Synthesis of 3-(2-oxopropyl)-2-arylisoindolinone derivatives via a three-component reaction of diaryliodonium salts with 2-formylbenzonitriles and phenylacetylenes

Abstract

A copper-catalyzed multicomponent cascade cyclization using readily available substrates, including 2-formylbenzonitriles, phenylacetylenes, and diaryliodonium salts, is achieved. A broad reaction scope is presented with good functional group compatibility, giving rise to a range of 3-(2-oxopropyl)-2-arylisoindolinones in moderate to good yields.

Introduction

Isoindolin-1-ones, including 3-(2-oxopropyl)-2-substituted isoindolinones that can be derived from isoindolinone derivatives, are a class of nitrogen-containing heterocyclic compounds that are usually employed as key structural scaffolds for organic synthesis and are very common structural motifs in natural products and pharmaceuticals exhibiting important biological activities (Scheme 1).^1–6 For example, pagoclone^7–9 and pazinaclone^10,11 are clinically utilized anxiolytic and sedative drugs, respectively. With the expanding role of 3-(2-oxopropyl)-2-substituted isoindolinones in medicinal chemistry, numerous methods have been developed for their synthesis over the past few decades.^12–27 A common method involves C–H functionalization, which employs N-substituted benzamides as reactants bearing either activating or directing groups.^28–33 Liu and Lu’s group developed an efficient rhodium-catalyzed coupling of α-allenols and N-methoxybenzamide derivatives to afford 3,3-disubstituted isoindolinones. ³⁴ Liu and Li’s groups have reported the coupling of propargyl alcohol derivatives and N-ethoxy or N-methoxybenzamides by employing an Rh(III) catalyst under argon, leading to a broad variety of substituted isoindolinones.^35,36 Jeganmohan has described an oxidative C–H coupling/cyclization cascade of allylic alcohols and N-alkyl/arylbenzamides to provide a broad range of 3-subtituted isoindolinones. ³⁷ In 2019, Li’s group published a cobalt-catalyzed oxidative C–H functionalization cyclization with α-diazoketones. ³⁸ In the methodologies mentioned above, the use of precious metal catalysts and highly functionalized starting materials limit expansion for the synthesis of compound libraries. Thus, the development of novel and efficient strategies to access 3-(2-oxopropyl)-2-substituted isoindolinone scaffolds remains highly desirable.

Scheme 1.

Selected active 3-(2-oxopropyl)-2-arylisoindolinones and synthetic strategies.

Multicomponent coupling reactions have emerged as a powerful strategy for the generation of molecular complexity in an atom-economical fashion.^39–44 The groups of Singh and Cai independently utilized o-formyl methylbenzoates, trimethylsilyl enol ethers, and aniline derivatives as the starting materials to synthesize various isoindolinones with zinc(II) or scandium(III) triflate catalysts in one pot (Scheme 1).^45,46 Recently, we reported a Cu-catalyzed three-component cascade cyclization using readily available substrates including 2-formylbenzonitriles, alkyl aryl ketones and diaryliodonium salts.⁴⁷ In continuation of these studies, we herein disclose a three-component cascade cyclization of diaryliodonium salts with 2-formylbenzonitriles and phenylacetylenes for the construction of various 3-(2-oxopropyl)-2-substituted isoindolinones.

Results and discussion

We began our optimization studies using 2-formylbenzonitrile (1a), ethynylbenzene (2a) and bis(4-bromophenyl)iodonium triflate (3a) in the presence of different catalysts to ultimately identify the most efficient catalytic system. The reaction of the substrate 1a (0.3 mmol) with ethynylbenzene 2a (2.0 equiv.) and diaryliodonium salt 3a (1.5 equiv.) in the presence of CuI (10 mol%) and the protic acid TfOH (1.5 equiv.) in 1,2-dichloroethane (DCE) was conducted at 110℃ over 2 h. To our delight, 2-(4-bromophenyl)-3-(2-oxo-2-phenylethyl)isoindolin-1-one (4a) was obtained in 45% yield (Table 1, entry 1). Of the catalysts examined, the yield rose to 79% when Cu(OTf)₂ was used (Table 1, entry 6). Other Cu(I) catalysts, such as CuCl, CuBr, Cu₂O, and Cu(Oac)₂ did not provide 4a in better yields (Table 1, entries 2–5). A brief solvent study showed that DCE was the most suitable for the transformation (Table 1, entries 7–10). Other protic acids, such as HOAc, TFA, HCOOH, and PTSA were employed as additives, but lower product yields were obtained under the same conditions (Table 1, entries 11–14).

Table 1.

Optimization of the reaction conditions. ^a

Entry	[Cu]	Additive	Solvent	Yield (%) b
1	CuI	TfOH	DCE	45
2	CuCl	TfOH	DCE	41
3	CuBr	TfOH	DCE	49
4	Cu2O	TfOH	DCE	21
5	Cu(Oac)2	TfOH	DCE	35
6	Cu(Otf)2	TfOH	DCE	79
7	Cu(Otf)2	TfOH	CH3CN	–
8	Cu(Otf)2	TfOH	THF	–
9	Cu(Otf)2	TfOH	Toluene	53
10	Cu(Otf)2	TfOH	DMF	–
11	Cu(Otf)2	HOAc	DCE	51
12	Cu(Otf)2	TFA	DCE	35
13	Cu(Otf)2	HCOOH	DCE	51
14	Cu(Otf)2	PTSA	DCE	12

a

Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), and 3a (0.45 mmol), additive (0.45 mmol), catalyst (10 mol%), solvent (2.0 mL), 110°C, 2 h.

b

Isolated yield.

After the optimization of the reaction conditions, we proceeded to explore the robustness of the protocol with respect to the substrates. The scope of phenylacetylenes 2 was thus explored (Table 2). To our delight, a range of phenylacetylenes 2, possessing both electron-donating and electron-deficient substituents at the 4-position, afforded 3-(2-oxopropyl)-2-arylisoindolinones 4a−g in 65−81% isolated yields, including halogen (4b−d), trifluoromethyl (4e), nitro (4f), and methyl (4g, h). In terms of position effect, para- and ortho-substituted phenylacetylenes afforded products 4g, h in 79−81% yields. A fused-ring substrate (8-acetylnaphthalen-2-ylium) was also found to be a suitable substrate, furnishing 4i in 85% yield. Heteroaromatic (2-ethynylthiophene) gave product 4k in 52% yield.

Table 2.

Scope of the phenylacetylenes scope.^a,b

a

Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), and 3a (0.45 mmol), TfOH (0.45 mmol), Cu(Otf)₂ (10 mol%), DCE (2.0 mL), 110°C, 2 h.

b

Isolated yield.

Next, the three-component cascade cyclization was carried out with different substituted 2-formylbenzonitriles 1 and diaryliodonium salts 3 under the optimized conditions (Table 3). The scope with respect to the diaryliodonium salts was explored in the coupling with 2-formylbenzonitrile (1a) and ethynylbenzene (2a). It was found that the reaction took place smoothly using a wide range of diaryliodonium salts bearing electron-donating, electron-withdrawing, and halogen groups, furnishing the corresponding products in 70–91% yields (4l–q). The annulation reaction also proceeded well when various substituted 2-formylbenzonitriles were used, delivering the 3-(2-oxopropyl)-2-arylisoindolinone 4r–t in good yields (66–79%).

Table 3.

Scope of the 2-formylbenzonitriles and diaryliodonium salts.^a,b

a

Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), and 3c (0.45 mmol), TfOH (0.45 mmol) and Cu(Otf)₂ (10 mol%) in DCE (2.0 mL), 110°C, 2 h.

b

Isolated yield.

To further understand the mechanism of this reaction, control experiments were investigated. Initially, we conducted a control reaction using phenylacetylene (2a) as the sole substrate (Scheme 2), and under our standard conditions, acetophenone (5) was isolated in 78% yield. To determine the source of the oxygen atom, H₂O (3 equiv.), which had been labeled with oxygen 18, was added to the reaction. To our delight, the reaction also delivered the Markovnikov-type hydration product 5-D in a good yield. This confirms that a Markovnikov-type alkyne hydration occurs first.^48–52 Next, the mechanism of the subsequent reaction is similar to the diaryliodonium salt induced three-component Mukaiyama–Mannich reaction with 2-formylbenzonitrile, alkyl aryl ketones, and diaryliodonium salts.

Scheme 2.

Control experiments.

On the basis of the control experiments and relevant literature, we tentatively propose a mechanism for this Cu-catalyzed transformation involving an N-arylnitrilium cation (Scheme 3). First, the reaction of 2-formylbenzonitrile (1a) with diaryliodonium salt (3a) gives the N-arylnitrilium cation A in the presence of the copper catalyst.⁴⁷ Next, the phenylnitrilium intermediate A is hydrolyzed to give intermediate B. Ethynylbenzene (2a) can form the complex C in the presence of the copper catalyst, followed by the hydration to produce intermediate D. ⁴⁹ Nucleophilic attack of the enol D affords intermediate E, and dehydration may give intermediate F. Finally, the conjugate addition of intermediate F affords the 3-(2-oxo-2-phenylethyl)-2-phenylisoindolin-1-one 4l.

Scheme 3.

Proposed reaction mechanism.

Conclusion

In summary, we have developed a Cu-catalyzed, three-component cascade cyclization using readily available substrates including 2-formylbenzonitriles, phenylacetylenes and diaryliodonium salts. Our reaction operates under simple conditions with broad functional group compatibility, and is applicable to various phenylacetylenes and diaryliodonium salts. A wide range of 3-(2-oxopropyl)-2-arylisoindolinone derivatives is obtained in good yields under simple reaction conditions. Further applications of this methodology are being pursued in our laboratory.

Experimental section

General information

All reactions were carried out under an air atmosphere. Reagents were purchased from Aldrich, Acros, or Alfa. The diaryliodonium salts 2 were prepared according to the literature.^53,54 Flash column chromatography was performed using silica gel (200–300 mesh). Analytical thin-layer chromatography was performed using glass plates precoated with 200–300 mesh silica gel impregnated with a fluorescent indicator (254 nm). Nuclear magnetic resonance (NMR) spectra were recorded in CDCl₃ on Bruker NMR-300 (300 MHz), NMR-400(400 MHz), or NMR-500 (500 MHz) spectrometer with tetramethylsilane (TMS) as an internal reference.

Preparation of Compounds 4; general procedure

A solution of 2-formylbenzonitrile 1 (0.3 mmol), terminal alkyne 2 (0.6 mmol), diaryliodonium salt 3 (0.45 mmol), TfOH (0.45 mmol), and Cu(OTf)₂ (0.03 mmol, 10 mol%) in DCE (2 mL) was stirred at 110°C for 2 h under nitrogen. After completion of the reaction (thin layer chromatography (TLC) monitoring), the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE, 1:4–1:2) to afford the pure product 4.

All the products are known and their structures were confirmed by NMR spectral comparison with literature data.^14,47,55

2-(4-Bromophenyl)-3-(2-oxo-2-phenylethyl)isoindolin-1-one ( 4a ):⁴⁷ yield: 99.79 mg (79%); white solid m.p. 150–153°C (lit.¹⁴ 150–151°C). ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.92 (m, 1H), 7.89–7.86 (m, 2H), 7.61–7.53 (m, 8H), 7.45–7.40 (m, 2H), 5.97 (dd, J = 9.2, 3.0 Hz, 1H), 3.51 (dd, J = 17.6, 3.0 Hz, 1H), 3.27–3.19 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.5, 166.6, 145.1, 136.1, 135.7, 133.9, 132.4, 132.2, 131.5, 128.8, 128.2, 124.3, 123.2, 118.8, 56.7, 41.8.

2-(4-Bromophenyl)-3-[2-(4-fluorophenyl)-2-oxoethyl]isoin dolin-1-one ( 4b ):⁴⁷ yield: 95.18 mg (75%); white solid m.p. 140–143°C (lit.⁵⁶ 141–143°C). ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.88 (m, 3H), 7.55–7.52 (m, 7H), 7.12 (t, J = 8.2 Hz, 2H), 5.96–5.94 (m, 1H), 3.49 (dd, J = 10.0, 3.0 Hz, 1H), 3.23–3.17 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 195.8, 166.9, 165.5 (d, J = 254.8 Hz), 144.9, 135.8, 132.7, 132.4, 131. 130.8 (d, J = 10.0 Hz), 128.9, 124.5 (d, J = 17.4 Hz), 123.1, 118.7, 115.9 (d, J = 21.8 Hz), 56.6, 41.6. ¹⁹F NMR (282 MHz, CDCl₃) δ -103.4.

2-(4-Bromophenyl)-3-[2-(4-chlorophenyl)-2-oxoethyl]iso indolin-1-one ( 4c ):⁴⁷ yield: 90.87 mg (69%); white solid m.p. 152–153°C (lit.⁵⁶ 152–154°C). ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.56–7.48 (m, 7H), 7.42 (d, J = 8.2 Hz, 2H), 5.98–5.94 (m, 1H), 3.52–3.47 (m, 1H), 3.23–3.17 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 196.3, 166.9, 144.8, 140.4, 135.7, 134.5, 132.8, 132.5, 131.5, 129.1, 128.9, 123.3, 118.6, 56.6, 41.8.

2-(4-Bromophenyl)-3-[2-(4-bromophenyl)-2-oxoethyl]iso indolin-1-one ( 4d ):⁴⁷ yield: 94.18 mg (65%); white solid m.p. 158–161°C. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.61–7.49 (m, 9H), 5.97–5.94 (m, 1H), 3.49 (dd, J = 10.0, 3.0 Hz, 1H), 3.23–3.16 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 196.5, 166.8, 144.8, 135.7, 134.8, 132.6, 132.5, 132.3, 131.6, 129.6, 129.2, 128.9, 124.5, 123.2, 118.7, 56.6, 41.8.

2-(4-Bromophenyl)-3-{2-oxo-2-[4-(trifluoromethyl)phenyl] ethyl}isoindolin-1-one ( 4e ):⁴⁷ yield: 92.24 mg (65%); white solid m.p. 130–132°C (lit.⁵⁶ 130–132°C). ¹H NMR (400 MHz, CDCl₃) δ 7.98–7.95 (m, 3H), 7.72 (d, J = 8.2 Hz, 2H), 7.60–7.50 (m, 7H), 5.98–5.95 (m, 1H), 3.54 (dd, J = 17.9, 2.8 Hz, 1H), 3.26 (dd, J = 17.9, 9.2 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 196.6, 166.7, 144.7, 132.6, 132.4, 129.1, 128.4, 124.4, 122.9, 118.8, 56.5, 42.1. ¹⁹F NMR (470 MHz, CDCl₃) δ -63.2.

2-(4-Bromophenyl)-3-[2-(4-nitrophenyl)-2-oxoethyl]isoin dolin-1-one ( 4f ):⁴⁷ yield: 97.20 mg (72%); yellow solid m.p. 162–166°C ¹H NMR (400 MHz, CDCl₃) δ 8.30–8.28 (m, 2H), 8.03–7.96 (m, 3H), 7.61–7.50 (m, 7H), 5.98–5.94 (m, 1H), 3.57 (dd, J = 17.9, 2.9 Hz, 1H), 3.28 (dd, J = 17.9, 9.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 196.1, 168.7, 150.7, 144.5, 144.4, 135.6, 132.4, 131.5, 129.3, 124.5, 124.0, 122.9, 118.9, 58.5, 42.5.

2-(4-Bromophenyl)-3-(2-oxo-2-p-tolylethyl)isoindolin-1-one ( 4g ):⁴⁷ yield: 101.83 mg (81%); white solid m.p. 140–143°C (lit.⁵⁶ 141–143°C). ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.93 (m, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.59–7.53 (m, 7H), 7.25–7.24 (m, 2H), 5.98–5.95 (m, 1H), 3.49 (dd, J = 9.5, 2.9 Hz, 1H), 3.22(dd, J = 18.0, 10.0 Hz, 1H), 2.41 (s, 3H). ¹³ C NMR (125 MHz, CDCl₃) δ 197.1, 166.9, 145.1, 144.9, 135.8, 133.7, 132.6, 132.4, 131.5, 129.5, 128.8, 128.0, 124.2, 124.3, 123.3, 118.6, 56.7, 41.7, 21.7.

2-(4-Bromophenyl)-3-(2-oxo-2-o-tolylethyl)isoindolin-1-one ( 4h ):⁴⁷ yield: 99.31 mg (79%); white solid m.p. 145–149°C ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 7.3 Hz, 1H), 7.60–7.53 (m, 7H), 7.46–7.35 (m, 2H), 7.28–7.25 (m, 1H), 7.18 (t, J = 7.8 Hz, 1H), 5.95–5.91 (m, 1H), 3.47 (dd, J = 10.0, 3.0 Hz, 1H), 3.22–3.16 (m, 1H), 2.54 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 200.7, 166.8, 145.3, 138.9, 136.5, 135.7, 132.6, 132.4, 132.3, 131.7, 128.8, 125.7, 124.5, 124.4, 123.0, 118.7, 56.8, 44.3, 21.6.

2-(4-Bromophenyl)-3-[2-(naphthalen-1-yl)-2-oxoethyl] isoindolin-1-one ( 4i ):⁴⁷ yield: 116.04 mg (85%); white solid m.p. 159–162°C ¹H NMR (400 MHz, CDCl₃) δ 8.64 (d, J = 8.3 Hz, 1H), 8.00–7.98 (d, J = 8.1 Hz, 1H), 7.94–7.86 (m, 2H), 7.67–7.52 (m, 10H), 7.42–7.37 (m, 1H), 6.03–5.99 (m, 1H), 3.64–3.57 (m, 1H), 3.40–3.41 (m, 1H). ¹³C NMR (125 MHz, CDCl3) δ 200.98, 166.7, 144.9, 135.7, 134.2, 133.7, 132.7, 132.5, 131.7, 130.2, 128.9, 128.6, 128.4, 126.8, 125.4, 124.7, 124.2, 124.1, 123.0, 118.8, 57.2, 44.8.

2-(4-Bromophenyl)-3-(2-oxo-2-(2,3,4,5-tetrafluorophenyl) ethyl)isoindolin-1-one ( 4j ):⁴⁷ yield: 107.33 mg (75%); white solid m.p. 153–156°C ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.93 (m, 1H), 7.58–7.47 (m, 8H), 5.90–5.86 (m, 1H), 3.55–3.48 (m, 1H), 3.23–3.14 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 192.1, 166.7, 144.6, 132.7, 132.5, 131.6, 129.1, 124.8, 124.5, 122.7, 119.1, 111.3, 56.7, 46.6. ¹⁹F NMR (470 MHz, CDCl₃) δ -133.7–133.9 (m), -135.8–136.1 (m), -145.0–145.3 (m), -152.3–152.6 (m).

2-(4-Bromophenyl)-3-[2-oxo-2-(thiophen-2-yl)ethyl]isoindo lin-1-one ( 4k ):⁴⁷ yield: 64.11 mg (52%); white solid m.p. 147–152°C ¹H NMR (300 MHz, CDCl₃) δ 7.95–7.92(m, 1H), 7.68 (dd, J = 4.8, 1.2 Hz, 1H), 7.56–7.52 (m, 8H), 7.08 (dd, J = 4.8, 3.8 Hz, 1H), 5.91 (dd, J = 9.2, 3.3 Hz, 1H), 3.45 (dd, J = 4.8, 3.8 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 190.0, 167.0, 144.7, 143.4, 135.7, 134.8, 132.6, 132.5, 132.3, 128.9, 128.4, 124.5, 124.3, 123.2, 118.8, 56.6, 42.3.

3-(2-Oxo-2-phenylethyl)-2-phenylisoindolin-1-one ( 4l ): ⁵⁵ yield: 89.31 mg (91%); white solid m.p. 165–168°C (lit.⁵⁵ 165–167°C). ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.95 (m, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.68–7.65 (m, 2H), 7.61–7.45 (m, 8H), 7.24 (d, J = 7.5 Hz, 1H), 6.04–6.01 (m, 1H), 3.57–3.53 (m, 1H), 3.27–3.20 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.7, 166.9, 145.2, 136.6, 136.3, 133.8, 132.4, 131.8, 129.4, 128.1, 125.6, 124.2, 123.2, 56.8, 41.9.

2-(4-Fluorophenyl)-3-(2-oxo-2-phenylethyl)isoindolin-1-one ( 4m ): ¹⁴ yield: 80.76 mg (78%); white solid m.p. 154–155°C (lit.¹⁴ 154–155°C). ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 8.5 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.57–7.45 (m, 8H), 7.14 (t, J = 8.0 Hz, 2H), 5.96–5.94 (m, 1H), 3.51–3.47 (m, 1H), 3.28–3.20 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.6, 166.8, 160.3 (d, J = 244.3 Hz), 145.2, 136.3, 133.9, 132.5, 131.6, 128.8, 128.7, 128.1, 125.2 (d, J = 8.2 Hz), 124.4, 123.4, 116.4 (d, J = 22.5 Hz), 57.3, 41.89. ¹⁹F NMR (470 MHz, CDCl₃) δ -115.9.

2-(4-Chlorophenyl)-3-(2-oxo-2-phenylethyl)isoindolin-1-one ( 4n ):⁵⁵ yield: 85.56 mg (79%); white solid m.p. 170–173°C (lit.⁵⁵ 171–172°C). ¹H NMR (400 MHz, CDCl₃) δ 7.94–7.92 (m, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.83–7.52 (m, 6H), 7.42 (t, J = 7.6 Hz, 2H), 7.40–7.38 (m, 2H), 5.96 (d, J = 7.2 Hz, 1H), 3.55–3.49 (m, 1H), 3.27–3.20 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.5, 166.9, 145.1, 135.2, 133.9, 132.6, 131.5, 130.9, 129.4, 128.8, 128.1, 124.2, 123.2, 56.8, 41.8.

3-(2-Oxo-2-phenylethyl)-2-p-tolylisoindolin-1-one ( 4o ):⁵⁵ yield: 83.92 mg (82%); white solid m.p. 179–182°C (lit.⁵⁵ 179–180°C). ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.94 (m, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.59–7.51 (m, 6H), 7.44 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 6.5 Hz, 2H), 5.97–5.95 (m, 1H), 3.56–3.52 (m, 1H), 3.24–3.17 (m, 1H), 2.36 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 197.7, 166.9, 145.2, 136.3, 135.6, 133.9, 133.7, 129.9, 128.7, 128.2, 123.6, 57.1, 41.8, 20.8.

2-(4-Methoxyphenyl)-3-(2-oxo-2 phenylethyl)isoindolin-1-one ( 4p ):⁵⁵ yield: 88.93 mg (83%); white solid m.p. 167–168°C (lit.⁵⁵ 166–168°C). ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.93 (m, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.54–7.50 (m, 6H), 7.43 (t, J = 7.6 Hz, 2H), 6.97–6.95 (m, 2H), 5.90–5.98 (m, 1H), 3.82 (s, 3H), 3.53–3.48 (m, 1H), 3.23–3.16 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.7, 166.9, 157.6, 145.2, 136.4, 133.7, 132.2, 131.9, 128.7, 128.2, 125.4, 124.1, 123.2, 114.6, 57.5, 55.5, 41.9.

3-(2-Oxo-2-phenylethyl)-2-(4-trifluoromethylphenyl)iso indolin-1-one ( 4q ):⁴⁷ yield: 82.97 mg (70%); white solid m.p. 151–153°C (lit.⁵⁶ 151–153°C). ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.96 (m, 1H), 7.88–7.82 (m, 4H), 7.70–7.67 (m, 2H), 7.62–7.54 (m, 4H), 7.44 (t, J = 7.4 Hz, 2H), 6.06 (dd, J = 9.6, 3.0 Hz, 1H), 3.52 (dd, J = 17.9, 3.0 Hz, 1H), 3.25 (dd, J = 18.0, 10.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.4, 167.1, 145.1, 139.9, 136.1, 133.9, 132.9, 131.3, 128.9, 128.8, 128.2, 126.6, 124.5, 123.2, 122.3, 56.6, 41.7. ¹⁹F NMR (470 MHz, CDCl₃) δ -62.3.

2-(4-Bromophenyl)-5-fluoro-3-(2-oxo-2-phenylethyl)iso indolin-1-one ( 4r ):⁴⁷ yield: 83.76 mg (66%); white solid m.p. 145–148°C ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 8.0 Hz, 2H), 7.60–7.53 (m, 7H), 7.46 (t, J = 7.6 Hz, 2H), 7.25–7.22 (m, 1H), 5.93–5.91 (m, 1H), 3.56–3.52 (m, 1H), 3.24–3.17 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.4, 165.8, 163.1 (d, J = 260.3 Hz), 140.5, 136.1, 135.4 (d, J = 8.7 Hz), 132.5, 128.9, 128.1, 124.5, 120.1, 119.9, 119.0, 110.7 (d, J = 23.4 Hz), 56.6, 41.7. ¹⁹F NMR (470 MHz, CDCl₃) δ -111.8.

2-(4-Bromophenyl)-5-chloro-3-(2-oxo-2-phenylethyl)iso indolin-1-one ( 4s ):⁴⁷ yield: 100.09 mg (76%); white solid m.p. 153–158°C ¹H NMR (400 MHz, CDCl₃) δ 7.90–7.86 (m, 3H), 7.64–7.44 (m, 9H), 5.95–5.92 (m, 1H), 3.59–3.55 (m, 1H), 3.26–3.18 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 197.1, 165.8, 146.7, 139.1, 135.9, 135.4, 134.2, 132.6, 130.0, 129.6, 128.8, 128.2, 125.3, 124.5, 123.9, 118.8, 56.3, 41.7.

2-(4-Bromophenyl)-5-methoxy-3-(2-oxo-2-phnylethyl)iso indolin-1-one ( 4t ):⁴⁷ yield: 103.11 mg (79%); white solid m.p. 155–157°C ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 7.7 Hz, 2H), 7.83 (d, J = 7.8 Hz, 1H), 7.60–7.51 (m, 5H), 7.48 (t, J = 7.8 Hz, 2H), 7.02–6.97 (m, 2H), 5.88 (d, J = 7.4 Hz, 1H), 3.80 (s, 3H), 3.53 (dd, J = 17.6, 2.5 Hz, 1H), 3.23 (dd, J = 17.7, 8.7 Hz, 1H).¹³C NMR (125 MHz, CDCl₃ δ 197.7, 166.7, 163.6, 147.2, 136.4, 136.1, 133.8, 132.3, 128.8, 128.2, 125.6, 124.1, 123.9, 118.3, 115.7, 107.9, 56.3, 55.7, 41.8.