Sage Journals: Discover world-class research

Abstract

A novel one-pot 1,3-dipolar cycloaddition/oxidation reaction of 1,4-quinones, aromatic aldehydes, and N-substituted amino esters to construct polysubstituted benzo[f]isoindole-4,9-diones induced by benzoic acid is reported. Based on optimized reaction conditions, various polysubstituted benzo[f]isoindole-4,9-diones derivatives are obtained in moderate yields. This straightforward methodology employs mild reaction conditions, a green oxidant, and readily available starting materials. Notably, a wide range of substrates is tolerated.

Keywords

benzoic acid [3+2] cycloaddition/oxidation one-pot tandem reaction

Introduction

Pyrrole and its derivatives are an important class of five-membered nitrogen-containing heterocyclic compounds that are present in numerous natural products and serve as intermediates in the synthesis of fine chemicals in the fields of medicine,^1,2 food, common chemicals,^3,4 printing and dyeing,^5–7 and so on. The benzo[f]isoindole framework is the core structure of natural products exhibiting important biological activities. Examples include bioactive molecules such as bhimamycins C and D (active against human ovarian cancer cell lines),^8–10 GR30921 (for solid tumors),¹¹ a potent anti-inflammatory that also exhibited analgesic activity,¹² and an azanaphthoquinone-pyrrole that plays an important role against different cancers¹⁰ (Scheme 1).

Scheme 1.

Representative examples of natural products containing a biological activity.

Due to their wide utility as biologically active agents and key intermediates in organic synthesis, pyrrole derivatives have attracted significant attention from organic chemists, and a variety of efficient methods have been developed for their synthesis. Examples include Hantzsch,^13–18 Trofimov,^19–22 Mannich^23–26 and Clauson–Kaas reactions,^27–30 Friedel–Crafts,^31–34 and [3+2] cycloadditions.^35–39 In recent years, metal-free catalysis of various organic transformations has gained more and more attention.^40,41 Benzoic acid, a high catalytically active, nontoxic, inexpensive, and readily available catalyst for the construction of five-membered heterocycles, has attracted the interest of numerous chemists.^42,43

Recently, compared with the present diversified routes to pyrrole derivatives, synthetic protocols to the benzo[f]isoindole-4,9-dione framework are relatively limited with only a few methods having been reported.^44–46 Lin et al.⁴⁵ have reported the silver(II)-mediated radical reactions of 2-substituted-1,4-naphthoquinones and α-keto acids to produce benzo[f]isoindole-4,9-diones. Our own team⁴⁶ has reported a molecular iodine induced 1,3-dipolar cycloaddition between quinone structures and diethyl N-substituted iminodiacetates to construct benzo[f]isoindole-4,9-diones, as shown in Scheme 2. Encouraged by this achievement and our ongoing study of quinones,^42,46–48 we herein report a straightforward and effective method for the construction of polysubstituted benzo[f]isoindole-4,9-dione 4 from 1,4-quinones, aromatic aldehydes, and N-substituted amino esters through a 1,3-dipolar cycloaddition/oxidation tandem reaction induced by benzoic acid.

Scheme 2.

Examples of benzo[f]isoindole-4,9-dione synthesis.

Results and discussion

Our initial investigations focused on examining the feasibility of the [3+2] cycloaddition reaction of 1,4-naphthoquinone (1a), benzaldehyde (2a), and diethyl iminodiacetate (3a) in the presence of an acid catalyst and optimization of the reaction conditions (Table 1).

Table 1.

Optimization of the reaction conditions^a.


Entry	Solvent	Acid (equiv.)	T (°C)	Yield (%)^b
1^c	Toluene	–	80	–
2^c	Toluene	PhCO₂H (1.0)	80	32
3^c	Toluene	PhCO₂H (1.0)	100	50
4^c	Toluene	PhCO₂H (1.0)	120	47
5	Toluene	PhCO₂H (1.0)	100	65
6	Toluene	PhCO₂H (0.5)	100	55
7	Toluene	PhCO₂H (1.5)	100	60
8	Toluene	AcOH (1.0)	100	47
9	Toluene	TsOH (1.0)	100	47
10	Toluene	TfOH (1.0)	100	56
11	Toluene	HI (1.0)	100	48
12	Toluene	FeCl₃ (1.0)	100	35
13	Toluene	AlCl₃ (1.0)	100	10
14	DMF	PhCO₂H (1.0)	100	50
15	DMSO	PhCO₂H (1.0)	100	52
16	THF	PhCO₂H (1.0)	100	55
17	MeCN	PhCO₂H (1.0)	100	51
18	DCM	PhCO₂H (1.0)	100	33
19^d	Toluene	PhCO₂H (1.0)	100	60
20^e	Toluene	PhCO₂H (1.0)	100	56
21^f	Toluene	PhCO₂H (1.0)	100	45

DMF: dimethylformamide; DMSO: dimethyl sulfoxide; THF: tetrahydrofuran; DCM: dichloromethane.

Reaction conditions: 1a (0.25 mmol), 2a (0.3 mmol), 3a (0.3 mmol), acid (0.25 mmol), and Å4 MS (0.125 g) in solvent (2.0 mL), stirring for 10 h at 100 °C under air.

Isolated yield.

Without Å4 MS.

2a (0.25 mmol).

3a (0.25 mmol).

Under N₂ condition.

No target compound 4a was formed in the absence of acid, but the desired product 4a was obtained in 32% yield when the 1 equiv. of PhCO₂H was added (Table 1, entry 2), indicating that acid was an important promoter in this transformation. Encouraged by this result, various reaction parameters were screened to improve the yield of 4a, including the reaction temperature, the acids, the solvent and the amount of staring material. Initially, we were pleased to find that the yield of the 4a increased to 50% when we increased the temperature to 100 °C; however, a further increase did not improve the yield (Table 1, entries 2–4). To our delight, the yield of 4a increased to 65% when Å4 molecular sieves (0.125 g) were added as a water absorbent (Table 1, entry 5). However, decreasing or increasing the loading of PhCO₂H resulted in lower yields (Table 1, entries 6 and 7). Subsequently, a variety of acids, including AcOH, TsOH, TfOH, and HI (45% aq), as well as Lewis acidic FeCl₃ and AlCl₃, were investigated in the reaction, but all resulted in lower yields of benzo[f]isoindole-4,9-dione 4a (Table 1, entries 8–13). Next, examination of different solvents revealed that toluene showed the best performance, and that other solvents tested were inferior to toluene with regard to the yield of the desired product 4a (dimethylformamide (DMF; 50%), dimethyl sulfoxide (DMSO; 52%), tetrahydrofuran (THF; 55%), MeCN (51%), and dichloromethane (DCM; 33%)) (Table 1, entries 14–18). Furthermore, when we reduced the number of equivalents of benzaldehyde (2a) and diethyl iminodiacetate (3a), the yield of the product 4a decreased (Table 1, entries 19 and 20). While investigating the reaction atmosphere, it was observed that the yield of 4a dropped to 45% under an atmosphere of nitrogen. This indicated that oxygen was an important co-oxidant in the reaction (Table 1, entry 21). The optimum reaction conditions were therefore found to be 1a (0.25 mmol), 2a (0.3 mmol), and 3a (0.3 mmol) induced by PhCO₂H (1.0 equiv.) in toluene (2 mL) under an atmosphere of air for 10 h.

With optimized reaction conditions in hand, we next evaluated the scope of the reaction for the construction of various benzo[f]isoindole-4,9-diones. A wide range of aromatic aldehydes 2 were reacted with 1,4-naphthoquinone (1a) and diethyl iminodiacetate (3a) (Table 2). Pleasingly, the results indicated that aldehydes with electron-neutral (H) or electron-withdrawing groups (e.g. 4-F, 4-Cl, 4-Br, 4-NO₂, 4-CN, 3-NO₂, 2-Cl) on the phenyl ring reacted smoothly to afford the desired benzo[f]isoindole-4,9-diones 4 in moderate yields (60%–66%). The reaction might be slightly sensitive to steric hindrance from the benzaldehyde, because the yield of the corresponding product 4g decreased when 2-chlorobenzaldehyde was subjected to the reaction.

Table 2.

Scope of the aromatic aldehyde^a,b.

Reaction conditions: 1a (0.25 mmol), 2a (0.3 mmol), 3a (0.3 mmol), PhCO₂H (0.25 mmol), Å4 MS (0.125 g), toluene (2.0 mL), 10 h, 100 °C, air.

Isolated yield.

In addition, benzaldehydes bearing electron-donating groups (e.g. 4-NMe₂, 4-Me, 4-MeO, 3-MeO, 2-MeO, 2,5-2MeO) gave similar results, that is, products 4i–n in yields of 53%–71%. Unfortunately, when 1-naphthaldehyde was employed in the reaction, the corresponding product 4o was obtained in a relatively low yield of 25% due to the formation of several unidentified byproducts. To our delight, the yields can up to 88% (4p) and 72% (4q) when thiophene-2-aldehyde and butyraldehyde were employed into this cyclization reaction due to its high reactivity.

In order to expand the application of this reaction, different amino acid esters were also investigated under the optimized reaction conditions, as shown in Table 3. When ethyl (methylamino)acetate (3r) and ethyl 2-(benzylamino)acetate (3s) were examined, the desired products 4r and 4t were obtained in good yields (65%–66%). Notably, when ethyl N-phenylglycinate (3t) was reacted with 1,4-naphthoquinone (1a) and benzaldehyde (2a), benzo[f]isoindole-4,9-dione 4t was obtained in only 40% yield due to the electronic effect of the benzene ring. In addition, 1,4-anthraquinone (1b) reacted with benzaldehyde (2a) and diethyl iminodiacetate (3a) to afford the expected product 4u in 68% yield.

Table 3.

Reaction with other N-substituted glycine esters 3 and 1,4-anthraquinone (1b)^a,b.

Reaction conditions: 1a (0.25 mmol), 2a (0.3 mmol), 3a (0.3 mmol), PhCO₂H (0.25 mmol), Å4 MS (0.125 g), toluene (2.0 mL), 10 h, 100 °C, air.

Isolated yield.

Taken together with previous results from the literature,⁴⁶ the above results have led us to propose a possible mechanism (Scheme 3). Initially, benzaldehyde would react with diethyl iminodiacetate in the presence of PhCO₂H to afford zwitterionic intermediate A. Subsequently, the 1,3-dipole B is formed by deprotonation and then reacts with 1,4-naphthoquinone (1a) to product intermediate C together with its isomer D through [3+2] cycloaddition. Finally, the corresponding compound C/D would be oxidized to give the product 4a.

Scheme 3.

A possible reaction mechanism for the synthesis of 4a.

Conclusion

In conclusion, we have successfully developed a simple and novel method for the synthesis of polysubstituted benzo[f]isoindole-4,9-diones through a PhCO₂H-induced [3+2] cycloaddition/oxidation tandem reaction. Under optimized reaction conditions, various easily accessible aromatic aldehydes, N-substituted amino esters, and 1,4-quinones were reacted to give the polysubstituted benzo[f]isoindole-4,9-diones derivatives in moderate-to-good yields. Moreover, the benzo[f]isoindole-4,9-dione products contain one or two ester groups, which can be further transformed into useful building blocks. Finally, thanks to the important biological activities of benzo[f]isoindole-4,9-diones, further studies in our laboratory will focus on expanding the scope of this method.

Experimental section

General information

All chemicals were purchased from commercial vendors and were used as received without further purification. The ¹H and ¹³C nuclear magnetic resonance (NMR) spectra were recorded with a Bruker AM 500 spectrometer at 500 and 125 MHz, respectively, in CDCl₃ using tetramethylsilane (TMS) as an internal standard. Chemical shifts (δ) are reported in parts per million (ppm) and the following abbreviations are used to identify the multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), b (broad), or combinations thereof. High-resolution mass spectrometry (HRMS) data were obtained with a Thermo Scientific LTQ Orbitrap XL mass spectrometer (ESI). Thin-layer chromatography was performed on pre-coated glass plates and visualized with UV light at 254 nm. Flash column chromatography was performed on brand silica gel (200–300 mesh size).

General procedure for the synthesis of 4a

1,4-Naphthoquinone (1a) (0.0395 g, 0.25 mmol), benzaldehyde (2a) (0.0318 g, 0.3 mmol), diethyl iminodiacetate (3a) (0.0567 g, 0.3 mmol), and benzoic acid (0.0305 g, 0.25 mmol) were dissolved in toluene (2.0 mL) in a thick-walled tube (10 mL). The reaction mixture was allowed to stir at 100 °C for 10 h under air condition, with monitoring determined by thin-layer chromatography (TLC) (PE/EtOAc = 4/1 (v/v)) and then cooled to room temperature. The mixture was poured into saturated aqueous Na₂CO₃ (10 mL) and extracted with EtOAc (3 × 10 mL). The organic phases were combined and dried over anhydrous Na₂SO₄. Evaporation of the solvent and purification of the residue by silica column chromatography (eluting solvent: petroleum ether/ethyl acetate = 4/1 (v/v)) gave product 4a as a white solid in 65% yield.

Ethyl 2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-3-phenyl-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4a): White solid; 65% yield; m.p.: 138–140 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.25 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 7.0 Hz, 1H), 7.73–7.68 (m, 1H), 7.68–7.64 (m, 1H), 7.53 (d, J = 6.0 Hz, 3H), 7.43 (d, J = 5.5 Hz, 2H), 4.82 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.5 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.62, 179.00, 167.41, 161.23, 140.99, 135.64, 134.79, 133.21, 133.15, 130.19 (2C), 130.06, 128.76 (2C), 128.68, 127.13, 126.54, 125.06, 123.33, 119.38, 62.11, 62.06, 47.83, 14.01, 13.97; HRMS (ESI): m/z calcd for C₂₅H₂₂NO₆ [M + H]: 432.14416; found: 432.14450.

Ethyl 2-(2-ethoxy-2-oxoethyl)-3-(4-fluorophenyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4b): Yellow solid; 64% yield; m.p.: 121–123 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.25 (dd, J = 7.5, 1.0 Hz, 1H), 8.11 (dd, J = 7.5, 1.5 Hz, 1H), 7.69 (dtd, J = 18.5, 7.5, 1.5 Hz, 2H), 7.58–7.38 (m, 2H), 7.23 (t, J = 9.0 Hz, 2H), 4.80 (s, 2H), 4.50 (q, J = 7.0 Hz, 2H), 4.24 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.5 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.76, 178.94, 167.40, 163.72 (d, ¹J_C-F = 250 Hz), 161.20, 139.86, 135.66, 134.74, 133.31 (d, ³J_C-F = 15 Hz) (2C), 132.45, 132.38, 127.23, 126.57, 125.23, 124.61 (d, ⁴J_C-F = 2.5 Hz), 123.35, 119.62, 116.10 (d, ²J_C-F = 22.5 Hz) (2C), 62.23, 62.22, 47.82, 14.06, 14.01; HRMS (ESI): m/z calcd for C₂₅H₂₁FNO₆ [M + H]: 450.13474; found: 450.13486.

Ethyl 3-(4-chlorophenyl)-2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4c): White solid; 60% yield; m.p.: 159–161 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.22 (dd, J = 7.5, 1.0 Hz, 1H), 8.07 (dd, J = 7.5, 1.0 Hz, 1H), 7.66 (dtd, J = 19.0, 7.5, 1.5 Hz, 2H), 7.54–7.46 (m, 2H), 7.46–7.34 (m, 2H), 4.79 (s, 2H), 4.48 (q, J = 7.5 Hz, 2H), 4.23 (q, J = 7.5 Hz, 2H), 1.47 (t, J = 7.5 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.55, 178.73, 167.33, 161.04, 139.51, 136.37, 135.52, 134.59, 133.32, 133.20, 131.70 (2C), 129.09 (2C), 127.13, 127.03, 126.48, 125.27, 123.28, 119.53, 62.64, 62.17, 47.81, 14.02, 13.95; HRMS (ESI): m/z calcd for C₂₅H₂₁ClNO₆ [M + H]: 466.10519; found: 466.10562.

Ethyl 3-(4-bromophenyl)-2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4d): Yellow solid; 53% yield; m.p.: 153–155 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.24 (d, J = 7.0 Hz, 1H), 8.10 (d, J = 7.0 Hz, 1H), 7.75–7.61 (m, 4H), 7.32 (d, J = 7.7 Hz, 2H), 4.80 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 4.24 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 6.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.63, 178.80, 167.31, 161.08, 139.53, 135.57, 134.63, 133.36, 133.23, 132.07 (2C), 131.89 (2C), 127.52, 127.19, 126.52, 125.33, 124.79, 123.33, 119.54, 62.20, 47.83, 14.02, 13.96; HRMS (ESI): m/z calcd for C₂₅H₂₁BrNO₆ [M + H]: 510.05468; found: 510.05524.

Ethyl 2-(2-ethoxy-2-oxoethyl)-3-(4-nitrophenyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4e): Yellow solid; 60% yield; m.p.: 184–186 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.39 (d, J = 8.5 Hz, 2H), 8.25 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.75–7.66 (m, 4H), 4.80 (s, 2H), 4.51 (q, J = 7.0 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.49 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.70, 178.62, 167.17, 160.97, 148.79, 137.88, 135.59, 135.33, 134.47, 133.68, 133.43, 131.80 (2C), 127.38, 126.62, 125.99, 123.90, 123.46 (2C), 120.11, 62.49, 62.45, 48.02, 14.08, 14.02; HRMS (ESI): m/z calcd for C₂₅H₂₁N₂O₈ [M + H]: 477.12924; found: 477.12967.

Ethyl 3-(4-cyanophenyl)-2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4f): Yellow solid; 65% yield; m.p.: 164–166 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.25 (d, J = 7.0 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.74–7.67 (m, 2H), 7.59 (d, J = 8.0 Hz, 2H), 4.78 (s, 2H), 4.50 (q, J = 7.0 Hz, 2H), 4.24 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.75, 178.72, 167.26, 161.06, 138.34, 135.65, 134.56, 133.71, 133.54, 133.47, 132.51 (2C), 131.45 (2C), 127.41, 126.67, 125.92, 123.49, 120.01, 118.18, 114.13, 62.50, 62.48, 48.05, 14.14, 14.08; HRMS (ESI): m/z calcd for C₂₆H₂₁N₂O₆ [M + H]: 457.13941; found: 457.13959.

Ethyl 3-(2-chlorophenyl)-2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4g): White solid; 48% yield; m.p.: 156–158 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.26 (dd, J = 7.5, 1.0 Hz, 1H), 8.10 (dd, J = 7.5, 1.0 Hz, 1H), 7.73–7.65 (m, 2H), 7.60–7.58 (m, 1H), 7.53–7.50 (m, 2H), 7.44–7.40 (m, 2H), 5.00 (d, J = 17.5 Hz, 1H), 4.58 (d, J = 17.5 Hz, 1H), 4.54–4.47 (m, 2H), 4.22–4.15 (m, 2H), 1.49 (t, J = 7.5 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.39, 178.69, 166.90, 160.98, 137.22, 135.64, 134.59, 134.39, 133.25, 133.06, 132.29, 131.51, 129.82, 128.05, 127.15, 127.10, 126.38, 125.20, 123.17, 120.17, 62.04, 61.96, 47.61, 13.89, 13.77; HRMS (ESI): m/z calcd for C₂₅H₂₁ClNO₆ [M + H]: 466.10519; found: 466.10568.

Ethyl 2-(2-ethoxy-2-oxoethyl)-3-(3-nitrophenyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4h): Yellow solid; 60% yield; m.p.: 168–170 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.42 (dd, J = 8.5, 1.0 Hz, 1H), 8.34–8.32 (m, 1H), 8.26 (dd, J = 8.5, 1.0 Hz, 1H), 8.09 (d, J = 7.0 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.76–7.67 (m, 3H), 4.82 (s, 2H), 4.51 (q, J = 7.0 Hz, 2H), 4.26 (q, J = 7.0 Hz, 2H), 1.49 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.56, 178.49, 167.06, 160.81, 148.16, 137.45, 136.72, 135.44, 134.35, 133.53, 133.28, 130.24, 129.80, 127.21, 126.48, 125.78, 125.42, 124.85, 123.22, 119.95, 62.44, 62.32, 47.89, 13.94, 13.90; HRMS (ESI): m/z calcd for C₂₅H₂₁N₂O₈ [M + H]: 477.12924; found: 477.12946.

Ethyl 3-(4-(dimethylamino)phenyl)-2-(2-ethoxy-2-oxoethy-l)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4i): Red solid; 60% yield; m.p.: 170–172 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.24 (dd, J = 8.0, 2.0 Hz, 1H), 8.14 (dd, J = 7.0 1.0 Hz, 1H), 7.70–7.64 (m, 2H), 7.29 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 9.0 Hz, 2H), 4.87 (s, 2H), 4.48 (q, J = 7.0 Hz, 2H), 4.24 (q, J = 7.5 Hz, 2H), 3.04 (s, 6H), 1.47 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.66, 179.37, 167.86, 161.50, 151.27, 142.62, 135.73, 135.20, 133.13, 133.03, 131.30 (2C), 127.09, 126.64, 124.83, 123.51, 118.95, 114.95, 111.73 (2C), 62.06, 62.02, 47.95, 40.18 (2C), 14.13, 14.07; HRMS (ESI): m/z calcd for C₂₇H₂₇N₂O₆ [M + H]: 475.18636; found: 475.18665.

Ethyl 2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-3-(p-tolyl)-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4j): Yellow solid; 53% yield; m.p.: 158–160 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.24 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 7.0 Hz, 1H), 7.72–7.64 (m, 2H), 7.34–7.30 (m, 4H), 4.82 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H), 2.45 (s, 3H), 1.48 (t, J = 7.5 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.53, 178.96, 167.43, 161.18, 141.23, 140.14, 135.57, 134.78, 133.09, 133.06, 129.99 (2C), 129.44 (2C), 127.03, 126.47, 125.53, 124.89, 123.28, 119.25, 62.00, 61.96, 47.76, 21.44, 13.97, 13.92; HRMS (ESI): m/z calcd for C₂₆H₂₄NO₆ [M + H]: 446.15981; found: 446.15988.

Ethyl 2-(2-ethoxy-2-oxoethyl)-3-(4-methoxyphenyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4k): Yellow solid; 53% yield; m.p.: 168–170 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.25 (dd, J = 7.5, 1.0 Hz, 1H), 8.12 (dd, J = 7.5, 1.0 Hz, 1H), 7.72–7.65 (m, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 4.83 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 4.23 (q, J = 7.0 Hz, 2H), 3.89 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.75, 179.14, 167.58, 161.34, 160.91, 141.21, 135.70, 134.94, 133.20, 133.17, 131.70 (2C), 127.16, 126.59, 124.99, 123.40, 120.50, 119.34, 114.30 (2C), 62.13, 62.09, 55.36, 47.84, 14.08, 14.02; HRMS (ESI): m/z calcd for C₂₆H₂₄NO₇ [M + H]: 462.15473; found: 462.15494.

Ethyl 2-(2-ethoxy-2-oxoethyl)-3-(3-methoxyphenyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4l): Yellow solid; 55% yield; m.p.: 148–150 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.25 (d, J = 7.5 Hz, 1H), 8.12 (d, J = 7.0 Hz, 1H), 7.72–7.66 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.99 (s, 1H), 4.84 (s, 2H), 4.51 (q, J = 7.0 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 3.84 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.37, 178.83, 167.38, 161.06, 159.55, 140.63, 135.47, 134.66, 133.09, 133.04, 129.78, 129.76, 126.99, 126.43, 124.91, 123.17, 122.24, 119.22, 115.75, 115.48, 61.98, 61.95, 55.18, 47.78, 13.92, 13.87; HRMS (ESI): m/z calcd for C₂₆H₂₄NO₇ [M + H]: 462.15473; found: 462.15512.

Ethyl 2-(2-ethoxy-2-oxoethyl)-3-(2-methoxyphenyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4m): Yellow solid; 71% yield; m.p.: 144–146 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.24 (dd, J = 8.0, 1.5 Hz, 1H), 8.10 (dd, J = 7.5, 1.0 Hz, 1H), 7.69–7.62 (m, 2H), 7.55–7.49 (m, 1H), 7.38 (dd, J = 7.5, 1.5 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.86 (d, J = 17.5 Hz, 1H), 4.76 (d, J = 17.5 Hz, 1H), 4.52–4.46 (m, 2H), 4.22–4.15 (m, 2H), 3.73 (s, 3H), 1.48 (t, J = 7.0 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.47, 178.98, 167.25, 161.39, 157.19, 137.81, 135.62, 134.83, 133.00, 132.95, 132.78, 131.87, 126.98, 126.38, 125.25, 123.29, 120.84, 119.43, 117.09, 111.09, 61.89, 61.74, 55.32, 47.43, 13.96, 13.91; HRMS (ESI): m/z calcd for C₂₆H₂₄NO₇ [M + H]: 462.15473; found: 462.15512.

Ethyl 3-(2,5-dimethoxyphenyl)-2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4n): Yellow solid; 53% yield; m.p.: 149–151 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.23 (dd, J = 8.0, 1.5 Hz, 1H), 8.10 (dd, J = 7.0, 1.0 Hz, 1H), 7.69–7.62 (m, 2H), 7.05 (dd, J = 9.0, 3.0 Hz, 1H), 6.97 (d, J = 6.0 Hz, 1H), 6.94 (d, J = 3 Hz, 1H), 4.87 (d, J = 17.5 Hz, 1H), 4.77 (d, J = 17.5 Hz, 1H), 4.55–4.43 (m, 2H), 4.24–4.13 (m, 2H), 3.77 (s, 3H), 3.67 (s, 3H), 1.48 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.06, 178.67, 167.10, 161.13, 153.26, 151.17, 137.23, 135.35, 134.60, 132.82, 132.78, 126.74, 126.17, 125.08, 123.03, 119.21, 117.69, 117.55, 116.82, 112.11, 61.68, 61.56, 55.65, 55.45, 47.28, 13.78, 13.71; HRMS (ESI): m/z calcd for C₂₇H₂₆NO₈ [M + H]: 492.16529; found: 492.16565.

Ethyl 2-(2-ethoxy-2-oxoethyl)-3-(naphthalen-1-yl)-4,9-dioxo-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4o): Yellow solid; 25% yield; m.p.: 144–146 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.26 (d, J = 7.5 Hz, 1H), 8.01 (t, J = 9.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 7.0 Hz, 1H), 7.59–7.53 (m, 3H), 7.48 (dd, J = 16.0, 7.0 Hz, 2H), 7.41–7.38 (m, 1H), 4.82 (d, J = 17.5 Hz, 1H), 4.59 (d, J = 17.5 Hz, 1H), 4.51 (q, J = 7.0 Hz, 2H), 4.08 (q, J = 7.0 Hz, 2H), 1.49 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.34, 179.02, 167.25, 161.29, 139.13, 135.77, 134.69, 133.60, 133.30, 133.19, 132.24, 130.69, 129.05, 128.75, 127.31, 127.23, 126.63, 126.57, 126.41, 125.51, 125.36, 124.66, 123.48, 120.90, 62.18, 61.98, 47.83, 14.09, 13.98; HRMS (ESI): m/z calcd for C₂₉H₂₄NO₆ [M + H]: 482.15981; found: 482.16006.

Ethyl 2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-3-(thiophen-2-yl)-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4p): Yellow solid; 88% yield; m.p.: 183–185 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.24 (d, J = 7.0 Hz, 1H), 8.14 (d, J = 7.0 Hz, 1H), 7.72–7.66 (m, 2H), 7.63 (d, J = 4.5 Hz, 1H), 7.25 (d, J = 3.0 Hz, 1H), 7.22–7.20 (m, 1H), 4.90 (s, 2H), 4.49 (q, J = 7.0 Hz, 2H), 4.25 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.44, 178.80, 167.27, 161.03, 135.47, 134.75, 133.31, 133.23, 133.00, 131.41, 129.66, 127.85, 127.52, 127.13, 126.64, 125.97, 123.27, 121.01, 62.25, 62.15, 47.87, 14.04, 13.96; HRMS (ESI): m/z calcd for C₂₃H₂₀NO₆S [M + H]: 438.10058; found: 438.10089.

Ethyl 2-(2-ethoxy-2-oxoethyl)-4,9-dioxo-3-propyl-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4q): White solid; 72% yield; m.p.: 120–122 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.23–8.20 (m, 2H), 7.72–7.68 (m, 2H), 5.00 (s, 2H), 4.46 (q, J = 7.5 Hz, 2H), 4.26 (q, J = 7.0 Hz, 2H), 3.13–3.10 (m, 2H), 1.65 (dq, J = 15.0, 7.5 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H), 1.05 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 180.74, 179.05, 167.15, 161.36, 143.79, 135.73, 134.93, 133.12, 133.09, 127.18, 126.45, 124.49, 123.24, 118.53, 62.25, 62.00, 46.61, 26.83, 22.17, 14.06, 13.99, 13.85; HRMS (ESI): m/z calcd for C₂₂H₂₄NO₆ [M + H]: 398.15981; found: 398.16022.

Ethyl 2-methyl-4,9-dioxo-3-phenyl-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4r): White solid; 65% yield; m.p.: 152–154 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.22 (dd, J = 7.0, 1.0 Hz, 1H), 8.12 (dd, J = 7.0, 1.0 Hz, 1H), 7.70–7.64 (m, 2H), 7.55–7.53 (m, 3H), 7.46 (dd, J = 7.5, 3.5 Hz, 2H), 4.55 (q, J = 7.0 Hz, 2H), 3.64 (s, 3H), 1.51 (t, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.56, 179.24, 161.58, 140.29, 135.33, 135.12, 133.17, 133.07, 130.38 (2C), 129.78, 129.02, 128.56 (2C), 126.93, 126.66, 126.41, 122.31, 118.71, 62.30, 33.83, 14.05; HRMS (ESI): m/z calcd for C₂₂H₁₈NO₄ [M + H]: 360.12303; found: 360.12354.

Ethyl 2-benzyl-4,9-dioxo-3-phenyl-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4s): Yellow solid; 66% yield; m.p.: 168–170 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.22 (dd, J = 7.5, 1.5 Hz, 1H), 8.12 (dd, J = 8.0, 2.0 Hz, 1H), 7.69–7.63 (m, 2H), 7.51–7.45 (m, 3H), 7.40 (d, J = 6.5 Hz, 2H), 7.25–7.21 (m, 3H), 6.90 (d, J = 6.5 Hz, 2H), 5.32 (s, 2H), 4.31 (q, J = 7.0 Hz, 2H), 1.22 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.52, 179.20, 161.53, 140.32, 136.00, 135.27, 135.16, 133.17, 133.05, 130.29 (2C), 129.75, 128.93, 128.64 (2C), 128.52 (2C), 127.81, 126.86, 126.64, 126.45 (2C), 126.37, 122.36, 118.66, 62.10, 49.08, 13.68; HRMS (ESI): m/z calcd for C₂₈H₂₂NO₄ [M + H]: 436.15433; found: 436.15472.

Ethyl 4,9-dioxo-2,3-diphenyl-4,9-dihydro-2H-benzo[f]isoindole-1-carboxylate (4t): White solid; 40% yield; m.p.: 186–188 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.26 (dd, J = 6.5, 2.0 Hz, 1H), 8.19 (dd, J = 6.5, 2.0 Hz, 1H), 7.72–7.68 (m, 2H), 7.36–7.26 (m, 8H), 7.17 (d, J = 7.0 Hz, 2H), 4.26 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.81, 179.67, 161.01, 139.63, 136.35, 135.67, 135.17, 133.55, 133.30, 130.86 (2C), 129.27, 129.26 (2C), 129.12, 128.68, 128.61, 127.97 (2C), 127.67 (2C), 127.02, 127.00, 121.63, 118.36, 62.34, 13.76; HRMS (ESI): m/z calcd for C₂₇H₂₀NO₄ [M + H]: 422.13868; found: 422.13916.

Ethyl 2-(2-ethoxy-2-oxoethyl)-4,11-dioxo-3-phenyl-4,11-dihydro-2H-naphtho[2,3-f]isoindole-1-carboxylate (4u): Yellow solid; 68% yield; m.p.: 144–146 °C; ¹H NMR (500 MHz, CDCl₃): δ 8.76 (s, 1H), 8.62 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.96 (d, J = 7.0 Hz, 1H), 7.63–7.60 (m, 2H), 7.58–7.54 (m, 3H), 7.46 (d, J = 5.0 Hz, 2H), 4.84 (s, 2H), 4.52 (q, J = 7.5 Hz, 2H), 4.24 (q, J = 7.0 Hz, 2H), 1.51 (t, J = 7.5 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 179.52, 178.94, 167.43, 161.40, 141.05, 134.78, 134.68, 132.07, 131.36, 130.26 (2C), 130.02, 129.86, 129.85, 129.21, 128.91, 128.89, 128.81, 128.74 (2C), 128.63, 125.19, 124.12, 120.20, 62.15, 62.08, 47.85, 14.02, 14.02; HRMS (ESI): m/z calcd for C₂₉H₂₄NO₆ [M + H]: 482.15981; found: 482.16013.

Supplemental Material

Supplementary_Material-revised – Supplemental material for Acid-induced intermolecular [3+2] cycloaddition/oxidation to synthesize polysubstituted benzo[f]isoindole-4,9-diones

Supplemental material, Supplementary_Material-revised for Acid-induced intermolecular [3+2] cycloaddition/oxidation to synthesize polysubstituted benzo[f]isoindole-4,9-diones by Zhang-qi Lin, Chao-dong Li, Yu-jin Li, Yong-jian Zhang, Zi-chun Zhou, Qing Ye and Jian-rong Gao in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by the Natural Science Foundation of China (Grant No. 21606201), the National Natural Science Foundation of Zhejiang (Grant No. LY13B020016), and the Technological Innovation Program of Zhejiang Province (Zhejiang Xinmiao Talents Program; Grant No. 2017R403066).

ORCID iD

Yu-jin Li

Supplemental material

Supplemental material for this article is available online.

References

Ortega

Crusats

Feliz

, et al. J Org Chem 2002; 67: 4170.

Saenz

Srirangarm

JK.

J Org Chem 2002; 67: 1699.

Bullington

Wolff

Jackson

PF.

J Org Chem 2002; 67: 9439.

Bazer

Burghardt

, et al. Amino Acids 2011; 40: 1053.

Lee

Swager

TM.

J Am Chem Soc 2003; 125: 6870.

Esteves

CIC

Ferreira

RCM

Raposo

MMM

, et al. Dyes Pigments 2018; 151: 211.

Wang

Miu

Yao

, et al. Dyes Pigments 2019; 162: 126.

Deblander

Van Aeken

Jacobs

, et al. Eur J Org Chem 2009; 2009: 4882.

Claessens

Jacobs

Van Aeken

, et al. J Org Chem 2008; 73: 7555.

10.

Pongprom

Bachitsch

Bauchinger

, et al. Monatsh Chem 2010; 141: 53.

11.

Boven

Erkelens

CAM

Luning

, et al. Br J Cancer 1990; 61: 709.

12.

Rajanarendar

Ramakrishna

Govardhan

, et al. Bioorg Med Chem Lett 2013; 23: 3954.

13.

Matiychuk

Martyack

Obushak

, et al. Chem Heterocycl Comp 2004; 40: 1218.

14.

Thomas

Thorsten

Tetrahedron Lett 2012; 53: 3056.

15.

Lei

Liu

, et al. Org Lett 2016; 18: 2479.

16.

Matiichuk

Frolov

Pokhodylo

, et al. Zh Org Khim 2018; 54: 793.

17.

Zhong

Fan

Yan

Tetrahedron Lett 2017; 58: 1292.

18.

Estévez

Villacampa

Menéndez

JC.

Chem Commun 2013; 49: 591.

19.

Petrova

Mikhaleva

Sobenina

, et al. Mendeleev Commun 1997; 4: 162.

20.

Saczewski

Fedorowicz

Gdaniec

, et al. J Org Chem 2017; 82: 9737.

21.

Vasil’tsov

Shmidt

Mikhaleva

, et al. Chem Heterocycl Comp 2001; 37: 1488.

22.

Madabhushi

Vangipuram

Mallu

KKR

, et al. Adv Synth Catal 2012; 354: 1413.

23.

Bur

Martin

SF.

Tetrahedron 2001; 57: 3221.

24.

Larouche-Gauthier

Bélanger

Org Lett 2008; 10: 4501.

25.

Kumar

Mir

Ramaraju

, et al. RSC Adv 2012; 2: 8922.

26.

Dubs

Hamashima

Sasamoto

, et al. J Org Chem 2008; 73: 5859.

27.

Gourlay

Molesworth

Ryan

, et al. Tetrahedron Lett 2006; 47: 799.

28.

Hosseini-Sarvari

Najafvand-Derikvandi

Jarrahpour

, et al. Chem Heterocycl Comp 2014; 49: 1732.

29.

Kotha

Todeti

Das

, et al. Tetrahedron Lett 2018; 59: 1023.

30.

Patil

Kumar

AV.

ChemistrySelect 2018; 3: 9812.

31.

Taylor

Jones

Williams

JMJ

, et al. Org Lett 2010; 12: 5740.

32.

Kim

Xue

Liu

, et al. Adv Synth Catal 2017; 359: 811.

33.

Gao

Zhang

Yang

, et al. J Org Chem 2018; 83: 11407.

34.

Wang

Huang

JH.

J Colloid Interf Sci 2019; 538: 499.

35.

Huisgen

Angew Chem 1963; 75: 604.

36.

Huang

Gao

JR.

J Org Chem 2014; 79: 1084.

37.

Huang

, et al. RSC Adv 2014; 4: 27250.

38.

Xing

, et al. Org Lett 2015; 17: 3690.

39.

Liu

Zhang

, et al. Adv Synth Catal 2018; 360: 2144.

40.

Huang

Dong

, et al. J Org Chem 2013; 78: 9424.

41.

Rypkema

Sinha

Francisco

JS.

J Phys Chem A 2015; 119: 4581.

42.

Zheng

You

Shu

, et al. Org Lett 2017; 19: 2262.

43.

Zheng

Zhuang

You

, et al. ChemistrySelect 2017; 2: 10762.

44.

Myers

Moore

Jr Whitter

, et al. J Org Chem 1980; 45: 1202.

45.

Lin

Chen

Lee

, et al. Eur J Org Chem 2010: 3876.

46.

Huang

Gao

, et al. RSC Adv 2014; 4: 15526.

47.

Huang

, et al. RSC Adv 2013; 3: 25840.

48.

Huang

Gao

Hou

, et al. Tetrahedron 2013; 69: 9033.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

2.56 MB

Acid-induced intermolecular [3+2] cycloaddition/oxidation to synthesize polysubstituted benzo[ f ]isoindole-4,9-diones

Abstract

Keywords

Introduction

Results and discussion

Conclusion

Experimental section

General information

General procedure for the synthesis of 4a

Supplemental Material

Supplementary_Material-revised – Supplemental material for Acid-induced intermolecular [3+2] cycloaddition/oxidation to synthesize polysubstituted benzo[f]isoindole-4,9-diones

Footnotes

Declaration of conflicting interests

Funding

ORCID iD

Supplemental material

References

Supplementary Material