Nickel-Catalyzed Amidoalkylation Reaction of γ-Hydroxy Lactams: An Access to 3-Substituted Isoindolinones.

An efficient Ni(ClO4)2·6H2O-promoted amidoalkylation reaction for the synthesis of 3-substituted isoindolinones involving various γ-hydroxy lactams and nucleophiles has been successfully developed. The transformation proceeds with both carbon (ketones and arenes) and heteroatom (alcohols, thiols, and amines) nucleophiles and in both intermolecular and intramolecular manners. The prominent features of the present strategy are wide substrate scope, excellent group tolerability, and moderate to good yields (up to 96% yield). The present strategy is also characterized by remarkable superiority over the current synthetic methods. Furthermore, the reaction could be scaled up to the multigram scale.

Introduction

It is well known that isoindolinones are important structural motifs in natural products and pharmaceuticals. Among isoindolinones, the 3-substituted isoindolinone moiety is frequently found in a few alkaloids.[1] For example, nuevamine 1 is the first known isoindoloisoquinoline alkaloid and lennoxamine 2 is an isoindolobenzazepine alkaloid; both of them are isolated from Berberis darwinii.[2] Pestalachloride A 3 is an antifungal alkaloid, which is isolated from Pestalotiopsis adust.[3] Pagoclone 4 and pazinaclone 5 are anticonvulsant and anxiolytic drugs,[4] PD-172938 6 shows affinity toward dopamine D4 receptors,[5] and compound 7 is a non-nucleoside HIV-1 reverse transcriptase inhibitor (Figure ).[6] Apart from these drug candidates, the 3-substituted isoindolinones show many other biological activities, including antipsychotic,[7] antihypertensive,[8] antiulcer,[9] and anxiolytic[10] properties.

Figure 1

Examples of naturally occurring and biologically active C(3)-substituted isoindolinones.

The development of a bond-forming reaction between electrophiles and nucleophiles needs a suitable catalyst system; various Lewis acids were successfully used for the activation of both electrophiles and nucleophiles.[11] On the other hand, acyliminium ions represent important electron-deficient carbocation intermediates in organic synthesis because they provide various biologically important natural and unnatural products via C–C and C-heteroatom bond-forming methodologies using an inter- or intramolecular path.[12,13] The removal of a good leaving group at the α-position of amides or lactams generates usually N-acyliminium ions, which act as more electron-deficient carbocations toward nucleophiles. In this regard, chiral thiourea derivatives,[14,15] superacidic reagents,[16] and Lewis[17] and Brønsted acidic[18] systems are used for the generation of N-acyliminium ions and subsequent amidoalkylation reactions (Scheme ). In addition, utilization of transition metals, such as AuI/AgI,[19] Sn(NTf)4,[20] and PdII–AgI,[21] for nucleophilic addition of γ-hydroxy lactams, CuII-catalyzed reaction for the addition of N-acyliminium ions and diaryl malonote,[22] and Pd for an asymmetric reaction between malonates and dihydroisoquinolines[23] is noteworthy. Herein, we report an efficient NiII-promoted amidoalkylation reaction for the synthesis of 3-substituted isoindolinones involving various γ-hydroxy lactams and a variety of C/N/O/S nucleophiles in both intermolecular and intramolecular amidoalkylation manners.

Scheme 1

Catalytic α-Amidoalkylation Reaction

Results and Discussion

Initially, for the template study of the amidoalkylation reaction of 1a and 2a to 3a, a broad set of reaction parameters were examined including the solvent, temperature, and different Lewis acid catalysts. Ni(ClO4)2·6H2O was found to be superior, as only 10 mol % of the catalyst was required to perform the amidoalkylation reaction at 100 °C and a quantitative yield of the product 3a was obtained in 3 h (Table , entry 1). Ni(ClO4)2·6H2O remained catalytically active for a wide range of temperatures (80–120 °C) and for polar solvents like 1,2-dichloroethane (DCE), tetrahydrofuran (THF), and acetonitrile (entries 1–5). However, in toluene, the reaction did not proceed at all even after 12 h (entry 6). Anhydrous SnCl2 or SnCl4 was also effective for the amidoalkylation reaction (entries 7 and 8). Moreover, Lewis acidic Sc(OTf)3, Y(OTf)3, Yb(OTf), La(OTf)3, In(OTf)3, and Cu(OTf)2 were also found to be less efficient to catalyze the amidoalkylation compared to Ni(ClO4)2·6H2O (entries 9–14). From the above screening, the supremacy of Ni(ClO4)2·6H2O over conventional Lewis acids including several widely used metal triflates to carry out the amidoalkylation reaction was established.

Table 1

Screening and Optimization of Reaction Conditionsa

entry	catalyst	solvent	temp (°C)	t (h)	yield%b
1	Ni(CI04)2·6H2O	DCE	100	3	92
2	Ni(CI04)2·6H2O	DCE	80	3	83
3	Ni(CI04)2·6H2O	DCE	120	3	92
4	Ni(CI04)2·6H2O	THF	100	5	67
5	Ni(CI04)2·6H2O	CH3CN	100	5	82
6	Ni(CI04)2·6H2O	toluene	100	12	0
7	SnCI2	DCE	100	12	0
8	SnCI4	DCE	100	12	0
9	Sc(OTf)3	DCE	100	12	75
10	Y(OTf)3	DCE	100	12	32
11	Yb(OTf)3	DCE	100	12	45
12	La(OTf)3	DCE	100	12	23
13	ln(OTf)3	DCE	100	12	18
14	Cu(OTf)2	DCE	100	12	23

Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), the catalyst (0.02 mmol) in the solvent (2 mL), a sealed tube.

Isolated yield.

After having the optimized conditions in hand, we next investigated the scope and limitation of the method. First, a variety of ketone derivatives (1a–o) were exposed to standard reaction conditions, and the results are summarized in Table . A variety of electronically rich, neutral and poor ketones were well tolerated under the standard conditions and afforded the corresponding substituted isoindolinones (3a–k) in good to excellent yields (85–96%). Various functional groups of ketones such as fluoro, chloro, bromo, nitro, cyano, alkyl, methoxy, and acetoxy, were well tolerated and produced the corresponding substituted isoindolinones (3a–k). Under standard reaction conditions, moderate to good yields (82–87%) were achieved for the reaction between 1-(4-nitrophenyl)ethan-1-one and various γ-hydroxy lactam derivatives [3-hydroxy-2-isopropylisoindolin-1-one, 3-hydroxy-2-phenylisoindolin-1-one, 3-hydroxy-2-(p-tolyl)isoindolin-1-one, 2-(4-fluorobenzyl)-3-hydroxyisoindolin-1-one, 2-(4-chlorobenzyl)-3-hydroxyisoindolin-1-one, 3-hydroxy-2-(4-methylbenzyl)isoindolin-1-one, and 2-(4-chlorophenethyl)-3-hydroxyisoindolin-1-one]. On the other hand, a relatively lower yield (82%) of the product was achieved in the case of 2-(4-fluorobenzyl)-3-hydroxyisoindolin-1-one, which suggests that both the generation and stability of the N-acyliminium ion are important for the reaction.

Table 2

Substrate Scope of the Intermolecular Amidoalkylation Reaction via Ketone Nucleophiles Catalyzed by Ni(ClO4)2·6H2Oa

Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Ni(ClO4)2·6H2O (10 mol %), DCE (2 mL), 100 °C, a sealed tube, 3 h, isolated yield.

Then, we investigated the scope of the amidoalkylation reaction with respect to arenes. Thus, 2-benzyl-3-hydroxyisoindolin-1-one was reacted with various arene derivatives (1,3,5-trimethoxybenzene, mesitylene, and 2-methylthiophene) under the standard conditions, and the results are presented in Table . As shown in Table , it is evident that arene derivatives were well tolerated to optimized conditions and afforded 3-substituted isoindolinones (5a–c) in good yields (90–92%).

Table 3

Substrate Scope of the Intermolecular Amidoalkylation Reaction via Arene Nucleophiles Catalyzed by Ni(ClO4)2·6H2Oa

Reaction conditions: 1 (0.2 mmol), 4 (0.24 mmol), Ni(ClO4)2·6H2O (10 mol %), DCE (2 mL), 100 °C, a sealed tube, 3 h, isolated yield.

The success of the above intermolecular amidoalkylation reaction encouraged us to investigate intramolecular cyclizations of the N-acyliminium ions for the synthesis of [2,3]-fused isoindolinone derivatives. Under standard reaction conditions, moderate to good yields (82–91%) were achieved for the reaction with a variety of γ-hydroxy-N-phenylethyl-lactams (Table ). On the other hand, electron-poor arenes such as 3-hydroxy-2-(4-(trifluoromethyl)phenethyl)isoindolin-1-one remained unreactive toward the cyclization reaction.

Table 4

Substrate Scope of the Intramolecular Amidoalkylation Reaction Catalyzed by Ni(ClO4)2·6H2Oa

Reaction conditions: 1 (0.2 mmol), 4 (0.24 mmol), Ni(ClO4)2·6H2O (10 mol %), DCE (2 mL), 100 °C, a sealed tube, 3 h, isolated yield.

Encouraged by the transformation proceeding with different carbon (ketones and arenes) nucleophiles in the intermolecular and intramolecular amidoalkylation discussed above, we tried to broaden the scope with different types of oxygen (alcohols), sulfur (thiols), and nitrogen (amines) nucleophiles. First, the reaction with different oxygen nucleophiles was tested, and the results are summarized in Table . Thus, a variety of primary and secondary alcohols were well tolerated under the standard conditions and afforded the corresponding 3-O-substituted isoindolinones (8a–l) with moderate to excellent yields (85–92%). Under standard reaction conditions, moderate to good yields (85–93%) were achieved for the reaction between ethanol and various γ-hydroxy lactam derivatives [2-(4-fluorobenzyl)-3-hydroxyisoindolin-1-one, 3-hydroxy-2-(4-methylbenzyl)isoindolin-1-one, 3-hydroxy-2-(p-tolyl)isoindolin-1-one, 3-hydroxy-2-phenylisoindolin-1-one, 2-(4-chlorophenethyl)-3-hydroxyisoindolin-1-one, and 2-(4-chlorophenyl)-3-hydroxyisoindolin-1-one].

Table 5

Substrate Scope of the Intermolecular Amidoalkylation Reaction via Alcohol Nucleophiles Catalyzed by Ni(ClO4)2·6H2Oa

Reaction conditions: 1 (0.2 mmol), 4 (0.24 mmol), Ni(ClO4)2·6H2O (10 mol %), DCE (2 mL), 100 °C, a sealed tube, 3 h, isolated yield.

Similarly, sulfur nucleophiles like ethanethiol, propane-1-thiol, butane-1-thiol, pentane-1-thiol, heptane-1-thiol, propane-2-thiol, cyclopentanethiol, and 2-methylpropane-1-thiol were also found to provide 3-S-substituted isoindolinone products (10a–h) in good yields (85–92%). Additionally, in the α-amidoalkylation reaction of heteroatom nucleophiles, sulfur nucleophiles like phenylmethanethiol, p-tolylmethanethiol, (4-chlorophenyl)methanethiol, (4-(tert-butyl)phenyl)methanethiol, and ethyl 2-mercaptoacetate were also tested and the results were delightful, we could obtain the corresponding 3-S-substituted isoindolinones in good yield (85−94%). To further augment the reactivity, we conducted the reaction between propane-1-thiol and various γ-hydroxy lactam derivatives [4-((1-hydroxy-3-oxoisoindolin-2-yl)methyl)benzonitrile, 3-hydroxy-2-phenylisoindolin-1-one, 3-hydroxy-2-(p-tolyl)isoindolin-1-one, 2-(4-chlorophenethyl)-3-hydroxyisoindolin-1-one, 3-hydroxy-2-phenethylisoindolin-1-one, 3-hydroxy-2-(4-methylphenethyl)isoindolin-1-one, and 3-hydroxy-2-(4-methoxybenzyl)isoindolin-1-one].

Also, nitrogen nucleophiles like thiomorpholine, morpholine, phenylmethanamine, (4-fluorophenyl)methanamine, (4-chlorophenyl)methanamine, (4-bromophenyl)methanamine, (2-chlorophenyl)methanamine, o-tolylmethanamine, and furan-2-ylmethanamine were found to provide corresponding 3-N-substituted isoindolinone products (12a–i) in good yields (81–95%). Additionally, in the α-amidoalkylation reaction of heteroatom nucleophiles, we conducted the reaction between thiomorpholine and various γ-hydroxy lactam derivatives [3-hydroxy-2-phenylisoindolin-1-one, 3-hydroxy-2-(p-tolyl)isoindolin-1-one, 3-hydroxy-2-isopropylisoindolin-1-one, 3-hydroxy-2-phenethylisoindolin-1-one, 3-hydroxy-2-(4-methoxyphenethyl)isoindolin-1-one, 2-(4-chlorophenethyl)-3-hydroxyisoindolin-1-one, 3-hydroxy-2-(4-methylphenethyl)isoindolin-1-one, 3-hydroxy-2-(4-methylbenzyl)isoindolin-1-one, and 2-(4-fluorobenzyl)-3-hydroxyisoindolin-1-one] and obtained good yields (85–92%) (Table and 7).

Table 6

Substrate Scope of the Intermolecular Amidoalkylation Reaction via Thiol Nucleophiles Catalyzed by Ni(ClO4)2·6H2Oa

Reaction conditions: 1 (0.2 mmol), 4 (0.24 mmol), Ni(ClO4)2·6H2O (10 mol %), DCE (2 mL), 100 °C, a sealed tube, 3 h, isolated yield.

Table 7

Substrate Scope of the Intermolecular Amidoalkylation Reaction via Amine Nucleophiles Catalyzed by Ni(ClO4)2·6H2Oa

Reaction conditions: 1 (0.2 mmol), 4 (0.24 mmol), Ni(ClO4)2·6H2O (10 mol %), DCE (2 mL), 100 °C, a sealed tube, 3 h, isolated yield.

To demonstrate the scalability of this process, gram-scale reactions were performed (Scheme ). 1-(4-Nitrophenyl)ethan-1-one, ethanol, propane-1-thiol, and thiomorpholine were well tolerated under the standard conditions and afforded the corresponding 3-substituted isoindolinones with good yields (85–96%).

Scheme 2

Gram-Scale Synthesis of 3-Substituted Isoindolinones

Based on these results and reported literature,[24] a possible reaction mechanism is proposed in Scheme . We propose that Ni(ClO4)2·6H2O acts as a Lewis acid to activate and facilitate the departure of a 3-hydroxyl group to form the acyliminium ions. The nucleophilic attack of different carbon (ketones and arenes) and heteroatom (alcohols, thiols, and amines) nucleophiles on the N-acyliminium ion forms a C–C bond or a C–X (O, S, and N) bond, followed by the deprotonation of the intermediate, affording the desired 3-substituted isoindolinones.

Scheme 3

Possible Reaction Pathways

Conclusions

In summary, we have developed an efficient and practical method for the synthesis of 3-substituted isoindolinones involving various γ-hydroxy lactams and nucleophiles through the amidoalkylation reaction promoted by Ni(ClO4)2·6H2O. The transformation proceeds with C/O/S/N nucleophiles in the intermolecular and intramolecular manners. Furthermore, the method offers several advantages such as a wide variety of substrates, excellent group tolerability, easy handling, and good yields (up to 96% yield). Moreover, the 3-substituted isoindolinones products could be prepared on a gram scale.

Experimental Section

General Details

Unless otherwise noted, all of the reagents were obtained commercially and used without further purification and reactions were monitored by thin-layer chromatography (TLC) using an ethyl acetate/petroleum ether (60–90 °C boiling mixture) mixture as the eluent. Column chromatography was performed on silica gel (200–300 mesh) using different percentages of ethyl acetate in petroleum ether. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 on a Bruker 400 MHz spectrometer with tetramethylsilane (TMS) as an internal standard. High-resolution mass spectra (HRMS) were recorded on the Q-TOF6510 instruments.

Synthesis of Isoindoline-1,3-dione Derivatives

In a 100 mL round-bottom flask, phthalic anhydride (7.4 g, 50 mmol) and the corresponding amine (50 mmol) were added to 50 mL of acetic acid, and the mixture was refluxed at 120 °C for 10 h. After completion of the reaction, water (100 mL) was added to the reaction mixture and the solution was extracted with CH2Cl2 (50 mL × 3). The combined organic layer was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified through column chromatography to afford the product isoindoline-1,3-dione derivatives.

Synthesis of γ-Hydroxy Lactam Derivatives

A 25 mL round-bottom flask was charged with isoindoline-1,3-dione derivatives (2 mmol), methanol (10 mL), and a stirring bar. The flask was cooled to 0 °C. Then, sodium borohydride (370 mg, 10 mmol) was added portionwise over 5 min. The reaction mixture was stirred for 3 h. The conversion was measured by TLC (ethyl acetate/petroleum ether). If all of the starting material was not consumed after 3 h, 5 additional equivalents of sodium borohydride were added every 30 min until full conversion was realized. Upon complete conversion of the isoindoline-1,3-dione derivatives, the methanol was removed under vacuum and the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate (20 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to leave the hydroxy lactams, which were then purified by column on silica gel using a mixture of ethyl acetate/petroleum ether as the eluent to furnish the γ-hydroxy lactam derivatives.

General Procedure for the Nickel-Catalyzed Amidoalkylation Reaction of γ-Hydroxy Lactams

A 35 mL sealed tube was charged with γ-hydroxy lactams (0.2 mmol), different nucleophiles (0.24 mol), and Ni(ClO4)2·6H2O (0.02 mol), and then 1,2-dichloroethane (DCE, 2 mL) was added. The resulting reaction mixture was kept at 100 °C for 8 h while it was periodically checked by TLC for completion of the reaction. The reaction mixture was cooled to room temperature and then extracted with dichloromethane (DCM, 2 × 10 mL). The organic layer was washed successively with water (2 × 10 mL) and brine (1 × 10 mL), followed by the removal of DCM under reduced pressure. The crude product was subjected to column chromatography (silica gel, gradient elution with different percentages of EtOAc in petroleum ether) to yield 3-substituted isoindolinones.

2-Benzyl-3-(2-oxo-2-phenylethyl)isoindolin-1-one (3a)[13a]

White solid (62.7 mg, 92%), mp = 97–98 °C. 1H NMR (400 MHz, CDCl3) δ 7.95–7.85 (m, 1H), 7.79 (d, J = 7.3 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.51–7.44 (m, 2H), 7.40 (dd, J = 14.5, 6.8 Hz, 3H), 7.20 (ddt, J = 13.9, 9.6, 6.9 Hz, 5H), 5.31–5.18 (m, 1H), 5.06 (d, J = 15.4 Hz, 1H), 4.53 (d, J = 15.4 Hz, 1H), 3.49 (dd, J = 17.6, 5.3 Hz, 1H), 3.14 (dd, J = 17.6, 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 197.09, 168.55, 145.90, 137.16, 136.30, 133.67, 131.84, 131.78, 128.71, 128.46, 128.05, 128.03, 128.00, 127.97, 127.52, 123.89, 122.88, 55.92, 44.66, 42.10. HRMS [electrospray ionization (ESI)] calcd for C23H20NO2 [M + H]+ 342.1489, found 342.1490.

2-Benzyl-3-(2-(4-nitrophenyl)-2-oxoethyl)isoindolin-1-one (3b)[25]

White solid (73.3 mg, 95%), mp = 158–160 °C. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.8 Hz, 2H), 7.93 (dd, J = 5.7, 2.5 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.60–7.45 (m, 2H), 7.44–7.35 (m, 1H), 7.16 (ddd, J = 24.9, 14.2, 7.1 Hz, 5H), 5.28 (t, J = 6.0 Hz, 1H), 4.88 (d, J = 15.5 Hz, 1H), 4.74 (d, J = 15.5 Hz, 1H), 3.47 (dd, J = 17.9, 5.9 Hz, 1H), 3.19 (dd, J = 17.9, 6.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 195.57, 168.54, 150.51, 145.32, 140.43, 137.11, 131.99, 131.78, 129.01, 128.77, 128.72, 127.90, 127.54, 124.11, 123.80, 122.51, 55.88, 45.00, 42.90. HRMS (ESI) calcd for C23H19N2O4 [M + H]+ 387.1339, found 387.1340.

4-(2-(2-Benzyl-3-oxoisoindolin-1-yl)acetyl)benzonitrile (3c)

White solid (70.3 mg, 96%), mp = 180–182 °C. 1H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 5.5, 2.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.57–7.45 (m, 2H), 7.41–7.31 (m, 1H), 7.24–7.02 (m, 5H), 5.26 (t, J = 6.0 Hz, 1H), 4.89 (d, J = 15.5 Hz, 1H), 4.70 (d, J = 15.5 Hz, 1H), 3.45 (dd, J = 17.9, 5.8 Hz, 1H), 3.15 (dd, J = 17.9, 6.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 195.77, 168.53, 145.37, 138.98, 137.09, 132.46, 131.97, 131.76, 128.71, 128.37, 127.89, 127.53, 124.06, 122.55, 117.70, 116.80, 55.85, 44.94, 42.61. HRMS (ESI) calcd for C24H19N2O2 [M + H]+ 367.1441, found 367.1440.

2-Benzyl-3-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)isoindolin-1-one (3d)

White solid (77.7 mg, 95%), mp = 162–163 °C. 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 5.6, 2.6 Hz, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.54–7.44 (m, 2H), 7.41–7.35 (m, 1H), 7.25–7.15 (m, 4H), 7.12 (t, J = 7.0 Hz, 1H), 5.26 (t, J = 6.1 Hz, 1H), 4.94 (d, J = 15.5 Hz, 1H), 4.66 (d, J = 15.5 Hz, 1H), 3.48 (dd, J = 17.8, 5.6 Hz, 1H), 3.17 (dd, J = 17.8, 6.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.15, 168.54, 145.55, 138.78, 137.10, 134.81 (q, J = 32.5 Hz), 131.93, 131.78, 128.61, 128.12 (q, J = 370 Hz), 125.70 (q, J = 3.5 Hz), 124.00, 122.65, 122.09, 55.89, 44.86, 42.53. HRMS (ESI) calcd for C24H19F3NO2 [M + H]+ 410.1362, found 410.1363.

2-Benzyl-3-(2-(2-nitrophenyl)-2-oxoethyl)isoindolin-1-one (3e)

White solid (71.8 mg, 93%), mp = 145–147 °C. 1H NMR (400 MHz, CDCl3) δ 8.18–7.97 (m, 1H), 7.95–7.79 (m, 1H), 7.66–7.41 (m, 5H), 7.37–7.20 (m, 5H), 6.83 (dd, J = 7.1, 1.7 Hz, 1H), 5.11 (dd, J = 16.1, 10.6 Hz, 2H), 4.55 (d, J = 15.4 Hz, 1H), 3.28 (ddd, J = 24.7, 18.3, 5.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 199.01, 168.56, 145.53, 145.11, 137.33, 136.78, 134.32, 132.01, 131.77, 130.92, 128.86, 128.60, 128.12, 127.64, 127.27, 124.45, 123.88, 122.85, 55.37, 45.55, 44.69. HRMS (ESI) calcd for C23H19N2O4 [M + H]+ 387.1339, found 387.1336.

2-Benzyl-3-(2-(4-fluorophenyl)-2-oxoethyl)isoindolin-1-one (3f)

White solid (67.0 mg, 93%), mp = 152–154 °C. 1H NMR (400 MHz, CDCl3) δ 7.90 (dd, J = 5.3, 3.0 Hz, 1H), 7.79 (dd, J = 8.7, 5.4 Hz, 2H), 7.47 (dd, J = 9.0, 5.5 Hz, 2H), 7.43–7.34 (m, 1H), 7.28–7.11 (m, 5H), 7.07 (t, J = 8.6 Hz, 2H), 5.24 (t, J = 6.2 Hz, 1H), 4.99 (d, J = 15.4 Hz, 1H), 4.59 (d, J = 15.4 Hz, 1H), 3.43 (dd, J = 17.6, 5.5 Hz, 1H), 3.11 (dd, J = 17.6, 6.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 195.43, 168.54, 166.00 (d, J = 255 Hz), 167.27, 164.72, 145.77, 137.16, 132.74 (d, J = 3.0 Hz), 131.86, 131.77, 130.78, 130.68, 128.59 (d, J = 17.1 Hz), 127.94, 127.50, 123.92, 122.77, 115.93, 115.71, 55.96, 44.75, 42.09. HRMS (ESI) calcd for C23H19FNO2 [M + H]+ 360.1394, found 360.1395.

2-Benzyl-3-(2-(2-chlorophenyl)-2-oxoethyl)isoindolin-1-one (3g)

White solid (69.8 mg, 93%), mp = 132–134 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.7 Hz, 1H), 7.55–7.39 (m, 3H), 7.34 (t, J = 6.7 Hz, 2H), 7.32–7.18 (m, 7H), 5.26–4.99 (m, 2H), 4.50 (d, J = 15.4 Hz, 1H), 3.57 (dd, J = 17.7, 4.9 Hz, 1H), 3.22 (dd, J = 17.7, 7.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 199.64, 168.49, 145.36, 138.14, 137.16, 132.40, 131.84, 131.80, 131.12, 130.73, 129.23, 128.81, 128.53, 127.95, 127.61, 127.05, 123.90, 122.78, 55.82, 45.95, 44.60. HRMS (ESI) calcd for C23H19ClNO2 [M + H]+ 376.1099, found 376.1097.

2-Benzyl-3-(2-(4-bromophenyl)-2-oxoethyl)isoindolin-1-one (3h)[26]

White solid (75.2 mg, 90%), mp = 137–138 °C. 1H NMR (400 MHz, CDCl3) δ 7.97–7.81 (m, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.57–7.50 (m, 2H), 7.47 (dd, J = 8.9, 5.3 Hz, 2H), 7.40–7.32 (m, 1H), 7.25–7.04 (m, 5H), 5.23 (t, J = 6.1 Hz, 1H), 4.98 (d, J = 15.4 Hz, 1H), 4.59 (d, J = 15.4 Hz, 1H), 3.42 (dd, J = 17.6, 5.5 Hz, 1H), 3.10 (dd, J = 17.6, 6.9 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 196.06, 168.52, 145.69, 137.14, 134.97, 131.99, 131.88, 131.77, 129.51, 128.91, 128.71, 128.54, 127.93, 127.52, 123.94, 122.74, 55.91, 44.77, 42.13. HRMS (ESI) calcd for C23H19BrNO2 [M + H]+ 420.0594, found 420.0595.

2-Benzyl-3-(2-(4-methoxyphenyl)-2-oxoethyl)isoindolin-1-one (3i)[26]

Yellow oil (63.1 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.96–7.84 (m, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.45 (dd, J = 8.8, 5.1 Hz, 2H), 7.42–7.34 (m, 1H), 7.28–7.08 (m, 5H), 6.88 (d, J = 8.9 Hz, 2H), 5.23 (dd, J = 6.8, 5.7 Hz, 1H), 5.07 (d, J = 15.4 Hz, 1H), 4.50 (d, J = 15.4 Hz, 1H), 3.85 (s, 3H), 3.43 (dd, J = 17.3, 5.3 Hz, 1H), 3.09 (dd, J = 17.3, 7.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 195.48, 168.55, 163.94, 146.03, 137.21, 131.79, 131.77, 130.41, 129.47, 128.67, 128.38, 127.99, 127.49, 123.82, 122.95, 113.87, 56.07, 55.55, 44.60, 41.67. HRMS (ESI) calcd for C24H22NO3 [M + H]+ 372.1594, found 372.1594.

2-Benzyl-3-(2-(naphthalen-2-yl)-2-oxoethyl)isoindolin-1-one (3j)

White solid (68.0 mg, 87%), mp = 172–174 °C. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.92–7.87 (m, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.61 (dd, J = 11.2, 4.1 Hz, 1H), 7.52 (dd, J = 18.0, 7.6 Hz, 2H), 7.46–7.38 (m, 3H), 7.34 (t, J = 7.7 Hz, 1H), 7.28 (d, J = 6.5 Hz, 2H), 7.21 (q, J = 7.3 Hz, 3H), 5.34–5.22 (m, 1H), 5.12 (d, J = 15.4 Hz, 1H), 4.55 (d, J = 15.4 Hz, 1H), 3.59 (dd, J = 17.3, 5.3 Hz, 1H), 3.24 (dd, J = 17.3, 7.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 200.56, 168.58, 145.75, 137.26, 134.52, 133.97, 133.60, 131.85, 130.07, 128.80, 128.62, 128.49, 128.47, 128.41, 128.00, 127.58, 126.69, 125.60, 124.26, 123.94, 122.80, 56.28, 45.05, 44.70. HRMS (ESI) calcd for C27H22NO2 [M + H]+ 392.1645, found 392.1645.

2-Benzyl-3-(2-(3,4-dimethylphenyl)-2-oxoethyl)isoindolin-1-one (3k)

White solid (63.5 mg, 86%), mp = 135–137 °C. 1H NMR (400 MHz, CDCl3) δ 7.97–7.73 (m, 1H), 7.59 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.7, 5.1 Hz, 2H), 7.41–7.36 (m, 1H), 7.24 (q, J = 7.3 Hz, 4H), 7.17 (dd, J = 10.4, 7.4 Hz, 2H), 5.22 (dd, J = 7.1, 5.5 Hz, 1H), 5.10 (d, J = 15.3 Hz, 1H), 4.48 (d, J = 15.3 Hz, 1H), 3.48 (dd, J = 17.4, 5.2 Hz, 1H), 3.11 (dd, J = 17.4, 7.4 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 196.97, 168.54, 146.04, 143.37, 137.23, 137.12, 134.34, 131.78, 129.94, 129.20, 128.69, 128.38, 128.06, 128.01, 127.96, 127.50, 125.82, 123.83, 122.97, 55.99, 44.57, 41.95, 20.07, 19.75. HRMS (ESI) calcd for C25H24NO2 [M + H]+ 370.1802, found 370.1803.

2-Isopropyl-3-(2-(4-nitrophenyl)-2-oxoethyl)isoindolin-1-one (3l)

White solid (55.4 mg, 82%), mp = 142–144 °C. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.8 Hz, 2H), 7.87–7.70 (m, 1H), 7.48–7.38 (m, 2H), 7.38–7.30 (m, 1H), 5.36 (dd, J = 8.6, 3.5 Hz, 1H), 4.24 (dt, J = 13.8, 6.9 Hz, 1H), 3.72 (dd, J = 17.9, 3.6 Hz, 1H), 3.38 (dd, J = 17.9, 8.7 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.45 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 196.17, 168.33, 150.65, 145.67, 140.75, 132.63, 131.63, 129.23, 128.53, 124.07, 123.47, 122.53, 55.65, 45.55, 43.72, 21.19, 20.53. HRMS (ESI) calcd for C19H19N2O4 [M + H]+ 339.1339, found 339.1339.

3-(2-(4-Nitrophenyl)-2-oxoethyl)-2-phenylisoindolin-1-one (3m)

White solid (64.7 mg, 87%), mp = 153–155 °C. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 2H), 7.97 (dd, J = 13.0, 5.2 Hz, 3H), 7.81–7.34 (m, 7H), 7.23 (t, J = 7.4 Hz, 1H), 5.97 (dd, J = 9.1, 3.0 Hz, 1H), 3.58 (dd, J = 17.9, 3.2 Hz, 1H), 3.26 (dd, J = 17.9, 9.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.32, 166.79, 150.64, 144.67, 140.55, 136.47, 132.51, 131.89, 129.46, 129.14, 129.03, 125.89, 124.40, 123.94, 123.35, 122.93, 56.79, 42.57. HRMS (ESI) calcd for C22H17N2O4 [M + H]+ 373.1183, found 373.1185.

3-(2-(4-Nitrophenyl)-2-oxoethyl)-2-(p-tolyl)isoindolin-1-one (3n)

White solid (64.8 mg, 84%), mp = 161–162 °C. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.8 Hz, 2H), 7.95 (dd, J = 18.9, 7.6 Hz, 3H), 7.57–7.40 (m, 5H), 7.22 (d, J = 8.1 Hz, 2H), 5.90 (dd, J = 9.0, 3.1 Hz, 1H), 3.56 (dd, J = 17.8, 3.3 Hz, 1H), 3.24 (dd, J = 17.8, 9.1 Hz, 1H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 196.38, 166.74, 150.58, 144.70, 140.58, 135.87, 133.79, 132.35, 131.99, 130.01, 129.15, 128.95, 124.27, 123.89, 123.58, 122.93, 57.01, 42.54, 20.97. HRMS (ESI) calcd for C23H19N2O4 [M + H]+ 387.1339, found 387.1340.

2-(4-Chlorobenzyl)-3-(2-(4-nitrophenyl)-2-oxoethyl)isoindolin-1-one (3o)

White solid (71.4 mg, 85%), mp = 165–166 °C. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 6.7 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.61–7.46 (m, 2H), 7.39 (d, J = 7.1 Hz, 1H), 7.12 (q, J = 8.4 Hz, 4H), 5.30 (t, J = 5.9 Hz, 1H), 4.76 (s, 2H), 3.41 (dd, J = 17.9, 6.5 Hz, 1H), 3.22 (dd, J = 17.9, 5.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 195.39, 168.66, 150.60, 145.24, 140.13, 135.71, 133.44, 132.17, 131.58, 129.31, 128.98, 128.83, 124.20, 123.86, 122.40, 55.96, 44.55, 43.11. HRMS (ESI) calcd for C23H18ClN2O4 [M + H]+ 421.0950, found 421.0952.

2-(4-Fluorobenzyl)-3-(2-(4-nitrophenyl)-2-oxoethyl)isoindolin-1-one (3p)

White solid (67.1 mg, 82%), mp = 171–173 °C. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 2H), 8.00–7.81 (m, 3H), 7.59–7.45 (m, 2H), 7.38 (d, J = 7.3 Hz, 1H), 7.21 (dd, J = 8.3, 5.5 Hz, 2H), 6.87 (t, J = 8.6 Hz, 2H), 5.27 (t, J = 6.0 Hz, 1H), 4.88 (d, J = 15.4 Hz, 1H), 4.65 (d, J = 15.4 Hz, 1H), 3.45 (dd, J = 18.0, 6.1 Hz, 1H), 3.24 (dd, J = 18.0, 6.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 195.52, 168.58, 161.643 (d, J = 245 Hz), 150.61, 145.28, 140.32, 132.94 (d, J = 3.1 Hz), 132.11, 131.65, 129.63 (d, J = 8.0 Hz), 129.02, 128.79, 124.14, 123.89, 122.49, 115.69, 115.47, 55.74, 44.29, 42.99. HRMS (ESI) calcd for C23H18FN2O4 [M + H]+ 405.1245, found 4051245.

2-(4-Methylbenzyl)-3-(2-(4-nitrophenyl)-2-oxoethyl)isoindolin-1-one (3q)

White solid (69.6 mg, 87%), mp = 163–165 °C. 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 8.7 Hz, 2H), 7.93 (dd, J = 5.4, 2.9 Hz, 1H), 7.85 (d, J = 8.7 Hz, 2H), 7.57–7.46 (m, 2H), 7.43–7.33 (m, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H), 5.26 (t, J = 6.0 Hz, 1H), 4.82 (d, J = 15.4 Hz, 1H), 4.70 (d, J = 15.4 Hz, 1H), 3.47 (dd, J = 17.8, 5.9 Hz, 1H), 3.16 (dd, J = 17.8, 6.2 Hz, 1H), 2.18 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 195.52, 168.50, 150.47, 145.32, 140.39, 137.25, 133.94, 131.93, 131.86, 129.36, 129.04, 128.69, 127.93, 124.10, 123.71, 122.45, 55.86, 44.76, 42.83, 20.95. HRMS (ESI) calcd for C24H21N2O4 [M + H]+ 401.1496, found 401.1497.

2-(4-Chlorophenethyl)-3-(2-(4-nitrophenyl)-2-oxoethyl)isoindolin-1-one (3r)

White solid (76.4 mg, 88%), mp = 132–134 °C. 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 8.8 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 6.7 Hz, 1H), 7.49 (tt, J = 13.0, 6.7 Hz, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.18 (q, J = 8.4 Hz, 4H), 5.21 (t, J = 6.0 Hz, 1H), 4.10–3.94 (m, 1H), 3.56–3.40 (m, 1H), 3.22–2.93 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 195.88, 168.57, 150.70, 145.28, 140.35, 137.54, 132.42, 131.92, 130.46, 129.18, 128.75, 128.70, 124.09, 123.74, 122.60, 55.79, 43.15, 42.88, 33.75. HRMS (ESI) calcd for C24H20ClN2O4 [M + H]+ 435.1106, found 435.1105.

2-Benzyl-3-(2,4,6-trimethoxyphenyl)isoindolin-1-one (5a)[21]

White solid (71.6 mg, 92%), mp = 102–104 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 5.1, 3.4 Hz, 1H), 7.44–7.31 (m, 2H), 7.25–6.99 (m, 6H), 6.16 (d, J = 2.0 Hz, 1H), 5.99 (s, 1H), 5.92 (d, J = 2.0 Hz, 1H), 5.14 (d, J = 14.7 Hz, 1H), 3.83 (d, J = 14.8 Hz, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.25 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.91, 161.69, 160.50, 160.14, 146.98, 137.91, 132.95, 130.86, 128.56, 128.12, 127.10, 126.99, 122.96, 121.83, 103.99, 91.24, 90.44, 55.79, 55.41, 55.32, 54.73, 44.15. HRMS (ESI) calcd for C24H24NO4 [M + H]+ 390.1700, found 390.1700.

2-Benzyl-3-mesitylisoindolin-1-one (5b)

White solid (61.4 mg, 90%), mp = 132–134 °C. 1H NMR (400 MHz, CDCl3) δ 8.04–7.85 (m, 1H), 7.53–7.36 (m, 2H), 7.26 (q, J = 6.0 Hz, 3H), 7.16–7.03 (m, 3H), 6.90 (s, 1H), 6.73 (s, 1H), 5.75 (s, 1H), 5.44 (d, J = 14.6 Hz, 1H), 3.60 (d, J = 14.7 Hz, 1H), 2.28 (s, 3H), 2.04 (s, 3H), 1.57 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 168.58, 145.15, 138.12, 138.08, 138.03, 137.24, 132.59, 131.80, 131.44, 129.68, 128.68, 128.52, 128.22, 128.01, 127.58, 123.67, 122.37, 59.29, 43.79, 20.89, 20.61, 18.53. HRMS (ESI) calcd for C24H24NO [M + H]+ 342.1852, found 342.1853.

2-Benzyl-3-(5-methylthiophen-2-yl)isoindolin-1-one (5c)[21]

White solid (58.3 mg, 91%), mp = 206–207 °C. 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 5.7, 2.8 Hz, 1H), 7.53–7.39 (m, 2H), 7.27 (dt, J = 12.0, 7.2 Hz, 6H), 6.83 (d, J = 3.3 Hz, 1H), 6.72–6.33 (m, 1H), 5.47 (s, 1H), 5.38 (d, J = 14.9 Hz, 1H), 3.90 (d, J = 14.9 Hz, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.77, 145.78, 141.60, 137.51, 137.21, 131.91, 131.25, 128.74, 128.65, 128.55, 128.50, 127.92, 127.58, 124.89, 123.74, 123.25, 59.07, 43.61, 15.54. HRMS (ESI) calcd for C20H18NOS [M + H]+ 320.1104, found 320.1105.

5,12b-Dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one (6a)[27]

White solid (41.8 mg, 89%), mp = 114–116 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = 7.5, 2.7 Hz, 2H), 7.68–7.56 (m, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.33–7.15 (m, 3H), 5.67 (s, 1H), 4.43 (dt, J = 12.7, 5.2 Hz, 1H), 3.59–3.38 (m, 1H), 3.07 (ddd, J = 15.5, 9.1, 6.1 Hz, 1H), 2.88 (dt, J = 15.9, 4.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.94, 144.25, 134.82, 134.37, 132.87, 131.52, 129.32, 128.50, 127.46, 126.72, 125.24, 123.88, 123.49, 59.15, 38.21, 29.45. HRMS (ESI) calcd for C16H14NO [M + H]+ 236.1070, found 236.1070.

2-Methyl-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one (6b)

White solid (45.3 mg, 91%), mp = 102–103 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (dd, J = 7.5, 3.6 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.07 (dd, J = 18.1, 7.7 Hz, 2H), 5.64 (s, 1H), 4.45–4.37 (m, 1H), 3.51–3.41 (m, 1H), 3.01 (dd, J = 9.1, 6.4 Hz, 1H), 2.88–2.79 (m, 1H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.96, 144.30, 136.35, 134.18, 132.87, 131.72, 131.49, 129.16, 128.46, 128.26, 125.77, 123.87, 123.50, 59.19, 38.37, 29.06, 21.26. HRMS (ESI) calcd for C17H16NO [M + H]+ 250.1226, found 250.1226.

2-Methoxy-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one (6c)[28]

White solid (46.1 mg, 87%), mp = 102–103 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (t, J = 7.9 Hz, 2H), 7.61 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.14 (dd, J = 15.6, 5.1 Hz, 2H), 6.80 (dd, J = 8.3, 2.2 Hz, 1H), 5.64 (s, 1H), 4.41 (dt, J = 12.6, 5.1 Hz, 1H), 3.82 (s, 3H), 3.53–3.41 (m, 1H), 3.01 (ddd, J = 15.3, 9.2, 6.0 Hz, 1H), 2.83 (dt, J = 15.5, 4.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.94, 158.32, 144.09, 135.40, 132.89, 131.55, 130.12, 128.53, 126.84, 123.91, 123.39, 112.55, 111.47, 59.23, 55.43, 38.48, 28.58. HRMS (ESI) calcd for C17H16NO2 [M + H]+ 266.1176, found 266.1176.

5-Phenyl-5,12b-dihydroisoindolo[1,2-a]isoquinolin-8(6H)-one (6d)

White solid (51.0 mg, 82%), mp = 178–180 °C. 1H NMR (400 MHz, CDCl3) δ 7.90 (t, J = 7.3 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.39–7.18 (m, 6H), 7.11 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 5.83 (s, 1H), 4.74 (dd, J = 13.2, 5.9 Hz, 1H), 4.25 (dd, J = 10.5, 6.0 Hz, 1H), 3.47 (dd, J = 13.0, 10.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.80, 144.94, 141.60, 138.22, 134.39, 132.62, 131.80, 130.17, 129.10, 128.85, 128.58, 127.37, 127.24, 126.86, 125.42, 123.95, 123.46, 59.56, 45.79, 45.18. HRMS (ESI) calcd for C16H13ClNO [M + H]+ 270.0680, found 270.0681.

2-Benzyl-3-methoxyisoindolin-1-one (8a)

Colorless oil (46.6 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.1 Hz, 1H), 7.60–7.45 (m, 3H), 7.40–7.21 (m, 5H), 5.71 (s, 1H), 5.19 (d, J = 14.7 Hz, 1H), 4.21 (d, J = 14.7 Hz, 1H), 2.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.48, 140.47, 136.87, 132.99, 132.10, 129.97, 128.72, 128.65, 128.63, 127.65, 123.68, 123.51, 85.64, 49.36, 43.15. HRMS (ESI) calcd for C16H16NO2 [M + H]+ 254.1176, found 254.1175.

2-Benzyl-3-ethoxyisoindolin-1-one (8b)

Colorless oil (47.5 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.1 Hz, 1H), 7.60–7.45 (m, 3H), 7.31 (ddd, J = 22.6, 16.7, 6.9 Hz, 5H), 5.71 (s, 1H), 5.15 (d, J = 14.7 Hz, 1H), 4.27 (d, J = 14.7 Hz, 1H), 3.15 (dq, J = 14.2, 7.1 Hz, 1H), 2.99 (dd, J = 15.9, 7.1 Hz, 1H), 1.09 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.38, 141.19, 137.00, 132.76, 132.03, 129.83, 128.70, 128.62, 128.59, 127.62, 123.63, 123.40, 85.56, 58.03, 43.33, 15.05. HRMS (ESI) calcd for C17H18NO2 [M + H]+ 268.1332, found 268.1332.

2-Benzyl-3-butoxyisoindolin-1-one (8c)

Colorless oil (51.9 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.1 Hz, 1H), 7.59–7.45 (m, 3H), 7.31 (ddd, J = 29.7, 15.5, 7.1 Hz, 5H), 5.71 (s, 1H), 5.17 (d, J = 14.7 Hz, 1H), 4.24 (d, J = 14.7 Hz, 1H), 3.09 (dd, J = 15.3, 6.5 Hz, 1H), 2.92 (dd, J = 15.3, 6.6 Hz, 1H), 1.45 (dq, J = 13.1, 6.5 Hz, 2H), 1.31 (dq, J = 15.1, 7.4 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.38, 141.20, 136.98, 132.80, 132.01, 129.81, 128.70, 128.62, 127.61, 123.62, 123.40, 85.43, 62.14, 43.26, 31.63, 19.35, 13.84. HRMS (ESI) calcd for C19H22NO2 [M + H]+ 296.1645, found 296.1645.

2-Benzyl-3-(heptyloxy)isoindolin-1-one (8d)

Colorless oil (57.3 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.1 Hz, 1H), 7.50 (ddd, J = 20.8, 13.7, 6.9 Hz, 3H), 7.37 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.26–7.22 (m, 1H), 5.70 (s, 1H), 5.16 (d, J = 14.7 Hz, 1H), 4.25 (d, J = 14.7 Hz, 1H), 3.08 (dd, J = 15.3, 6.6 Hz, 1H), 2.91 (dd, J = 15.4, 6.6 Hz, 1H), 1.45 (dd, J = 10.6, 6.1 Hz, 2H), 1.23 (s, 8H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.35, 141.24, 137.03, 132.81, 132.00, 129.80, 128.81–128.51, 127.61, 123.61, 123.41, 85.49, 62.45, 43.31, 31.78, 29.56, 29.05, 26.13, 22.61, 14.11. HRMS (ESI) calcd for C22H28NO2 [M + H]+ 338.2115, found 338.2115.

2-Benzyl-3-cyclobutoxyisoindolin-1-one (8e)

Colorless oil (52.2 mg, 89%). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 6.4 Hz, 1H), 7.56–7.44 (m, 3H), 7.29 (ddd, J = 22.7, 13.7, 7.0 Hz, 5H), 5.63 (s, 1H), 5.17 (d, J = 14.7 Hz, 1H), 4.22 (d, J = 14.8 Hz, 1H), 3.67 (dd, J = 15.1, 7.6 Hz, 1H), 2.00 (dd, J = 16.5, 8.2 Hz, 2H), 1.86 (dd, J = 19.1, 10.1 Hz, 1H), 1.59 (dtd, J = 15.3, 10.4, 6.2 Hz, 2H), 1.29–1.19 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 167.37, 141.80, 137.00, 132.53, 131.88, 129.80, 128.71, 128.58, 128.55, 127.61, 123.75, 123.51, 84.88, 67.47, 43.19, 32.45, 31.58, 12.84. HRMS (ESI) calcd for C19H22NO2 [M + H]+ 296.1645, found 296.1645.

2-Benzyl-3-(cyclopentyloxy)isoindolin-1-one (8f)

Colorless oil (53.4 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.1 Hz, 1H), 7.51 (ddd, J = 17.5, 11.9, 7.1 Hz, 3H), 7.37–7.22 (m, 5H), 5.64 (s, 1H), 5.25 (d, J = 14.9 Hz, 1H), 4.24 (d, J = 14.9 Hz, 1H), 3.92–3.70 (m, 1H), 1.76–1.62 (m, 4H), 1.45 (ddt, J = 15.2, 12.3, 7.7 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 167.41, 142.31, 137.08, 132.50, 131.93, 129.73, 128.74, 128.37, 128.35, 128.32, 127.59, 123.75, 123.56, 85.38, 77.06, 43.23, 33.72, 33.50, 23.32, 23.22. HRMS (ESI) calcd for C20H22NO2 [M + H]+ 308.1645, found 308.1645.

2-Benzyl-3-(isopentyloxy)isoindolin-1-one (8g)

Colorless oil (54.4 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.2 Hz, 1H), 7.57–7.44 (m, 3H), 7.37 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.27–7.23 (m, 1H), 5.71 (s, 1H), 5.16 (d, J = 14.6 Hz, 1H), 4.26 (d, J = 14.7 Hz, 1H), 3.19–3.04 (m, 1H), 2.93 (dd, J = 15.7, 6.9 Hz, 1H), 1.64 (dt, J = 13.4, 6.7 Hz, 1H), 1.35 (ddt, J = 20.4, 13.7, 6.8 Hz, 2H), 0.82 (dd, J = 14.3, 6.6 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 141.21, 137.01, 132.79, 132.03, 129.83, 129.79, 128.71, 128.68, 128.61, 127.62, 123.62, 123.38, 85.51, 60.77, 43.33, 38.42, 24.90. HRMS (ESI) calcd for C20H24NO2 [M + H]+ 310.1802, found 310.1803.

2-Benzyl-3-(3-methoxypropoxy)isoindolin-1-one (8h)

Colorless oil (52.3 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.2 Hz, 1H), 7.57–7.44 (m, 3H), 7.31 (ddd, J = 23.7, 17.1, 7.0 Hz, 5H), 5.70 (s, 1H), 5.17 (d, J = 14.7 Hz, 1H), 4.24 (d, J = 14.7 Hz, 1H), 3.39 (dt, J = 9.0, 4.6 Hz, 2H), 3.29 (s, 3H), 3.24–3.17 (m, 1H), 3.07–2.97 (m, 1H), 1.77–1.69 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 167.35, 141.08, 137.00, 132.76, 132.06, 129.87, 128.73, 128.63, 128.61, 127.71, 127.64, 123.65, 123.42, 85.43, 69.32, 59.47, 58.60, 43.23, 29.72. HRMS (ESI) calcd for C19H22NO3 [M + H]+ 312.1594, found 312.1594.

2-Benzyl-3-(benzyloxy)isoindolin-1-one (8i)

Colorless oil (55.6 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 6.4 Hz, 1H), 7.55–7.45 (m, 3H), 7.36 (d, J = 7.1 Hz, 2H), 7.33–7.22 (m, 6H), 7.17 (d, J = 7.0 Hz, 2H), 5.84 (s, 1H), 5.16 (d, J = 14.7 Hz, 1H), 4.28 (d, J = 14.7 Hz, 1H), 4.10 (d, J = 11.2 Hz, 1H), 3.99 (d, J = 11.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.47, 140.93, 137.33, 136.94, 132.84, 132.26, 130.09, 128.81, 128.71, 128.52, 127.94, 127.88, 127.74, 123.77, 123.64, 85.67, 64.77, 43.52. HRMS (ESI) calcd for C22H20NO2 [M + H]+ 330.1489, found 330.1490.

2-Benzyl-3-phenethoxyisoindolin-1-one (8j)

Colorless oil (62.4 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.88–7.79 (m, 1H), 7.52–7.44 (m, 2H), 7.34–7.19 (m, 9H), 7.12 (d, J = 7.2 Hz, 2H), 5.66 (s, 1H), 4.98 (d, J = 14.7 Hz, 1H), 3.87 (d, J = 14.7 Hz, 1H), 3.25 (dd, J = 15.7, 7.1 Hz, 1H), 3.18–3.07 (m, 1H), 2.72 (t, J = 6.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.37, 140.83, 138.80, 137.00, 132.77, 132.05, 129.89, 129.11, 128.69, 128.62, 128.43, 127.60, 126.48, 123.66, 123.48, 85.39, 63.15, 43.03, 36.05. HRMS (ESI) calcd for C23H22NO2 [M + H]+ 344.4645, found 344.1645.

2-Benzyl-3-(p-tolyloxy)isoindolin-1-one (8k)

Colorless oil (61.7 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 6.5 Hz, 1H), 7.59–7.47 (m, 3H), 7.36 (d, J = 7.0 Hz, 2H), 7.27 (dt, J = 20.3, 7.2 Hz, 3H), 7.10 (dd, J = 20.4, 7.9 Hz, 4H), 5.83 (s, 1H), 5.17 (d, J = 14.7 Hz, 1H), 4.27 (d, J = 14.7 Hz, 1H), 4.02 (dd, J = 42.6, 10.9 Hz, 2H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.47, 141.02, 137.70, 136.94, 134.25, 132.83, 132.22, 130.02, 129.20, 128.78, 128.71, 128.01, 127.70, 123.75, 123.62, 85.58, 64.75, 43.46, 21.23. HRMS (ESI) calcd for C22H20NO2 [M + H]+ 330.1489, found 330.1490.

3-(Benzhydryloxy)-2-benzylisoindolin-1-one (8l)

Colorless oil (73.7 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.33–7.14 (m, 16H), 7.01 (d, J = 7.5 Hz, 1H), 5.84 (s, 1H), 5.29 (s, 1H), 5.04 (d, J = 15.1 Hz, 1H), 3.81 (d, J = 15.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.50, 142.40, 140.39, 141.43, 136.98, 132.45, 131.83, 129.81, 128.78, 128.73, 128.39, 128.32, 128.30, 127.87, 127.65, 127.43, 137.31, 126.71, 124.05, 123.46, 85.51, 78.93, 43.11. HRMS (ESI) calcd for C28H24NO2 [M + H]+ 406.1802, found 406.1803.

3-Ethoxy-2-(4-fluorobenzyl)isoindolin-1-one (8m)

Colorless oil (53.0 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.3 Hz, 1H), 7.53 (ddd, J = 10.6, 10.0, 5.4 Hz, 3H), 7.37 (dd, J = 8.3, 5.5 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 5.71 (s, 1H), 5.07 (d, J = 14.7 Hz, 1H), 4.28 (d, J = 14.7 Hz, 1H), 3.19–3.05 (m, 1H), 3.04–2.92 (m, 1H), 1.09 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.35, 162.28 (d, J = 245 Hz), 141.08, 132.86 (d, J = 3.1 Hz), 132.64, 132.12, 130.39, 130.37, 130.34, 130.31, 129.89, 123.53 (d, J = 22 Hz), 123.42, 115.63, 115.42, 85.58, 57.96, 42.66, 15.01. HRMS (ESI) calcd for C17H17FNO2 [M + H]+ 286.1238, found 286.1239.

3-Ethoxy-2-(4-methylbenzyl)isoindolin-1-one (8n)

Colorless oil (48.9 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.1 Hz, 1H), 7.52 (ddd, J = 19.0, 12.7, 6.8 Hz, 3H), 7.27 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 5.70 (s, 1H), 5.13 (d, J = 14.6 Hz, 1H), 4.20 (d, J = 14.6 Hz, 1H), 3.25–2.89 (m, 2H), 2.31 (s, 3H), 1.10 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.32, 141.22, 137.28, 133.95, 132.83, 131.97, 129.78, 129.35, 128.62, 123.58, 123.36, 85.43, 58.03, 43.00, 21.11, 15.09. HRMS (ESI) calcd for C18H20NO2 [M + H]+ 282.1489, found 282.1490.

3-Ethoxy-2-(p-tolyl)isoindolin-1-one (8o)

Colorless oil (45.4 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.4 Hz, 1H), 7.73–7.48 (m, 5H), 6.98 (d, J = 9.0 Hz, 2H), 6.35 (s, 1H), 3.83 (s, 3H), 3.27 (dd, J = 8.8, 7.2 Hz, 1H), 3.03 (dd, J = 8.8, 7.2 Hz, 1H), 1.04 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.60, 157.32, 140.57, 132.81, 132.51, 130.35, 130.10, 124.00, 123.78, 123.30, 114.35, 87.64, 58.01, 55.47, 15.00. HRMS (ESI) calcd for C17H18NO2 [M + H]+ 268.1332, found 268.1333.

3-Ethoxy-2-phenylisoindolin-1-one (8p)

Colorless oil (42.5 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.7 Hz, 2H), 7.69–7.55 (m, 3H), 7.44 (t, J = 8.0 Hz, 2H), 7.27–7.22 (m, 1H), 6.47 (s, 1H), 3.23 (dt, J = 14.1, 7.1 Hz, 1H), 3.02 (dq, J = 14.2, 7.1 Hz, 1H), 1.03 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.66, 140.49, 137.50, 132.73, 130.19, 129.07, 125.26, 123.89, 123.33, 121.77, 87.13, 57.68, 14.96. HRMS (ESI) calcd for C16H16NO2 [M + H]+ 254.1176, found 254.1178.

2-(4-Chlorophenethyl)-3-ethoxyisoindolin-1-one (8q)

Colorless oil (53.6 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.2 Hz, 1H), 7.54 (dt, J = 23.4, 6.9 Hz, 3H), 7.27–7.14 (m, 4H), 5.66 (s, 1H), 4.11–3.92 (m, 1H), 3.57–3.39 (m, 1H), 3.10 (dd, J = 15.1, 8.0 Hz, 1H), 3.07–2.87 (m, 3H), 1.11 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.57, 140.98, 137.25, 132.79, 132.34, 132.00, 130.13, 129.87, 128.73, 123.44, 123.36, 86.35, 57.74, 40.84, 33.83, 15.07. HRMS (ESI) calcd for C18H19ClNO2 [M + H]+ 316.1099, found 316.1099.

2-(4-Chlorophenyl)-3-ethoxyisoindolin-1-one (8r)

Colorless oil (49.9 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 17.9, 8.2 Hz, 3H), 7.71–7.51 (m, 3H), 7.38 (d, J = 8.8 Hz, 2H), 6.41 (s, 1H), 3.29–2.86 (m, 2H), 1.02 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.53, 140.25, 136.21, 132.95, 132.47, 130.29, 130.24, 129.07, 123.91, 123.35, 122.42, 122.39, 86.94, 57.58, 14.94. HRMS (ESI) calcd for C16H15ClNO2 [M + H]+ 288.0786, found 288.0786.

2-Benzyl-3-(3-chloropropoxy)isoindolin-1-one (8s)

Colorless oil (57.3 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.2 Hz, 1H), 7.58–7.45 (m, 3H), 7.38–7.23 (m, 5H), 5.71 (s, 1H), 5.15 (d, J = 14.7 Hz, 1H), 4.29 (d, J = 14.7 Hz, 1H), 3.59 (t, J = 6.3 Hz, 2H), 3.24 (dt, J = 9.3, 5.8 Hz, 1H), 3.08–2.99 (m, 1H), 1.86 (dd, J = 11.7, 5.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.35, 140.79, 136.95, 132.71, 132.20, 130.01, 128.76, 128.60, 127.70, 123.72, 123.44, 85.48, 58.60, 43.42, 41.51, 32.21. HRMS (ESI) calcd for C18H19ClNO2 [M + H]+ 316.1099, found 316.1097.

2-Benzyl-3-(ethylthio)isoindolin-1-one (10a)

Colorless oil (52.1 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H), 7.57 (s, 2H), 7.51–7.44 (m, 1H), 7.30 (dq, J = 13.7, 7.3 Hz, 5H), 5.38 (d, J = 14.7 Hz, 1H), 5.28 (s, 1H), 4.39 (d, J = 14.7 Hz, 1H), 1.96 (dd, J = 12.3, 7.5 Hz, 1H), 1.87–1.79 (m, 1H), 0.96 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.33, 143.66, 136.91, 132.16, 131.95, 128.86, 128.79, 128.60, 127.67, 123.61, 123.56, 62.85, 42.85, 20.21, 14.14. HRMS (ESI) calcd for C17H18NSO [M + H]+ 284.1104, found 284.1102.

2-Isopropyl-3-(propylthio)isoindolin-1-one (10b)

Colorless oil (54.1 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 6.1 Hz, 2H), 7.45 (ddd, J = 8.0, 4.6, 3.6 Hz, 1H), 5.57 (s, 1H), 4.34 (dt, J = 13.8, 6.9 Hz, 1H), 2.00 (dt, J = 11.9, 7.4 Hz, 1H), 1.76 (dt, J = 11.9, 7.2 Hz, 1H), 1.52 (dd, J = 14.7, 6.9 Hz, 6H), 1.29 (dt, J = 14.3, 7.2 Hz, 2H), 0.79 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.72, 143.71, 132.71, 131.75, 128.66, 123.17, 123.03, 63.23, 45.47, 27.85, 22.06, 20.52, 20.04, 13.59. HRMS (ESI) calcd for C14H20NOS [M + H]+ 250.1260, found 250.1261.

2-Benzyl-3-(propylthio)isoindolin-1-one (10c)

Colorless oil (56.0 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 12.6 Hz, 2H), 7.52–7.43 (m, 1H), 7.29 (ddd, J = 22.2, 13.8, 6.9 Hz, 5H), 5.37 (d, J = 14.7 Hz, 1H), 5.27 (s, 1H), 4.39 (d, J = 14.7 Hz, 1H), 1.90 (dt, J = 12.3, 7.4 Hz, 1H), 1.82–1.69 (m, 1H), 1.28 (dt, J = 14.5, 7.2 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.35, 143.69, 136.91, 132.10, 131.95, 128.85, 128.78, 128.60, 127.66, 123.60, 123.52, 62.70, 42.85, 28.02, 22.36, 13.59. HRMS (ESI) calcd for C19H22NOS [M + H]+ 312.1417, found 312.1418.

2-Benzyl-3-(pentylthio)isoindolin-1-one (10d)

Colorless oil (56.6 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 5.1 Hz, 2H), 7.48 (dd, J = 9.0, 3.8 Hz, 1H), 7.37–7.23 (m, 5H), 5.37 (d, J = 14.7 Hz, 1H), 5.27 (s, 1H), 4.38 (d, J = 14.7 Hz, 1H), 1.92 (dt, J = 12.3, 7.3 Hz, 1H), 1.83–1.68 (m, 1H), 1.26 (d, J = 5.9 Hz, 2H), 1.20–1.10 (m, 4H), 0.79 (t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.36, 143.70, 136.92, 132.09, 131.96, 128.84, 128.81, 128.78, 128.60, 127.66, 123.59, 123.52, 62.74, 42.85, 31.03, 28.59, 25.94, 22.06, 13.85. HRMS (ESI) calcd for C20H24NOS [M + H]+ 326.1573, found 326.1574.

2-Benzyl-3-(heptylthio)isoindolin-1-one (10e)

Colorless oil (60.0 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 5.0 Hz, 2H), 7.51–7.42 (m, 1H), 7.29 (ddd, J = 22.5, 14.0, 7.1 Hz, 5H), 5.37 (d, J = 14.7 Hz, 1H), 5.27 (s, 1H), 4.38 (d, J = 14.7 Hz, 1H), 1.93 (dt, J = 12.4, 7.3 Hz, 1H), 1.83–1.72 (m, 1H), 1.19 (ddd, J = 30.5, 14.7, 7.1 Hz, 10H), 0.85 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.35, 143.70, 136.93, 132.08, 131.97, 128.83, 128.78, 128.60, 127.65, 123.59, 123.52, 62.75, 42.85, 31.57, 29.91, 29.82, 29.63, 25.97, 22.53, 14.06 (s). HRMS (ESI) calcd for C22H28NOS [M + H]+ 354.1886, found 354.1885.

2-Benzyl-3-(isopropylthio)isoindolin-1-one (10f)

Colorless oil (54.6 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 6.1 Hz, 2H), 7.52–7.44 (m, 1H), 7.28 (dq, J = 18.4, 7.0 Hz, 5H), 5.40 (d, J = 14.7 Hz, 1H), 5.31 (s, 1H), 4.42 (d, J = 14.7 Hz, 1H), 2.34 (dt, J = 13.6, 6.8 Hz, 1H), 1.11 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.25, 143.88, 136.92, 132.02, 131.79, 128.87, 128.81, 128.52, 127.66, 123.80, 123.66, 63.20, 42.88, 32.51, 24.92, 24.34. HRMS (ESI) calcd for C18H20NOS [M + H]+ 298.1260, found 298.1261.

2-Benzyl-3-(cyclopentylthio)isoindolin-1-one (10g)

Colorless oil (59.4 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.5 Hz, 1H), 7.56 (dd, J = 7.0, 5.5 Hz, 2H), 7.50–7.39 (m, 1H), 7.38–7.16 (m, 5H), 5.39 (d, J = 14.7 Hz, 1H), 5.29 (s, 1H), 4.42 (d, J = 14.7 Hz, 1H), 2.32 (dd, J = 15.3, 7.8 Hz, 1H), 1.78–1.67 (m, 1H), 1.65–1.46 (m, 2H), 1.43–1.23 (m, 4H), 1.19–1.09 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 167.28, 144.10, 136.94, 131.95, 131.76, 128.79, 128.75, 128.61, 128.58, 128.56, 127.65, 123.83, 123.63, 63.24, 42.90, 39.66, 34.56, 34.10, 24.72, 24.44. HRMS (ESI) calcd for C20H22NOS [M + H]+ 324.1417, found 324.1418.

2-Benzyl-3-(isobutylthio)isoindolin-1-one (10h)

Colorless oil (54.1 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H), 7.60–7.51 (m, 2H), 7.51–7.44 (m, 1H), 7.30 (ddd, J = 22.5, 13.9, 7.0 Hz, 5H), 5.37 (d, J = 14.7 Hz, 1H), 5.28 (s, 1H), 4.37 (d, J = 14.7 Hz, 1H), 1.80 (dd, J = 12.0, 6.7 Hz, 1H), 1.63 (dd, J = 11.9, 6.9 Hz, 1H), 1.46 (dt, J = 13.3, 6.7 Hz, 1H), 0.81 (t, J = 6.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 167.39, 143.64, 136.91, 132.10, 131.98, 128.85, 128.81, 128.78, 128.61, 127.67, 123.59, 123.49, 62.59, 42.85, 34.60, 28.07, 22.14, 22.08. HRMS (ESI) calcd for C19H22NOS [M + H]+ 312.1417, found 312.1417.

2-Benzyl-3-(benzylthio)isoindolin-1-one (10i)

Colorless oil (64.2 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.2 Hz, 1H), 7.55–7.45 (m, 3H), 7.33–7.24 (m, 5H), 7.21–7.12 (m, 3H), 6.95 (d, J = 6.9 Hz, 2H), 5.30 (s, 1H), 5.22 (d, J = 14.8 Hz, 1H), 4.26 (d, J = 14.8 Hz, 1H), 3.09 (d, J = 2.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.25, 143.15, 137.04, 136.90, 132.22, 132.08, 129.02, 128.83, 128.80, 128.75, 128.61, 128.50, 127.70, 127.12, 123.68, 123.59, 63.24, 42.89, 31.29. HRMS (ESI) calcd for C22H20NOS [M + H]+ 346.1260, found 346.1261.

2-Benzyl-3-((4-methylbenzyl)thio)isoindolin-1-one (10j)

Colorless oil (67.5 mg, 94%). H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.3 Hz, 1H), 7.50 (tt, J = 14.1, 7.3 Hz, 3H), 7.35–7.21 (m, 5H), 7.00 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 7.9 Hz, 2H), 5.31–5.19 (m, 2H), 4.28 (d, J = 14.8 Hz, 1H), 3.12–3.00 (m, 2H), 2.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.28, 143.29, 136.95, 136.79, 133.82, 132.21, 132.08, 129.21, 128.97, 128.82, 128.70, 128.68, 128.65, 128.62, 127.69, 123.68, 123.58, 63.26, 42.92, 31.01, 21.13. HRMS (ESI) calcd for C23H22NOS [M + H]+ 360.1417, found 360.1417.

2-Benzyl-3-((4-chlorobenzyl)thio)isoindolin-1-one (10k)

Colorless oil (69.7 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.9 Hz, 1H), 7.53–7.43 (m, 3H), 7.33–7.24 (m, 5H), 7.13 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 5.30 (s, 1H), 5.23 (d, J = 14.8 Hz, 1H), 4.26 (d, J = 14.8 Hz, 1H), 3.05 (q, J = 13.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 167.25, 142.98, 136.78, 135.72, 132.86, 132.26, 131.98, 130.04, 129.08, 128.85, 128.62, 128.58, 128.57, 128.54, 127.75, 123.68, 123.62, 63.19, 42.97, 30.51. HRMS (ESI) calcd for C22H19ClNOS [M + H]+ 380.0870, found 380.0872.

2-Benzyl-3-((4-(tert-butyl)benzyl)thio)isoindolin-1-one (10l)

Colorless oil (73.1 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 6.9 Hz, 1H), 7.54–7.40 (m, 3H), 7.37–7.21 (m, 5H), 7.22–7.13 (m, 2H), 6.89 (d, J = 8.1 Hz, 2H), 5.27 (d, J = 15.7 Hz, 2H), 4.31 (d, J = 14.7 Hz, 1H), 3.08 (dd, J = 28.7, 12.9 Hz, 2H), 1.27 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 167.33, 150.03, 143.31, 136.97, 133.84, 132.16, 132.03, 128.95, 128.84, 128.66, 128.64, 128.48, 127.70, 125.42, 123.69, 123.56, 63.25, 42.93, 34.49, 31.36, 30.84. HRMS (ESI) calcd for C26H28NOS [M + H]+ 402.1886, found 402.1886.

Ethyl 2-((2-Benzyl-3-oxoisoindolin-1-yl)thio)acetate (10m)

Colorless oil (58.0 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.5 Hz, 1H), 7.67–7.44 (m, 3H), 7.37–7.16 (m, 5H), 5.35 (d, J = 16.0 Hz, 2H), 4.37 (d, J = 14.8 Hz, 1H), 3.98 (tdd, J = 10.8, 7.2, 3.6 Hz, 2H), 2.66 (q, J = 15.3 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.40, 167.10, 142.13, 136.69, 132.26, 132.21, 129.28, 128.85, 128.57, 127.75, 123.77, 123.67, 62.69, 61.75, 42.89, 28.82, 13.95. HRMS (ESI) calcd for C19H20NO3S [M + H]+ 342.1158, found 342.1159.

4-((1-Oxo-3-(propylthio)isoindolin-2-yl)methyl)benzonitrile (10n)

Colorless oil (58.6 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.6 Hz, 1H), 7.66–7.57 (m, 4H), 7.55–7.45 (m, 3H), 5.33 (d, J = 15.2 Hz, 1H), 5.29 (s, 1H), 4.53 (d, J = 15.1 Hz, 1H), 1.90–1.72 (m, 2H), 1.28 (dd, J = 14.6, 7.3 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.56, 143.45, 142.41, 132.59, 132.49, 131.44, 129.18, 129.11, 123.68, 118.56, 111.65, 63.05, 42.73, 28.02, 22.23, 13.53. HRMS (ESI) calcd for C19H19N2OS [M + H]+ 323.1213, found 323.1213.

2-Phenyl-3-(propylthio)isoindolin-1-one (10o)

Colorless oil (48.1 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.6 Hz, 1H), 7.58 (ddt, J = 35.2, 28.4, 8.0 Hz, 7H), 7.27 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 1.98 (dt, J = 12.2, 7.3 Hz, 1H), 1.82 (dt, J = 12.2, 7.4 Hz, 1H), 1.32–1.13 (m, 2H), 0.70 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.58, 143.07, 136.52, 132.66, 131.97, 129.16, 129.13, 128.97, 125.94, 124.09, 123.84, 123.77, 123.61, 64.68, 28.66, 22.19, 13.43. HRMS (ESI) calcd for C17H18NOS [M + H]+ 284.1104, found 284.1105.

3-(Propylthio)-2-(p-tolyl)isoindolin-1-one (10p)

Colorless oil (48.1 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.6 Hz, 1H), 7.66 (q, J = 7.7 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 6.03 (s, 1H), 3.84 (s, 3H), 2.00 (dt, J = 12.2, 7.3 Hz, 1H), 1.83 (dt, J = 12.2, 7.4 Hz, 1H), 1.33–1.11 (m, 2H), 0.72 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.66, 157.85, 143.06, 132.46, 129.10, 126.07, 123.76, 123.59, 114.35, 65.41, 55.47, 28.77, 22.22, 13.47. HRMS (ESI) calcd for C18H20NOS [M + H]+ 298.1260, found 298.1262.

2-Phenethyl-3-(propylthio)isoindolin-1-one (10q)

Colorless oil (54.1 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.5 Hz, 1H), 7.62–7.50 (m, 2H), 7.50–7.39 (m, 1H), 7.29–7.13 (m, 5H), 5.20 (s, 1H), 4.22 (ddd, J = 14.1, 8.2, 6.3 Hz, 1H), 3.73–3.57 (m, 1H), 3.12–2.88 (m, 2H), 1.77 (dtd, J = 14.3, 12.3, 7.4 Hz, 2H), 1.24 (dt, J = 14.6, 7.3 Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.50, 143.60, 138.75, 132.12, 131.95, 128.79, 128.77, 128.63, 126.56, 123.48, 123.26, 63.92, 40.84, 34.56, 28.07, 22.30, 13.54. HRMS (ESI) calcd for C19H22NOS [M + H]+ 312.1417, found 312.1418.

2-(4-Chlorophenethyl)-3-(propylthio)isoindolin-1-one (10r)

Colorless oil (60.7 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 4.8 Hz, 2H), 7.55–7.43 (m, 1H), 7.32–7.15 (m, 4H), 5.24 (s, 1H), 4.19 (ddd, J = 14.2, 8.2, 6.4 Hz, 1H), 3.76–3.42 (m, 1H), 3.11–2.80 (m, 2H), 1.77 (ddt, J = 45.9, 12.2, 7.4 Hz, 2H), 1.25 (dt, J = 14.6, 7.3 Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.52, 143.48, 137.17, 132.37, 132.05, 131.98, 130.13, 128.87, 128.75, 123.52, 123.29, 63.86, 40.62, 33.86, 28.01, 22.27, 13.53. HRMS (ESI) calcd for C19H21ClNOS [M + H]+ 346.1027, found 346.1028.

2-(4-Methoxybenzyl)-3-(propylthio)isoindolin-1-one (10s)

Colorless oil (51.7 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.5 Hz, 1H), 7.62–7.52 (m, 2H), 7.5–7.41 (m, 1H), 7.28 (t, J = 6.4 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.31 (d, J = 14.5 Hz, 1H), 5.26 (s, 1H), 4.32 (d, J = 14.5 Hz, 1H), 3.77 (s, 3H), 1.83 (ddt, J = 53.5, 12.2, 7.4 Hz, 2H), 1.29 (dt, J = 14.4, 7.2 Hz, 2H), 0.81 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.27, 159.13, 143.69, 132.04, 129.97, 129.07, 128.81, 123.55, 123.47, 114.13, 62.56, 55.28, 42.23, 27.97, 22.35, 13.57. HRMS (ESI) calcd for C19H22NO2S [M + H]+ 328.1366, found 328.1365.

2-(4-Methylphenethyl)-3-(propylthio)isoindolin-1-one (10t)

Colorless oil (53.3 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H), 7.55 (s, 2H), 7.51–7.37 (m, 1H), 7.11 (dd, J = 25.2, 7.8 Hz, 4H), 5.23 (s, 1H), 4.20 (ddd, J = 14.1, 8.1, 6.4 Hz, 1H), 3.71–3.54 (m, 1H), 3.04–2.81 (m, 2H), 2.30 (s, 3H), 1.77 (ddt, J = 26.8, 12.3, 7.4 Hz, 2H), 1.24 (dt, J = 14.6, 7.3 Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.48, 143.63, 136.03, 135.61, 132.16, 131.91, 129.31, 129.29, 128.77, 128.66, 128.63, 123.49, 123.25, 63.90, 40.89, 34.11, 28.07, 22.32, 21.06, 13.54. HRMS (ESI) calcd for C20H24NOS [M + H]+ 326.1573, found 326.1573.

2-Benzyl-3-thiomorpholinoisoindolin-1-one (12a)

White solid (61.6 mg, 95%), mp = 110–112 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.8 Hz, 1H), 7.55–7.45 (m, 2H), 7.43 (d, J = 7.1 Hz, 1H), 7.35–7.23 (m, 5H), 5.21 (d, J = 14.6 Hz, 1H), 4.91 (s, 1H), 4.31 (d, J = 14.6 Hz, 1H), 3.03–2.65 (m, 4H), 2.59 (d, J = 4.4 Hz, 4H). 13C NMR (100 MHz, CDCl3) δ 167.46, 142.07, 137.45, 132.72, 131.52, 129.15, 128.69, 128.44, 127.52, 123.82, 123.36, 78.71, 50.07, 43.62, 28.54. HRMS (ESI) calcd for C19H21N2OS [M + H]+ 325.1369, found 325.1370.

2-Benzyl-3-morpholinoisoindolin-1-one (12b)[29]

White solid (57.3 mg, 93%), mp = 130–131 °C. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 6.6 Hz, 1H), 7.48 (dt, J = 13.8, 6.5 Hz, 3H), 7.36–7.18 (m, 5H), 5.22 (d, J = 14.6 Hz, 1H), 4.96 (s, 1H), 4.34 (d, J = 14.6 Hz, 1H), 3.65 (t, J = 4.4 Hz, 4H), 2.73–2.55 (m, 2H), 2.52–2.27 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 167.44, 141.87, 137.44, 132.80, 131.43, 129.17, 128.67, 128.52, 127.51, 123.89, 123.49, 77.38, 67.34, 47.64, 43.61. HRMS (ESI) calcd for C20H24NO2 [M + H]+ 326.1573, found 326.1574.

2-Benzyl-3-(benzylamino)isoindolin-1-one (12c)

Colorless oil (59.0 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.3 Hz, 1H), 7.59–7.41 (m, 3H), 7.27 (tt, J = 10.6, 7.4 Hz, 8H), 7.15 (d, J = 7.1 Hz, 2H), 5.32 (s, 1H), 5.17 (d, J = 15.0 Hz, 1H), 4.34 (d, J = 15.0 Hz, 1H), 3.35 (d, J = 13.0 Hz, 1H), 3.24 (d, J = 13.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 167.75, 143.31, 139.67, 137.42, 132.84, 131.89, 129.19, 128.85, 128.44, 128.29, 128.09, 128.09, 127.63, 127.20, 123.56, 123.22, 72.33, 45.60, 43.26. HRMS (ESI) calcd for C22H21N2O [M + H]+ 329.1648, found 329.1648.

2-Benzyl-3-((4-fluorobenzyl)amino)isoindolin-1-one (12d)

Colorless oil (56.1 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 1H), 7.57–7.44 (m, 3H), 7.37–7.20 (m, 5H), 7.08 (dd, J = 8.2, 5.7 Hz, 2H), 6.92 (t, J = 8.6 Hz, 2H), 5.33 (s, 1H), 5.13 (d, J = 15.0 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 3.31 (d, J = 13.0 Hz, 1H), 3.19 (d, J = 13.0 Hz, 1H), 2.16 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 167.76, 161.98 (d, J = 244 Hz), 143.18, 137.40, 135.39 (d, J = 2.7 Hz), 132.79, 131.91, 129.62 (d, J = 7.9 Hz), 129.22, 128.86, 128.26, 128.22, 127.66, 123.57, 123.18, 115.26, 115.05, 72.38, 44.80, 43.37. HRMS (ESI) calcd for C22H20FN2O [M + H]+ 347.1154, found 347.1155.

2-Benzyl-3-((4-chlorobenzyl)amino)isoindolin-1-one (12e)

Colorless oil (61.5 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.1 Hz, 1H), 7.57–7.43 (m, 3H), 7.39–7.15 (m, 7H), 7.04 (d, J = 8.3 Hz, 2H), 5.33 (s, 1H), 5.11 (d, J = 15.0 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 3.24 (dd, J = 47.1, 13.3 Hz, 2H), 2.17 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 167.75, 143.11, 138.20, 137.38, 132.84, 132.78, 131.93, 129.40, 129.25, 128.86, 128.46, 128.25, 127.67, 123.58, 123.18, 72.40, 44.84, 43.40. HRMS (ESI) calcd for C22H20ClN2O [M + H]+ 363.1259, found 363.1260.

2-Benzyl-3-((4-bromobenzyl)amino)isoindolin-1-one (12f)

Colorless oil (70.6 mg, 87%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.1 Hz, 1H), 7.63–7.45 (m, 3H), 7.42–7.21 (m, 7H), 6.99 (d, J = 8.2 Hz, 2H), 5.33 (s, 1H), 5.12 (d, J = 15.0 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 3.23 (dd, J = 48.1, 13.3 Hz, 2H), 2.12 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 167.75, 143.06, 138.67, 137.34, 132.77, 131.94, 131.43, 129.75, 129.26, 128.87, 128.25, 127.68, 123.60, 123.16, 120.94, 72.37, 44.88, 43.42. HRMS (ESI) calcd for C22H20BrN2O [M + H]+ 407.0754, found 407.0755.

2-Benzyl-3-((2-chlorobenzyl)amino)isoindolin-1-one (12g)

Colorless oil (60.8 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 6.8 Hz, 1H), 7.51 (dt, J = 13.7, 6.0 Hz, 3H), 7.35–7.22 (m, 6H), 7.16 (p, J = 6.9 Hz, 2H), 7.10–7.02 (m, 1H), 5.30 (s, 1H), 5.18 (d, J = 15.0 Hz, 1H), 4.25 (d, J = 15.0 Hz, 1H), 3.44 (dd, J = 67.5, 13.4 Hz, 2H), 2.35 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 167.62, 143.11, 137.35, 137.31, 133.78, 132.85, 131.86, 130.39, 129.49, 129.23, 128.84, 128.63, 128.28, 127.61, 126.97, 123.54, 123.27, 72.12, 43.71, 43.06. HRMS (ESI) calcd for C22H20ClN2O [M + H]+ 363.1259, found 363.1259.

2-Benzyl-3-(pentylthio)isoindolin-1-one (12h)

Colorless oil (62.9 mg, 92%). 1H NMR [400 MHz, dimethyl sulfoxide (DMSO)-d6] δ 7.76 (d, J = 7.4 Hz, 1H), 7.62 (s, 2H), 7.57–7.50 (m, 1H), 7.40 (d, J = 7.3 Hz, 2H), 7.33 (t, J = 7.4 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 7.08 (d, J = 10.3 Hz, 4H), 5.43 (d, J = 4.8 Hz, 1H), 4.90 (d, J = 15.1 Hz, 1H), 4.50 (d, J = 15.1 Hz, 1H), 3.80–3.60 (m, 1H), 3.22 (dd, J = 12.8, 4.3 Hz, 1H), 2.99 (dd, J = 12.7, 8.7 Hz, 1H), 2.13 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 167.23, 144.30, 138.68, 138.43, 136.49, 133.02, 132.23, 130.18, 129.48, 129.22, 128.93, 128.43, 127.52, 127.17, 126.00, 123.99, 123.02, 73.03, 42.80, 42.71, 18.96. HRMS (ESI) calcd for C23H23N2O [M + H]+ 343.1805, found 343.1805.

2-Benzyl-3-((furan-2-ylmethyl)amino)isoindolin-1-one (12i)

Colorless oil (59.8 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.3 Hz, 1H), 7.60–7.44 (m, 3H), 7.38–7.22 (m, 5H), 7.22–7.11 (m, 1H), 6.88 (dd, J = 5.0, 3.5 Hz, 1H), 6.71 (d, J = 2.7 Hz, 1H), 5.31 (s, 1H), 5.19 (d, J = 15.0 Hz, 1H), 4.35 (d, J = 15.0 Hz, 1H), 3.61 (d, J = 13.9 Hz, 1H), 3.43 (d, J = 13.9 Hz, 1H), 2.26 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 167.67, 143.39, 142.99, 137.30, 132.73, 131.95, 129.26, 128.86, 128.29, 127.67, 126.67, 124.83, 124.70, 123.59, 123.19, 71.95, 43.28, 40.65. HRMS (ESI) calcd for C20H19N2O2 [M + H]+ 319.1441, found 319.1442.

2-Phenyl-3-thiomorpholinoisoindolin-1-one (12j)

White solid (55.8 mg, 90%), mp = 101–103 °C. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.4 Hz, 1H), 7.66–7.58 (m, 1H), 7.58–7.48 (m, 4H), 7.44 (t, J = 7.8 Hz, 2H), 7.27 (dd, J = 9.7, 4.9 Hz, 1H), 5.85 (s, 1H), 3.02–2.82 (m, 2H), 2.74–2.56 (m, 2H), 2.58–2.35 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 166.81, 142.05, 138.08, 132.59, 132.30, 129.52, 129.08, 126.24, 125.15, 123.86, 123.39, 81.76, 50.44, 28.46. HRMS (ESI) calcd for C18H19N2OS [M + H]+ 311.1213, found 311.1213.

3-Thiomorpholino-2-(p-tolyl)isoindolin-1-one (12k)

White solid (54.9 mg, 88%), mp = 95–97 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 7.4 Hz, 1H), 7.55 (tt, J = 14.2, 7.2 Hz, 3H), 7.36 (d, J = 8.2 Hz, 2H), 7.24 (t, J = 9.1 Hz, 2H), 5.80 (s, 1H), 2.97–2.81 (m, 2H), 2.70–2.58 (m, 2H), 2.55–2.40 (m, 4H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 166.85, 142.15, 136.14, 135.45, 132.70, 132.18, 129.74, 129.44, 125.23, 123.75, 123.36, 81.92, 50.47, 28.48, 21.12. HRMS (ESI) calcd for C19H21N2OS [M + H]+ 325.1369, found 325.1369.

2-Isopropyl-3-thiomorpholinoisoindolin-1-one (12l)

White solid (46.9 mg, 85%), mp = 94–95 °C. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.0 Hz, 1H), 7.48 (dt, J = 19.2, 6.4 Hz, 3H), 5.13 (s, 1H), 4.31 (dt, J = 13.7, 6.8 Hz, 1H), 3.25–2.35 (m, 8H), 1.43 (dd, J = 15.3, 6.9 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 167.32, 141.60, 133.28, 131.06, 128.96, 123.40, 123.07, 79.46, 44.43, 28.36, 21.42, 19.82. HRMS (ESI) calcd for C15H21N2OS [M + H]+ 277.1369, found 277.1369.

2-Phenethyl-3-thiomorpholinoisoindolin-1-one (12m)

White solid (62.2 mg, 92%), mp = 90–91 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 5.1 Hz, 2H), 7.48 (dd, J = 9.0, 3.8 Hz, 1H), 7.37–7.23 (m, 5H), 5.37 (d, J = 14.7 Hz, 1H), 5.27 (s, 1H), 4.38 (d, J = 14.7 Hz, 1H), 1.92 (dt, J = 12.3, 7.3 Hz, 1H), 1.83–1.68 (m, 1H), 1.26 (d, J = 5.9 Hz, 2H), 1.20–1.10 (m, 4H), 0.79 (t, J = 6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 167.51, 142.09, 139.29, 132.85, 131.33, 129.06, 128.82, 128.59, 126.50, 123.51, 123.21, 79.78, 50.03, 41.14, 34.95, 28.60. HRMS (ESI) calcd for C20H23N2OS [M + H]+ 339.1526, found 339.1527.

2-(4-Methoxyphenethyl)-3-thiomorpholinoisoindolin-1-one (12n)

White solid (64.0 mg, 87%), mp = 132–134 °C. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.0 Hz, 1H), 7.46 (ddt, J = 28.7, 14.8, 6.8 Hz, 3H), 7.16 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 4.79 (s, 1H), 4.07 (ddd, J = 13.7, 7.8, 6.0 Hz, 1H), 3.77 (s, 3H), 3.58–3.40 (m, 1H), 3.01–2.87 (m, 2H), 2.87–2.49 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 167.48, 158.27, 142.11, 132.87, 131.31, 131.21, 129.72, 129.03, 123.46, 123.22, 114.00, 79.77, 55.27, 41.31, 33.96, 28.60. HRMS (ESI) calcd for C21H25N2O2S [M + H]+ 369.1631, found 369.1631.

2-(4-Chlorophenethyl)-3-thiomorpholinoisoindolin-1-one (12o)

White solid (67.0 mg, 90%), mp = 113–115 °C. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.1 Hz, 1H), 7.47 (ddd, J = 26.7, 13.1, 7.0 Hz, 3H), 7.29–7.23 (m, 2H), 7.19 (d, J = 8.3 Hz, 2H), 4.82 (s, 1H), 4.07 (ddd, J = 13.9, 7.9, 6.1 Hz, 1H), 3.64–3.38 (m, 1H), 2.96 (qd, J = 13.8, 6.9 Hz, 2H), 2.89–2.44 (m, 8H). 13C NMR (100 MHz, CDCl3) δ 167.55, 141.94, 137.65, 132.71, 132.29, 131.44, 130.14, 129.14, 128.69, 123.56, 123.26, 79.79, 50.05, 40.98, 34.19, 28.58. HRMS (ESI) calcd for C20H22ClN2OS [M + H]+ 373.1136, found 373.1138.

2-(4-Fluorobenzyl)-3-thiomorpholinoisoindolin-1-one (12p)

White solid (62.9 mg, 92%), mp = 121–123 °C. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 6.9 Hz, 1H), 7.49 (ddd, J = 22.8, 11.5, 6.9 Hz, 3H), 7.30 (dt, J = 8.6, 4.4 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H), 5.14 (d, J = 14.6 Hz, 1H), 4.90 (s, 1H), 4.30 (d, J = 14.6 Hz, 1H), 2.69 (dd, J = 78.8, 24.8 Hz, 8H). 13C NMR (100 MHz, CDCl3) δ 167.41, 162.18 (d, J = 254 Hz), 160.96, 141.98, 133.29 (d, J = 3.1 Hz), 132.59, 131.60, 130.13 (d, J = 8.1 Hz), 129.20, 123.82, 123.39, 115.63, 115.42, 78.72, 50.05, 42.86, 28.52. HRMS (ESI) calcd for C19H20FN2OS [M + H]+ 343.1275, found 343.1275.

2-(4-Methylbenzyl)-3-thiomorpholinoisoindolin-1-one (12q)

White solid (59.5 mg, 88%), mp = 125–127 °C. 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 6.7 Hz, 1H), 7.48 (tt, J = 13.8, 6.8 Hz, 2H), 7.41 (d, J = 7.1 Hz, 1H), 7.21 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 5.19 (d, J = 14.5 Hz, 1H), 4.89 (s, 1H), 4.23 (d, J = 14.5 Hz, 1H), 2.69 (dt, J = 62.0, 4.5 Hz, 8H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 167.36, 142.12, 137.13, 134.38, 132.78, 131.46, 129.34, 129.09, 128.42, 123.73, 123.35, 78.56, 50.05, 43.28, 28.56, 21.13. HRMS (ESI) calcd for C20H24NOS [M + H]+ 326.1573, found 326.1574.