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. 2022 May 25;27(11):3393. doi: 10.3390/molecules27113393

Cu(I)/Pd(II)-Catalyzed Intramolecular Hydroamidation and C-H Dehydrogenative Coupling of ortho-Alkynyl-N-arylbenzamides for Access to Isoindolo[2,1-a]Indol-6-Ones

Baoxin Tang 1, Ruimao Hua 1,2,*
Editor: Roman Dembinski
PMCID: PMC9181885  PMID: 35684329

Abstract

An efficient, atom-economic and one-pot synthesis of isoindolo[2,1-a]indol-6-ones via CuI/Pd(OAc)2-catalyzed intramolecular hydroamidation of alkynyl group, and C-H dehydrogenative coupling of ortho-alkynyl-N-arylbenzamides has been developed. This transformation occurs with the use of oxygen as the oxidant, and water is the only by-product. The reaction shows a high tolerance to a variety of functional groups, and affords isoindolo[2,1-a]indol-6-ones in good to high yields.

Keywords: ortho-alkynyl-N-arylbenzamide; C-H dehydrogenative coupling; hydroamidation of alkyne; isoindolo[2,1-a]indol-6-one

1. Introduction

Indole alkaloids are the important class of nitrogen-heterocyclic compounds with interesting physiological and biological activities in natural products, medicines, and agrochemicals [1,2,3]. Among them, 6H-isoindolo[2,1-a]indol-6-ones, a tetracyclic fused indole and isoindoline ring system, have received increasing attention due to their highly potential application with anticancer activity [4,5], affinity for hNK1 receptor [6], affinity for the melatonin binding site MT3 [7] (Figure 1), and used as a precursor for the synthesis of NorA pump inhibitors [8,9]. Therefore, there has been increasing interest in the developments of the efficient methodologies for the synthesis of 6H-isoindolo[2,1-a]indol-6-ones [10].

Figure 1.

Figure 1

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Representative structures of 6H-isoindolo[2,1-a]-indol-6-ones.

In the reported procedures, there are two reaction systems for the synthesis of 6H-isoindolo[2,1-a]indol-6-ones starting from ortho-alkynyl-N-arylbenzamides (Figure 1) [11,12]. One is the hypervalent iodine, PhI(OAc)2 (PIDA)-mediated intramolecular cascade oxidative cyclization of ortho-(1-arylethynyl)-N-arylbenzamides affording 11-aryl-6H-isoindolo[2,1-a]indol-6-ones at room temperature in trifluoroethanol (TFE), but Ar1 groups are limited to phenyl and electron-rich aryl groups (Scheme 1, Equation (1)) [11]. The other is CuI-catalyzed radical cascade cyclization of ortho-alkynyl-N-arylbenzamides in the presence of di-t-butyl peroxide (DTBP) in t-BuCN at 120~140 °C giving three products of 6H-isoindolo[2,1-a]indol-6-ones (Scheme 1, Equation (2)) [12].

Scheme 1.

Scheme 1

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6H-Isoindolo[2,1-a]indol-6-ones from ortho-alkynyl-N-arylbenzamides.

In recent years, we have been interested in the applications of ortho-alkynyl aromatic aldehydes/ketones [13] and functionalized benzamides [14,15] in the synthesis of hetero-/carbo-cyclic compounds. Therefore, in continuation of our interests in development of synthetic methods for the synthesis of nitrogen-heterocyclic compounds via alkyne annulations [16,17,18], we herein describe a CuI/Pd(OAc)2-catalyzed formation of 11-aryl-6H-isoindolo-[2,1-a]-indol-6-ones bearing different functional group(s) from ortho-(1-arylethynyl)-N-arylbenzamides by the stepwise hydroamidation of the alkynyl group [19], and C-H dehydrogenative coupling reaction [20] with the use of O2 as the oxidant (Scheme 1, Equation (3)).

2. Results and Discussion

As the designed reaction shows in Scheme 1, the construction of 6H-isoindolo-[2,1-a]indol-6-ones from ortho-(1-arylethynyl)-N-arylbenzamides includes the hydroamidation of alkynyl group, and the C-H oxidative dehydrocoupling reaction. Our initial studies focused on optimizing the reaction conditions for the intramolecular hydroamidation of ortho-(1-arylethynyl)-N-arylbenzamides (1a) under N2 atmosphere at 80 °C with the use of different catalysts, solvents, and additives (Table 1). When FeCl3, Cu(OAc)2, Pd(OAc)2, and CuI were used as the catalysts (entries 1–4), CuI shows the highest catalytic activity in DMF to catalyze the hydroamidation giving 38% yield of (Z)-3-benzylidene-2-phenylisoindolin-1-one (2a), which is a known compound, and its X-ray diffraction studies confirm the structure unambiguously [21]. The use of DMSO, MeCN, NMP, 1,4-dioxane, and toluene as the solvents to replace DMF resulted in the decrease of yields (entries 5–9). The addition of nitrogen-containing ligands could improve the catalytic activity of CuI in DMF, and the yield was up to 92% with the use of L-proline (entries 10–12). In addition, it has been found that CuCl and CuBr prove less effective in DMF with the use of L-proline as the ligand (entries 13–14).

Table 1.

Optimizing reaction conditions for hydroamidation a.

graphic file with name molecules-27-03393-i001.jpg
Entry Catalyst Ligand Solvent Yield (%) b
1 FeCl3 - DMF 0
2 Cu(OAc)2 - DMF 0
3 Pd(OAc)2 - DMF 0
4 CuI - DMF 38
5 CuI - DMSO 35
6 CuI - MeCN 18
7 CuI - NMP <5
8 CuI 1,4-dioxane 12
9 CuI - toluene 20
10 CuI 1,10-phen DMF 72
11 CuI TMEDA DMF 51
12 CuI L-proline DMF 92
13 CuCl L-proline DMF 80
14 CuBr L-proline DMF 82
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a Reactions were carried out using 1a (0.5 mmol), catalyst (5 mol %, 0.025 mmol), ligand (15 mol %, 0.075 mmol), solvent (1.0 mL), in N2, at 80 °C for 6 h. b Isolated yields.

After the reaction was finished under the conditions indicated in entry 12 of Table 1, a catalytic amount of Pd(OAc)2 (5 mol %) was directly added to the reaction mixture to promote the oxidative C-H dehydrogenative coupling reaction with the use of different oxidants and additional solvent. As shown in Table 2, with the addition of HOAc as the additional solvent, and oxygen (1 atm), 1,4-benzoquinone, K2S2O8, or Cu(OAc)2 as the oxidants, the desired 11-phenyl-6H-isoindolo- [2,1-a]indol-6-one (2aaa) was formed, and the green oxidant oxygen exhibits the best result (entries 1–4). The use of p-TsOH and TFA to replace HOAc could significantly improve the yields of 2aaa (entries 5–6). These results could be explained by the AcO- group being replaced by TsO- or CF3COO- groups to increase the electrophilicity of the Pd(II) center to enhance the catalytic activity for activation of aromatic C-H bond [22,23]. However, either increasing or decreasing the reaction temperature could not further improve the yield of 2aaa (entries 7–8).

Table 2.

Optimizing conditions for C-H oxidative dehydrocoupling reaction a.

graphic file with name molecules-27-03393-i002.jpg
Entry Oxidant Additive Temp (°C) Yield (%) b
1 O2 HOAc 80 51
2 c 1,4-benzoquinone HOAc 80 40
3 c K2S2O8 HOAc 80 <5
4 c Cu(OAc)2 HOAc 80 16
5 d O2 p-TsOH 80 78
6 O2 TFA 80 83
7 O2 TFA 100 76
8 O2 TFA 60 58
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a Reaction conditions: (1) 1a (0.5 mmol), CuI (5 mol %, 0.025 mmol), L-proline (15 mol %, 0.075 mmol), DMF (1.0 mL), in N2, at 80 °C for 6 h; (2) Pd(OAc)2 (5 mol %), O2 (1 atm), additional solvent (1.0 mL), temp., 18 h. b Isolated yields. c Oxidant (3.0 equiv). d p-TsOH (~30 equiv).

The combined reaction conditions shown in entry 12 of Table 1 and entry 6 of Table 2 were then used to investigate the scope and generality of isoindolo[2,1-a]indol-6-one formation with the use of various substrates bearing electron-donating and electron-withdrawing groups in the aromatic rings. Based on the results shown in Scheme 2, several features of the relationship between electron effect or steric effect and yields can be concluded: (1) Substrates with either electron-rich Ar or electron-rich Ar1 ring afford the corresponding products in relatively high yields (e.g., 2aab, 2acc, 2aad vs. 2aae, 2aga, 2aha, 2aia). (2) When both Ar and Ar1 were electron-rich groups, the desired products were obtained in high isolated yields (e.g., 2adb, 2aeb, 2afb, 2afd). (3) The steric effect is of importance to affect the reactivity, Ar ring bearing ortho-methyl group decreases the reactivity to some extent, giving the products in relatively low yields compared to the substrates with para-methyl-substituted Ar rings (2aba, 2abb vs. 2ada, 2adb). (4) The reactions of the substrates having either electron-donating group (OMe) or electron-withdrawing group (F) in Ar2 ring produced the expected products in 73% (2baa) and 77% (2caa), respectively. (5) Under the standard reaction conditions, it shows a good tolerance to a variety of valuable and important functional groups in aromatic rings: the aromatic C(sp2)-Cl, C(sp2)-F bonds, and CF3, CN functional groups in the obtained products (2aae, 2aga, 2aha, 2aia, 2afe, 2aff, 2agb, 2ahb, 2aib, 2caa) have highly potential applications in further transformations.

Scheme 2.

Scheme 2

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Substrate scope of isoindolo[2,1-a]indol-6-one synthesis.

The isolated 2a could be completely converted into 2aaa in the presence of Pd(OAc)2 under oxygen atmosphere in a solvents mixture of TFA and DMF (1:1 in volume) at 80 °C for 18 h, confirming that 2a is an intermediate in the formation of 2aaa (Equation (4)). In addition, a large kinetic isotope effect (KIE, kH/kD) of 4.9 was observed in the oxidative C-H/C-H and C-H/C-D dehydrogenative coupling reactions for the formation of 2ada and 2ada-d5 from the corresponding intermediates (Equation (5)), indicating that the activation of C-H bond and their coupling reaction may be the rate-limiting step in the stepwise transformation.

3. Materials and Methods

3.1. General Methods

All commercial reagents are analytically pure and were used directly without further purification. Nuclear magnetic resonance (NMR) spectra were recorded on an ECA-400 spectrometer (JEOL, Tokyo, Japan) using CDCl3 as solvent at 298 K. 1H NMR (400 MHz) chemical shifts (δ) were referenced to internal standard TMS (for 1H, δ = 0.00 ppm). 13C NMR (101 MHz) chemical shifts were referenced to internal solvent CDCl3 (for 13C, δ = 77.16 ppm). The high-resolution mass spectra (HRMS) were obtained on a micrOTOF-Q II spectrometer (Agilent, California, CA, USA) with electron spray ionization (ESI), or on a FT-ICR-MS spectrometer (Solarix Bruker, Bremen, Germany) with Matrix-Assisted Laser Desorption Ionization (MALDI). Single crystals of 2a were obtained by slow evaporation of their solution in a mixture solvent of CHCl2 and petroleum ether (1:3 in volume). ortho-(1-Arylethynyl)-N-arylbenzamides (substrates) were prepared according to a modified literature method [24], and the characterization data of new substrates are reported below. All the NMR charts for the prepared starting materials, and the products are reported in the Supplementary Materials.

3.2. Characterization Data of Substrates

N-Phenyl-ortho-(o-tolylethynyl)benzamide (1aba). White solid, mp 115–117 °C. 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.09−8.06 (m, 1H), 7.63−7.62 (m, 3H), 7.49–7.42 (m, 3H), 7.33–7.20 (m, 4H), 7.17–7.09 (m, 2H), 2.42 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.7, 140.6, 138.0, 136.0, 133.6, 132.1, 130.9, 130.2, 129.9, 129.4, 129.1, 129.0, 125.9, 124.6, 121.7, 120.1, 120.0, 95.6, 91.0, 20.8; HRMS (ESI) m/z: [M + Na]+ calcd for C22H17NONa 334.1202; found 334.1202.

N-Phenyl-ortho-(m-tolylethynyl)benzamide (1aca). White solid, mp 106–108 °C. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.07–8.05 (m, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.60–7.57 (m, 1H), 7.45–7.38 (m, 2H), 7.33–7.25 (m, 4H), 7.22–7.09 (m, 3H), 2.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.6, 138.4, 138.1, 136.1, 133.4, 132.4, 130.9, 130.3, 130.2, 129.1, 129.0, 128.8, 128.5, 124.5, 121.7, 120.1, 119.8, 96.9, 87.0, 21.2; HRMS (ESI) m/z: [M + Na]+ calcd for C22H17NONa 334.1202; found 334.1201.

N-Phenyl-ortho-((p-propylphenyl)ethynyl)benzamide (1aea). White solid, mp 115–117 °C. 1H NMR (400 MHz, CDCl3) δ 9.30 (s, 1H), 8.12–8.09 (m, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.61–7.59 (m, 1H), 7.46–7.41 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.15–7.09 (m, 3H), 2.58 (t, J = 7.6 Hz, 2H), 1.68–1.58 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.5, 144.5, 138.1, 135.8, 133.5, 131.7, 130.9, 130.4, 129.1, 128.9, 128.9, 124.5, 120.1, 119.9, 119.1, 97.1, 86.8, 38.1, 24.3, 13.8; HRMS (ESI) m/z: [M + Na]+ calcd for C24H21NONa 362.1515; found 362.1515.

ortho-((p-Fluorophenyl)ethynyl)-N-phenylbenzamide (1aga). White solid, mp 153–155 °C. 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.10–8.07 (m, 1H), 7.66–7.61 (m, 3H), 7.50–7.43 (m, 4H), 7.34 (t, J = 7.2 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.06–7.01 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 164.6, 163.2 (d, JC-F = 252.5 Hz), 138.1, 136.3, 133.8 (d, JC-F = 8.1 Hz), 133.5, 131.0, 130.3, 129.3, 124.7, 120.0, 119.6, 118.1 (d, JC-F = 4.0 Hz), 116.2 (d, JC-F = 22.2 Hz), 95.5, 87.1; HRMS (ESI) m/z: [M + H]+ calcd for C21H15FNO 316.1132; found 316.1132.

ortho-((p-Chlorophenyl)ethynyl)-N-phenylbenzamide (1aha). White solid, mp 146–148 °C. 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.05–8.02 (m, 1H), 7.66–7.59 (m, 3H), 7.49–7.43 (m, 2H), 7.39–7.28 (m, 6H), 7.14 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 164.7, 138.0, 136.4, 135.5, 133.5, 133.0, 131.0, 130.2, 129.3, 129.2, 129.1, 124.7, 120.5, 120.0, 119.4, 95.2, 88.2; HRMS (ESI) m/z: [M + H]+ calcd for C21H15ClNO 332.0837; found 332.0836.

N-Phenyl-ortho-((p-(trifluoromethyl)phenyl)ethynyl)benzamide (1aia). White solid, mp 143–145 °C. 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.95–7.91 (m, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.60–7.57 (m, 1H), 7.56–7.48 (m, 4H), 7.46–7.38 (m, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.13 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 164.9, 138.0, 137.1, 133.5, 132.0, 130.8, 130.7 (q, JC-F = 32.3 Hz), 129.9, 129.5, 129.2, 125.5 (q, JC-F = 3.0 Hz), 124.7, 123.8 (q, JC-F = 273.7 Hz), 120.0, 119.2, 94.4, 89.4; HRMS (ESI) m/z: [M + Na]+ calcd for C22H14F3NONa 388.0920; found 388.0919.

ortho-([1,1′-Biphenyl]-4-ylethynyl)-N-phenylbenzamide (1aja). White solid, mp 141–143 °C. 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.13–8.10 (m, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.66–7.63 (m, 1H), 7.60–7.51 (m, 6H), 7.49–7.42 (m, 4H), 7.38–7.31 (m, 3H), 7.13 (t, J = 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 164.6, 142.1, 140.1, 138.1, 136.1, 133.6, 132.2, 131.0, 130.4, 129.2, 129.2, 129.0, 128.0, 127.4, 127.1, 124.6, 120.8, 120.1, 119.7, 96.6, 88.0; HRMS (ESI) m/z: [M + H]+ calcd for C27H20NO 374.1539; found 374.1539.

N-(p-Tolyl)-ortho-(o-tolylethynyl)benzamide (1abb). White solid, mp 98–100 °C. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.54–7.49 (m, 3H), 7.39–7.27 (m, 3H), 7.22–7.17 (m, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.10–7.02 (m, 3H), 2.37 (s, 3H), 2.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.6, 140.3, 136.2, 135.5, 133.8, 133.2, 131.9, 130.4, 129.6, 129.6, 129.4, 129.1, 128.6, 125.6, 121.8, 120.0, 119.9, 95.0, 91.0, 20.8, 20.6; HRMS (ESI) m/z: [M + Na]+ calcd for C23H19NONa 348.1359; found 348.1358.

N-(p-Tolyl)-ortho-(m-tolylethynyl)benzamide (1acb). White solid, mp 119–121 °C. 1H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.06–8.04 (m, 1H), 7.58–7.53 (m, 3H), 7.43–7.36 (m, 2H), 7.28–7.25 (m, 2H), 7.22–7.13 (m, 2H), 7.10 (d, J = 8.0 Hz, 2H), 2.30 (s, 3H), 2.26 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.4, 138.3, 136.1, 135.5, 134.0, 133.4, 132.4, 130.7, 130.2, 130.1, 129.5, 128.9, 128.7, 128.5, 121.7, 120.1, 119.7, 96.7, 87.1, 21.2, 20.9; HRMS (ESI) m/z: [M + H]+ calcd for C23H20NO 326.1539; found 326.1539.

N-(p-Tolyl)-ortho-(p-tolylethynyl)benzamide (1adb). White solid, mp 125–127 °C. 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.13–8.09 (m, 1H), 7.61–7.58 (m, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.44–7.41 (m, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.13 (t, J = 8.0 Hz, 4H), 2.36 (s, 3H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 139.7, 135.8, 135.6, 134.1, 133.5, 131.7, 130.8, 130.4, 129.6, 129.5, 128.9, 120.1, 119.8, 118.9, 96.9, 86.9, 21.7, 21.0; HRMS (ESI) m/z: [M + Na]+ calcd for C23H19NONa 348.1359; found 348.1358.

ortho-((p-Propylphenyl)ethynyl)-N-(p-tolyl)benzamide (1aeb). White solid, mp 116–118 °C. 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.95 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.2 Hz, 1H), 7.34–7.23 (m, 4H), 7.04 (t, J = 8.0 Hz, 4H), 2.51 (t, J = 7.6 Hz, 2H), 2.26 (s, 3H), 1.62–1.52 (m, 2H), 0.89 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 143.9, 135.8, 135.5, 133.6, 133.1, 131.4, 130.4, 129.8, 129.3, 128.5, 128.4, 119.9, 119.7, 119.0, 96.5, 86.7, 37.7, 24.1, 20.7, 13.6; HRMS (ESI) m/z: [M + H]+ calcd for C25H24NO 354.1852; found 354.1852.

ortho-((p-Methoxyphenyl)ethynyl)-N-(p-tolyl)benzamide (1afb). White solid, mp 105–107 °C. 1H NMR (400 MHz, CDCl3) δ 9.28 (s, 1H), 8.11–8.08 (m, 1H), 7.59–7.53 (m, 3H), 7.44–7.36 (m, 4H), 7.11 (d, J = 7.6 Hz, 2H), 6.86–6.83 (m, 2H), 3.79 (s, 3H), 2.31 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.3, 160.4, 135.7, 135.6, 134.0, 133.4, 133.3, 130.8, 130.3, 129.6, 128.7, 120.1, 119.9, 114.3, 113.9, 96.9, 86.3, 55.4, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for C23H20NO2 342.1489; found 342.1488.

ortho-((p-Fluorophenyl)ethynyl)-N-(p-tolyl)benzamide (1agb). White solid, mp 142–144 °C. 1H NMR (400 MHz, CDCl3) δ 9.02 (s, 1H), 8.05–8.02 (m, 1H), 7.60–7.57 (m, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.46–7.41 (m, 4H), 7.12 (d, J = 8.0 Hz, 2H), 7.01 (t, J = 8.4 Hz, 2H), 2.32 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.5, 163.1 (d, JC-F = 251.5 Hz), 136.4, 135.5, 134.2, 133.8 (d, JC-F = 9.1 Hz), 133.4, 130.8, 130.2, 129.7, 129.2, 120.0, 119.5, 118.2 (d, JC-F = 3.0 Hz), 116.1 (d, JC-F = 22.2 Hz), 95.3, 87.2, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for C22H17FNO 330.1289; found 330.1288.

ortho-((p-Chlorophenyl)ethynyl)-N-(p-tolyl)benzamide (1ahb). White solid, mp 155–157 °C. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.01–7.98 (m, 1H), 7.58–7.56 (m, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.43–7.40 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 3.32 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.5, 136.5, 135.5, 134.3, 133.5, 133.0, 130.9, 130.3, 129.8, 129.4, 129.1, 127.8, 120.6, 120.0, 119.4, 95.2, 88.3, 21.1; HRMS (ESI) m/z: [M + H]+ calcd for C22H17ClNO 346.0993; found 346.0993.

N-(p-Tolyl)-ortho-((p-(trifluoromethyl)phenyl)ethynyl)benzamide (1aib). White solid, mp 154–159 °C. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.97–7.94 (m, 1H), 7.61–7.51 (m, 7H), 7.45–7.40 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 2.32 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.7, 137.1, 135.4, 134.4, 133.5, 132.0, 130.8 (q, JC-F = 33.3 Hz), 130.7, 129.9, 129.7, 129.6, 126.0, 125.6 (q, JC-F = 3.0 Hz), 123.9 (q, JC-F = 273.7 Hz), 120.0, 119.1, 94.4, 89.5, 21.0; HRMS (ESI) m/z: [M + H]+ calcd for C23H17F3NO 380.1257; found 380.1256.

ortho-([1,1′-Biphenyl]-4-ylethynyl)-N-(p-tolyl)benzamide (1ajb). White solid, mp 216–218 °C. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.16–8.13 (m, 1H), 7.68–7.65 (m, 1H), 7.62–7.54 (m, 8H), 7.52–7.44 (m, 4H), 7.40–7.36 (m, 1H), 7.15 (d, J = 8.4 Hz, 2H), 2.33 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.4, 142.1, 140.1, 136.1, 135.6, 134.3, 133.6, 132.3, 131.0, 130.5, 129.8, 129.2, 129.1, 128.1, 127.4, 127.2, 120.8, 120.1, 119.7, 96.6, 88.1, 21.1; HRMS (ESI) m/z: [M + H]+ calcd for C28H22NO 388.1696; found 388.1695.

N-(p-Isopropylphenyl)-ortho-(phenylethynyl)benzamide (1aac). White solid, mp 105–107 °C. 1H NMR (400 MHz, CDCl3) δ 9.26 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 7.42–7.39 (m, 2H), 7.33–7.22 (m, 5H), 7.10 (d, J = 8.0 Hz, 2H), 2.89–2.78 (m, 1H), 1.21 (d, J = 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 164.5, 144.8, 136.2, 135.7, 133.2, 131.6, 130.4, 129.7, 129.0, 128.7, 128.4, 126.7, 121.9, 120.1, 119.6, 96.0, 87.3, 33.5, 23.9; HRMS (ESI) m/z: [M + Na]+ calcd for C24H21NONa 362.1515; found 362.1515.

N-(p-Cyanophenyl)-ortho-(phenylethynyl)benzamide (1aae). Pale yellow solid, mp 118–120 °C. 1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 8.13–8.10 (m, 1H), 7.79–7.75 (m, 2H), 7.68–7.65 (m, 1H), 7.61–7.57 (m, 2H), 7.53–7.46 (m, 4H), 7.43–7.35 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 164.8, 142.0, 135.0, 133.8, 133.5, 131.7, 131.6, 130.6, 129.8, 129.4, 128.9, 121.6, 119.9, 119.7, 118.9, 107.4, 97.2, 87.1; HRMS (ESI) m/z: [M + H]+ calcd for C22H15N2O 323.1179; found 323.1178.

N-(p-Cyanophenyl)-ortho-((p-methoxyphenyl)ethynyl)benzamide (1afe). Pale yellow solid, mp 165–167 °C. 1H NMR (400 MHz, CDCl3) δ 9.64 (s, 1H), 8.08–8.05 (m, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.62–7.55 (m, 3H), 7.50–7.37 (m, 4H), 6.90–6.86 (m, 2H), 3.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.8, 160.7, 142.1, 134.6, 133.5, 133.4, 133.3, 131.5, 130.4, 128.9, 120.1, 119.8, 118.9, 114.5, 113.4, 107.2, 97.5, 86.0, 55.5; HRMS (ESI) m/z: [M + H]+ calcd for C23H17N2O2 353.1285; found 353.1284.

ortho-((p-Methoxyphenyl)ethynyl)-N-(p-(trifluoromethyl)phenyl)benzamide (1aff). White solid, mp 130–132 °C. 1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.51 (t, J = 8.4 Hz, 3H), 7.40–7.30 (m, 4H), 6.84–6.81 (m, 2H), 3.78 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.9, 160.6, 141.3, 135.1, 133.4, 133.2, 133.1, 130.2, 128.7, 126.3 (q, JC-F = 4.0 Hz), 126.0 (q, JC-F = 32.3 Hz), 124.2 (q, JC-F = 272.7 Hz), 120.2, 119.7, 114.4, 113.7, 97.2, 86.1, 55.3; HRMS (ESI) m/z: [M + H]+ calcd for C23H17F3NO2 396.1206; found 396.1206.

p-Methoxy-N-phenyl-ortho-(phenylethynyl)benzamide (1baa). White solid, mp 163–165 °C. 1H NMR (400 MHz, CDCl3) δ 9.33 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 7.6 Hz, 2H), 7.52–7.49 (m, 2H), 7.39–7.28 (m, 5H), 7.13–7.08 (m, 2H), 6.99–6.96 (m, 1H), 3.85 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.1, 161.3, 138.3, 132.6, 131.8, 129.5, 129.1, 128.8, 128.2, 124.3, 121.7, 121.0, 120.0, 118.0, 115.5, 96.5, 87.5, 55.7; HRMS (ESI) m/z: [M + H]+ calcd for C22H18NO2 328.1332; found 328.1331.

p-Fluoro-N-phenyl-ortho-(phenylethynyl)benzamide (1caa). White solid, mp 164–166 °C. 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.09–8.06 (m, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.47–7.44 (m, 2H), 7.40–7.23 (m, 6H), 7.14–7.06 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 163.7, 163.6 (d, JC-F = 252.5 Hz), 138.0, 132.9 (d, JC-F = 10.1 Hz), 132.4 (d, JC-F = 3.0 Hz), 131.8, 129.7, 129.2, 128.8, 124.6, 121.9 (d, JC-F = 10.1 Hz), 120.1, 120.0, 119.8, 116.6 (d, JC-F = 21.2 Hz), 97.5, 86.2; HRMS (ESI) m/z: [M + H]+ calcd for C21H15FNO 316.1132; found 316.1132.

3.3. Typical Experimental Procedure for the Synthesis of 11-Phenyl-6H-Isoindolo[2,1-a]Indol-6-One (2aaa)

A mixture of N-phenyl-ortho-(phenylethynyl)benzamide (1aaa, 148.7 mg, 0.5 mmol), CuI (4.8 mg, 0.025 mmol), and L-proline (8.6 mg, 0.075 mmol) in DMF (1.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at 80 °C for 6 h under nitrogen atmosphere. After the reaction mixture was cooled to room temperature, Pd(OAc)2 (5.6 mg, 0.025 mmol) and TFA (1.0 mL) was added directly, and the obtained mixture was further heated at 80 °C for 18 h under oxygen atmosphere (1 atm). It was then poured into a solvent mixture of water (15.0 mL) and ethyl acetate (20.0 mL), and the two phases were then separated. The aqueous layer was extracted with ethyl acetate (3 × 15.0 mL). After the combined organic extracts were dried over MgSO4 overnight, the filtered solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate as eluent to afford 2aaa as a pale yellow solid (122.1 mg, 83%).

3.4. Characterization Data of Products

11-Phenyl-6H-isoindolo[2,1-a]indol-6-one (2aaa) [11]. Pale yellow solid (122 mg, 83% yield), mp 223–225 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.71–7.68 (m, 2H), 7.58–7.52 (m, 4H), 7.48–7.43 (m, 1H), 7.42–7.37 (m, 1H), 7.35–7.28 (m, 2H), 7.20–7.15 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.7, 134.8, 134.3, 134.1, 134.0, 133.9, 133.7, 132.3, 129.2, 129.1, 128.9, 128.4, 126.9, 125.5, 124.2, 121.4, 121.3, 120.7, 113.6; HRMS (MALDI) m/z: [M]+ calcd for C21H13NO 295.0092; found 295.0091.

11-(o-Tolyl)-6H-isoindolo[2,1-a]indol-6-one (2aba). Pale yellow solid (110.3 mg, 71% yield), mp 172–174 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.43–7.36 (m, 3H), 7.35−7.17 (m, 5H), 7.13−7.05 (m, 2H), 2.29 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6, 137.2, 135.0, 134.9, 134.7, 134.0, 133.6, 133.5, 131.2, 130.8, 130.3, 128.7, 128.6, 126.6, 126.1, 125.3, 124.0, 121.6, 121.5, 119.6, 113.5, 20.2; HRMS (MALDI) m/z: [M]+ calcd for C22H15NO 309.1149; found 309.1147.

11-(m-Tolyl)-6H-isoindolo[2,1-a]indol-6-one (2aca) [11]. Pale yellow solid (124.0 mg, 80% yield), mp 219–221 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.58–7.48 (m, 4H), 7.46–7.37 (m, 2H), 7.34–7.24 (m, 3H), 7.19–7.15 (m, 1H), 2.47 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.7, 138.9, 134.9, 134.2, 134.1, 134.0, 133.9, 133.7, 132.2, 129.7, 129.2, 129.1, 128.8, 126.9, 126.2, 125.5, 124.1, 121.5, 121.3, 120.9, 113.6, 21.7; HRMS (MALDI) m/z: [M]+ calcd for C22H15NO 309.1149; found 309.1152.

11-(p-Tolyl)-6H-isoindolo[2,1-a]indol-6-one (2ada) [11]. Pale yellow solid (133.9 mg, 87% yield), mp 174–176 °C. 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.57–7.53 (m, 3H), 7.51–7.49 (m, 1H), 7.38–7.30 (m, 3H), 7.29–7.23 (m, 2H), 7.16–7.11 (m, 1H), 2.45 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6, 138.3, 134.8, 134.1, 134.0, 133.9, 133.8, 133.6, 129.8, 129.3, 128.9, 128.7, 126.8, 125.4, 124.1, 121.4, 121.3, 120.7, 113.6, 21.5; HRMS (MALDI) m/z: [M]+ calcd for C22H15NO 309.1149; found 309.1147.

11-(p-Propylphenyl)-6H-isoindolo[2,1-a]indol-6-one (2aea). Pale yellow solid (146.7 mg, 87% yield), mp 181–183 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.60–7.56 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.39–7.23 (m, 5H), 7.17–7.12 (m, 1H), 2.68 (t, J = 8.0 Hz, 2H), 1.78–1.68 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6, 143.1, 134.8, 134.2, 134.0, 133.9, 133.8, 133.6, 129.5, 129.2, 128.9, 128.7, 126.8, 125.4, 124.1, 121.5, 121.3, 120.8, 113.6, 38.1, 24.6, 14.1; HRMS (MALDI) m/z: [M]+ calcd for C24H19NO 337.1462; found 337.1459.

11-(p-Methoxyphenyl)-6H-isoindolo[2,1-a]indol-6-one (2afa). Pale yellow solid (140.4 mg, 86% yield), mp 195−197 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.42−7.37 (m, 1H), 7.34−7.27 (m, 2H), 7.20−7.15 (m, 1H), 7.08 (d, J = 7.2 Hz, 2H), 3.91 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6, 159.8, 134.9, 134.3, 134.0, 133.9, 133.8, 133.7, 130.3, 128.7, 126.9, 125.5, 124.5, 124.1, 121.4, 121.2, 120.5, 114.6, 113.6, 55.5; HRMS (MALDI) m/z: [M]+ calcd for C22H15NO2 325.1098; found 325.1098.

11-(p-Fluorophenyl)-6H-isoindolo[2,1-a]indol-6-one (2aga). Pale yellow solid (110.2 mg, 70% yield), mp 230–232 °C. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.69–7.64 (m, 2H), 7.52–7.46 (m, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.35–7.29 (m, 2H), 7.27–7.22 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 162.8 (d, JC-F = 249.5 Hz), 162.6, 134.6, 134.3, 134.0 (d, JC-F = 3.0 Hz), 133.8, 133.7, 130.9, 130.8, 129.0, 128.3, 128.2, 127.0, 125.5, 124.2, 121.1 (d, JC-F = 5.1 Hz), 119.5, 116.3 (d, JC-F = 21.2 Hz), 113.7; 19F NMR (376 MHz, CDCl3) δ -112.6; HRMS (MALDI) m/z: [M]+ calcd for C21H12FNO 313.0898; found 313.0896.

11-(p-Chlorophenyl)-6H-isoindolo[2,1-a]indol-6-one (2aha). Pale yellow solid (118.8 mg, 72% yield), mp 208–210 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.63–7.60 (m, 2H), 7.53–7.50 (m, 3H), 7.47 (d, J = 8.0 Hz, 1H), 7.43–7.38 (m, 1H), 7.34–7.29 (m, 2H), 7.20–7.15 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.6, 134.5, 134.4, 134.3, 133.9, 133.8, 133.8, 133.7, 130.8, 130.4, 129.5, 129.1, 127.1, 125.6, 124.3, 121.2, 121.0, 119.3, 113.7; HRMS (MALDI) m/z: [M]+ calcd for C21H12ClNO 329.0602; found 329.0600.

11-(p-(Trifluoromethyl)phenyl)-6H-isoindolo[2,1-a]indol-6-one (2aia). Pale yellow solid (120.1 mg, 66% yield), mp 196–198 °C. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.83–7.74 (m, 4H), 7.72 (d, J = 7.2 Hz, 1H), 7.49–7.44 (m, 2H), 7.41–7.36 (m, 1H), 7.32–7.27 (m, 2H), 7.18–7.13 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.5, 136.2, 135.0, 134.3, 133.9, 133.8, 133.7, 133.4, 130.3 (q, JC-F = 32.3 Hz), 129.4, 129.3, 127.1, 126.1 (q, JC-F = 4.0 Hz), 125.6, 124.4, 124.2 (q, JC-F = 272.7 Hz), 121.2, 120.9, 118.8, 113.7; 19F NMR (376 MHz, CDCl3) δ -62.4; HRMS (MALDI) m/z: [M]+ calcd for C22H12F3NO 363.0866; found 363.0869.

11-([1,1′-Biphenyl]-4-yl)-6H-isoindolo[2,1-a]indol-6-one (2aja). Pale yellow solid (144.3 mg, 78% yield), mp 234−236 °C. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 8.0 Hz, 1H), 7.81−7.78 (m, 5H), 7.71–7.68 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.45–7.30 (m, 4H), 7.23–7.18 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.7, 141.4, 140.7, 134.9, 134.5, 134.2, 134.1, 134.0, 133.8, 131.4, 129.6, 129.1, 129.0, 127.9, 127.8, 127.2, 127.0, 125.6, 124.3, 121.4, 120.4, 113.7; HRMS (MALDI) m/z: [M]+ calcd for C27H17NO 371.1305; found 371.1306.

2-Methyl-11-phenyl-6H-isoindolo[2,1-a]indol-6-one (2aab) [11]. Pale yellow solid (136.1 mg, 88% yield), mp 178–180 °C. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 1H), 7.75–7.72 (m, 1H), 7.69–7.66 (m, 2H), 7.57–7.52 (m, 3H), 7.48–7.43 (m, 1H), 7.39–7.34 (m, 1H), 7.31–7.24 (m, 2H), 7.14–7.10 (m, 1H), 2.37 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.5, 134.8, 134.5, 134.3, 134.0, 133.8, 133.6, 132.4, 132.0, 129.1, 128.7, 128.4, 128.0, 125.4, 121.4, 121.2, 120.5, 113.2, 21.7; HRMS (ESI) m/z: [M + H]+ calcd for C22H16NO 310.1226; found 310.1228.

2-Methyl-11-(o-tolyl)-6H-isoindolo[2,1-a]indol-6-one (2abb). Pale yellow solid (124.8 mg, 77% yield), mp 161–163 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.52–7.39 (m, 4H), 7.36–7.32 (m, 1H), 7.28–7.21 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H), 2.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.4, 138.8, 134.8, 134.3, 134.2, 134.0, 133.7, 133.5, 132.3, 131.9, 129.6, 129.1, 129.0, 128.6, 127.9, 126.2, 125.3, 121.4, 121.1, 120.6, 113.1, 21.7, 21.6; HRMS (MALDI) m/z: [M]+ calcd for C23H17NO 323.1305; found 323.1310.

2-Methyl-11-(m-tolyl)-6H-isoindolo[2,1-a]indol-6-one (2acb). Pale yellow solid (137.9 mg, 85% yield), mp 162–165 °C. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.50–7.41 (m, 3H), 7.40–7.35 (m, 1H), 7.31–7.26 (m, 3H), 7.13 (d, J = 7.6 Hz, 1H), 2.48 (s, 3H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6, 138.8, 134.9, 134.4, 134.4, 134.1, 133.8, 133.6, 132.4, 132.0, 129.7, 129.2, 129.0, 128.7, 128.0, 126.2, 125.4, 121.5, 121.2, 120.7, 113.2, 21.7, 21.6; HRMS (MALDI) m/z: [M]+ calcd for C23H17NO 323.1305; found 323.1302.

2-Methyl-11-(p-tolyl)-6H-isoindolo[2,1-a]indol-6-one (2adb). Pale yellow solid (145.7 mg, 90% yield), mp 206−208 °C. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.57−7.52 (m, 3H), 7.37−7.33 (m, 3H), 7.29−7.23 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.5, 138.3, 134.8, 134.4, 134.2, 134.0, 133.7, 133.5, 132.0, 129.8, 129.4, 129.0, 128.6, 127.9, 125.3, 121.4, 121.2, 120.6, 113.2, 21.6, 21.5; HRMS (ESI) m/z: [M + H]+ calcd for C23H18NO 324.1383; found 324.1384.

2-Methyl-11-(p-propylphenyl)-6H-isoindolo[2,1-a]indol-6-one (2aeb). Pale yellow solid (159.8 mg, 91% yield), mp 133–135 °C. 1H NMR (400 MHz, CDCl3) δ 7.75–7.71 (m, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.54–7.52 (m, 2H), 7.49 (d, J = 7.6 Hz, 1H), 7.31–7.25 (m, 4H), 7.21–7.15 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 2.66 (t, J = 7.6 Hz, 2H), 2.32 (s, 3H), 1.77–1.66 (m, 2H), 1.01 (d, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 162.3, 142.9, 134.7, 134.3, 134.1, 133.9, 133.6, 133.4, 131.9, 129.6, 129.1, 128.9, 128.4, 127.8, 125.1, 121.4, 121.1, 120.5, 113.1, 38.0, 24.6, 21.6, 14.1; HRMS (MALDI) m/z: [M]+ calcd for C25H21NO 351.1618; found 351.1616.

11-(p-Methoxyphenyl)-2-methyl-6H-isoindolo[2,1-a]indol-6-one (2afb). Pale yellow solid (148.9 mg, 88% yield), mp 158–160 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.60–7.57 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.37–7.32 (m, 1H), 7.27–7.22 (m, 2H), 7.11–7.05 (m, 3H), 3.89 (s, 3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.4, 159.7, 134.8, 134.4, 134.0, 133.9, 133.7, 133.5, 132.0, 130.3, 128.5, 127. 9, 125.3, 124.6, 121.4, 121.0, 120.3, 114.5, 113.2, 55.5, 21.6; HRMS (ESI) m/z: [M + H]+ calcd for C23H18NO2 340.1332; found 340.1333.

11-(p-Fluorophenyl)-2-methyl-6H-isoindolo[2,1-a]indol-6-one (2agb). Pale yellow solid (124.3 mg, 76% yield), mp 157–159 °C. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 1H), 7.76–7.37 (m, 1H), 7.68–7.62 (m, 2H), 7.49–7.46 (m, 1H), 7.41–7.36 (m, 1H), 7.32–7.21 (m, 4H), 7.15–7.11 (m, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.8 (d, JC-F = 248.5 Hz), 162.5, 161.5, 134.6, 134.2, 134.0, 133.9, 133.7, 131.9, 130.9, 130.8, 128.9, 128.4 (d, JC-F = 3.0 Hz), 128.1, 125.5, 121.1 (d, JC-F = 13.1 Hz), 119.3, 116.2 (d, JC-F = 22.2 Hz), 113.3, 21.7; 19F NMR (376 MHz, CDCl3) δ -112.7; HRMS (MALDI) m/z: [M]+ calcd for C22H14FNO 327.1054; found 327.1053.

11-(p-Chlorophenyl)-2-methyl-6H-isoindolo[2,1-a]indol-6-one (2ahb). Pale yellow solid (131.7 mg, 77% yield), mp 222−224 °C. 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.57−7.52 (m, 3H), 7.37−7.33 (m, 3H), 7.29−7.23 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.5, 138.3, 134.8, 134.4, 134.2, 134.0, 133.7, 133.5, 132.0, 129.8, 129.4, 129.0, 128.6, 127.9, 125.3, 121.4, 121.2, 120.6, 113.2, 21.6, 21.5; HRMS (ESI) m/z: [M + H]+ calcd for C22H15ClNO 344.0837; found 344.0836.

2-Methyl-11-(p-(trifluoromethyl)phenyl)-6H-isoindolo[2,1-a]indol-6-one (2aib). Pale yellow solid (132.2 mg, 70% yield), mp 180–182 °C. 1H NMR (400 MHz, CDCl3) δ 7.81–7.75 (m, 5H), 7.71 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.40–7.35 (m, 1H), 7.30–7.26 (m, 1H), 7.23 (s, 1H), 7.12–7.09 (m, 1H), 2.36 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.4, 136.4, 135.1, 134.3, 134.1, 133.9, 133.8, 133.7, 131.8, 130.2 (q, JC-F = 33.3 Hz), 129.4, 129.1, 128.3, 126.1 (q, JC-F = 4.0 Hz), 125.5, 124.2 (q, JC-F = 272.7 Hz), 121.0, 120.9, 118.7, 113.3, 21.6; 19F NMR (376 MHz, CDCl3) δ -62.4; HRMS (MALDI) m/z: [M]+ calcd for C23H14F3NO 377.1022; found 377.1020.

11-([1,1′-Biphenyl]-4-yl)-2-methyl-6H-isoindolo[2,1-a]indol-6-one (2ajb). Pale yellow solid (153.8 mg, 80% yield), mp 235–237 °C. 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.6 Hz, 1H), 7.81–7.75 (m, 5H), 7.71–7.68 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.52–7.47 (m, 2H), 7.43–7.37 (m, 3H), 7.33–7.29 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 2.41 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.6, 141.2, 140.6, 134.8, 134.6, 134.3, 134.1, 133.9, 133.7, 132.1, 131.5, 129.5, 129.1, 128.8, 128.1, 127.8, 127.2, 125.5, 121.5, 121.3, 120.2, 113.3, 21.7; HRMS (MALDI) m/z: [M]+ calcd for C28H19NO 385.1462; found 385.1467.

2-Isopropyl-11-phenyl-6H-isoindolo[2,1-a]indol-6-one (2aac). Pale yellow solid (150.1 mg, 89% yield), mp 141−143 °C. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 7.6 Hz, 1H), 7.72−7.66 (m, 3H), 7.56−7.49 (m, 3H), 7.46−7.42 (m, 1H), 7.35−7.31 (m, 2H), 7.26−7.18 (m, 2H), 2.97−2.89 (m, 1H), 1.26 (d, J = 6.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 162.5, 145.2, 134.8, 134.5, 134.2, 134.0, 133.6, 132.5, 132.2, 129.2, 129.1, 128.7, 128.3, 125.6, 125.3, 121.1, 120.7, 118.8, 113.4, 34.5, 24.5; HRMS (ESI) m/z: [M + H]+ calcd for C24H20NO 338.1539; found 338.1541.

2-Methoxy-11-phenyl-6H-isoindolo[2,1-a]indol-6-one (2aad) [11]. Pale yellow solid (143.2 mg, 88% yield), mp 193–195 °C. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.57–7.50 (m, 3H), 7.46 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.27 (t, J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.90 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.3, 157.2, 135.2, 135.1, 134.7, 134.1, 133.5, 132.4, 129.2, 129.0, 128.8, 128.5, 128.4, 125.4, 121.2, 120.4, 114.5, 114.2, 105.2, 55.9; HRMS (MALDI) m/z: [M]+ calcd for C22H15NO2 325.1098; found 325.1098.

2-Cyano-11-phenyl-6H-isoindolo[2,1-a]indol-6-one (2aae). Pale yellow solid (107.7 mg, 67% yield), mp 209–211 °C. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 1H), 7.87–7.82 (m, 2H), 7.69–7.58 (m, 6H), 7.54–7.46 (m, 2H), 7.43–7.38 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.5, 135.9, 135.6, 134.5, 134.4, 134.3, 133.5, 131.1, 130.3, 129.9, 129.5, 129.1, 129.0, 126.1, 126.0, 122.0, 120.7, 119.5, 114.2, 107.6; HRMS (MALDI) m/z: [M]+ calcd for C22H12N2O 320.0945; found 320.0950.

2-Methoxy-11-(p-methoxyphenyl)-6H-isoindolo[2,1-a]indol-6-one (2afd). Pale yellow solid (160.1 mg, 90% yield), mp 170–172 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.59–7.54 (m, 2H), 7.48 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.08–7.03 (m, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.87–6.84 (m, 1H), 3.89 (s, 3H), 3.78 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.2, 159.7, 157.1, 135.2, 134.7, 134.6, 134.0, 133.4, 130.2, 128.5, 128.5, 125.2, 124.5, 121.0, 120.2, 114.6, 114.2, 114.0, 105.2, 55.8, 55.5; HRMS (MALDI) m/z: [M]+ calcd for C23H17NO3 355.1203; found 355.1201.

2-Cyano-11-(p-Methoxyphenyl)-6H-isoindolo[2,1-a]indol-one (2afe). Pale yellow solid (118.6 mg, 68% yield), mp 181–183 °C. 1H NMR (400 MHz, CDCl3) δ 8.01 (d, J = 8.8 Hz, 1H), 7.83–7.80 (m, 2H), 7.63–7.56 (m, 4H), 7.50–7.45 (m, 1H), 7.40–7.36 (m, 1H), 7.14–7.09 (m, 2H), 3.93 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.4, 160.3, 135.6, 135.4, 134.6, 134.5, 134.4, 133.4, 130.2, 129.6, 126.0, 125.9, 123.2, 121.8, 119.6, 119.5, 115.0, 114.1, 107.5, 55.6; HRMS (MALDI) m/z: [M]+ calcd for C23H14N2O2 350.1050; found 350.1048.

11-(p-Methoxyphenyl)-2-(trifluoromethyl)-6H-isoindolo[2,1-a]indol-6-one (2aff). Pale yellow solid (142.3 mg, 72% yield), mp 155–157 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.6 Hz, 1H), 7.74–7.71 (m, 2H), 7.59–7.51 (m, 4H), 7.43–7.38 (m, 1H), 7.32–7.27 (m, 1H), 7.11–7.08 (m, 2H), 3.91 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 162.4, 160.1, 135.3, 135.0, 134.5, 134.1, 134.0, 133.4, 130.2, 129.2, 126.3 (q, JC-F = 32.3 Hz), 125.7, 124.6 (q, JC-F = 273.7 Hz), 123.6 (q, JC-F = 3.0 Hz), 123.5, 121.5, 120.0, 118.6 (q, JC-F = 4.0 Hz), 114.8, 113.5, 55.5; 19F NMR (376 MHz, CDCl3) δ -61.2; HRMS (MALDI) m/z: [M]+ calcd for C23H14F3NO2 393.0972; found 393.0969.

9-Methoxy-11-phenyl-6H-isoindolo[2,1-a]indol-6-one (2baa). Pale yellow solid (118.4 mg, 73% yield), mp 173–175 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.69–7.65 (m, 3H), 7.56–7.51 (m, 3H), 7.46–7.42 (m, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.07 (s, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.78 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 164.4, 162.5, 136.8, 133.9, 133.8, 133.7, 132.4, 129.1, 129.1, 128.4, 127.1, 126.9, 126.3, 123.8, 121.3, 120.4, 113.6, 113.4, 107.5, 55.8; HRMS (MALDI) m/z: [M]+ calcd for C22H15NO2 325.1098; found 325.1103.

9-Fluoro-11-phenyl-6H-isoindolo[2,1-a]indol-6-one (2caa). Pale yellow solid (120.7 mg, 77% yield), mp 195–197 °C. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.77–7.72 (m, 1H), 7.68–7.50 (m, 2H), 7.59–7.53 (m, 3H), 7.50–7.46 (m, 1H), 7.37–7.32 (m, 1H), 7.26–7.17 (m, 2H), 7.00–6.94 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 166.5 (d, JC-F = 254.5 Hz), 161.6, 137.1 (d, JC-F = 11.1 Hz), 134.0, 133.8, 132.9 (d, JC-F = 4.0 Hz), 131.9, 129.9, 129.3, 129.0, 128.8, 127.6, 127.5 (d, JC-F = 11.1 Hz), 124.3, 121.7, 121.6, 115.9 (d, JC-F = 24.2 Hz), 113.6, 109.1 (d, JC-F = 25.3 Hz); 19F NMR (376 MHz, CDCl3) δ -103.9; HRMS (MALDI) m/z: [M]+ calcd for C21H12FNO 313.0898; found 313.0896.

3.5. Typical Experimental Procedure for the Synthesis of (Z)-3-Benzylidene-2-Phenylisoindolin-1-One (2a)

A mixture of N-phenyl-ortho-(phenylethynyl)benzamide (1aaa, 297.4 mg, 1.0 mmol), CuI (9.5 mg, 0.05 mmol), and L-proline (17.3 mg, 0.15 mmol) in DMF (2.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at 80 °C for 6 h under nitrogen atmosphere. After the reaction mixture was cooled to room temperature, it was then poured into a solvent mixture of water (15.0 mL) and ethyl acetate (20.0 mL), and the two phases were then separated. The aqueous layer was extracted with ethyl acetate (3 × 20.0 mL). After the combined organic extracts were dried over MgSO4 overnight, the filtered solution was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate as eluent to afford 2a as a white solid (273.6 mg, 92%).

3.6. Characterization Data of Intermediates 2a, 2d and 2d-d5

(Z)-3-Benzylidene-2-phenylisoindolin-1-one (2a) [25]. White solid, mp 198–200 °C. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.09–7.04 (m, 5H), 6.97–6.89 (m, 3H), 6.86–6.82 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 168.0, 138.8, 136.0, 134.4, 133.7, 132.5, 129.3, 129.2, 128.3, 127.9, 127.3, 126.8, 126.7, 124.0, 119.5, 107.7; HRMS (ESI) m/z: [M + H]+ calcd for C21H16NO 298.1226; found 298.1230.

(Z)-3-(p-Methylbenzylidene)-2-phenylisoindolin-1-one (2d). White solid (283.7 mg, 91% yield), mp 187–189 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.66–7.61 (m, 1H), 7.53–7.48 (m, 1H), 7.10–7.05 (m, 5H), 6.78 (s, 1H), 6.74–6.69 (m, 4H), 2.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.0, 138.9, 136.6, 136.1, 133.8, 132.4, 130.7, 129.2, 129.1, 128.2, 128.0, 127.8, 127.3, 126.6, 123.9, 119.4, 108.0, 21.2; HRMS (ESI) m/z: [M + H]+ calcd for C22H18NO 312.1383; found 312.1387.

(Z)-3-(p-Methylbenzylidene)-2-(phenyl-d5)isoindolin-1-one (2d-d5). White solid (0.5 mmol-scale, 145.5 mg, 92% yield), mp 188−190 °C. 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 6.78 (s, 1H), 6.74−6.69 (m, 4H), 2.17 (s, 3H); HRMS (ESI) m/z: [M + H]+ calcd for C22H13D5NO 317.1697; found 317.1671.

4. Conclusions

In summary, in the presence of CuI and Pd(OAc)2, ortho-alkynyl-N-arylbenzamides undergo a stepwise intramolecular hydroamidation of alkynyl group, and C-H dehydrogenative coupling reaction in oxygen atmosphere to give isoindolo[2,1-a]indol-6-one derivatives under mild reaction conditions. The reaction conditions show a high tolerance to a variety of functional groups such as Cl, F, CF3, CN and OMe, some of them being useful for further transformations.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/molecules27113393/s1: the typical procedure for the synthesis of starting materials [26,27], the copies of NMR charts of new starting materials, and all products, as well as X-ray structural details of 2a.

Click here for additional data file. (6.4MB, zip)

Author Contributions

Investigation, writing—original draft preparation, B.T.; conceptualization, supervision, writing—review and editing, R.H. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the final products are not available from the authors.

Funding Statement

This project was supported by the National Natural Science Foundation of China (21673124, 21972072).

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

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Associated Data

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