d, J = 14.4 Hz, 1 H), 1.62 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.1, 165.7, 152.7, 142.6, 135.5, 132.1, 128.5, 128.4, 127.3, 127.0, 125.8, 124.9, 123.3, 123.1, 122.7, 121.4, 109.4, 48.6, 43.8, 41.9, 24.8; HRMS m/z Calcd for C24H20N2OS [M+H]+ 385.1375 found 385.1367 [M+Na]+ 407.1194 found 407.1187.
(±)-1-benzyl-3-methyl-3-(thiophen-2-ylmethyl)indolin-2-one (2hd)
60% yield, an inseparable white solid; isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.35–7.26 (m, 4 H), 7.17–7.05 (m, 2 H), 6.96 (dd, J = 5.2, 0.8 Hz, 1 H), 6.80–6.72 (m, 3 H), 6.62 (d, J = 3.2 Hz, 1H), 6.50 (d, J = 7.6 Hz, 1 H), 5.04 (d, J = 16.0 Hz, A of AB, 1 H), 4.52 (d, J = 16.0 Hz, B of AB, 1 H), 3.52 (d, J = 14.4 Hz, 1 H), 3.30 (d, J = 14.4 Hz, 1 H), 1.54 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.5, 142.8, 138.0, 133.0, 128.6, 128.1, 127.4, 127.2, 127.1, 126.7, 126.3, 124.3, 123.0, 122.4, 109.3, 50.3, 43.5, 38.4, 19.5; HRMS m/z Calcd for C21H20NOSK [M+K]+ 356.1053, found 356.1094. Minor isomer: (±)-1-benzyl-3-methyl-3-(thiophen-3-ylmethyl)indolin-2-one.
(±)-1-benzyl-3-((5-chlorothiophen-2-yl)methyl)-3-methylindolin-2-one (2he)
64% yield, yellow oil; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 7.32–7.30 (m, 1 H), 7.27 (dd, J = 7.2, 0.8 Hz, 1 H), 7.23–7.18 (m, 2 H), 7.14 (td, J = 7.6, 1.2 Hz, 1 H), 7.09–7.05 (m, 1 H), 6.80–6.76 (m, 2 H), 6.57–6.54 (m, 2 H), 6.39 (d, J = 3.6 Hz, 1 H), 5.11 (d, J = 16.0 Hz, A of AB, 1 H), 4.48 (d, J = 16.0 Hz, B of AB, 1 H), 3.41 (d, J = 14.4 Hz, 1 H), 3.18 (d, J = 14.4 Hz, 1 H), 1.52 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.2, 142.9, 137.0, 135.3, 132.5, 128.8, 128.6, 128.5, 127.4, 126.7, 126.5, 125.4, 122.8, 122.6, 109.5, 49.8, 43.6, 39.0, 23.9; HRMS m/z Calcd for C21H18ClNOS [M+H]+ 368.0876, found 368.0907.
(±)-1-allyl-3-(benzothiophen-2-ylmethyl)-3-methylindolin-2-one (2ia)
28% yield, an inseparable yellow solid; isomers ratio = 10:1; major isomer: 1H NMR (400 MHz, CDCl3): δ = 7.58 (d, J = 8.0 Hz, 1 H), 7.56–7.54 (m, 1 H), 7.30 (dd, J = 7.2, 0.8 Hz, 1 H), 7.24–7.20 (m, 2 H), 7.19–7.15 (m, 1 H), 7.12–7.08 (m, 1 H), 6.84 (s, 1 H), 6.65 (d, J = 7.2 Hz, 1 H), 5.49–5.42 (m, 1 H), 4.75–4.73 (m, 1 H), 4.65–4.60 (m, 1 H), 4.33–4.27 (m, 1 H), 4.07–4.01 (m, 1 H), 3.53 (d, J = 14.2 Hz, A of AB, 1 H), 3.31 (d, J = 14.2 Hz, B of AB, 1 H), 1.54 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 179.2, 142.8, 139.7, 139.5, 139.1, 132.8, 130.9, 128.2, 123.8, 123.6, 123.1, 123.0, 124.4, 121.8, 118.3, 116.7, 109.1, 49.7, 42.0, 39.2, 23.8; HRMS m/z Calcd for C21H19NOS [M+Na]+ 356.1058, found 356.1076. Minor isomer: (±)-1-allyl-3-(benzothiophen-3-ylmethyl)-3-methylindolin-2-one.
(±)-1-allyl-3-(benzo[d]thiazol-2-ylmethyl)-3-methylindolin-2-one (2ib)
34% yield, an inseparable yellow solid; isomers ratio = 5:1; 1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.6 Hz, 1 H), 7.69 (dd, J = 8.0, 0.4 Hz, 1 H), 7.38–7.34 (m, 1 H), 7.28–7.24 (m, 2 H), 7.17 (td, J = 8.0, 1.2 Hz, 1 H), 7.01 (td, J = 7.6, 0.8 Hz, 1 H), 6.72 (d, J = 7.6 Hz, 1 H), 5.74–5.65 (m, 1 H), 5.05–5.01 (m, 2 H), 4.40–4.34 (m, 1 H), 4.27–4.21 (m, 1 H), 3.74 (d, J = 14.4 Hz, A of AB, 1 H), 3.58 (d, J = 14.4 Hz, B of AB, 1 H), 1.58 (s, 3 H); 3C NMR (100 MHz, CDCl3): δ = 178.9, 165.6, 152.8, 142.6, 135.4, 132.1, 131.3, 128.2, 125.7, 124.8, 123.3, 122.9, 122.5, 121.3, 117.4, 109.1, 48.4, 42.4, 41.7, 24.5; HRMS m/z Calcd for C20H18N2OS [M+H]+ 335.1218, found 335.1219.
(±)-2-((4-methylisochroman-4-yl)methyl)benzo[d] oxazole (2ja)
31% yield, yellow oil; 1H NMR (400 MHz, CDCl3): δ = 7.70–7.68 (m, 1 H), 7.47–7.45 (m, 1 H), 7.30 (td, J = 3.6, 1.2 Hz, 2 H), 7.26–7.24 (m, 1 H), 7.19–7.16 (m, 2 H), 7.00–6.98 (m, 1 H), 4.87 (d, J = 15.0 Hz, A of AB, 1 H), 4.82 (d, J = 15.0 Hz, B of AB, 1 H), 4.09 (d, J = 11.6 Hz, A′ of A′B′, 1 H), 3.57 (d, J = 11.6 Hz, B′ of A′B′, 1 H), 3.37 (d, J = 14.0 Hz, A′′ of A′′B′′, 1 H), 3.25 (d, J = 14.0 Hz, B′′ of A′′B′′, 1 H), 1.38 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 164.5, 150.8, 141.3, 140.4, 133.7, 126.9, 126.6, 125.8, 124.6, 124.3, 124.2, 119.8, 110.4, 73.7, 69.0, 39.3, 37.2, 22.8; HRMS m/z Calcd for C18H17NO2 [M+H]+ 280.1338, found 280.1337.
(±)-2-((4-methylisochroman-4-yl)methyl)benzo[d] thiazole (2jb)
65% yield, yellow solid; 1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.0 Hz, 1 H), 7.75 (dd, J = 8.0, 0.4 Hz, 1 H), 7.47–7.43 (m, 1 H), 7.36–7.31 (m, 1 H), 7.22–7.18 (m, 2 H), 7.01–6.99 (m, 1 H), 4.80 (ψs, 2 H), 4.04 (d, J = 11.6 Hz, A of AB, 1 H), 3.58 (d, J = 11.6 Hz, B of AB, 1 H), 3.57 (d, J = 14.0 Hz, A′ of A′B′, 1 H), 3.42 (d, J = 14.0 Hz, B′ of A′B′, 1 H), 1.41 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 167.8, 153.0, 140.4, 135.6, 134.2, 126.9, 126.1, 125.9, 124.8, 124.4, 122.8, 121.3, 73.6, 69.0, 44.4, 37.6, 23.9; HRMS m/z Calcd for C18H17NOS [M+H]+ 296.1109, found 296.1105.
(±)- 5-((4-methylisochroman-4-yl)methyl)thiophene-2-carbaldehyde (2jc)
57% yield, yellow solid; isomers ratio > 20:1; 1H NMR (400 MHz, CDCl3): δ = 9.78 (s, 1 H), 7.83 (d, J = 3.6 Hz, 1 H), 7.39 (dd, J = 7.6, 1.2 Hz, 1 H), 7.25–7.17 (m, 2 H), 7.02 (dd, J = 7.2, 1.2 Hz, 1 H), 6.96 (d, J = 3.6 Hz, 1 H), 4.69 (d, J = 8.8 Hz, A of AB, 1 H), 4.66 (d, J = 8.8 Hz, B of AB, 1 H), 3.70 (d, J = 11.6 Hz, A′ of A′B′, 1 H), 3.48 (d, J = 11.6 Hz, B′ of A′B′, 1 H), 3.31 (d, J = 14.4 Hz, A′′ of A′′B′′, 1 H), 3.17 (d, J = 14.4 Hz, B′′ of A′′B′′, 1 H), 1.24 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ = 182.6, 151.8, 142.6, 140.2, 136.4, 133.9, 128.9, 126.8, 126.6, 126.0, 124.3, 73.4, 68.9, 41.5, 37.5, 23.3; HRMS m/z Calcd for C16H16O2S [M+H]+ 273.0949, found 273.0943.

4. Conclusions

In summary, we developed a palladium-catalyzed domino arylation reaction for the formation of biologically relevant 3,3-disubstituted dihydrobenzofurans, indolines, indolinones and isochromanes in moderate to excellent yields (28–92%) with moderate to good regioselectivities (5:1 to > 20:1 ir) using Pd(PPh3)2Cl2/(±)-BINAP as the catalyst. We employed not only sulphur-containing heterocycles, but also oxygen-containing ones as efficient reagents for the tandem arylation, compared with Fagnou’s work (they just developed sulphur-containing heterocycles as coupling reagents). In addition, our catalytic system was also expanded to synthesize isochromanes. Generally, substituted or unsubstituted thiophenes, reacted with 2-substituted phenylbromides, afforded the products with high regioselectivities (>20:1 ir). The synthesized new compounds were well characterized through different spectroscopic techniques, such as 1H and 13C NMR, and mass spectral analysis.

Supplementary Materials

The following are available online at https://0-www-mdpi-com.brum.beds.ac.uk/2073-4344/10/9/1084/s1. Copies of 1H and 13C NMR spectra for the new compounds.

Author Contributions

G.Y. and C.L. conceived the experiments and wrote the main manuscript. S.L., D.J., G.D., J.F. and X.W. conducted the experiments. G.Y., C.L. and L.Z. supervised the experimental works. C.L. was responsible for mass spectrometry of all compounds. H.C., C.Y., Z.Y., X.S. and X.L. analyzed the results. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Project of Science and Technology Department of Sichuan Province (No. 2020YFH0129), the National Key R & D Program of China (No. 2019YFD1002100, 2018YFD0200500), the Biotechnology and Medicine of the Major Scientific and Technological Project of Sichuan Province (No. 2017NZDZX0003), the Program Sichuan Veterinary Medicine and Drug Innovation Group of China Agricultural Research System (No. SCCXTD-2020–18), the National Natural Sciences Foundation of China (No. 51603064) and the Natural Sciences Foundation of Hubei province in China (No. 2016CFB126).

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 10 01084 g001 550
Figure 1. Representatives of natural and artificial bioactive benzofurans and 3,3-disubstituted indoles I–VI.
Figure 1. Representatives of natural and artificial bioactive benzofurans and 3,3-disubstituted indoles I–VI.
Catalysts 10 01084 g001
Catalysts 10 01084 g002 550
Figure 2. The tandem Heck/arylation for the synthesis of dihydrobenzo-furans, indolines, indolinones and isochromanes.
Figure 2. The tandem Heck/arylation for the synthesis of dihydrobenzo-furans, indolines, indolinones and isochromanes.
Catalysts 10 01084 g002
Catalysts 10 01084 sch001 550
Scheme 1. Synthesis of 3,3-disubstituted dihydrobenzofruans.
Scheme 1. Synthesis of 3,3-disubstituted dihydrobenzofruans.
Catalysts 10 01084 sch001
Catalysts 10 01084 sch002 550
Scheme 2. Synthesis of 3,3-disubstituted indolines.
Scheme 2. Synthesis of 3,3-disubstituted indolines.
Catalysts 10 01084 sch002
Catalysts 10 01084 sch003 550
Scheme 3. Synthesis of 3,3-disubstituted indolinones.
Scheme 3. Synthesis of 3,3-disubstituted indolinones.
Catalysts 10 01084 sch003
Catalysts 10 01084 sch004 550
Scheme 4. Synthesis of 4,4-disubstituted isochromanes.
Scheme 4. Synthesis of 4,4-disubstituted isochromanes.
Catalysts 10 01084 sch004
Table
Table 1. The condition optimization of the model reaction a.
Table 1. The condition optimization of the model reaction a.
Catalysts 10 01084 i001
EntryPd SaltAdditiveBaseYield b
1Pd(OAc)2PivOHK2CO361
2Pd2(dba)3PivOHK2CO316
3Pd(dppf)2Cl2PivOHK2CO339
4Pd(PPh3)4PivOHK2CO361
5PdCl2PivOHK2CO354
6Pd/CPivOHK2CO3- c
7Pd(PPh3)2Cl2PivOHK2CO380
8Pd(PPh3)2Cl2PivOHKOAc57
9Pd(PPh3)2Cl2PivOHK3PO415
10Pd(PPh3)2Cl2PivOHKOtBu55
11Pd(PPh3)2Cl2PivOHNa2CO322
12Pd(PPh3)2Cl2PivOHCs2CO365
13Pd(PPh3)2Cl2PivOHLiOH·H2O31
14Pd(PPh3)2Cl2PivOHNaOH25
15Pd(PPh3)2Cl2PivOHKOH42
16Pd(PPh3)2Cl2PivOHTEA- c
17Pd(PPh3)2Cl2 (1 mol%)PivOHK2CO359
18Pd(PPh3)2Cl2 (3 mol%)PivOHK2CO375
19Pd(PPh3)2Cl2- dK2CO366
20Pd(PPh3)2Cl2CsFK2CO361
21Pd(PPh3)2Cl2Ag2CO3K2CO3<20%
22Pd(PPh3)2Cl2AgNO3K2CO320%
a Reaction conditions: aryl bromide (0.1 mmol), benzothiophene (0.4 mmol), Pd salt (5 mol%), (±)-BINAP (6 mol%), PivOH (0.3 equiv), base (2.0 equiv) and DMA (0.5 mL), 110 °C, 30 h. b Isolated by column chromatography with ≥ 10:1 regioselectivity. c No product. d No additive. PivOH = pivalic acid, TEA = triethylamine, DMA = N,N-dimethylacetamide, dba = dibenzylideneacetone and dppf = 1,1′-bis(diphenyl phosphino)ferrocene.
Table
Table 2. The effect of the ligand and solvent on the model tandem reaction a.
Table 2. The effect of the ligand and solvent on the model tandem reaction a.
Catalysts 10 01084 i002
EntryLigandSolventYield b
1Ph3PDMA36
2Cy3PDMA56
3Cy3P·HBF4DMA61
4tBu3P·HBF4DMA50
5dppeDMA60
6dppbDMA62
7dpppDMA65
8(±)-BINAPDMA80
9(±)-BINAPDMF76
10(±)-BINAPPhMe59
11(±)-BINAPACN44
12(±)-BINAPPhCN<10
13(±)-BINAPDMSO-c
14(±)-BINAP1,4-dioxane<10
15(±)-BINAPDMA (90 °C)75
a Reaction conditions: aryl bromide (0.1 mmol), benzothiophene (0.4 mmol), Pd(PPh3)2Cl2 (5 mol%), ligand (6 mol%), PivOH (0.3 equiv), K2CO3 (2.0 equiv) and solvent (0.5 mL), 110 °C, 30 h. b Isolated by column chromatography with ≥ 10:1 regioselectivity. c No product. DMF = N,N-dimethylformamide, ACN = acetonitrile, DMSO = dimethyl sulfoxide, dppe = 1,2-bis(diphenylphosphino)ethane, dppb = 1,4-bis(diphenylphosphino)butane and dppp = 1,3-bis(diphenylphosphino)propane.

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Yue, G.; Li, S.; Jiang, D.; Ding, G.; Feng, J.; Chen, H.; Yang, C.; Yin, Z.; Song, X.; Liang, X.; et al. Syntheses of 3,3-Disubstituted Dihydrobenzofurans, Indolines, Indolinones and Isochromanes by Palladium-Catalyzed Tandem Reaction Using Pd(PPh3)2Cl2/(±)-BINAP as a Catalytic System. Catalysts 2020, 10, 1084. https://0-doi-org.brum.beds.ac.uk/10.3390/catal10091084

AMA Style

Yue G, Li S, Jiang D, Ding G, Feng J, Chen H, Yang C, Yin Z, Song X, Liang X, et al. Syntheses of 3,3-Disubstituted Dihydrobenzofurans, Indolines, Indolinones and Isochromanes by Palladium-Catalyzed Tandem Reaction Using Pd(PPh3)2Cl2/(±)-BINAP as a Catalytic System. Catalysts. 2020; 10(9):1084. https://0-doi-org.brum.beds.ac.uk/10.3390/catal10091084

Chicago/Turabian Style

Yue, Guizhou, Sicheng Li, Dan Jiang, Gang Ding, Juhua Feng, Huabao Chen, Chunping Yang, Zhongqiong Yin, Xu Song, Xiaoxia Liang, and et al. 2020. "Syntheses of 3,3-Disubstituted Dihydrobenzofurans, Indolines, Indolinones and Isochromanes by Palladium-Catalyzed Tandem Reaction Using Pd(PPh3)2Cl2/(±)-BINAP as a Catalytic System" Catalysts 10, no. 9: 1084. https://0-doi-org.brum.beds.ac.uk/10.3390/catal10091084

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