A general, simple and green process to access pyrrolo[2,1-a]isoquinolines using a KI/TBHP catalytic system

Abstract

A novel KI/TBHP-catalyzed 1,3-dipolar cycloaddition/oxidation/aromatization cascade reaction provided general, efficient and green access to biologically important pyrrolo[2,1-a]isoquinolines. The product pyrrolo[2,1-a]isoquinolines were obtained from reactions between simple, readily available dipolarophiles and tetrahydroisoquinolines in moderate to excellent yields The reaction was environmentally benign in the adoption of nontoxic KI as a catalyst and IOH was generated in situ from the oxidation reaction of KI and TBHP.

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Introduction

Recently, various challenging metal-free reactions have been developed via hypervalent iodine,¹ molecular iodine,² DDQ,³ strong base⁴ etc. as catalysts. Very recently, a novel class of iodide-based oxidation catalysts was introduced by Ishihara and co-workers,⁵ and the most important features of this catalytic system are that the oxidation reactions require no metals and that water or tert-butyl alcohol is the only by-product derived from the co-oxidant. Comparing to molecular iodine, iodide is cheaper, non-toxic and safe to the environment. This green and efficient method has attracted various chemists to synthesize abundant important compounds such as 2-acyl-2,3-dihydrobenzofuran derivatives,^5b 2-aminobenzoxazoles,⁶ N-nitrosamines,⁷ amides,⁸ 2-aryl benzothiazoles,⁹ sulfonated oxindoles,¹⁰ α-amino acid esters,¹¹ tert-butyl peresters,¹² allylic ester,¹³ N-sulfonyl formamidine,¹⁴ benzylic esters,¹⁵ highly functionalized [6,6,5] tricyclic frameworks¹⁶ and iodophenols¹⁷ et al.

The pyrrolo[2,1-a]isoquinoline structure occurs in lamellarin alkaloids, a newly discovered family of marine natural products that exhibit a wide spectrum of biological activities containing potent inhibitor of human topoisomerase I, inhibition of HIV integrase and potential antitumor activities (Fig. 1).¹⁸ So far, various approaches to the synthesis of this useful carbon skeleton have been developed,¹⁹ especially the powerful 1,3-dipolar cycloaddition.^19m-s Very recently, iodine-catalyzed 1,3-dipolar cycloaddition/oxidation/aromatization cascade with hydrogen peroxide as the terminal oxidant to pyrrolo[2,1-a]isoquinolines was reported by our group (Scheme 1, eqn 1).^19s As part of our ongoing research program the functionalized quinone structures^19s,20 and inspired by the reported iodide-based oxidation catalysts, we herein report a general, simple and green access to pyrrolo[2,1-a]isoquinolines using KI/TBHP catalytic system (Scheme 1, eqn 2). The reaction was environmentally benign in adoption of nontoxic KI as catalyst and IOH was generated in situ from the oxidation reaction of KI and TBHP.

Fig. 1 Biologically important pyrrolo[2,1-a]isoquinoline lamellarin alkaloids.

Scheme 1 Methods for the construction of pyrrolo[2,1-a]isoquinolines.

Results and discussion

Initially, we focused on examining the feasibility of the reaction of 1,4-naphthoquinone (1a) with ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetate (2a) and optimizing the reaction conditions. Excitingly, the proposed reaction between 1a and 2a did indeed occur in the presence of KI (20 mol%) and 70% aqueous TBHP (3 equiv.) in DMF (80 °C) for 10 h to afford the corresponding product (3a) in 60% yield (Table 1, entry 1). This result was due to iodine generated in situ from the oxidation reaction of iodide with TBHP. Several other solvents were also examined, but the yield of 3a was not improved in all these tested solvents comparing with DMF (entry 2–6). The yield of 3a was still not increased when the amount of KI was up to 30 mol% (entry 7). However, the yield of 3a was increased slightly when the amount of 70% aqueous TBHP was increased to 6 equiv. (entry 8). When the amount of 2a increased to 1.5 equiv., the yield of 3a was up to 73% (entry 9). Encouraged by these results, we further increased the amount of 2a to 1.7 equiv., the yield of 3a was obtained in 87% (entry 10). However, the yield of 3a decreased slightly when the amount of 2a increased to 2 equiv. (entry 11). To further improve the economy of the reaction, the amount of KI decreased to 0.1 equiv., 3a was only obtained in 70% yield (entry 12). Another oxidant (35% aqueous H₂O₂) was added instead of 70% aqueous TBHP, we only obtained 3a in 50% yield (entry 13). Finally, the best yield of 3a (87%) was obtained from the reaction of 1a (1 mmol), 2a (1.7 mmol), KI (20 mol %), and 70% aqueous TBHP (3 mmol) in DMF (5 mL) at 80 °C for 9 h (entry 10).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Temp (°C)	Time (h)	KI (equiv.)	1a : 2a	Yield of 3a^b (%)
a Compound 1a (1.0 mmol), 2a (1.2–2.0 mmol), KI (10–30 mol%) and 70% aqueous TBHP (3–6 equiv.) in solvent (5 mL) were stirred for several hours at the specified temperature until 1a was consumed.b Isolated yield.c The amount of 70% aqueous TBHP was increased to 6 equiv.d 3 equiv. 35% aqueous H2O2 was added instead of 70% aqueous TBHP.
1	DMF	80	10	0.2	1 : 1.2	60
2	EtOH	Reflux	15	0.2	1 : 1.2	57
3	CH3CN	Reflux	30	0.2	1 : 1.2	51
4	CHCl3	Reflux	28	0.2	1 : 1.2	47
5	THF	Reflux	17	0.2	1 : 1.2	54
6	1,4-Dioxane	Reflux	16	0.2	1 : 1.2	57
7	DMF	80	10	0.3	1 : 1.2	57
8^c	DMF	80	10	0.2	1 : 1.2	61
9	DMF	80	9	0.2	1 : 1.5	73
10	DMF	80	9	0.2	1 : 1.7	87
11	DMF	80	9	0.2	1 : 2.0	86
12	DMF	80	14	0.1	1 : 1.7	70
13^d	DMF	80	12	0.2	1 : 1.7	50

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With the optimal reaction conditions established, we then examined the substrate scope of this KI/TBHP catalytic system to construct pyrrolo[2,1-a]isoquinolines (Scheme 2).

Scheme 2 Reaction of different dipolarophiles with tetrahydroisoquinolines.

As the reaction of 1a, 1,4-anthraquinone (1b) was also reacted smoothly with 2a and the corresponding products (3b) was yielded in 93%. However, when N-phenyl maleimides (1c) was employed under the optimal condition, the corresponding product (3c) was only obtained in 70% yield. When the amount of TBHP was up to 6 equiv., the yield of 3c increased to 94%. Then several other N-substituted maleimides (1d–1h) reacted with 2a in the presence of 6 equiv. TBHP and the corresponding products (3d–3h) were obtained in good yields (74–94%). More importantly, other dipolarophiles, such as activated alkynes and acrylates, also reacted smoothly with 2a to afford the desired products in moderate yields 78% and 50%. To further evaluate the substrate scope, we examined various tetrahydroisoquinoline derivatives 2. Excitingly, 3k was obtained in 90% yield when ethyl 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetate (2b) was employed. Similarly, the desired products 3l and 3m were both obtained in 80% when 1,4-anthraquinone (1b) and N-phenylmaleimide (1c) reacted with 2b. Encouraged by these results, we prepared some tetrahydroisoquinoline derivatives containing various ester groups (methyl, ethyl, tertiary butyl, and benzyl) and allowed them to react with 1,4-naphthoquinone (1a) or N-phenylmaleimide (1c). The corresponding products 3m–3r were also obtained in good yields, except the lower yield of 3p and 3q in 61% and 58% due to the steric of tert-butyl group. The yields obtained using the protocol described here were comparable to those reported in ref. 19s (Scheme 2, yields in parentheses), indicating that the products can be synthesized effectively via 1,3-dipolar cycloaddition/oxidation/aromatization cascade reaction. This approach could therefore be considered a proper alternative to the reported process catalyzed by iodine reported in ref. 19s. Moreover, the paper's merit lay in the adoption of environmentally benign catalyst (KI) which was favorable and highly pursued nowadays.

According to the above experimental results and previous reports,^{5,7,8b,11–14,19s,21} a plausible mechanism was proposed (Scheme 3). Initially tertiary amine (2a) was oxidized to isoquinolinium salt A by IOH, which was oxidized from KI by TBHP.²² Then 1,3-dipole B was formed by elimination of HI with 2a served as tertiary amine base, and then the 1,3-dipolar cycloaddition reaction between B and 1a to afford the addition intermediate D. Finally, 3a was formed through sequential oxidation. At the same time, intermediate C was reoxidized to IOH and 2a in the presence of excess TBHP.²³

Scheme 3 Proposed mechanism.

Conclusions

In summary, we have developed a novel protocol for the synthesis of pyrrolo[2,1-a]isoquinolines using KI/TBHP catalytic system. The reaction is environmentally benign in adoption of nontoxic KI as catalyst and IOH is generated in situ from the oxidation reaction of KI and TBHP. This novel KI/TBHP-catalyzed 1,3-dipolar cycloaddition/oxidation/aromatization cascade reaction provides a general, efficient and green access to biologically important pyrrolo[2,1-a]isoquinolines and more transformations by this useful catalytic system are currently underway in our laboratory.

Experimental

General information

All solvents were purified and dried using standard methods prior to use. Commercially available reagents were used without further purification. ¹H NMR spectra were recorded on an NMR instrument operated at 500 MHz. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl₃: δ 7.26 ppm). ¹³C NMR spectra were recorded on an NMR instrument operated at 125 MHz with complete proton decoupling. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDCl₃: δ 77.1 ppm). MS and HRMS were measured in EI or ESI mode and the mass analyzer of the HRMS was TOF. Thin layer chromatography was performed on pre-coated glass back plates and visualized with UV light at 254 nm. Flash column chromatography was performed on silica gel.

Representative procedure for the synthesis of 3a

A dipolarophile 1a (1.0 mmol) was added to a mixture of a tetrahydroisoquinoline 2a (1.7 mmol), 70% aqueous TBHP (3–6 mmol), and potassium iodide (0.2 mmol) in DMF (5.0 mL). The solution was stirred for 9 h at 80 °C. After 1a was completely consumed (as indicated by TLC and GC-MS), the reaction mixture was washed with aqueous Na₂S₂O₃, dried over magnesium sulfate, and concentrated in vacuo. Purification of the crude product by flash chromatography on silica gel with CH₂Cl₂ as the eluent provided desired products 3a.

Ethyl 9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3a)^19m. Yellow solid, yield 87% (0.323 g), mp 144–145 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 9.01 (d, J = 8.0 Hz, 1H), 8.31–8.30 (m, 1H), 8.23–8.21 (m, 1H), 7.75–7.69 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 6.5 Hz, 1H), 7.29–7.27 (m, 1H), 4.56 (q, J = 7.0 Hz, 2H), 4.30 (t, J = 6.5 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H), 1.51 (t, J = 7.0 Hz, 3H); IR ν/cm⁻¹ (KBr) 1704, 1660, 1524, 1465, 1413, 1384, 1311, 1268, 1227, 1141, 1108, 1047, 1010, 984, 790, 729, 711; GC-MS m/z 372.0 [M + 1]⁺, 326.7, 301.0, 243.6, 77.8, 51.0.

Ethyl 9,16-dioxo-5,6,9,16-tetrahydronaphtho[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3b)^19s. Orange solid, yield 93% (0.392 g), mp 234–235 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 9.00 (d, J = 8.0 Hz, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 7.95–7.94 (m, 2H), 7.55–7.54 (m, 2H), 7.41 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 4.57 (q, J = 7.0 Hz, 2H), 4.22 (t, J = 6.5 Hz, 2H), 3.06 (t, J = 6.5 Hz, 2H), 1.54 (t, J = 7.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 179.4, 179.2, 161.6, 135.5, 134.8, 134.6, 133.5, 132.1, 131.2, 129.9, 129.8, 129.7, 129.2, 129.0, 128.8, 128.7, 128.5, 127.3, 127.3, 126.4, 126.1, 124.0, 118.2, 62.5, 43.1, 29.1, 14.1; IR ν/cm⁻¹ (KBr) 1665, 1461, 1267, 1016, 751; HRMS (ESI-TOF) m/z calcd for C₂₇H₂₀NO₄ [M + H]⁺ 422.1392, found 422.1388.

Ethyl 9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-pyrrolo[3′,4′:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3c)^19m. White solid, yield 94% (0.363 g), mp 190–191 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.59 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 7.0 Hz, 2H), 7.43–7.36 (m, 5H), 7.29 (d, J = 7.5 Hz, 1H), 4.77 (q, J = 8.0 Hz, 2H), 4.44 (q, J = 7.0 Hz, 2H), 3.18 (t, J = 7.0 Hz, 2H), 1.48 (t, J = 8.0 Hz, 3H); IR ν/cm⁻¹ (KBr) 1759, 1709, 1551, 1482, 1421, 1384, 1341, 1301, 1279, 1198, 1155, 1111, 1090, 1051, 945, 895, 862, 823, 759; GC-MS m/z 386.8 [M + 1]⁺, 385.8, 339.9, 314.0, 270.1, 139.1.

Ethyl 10-(4-methoxyphenyl)-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo-[3′,4′:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate (3d)¹⁹ⁿ. White solid, yield 74% (0.308 g), mp 168–169 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.57 (d, J = 7.5 Hz, 1H), 7.41–7.35 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.28–7.27 (m, 1H), 7.00 (d, J = 9.0 Hz, 2H), 4.75 (t, J = 7.0 Hz, 2H), 4.42 (q, J = 7.5 Hz, 2H), 3.84 (s, 3H), 3.17 (t, J = 7.0 Hz, 2H), 1.47 (t, J = 7.5 Hz, 3H); IR ν/cm⁻¹ (KBr) 1761, 1707, 1514, 1385, 1280, 1250, 1194, 1159, 1111, 1031, 809, 743; GC-MS m/z 417.3 [M + 1]⁺, 385.1, 325.6, 288.2, 236.1, 156.7, 71.1.

Ethyl 10-(4-nitrophenyl)-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo-[3′,4′:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate (3e)¹⁹ⁿ. Yellow solid, yield 81% (0.349 g), mp 206–207 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.55 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 9.0 Hz, 2H), 7.72 (d, J = 9.5 Hz, 2H), 7.46–7.40 (m, 2H), 7.32 (d, J = 7.0 Hz, 1H), 4.80 (t, J = 6.5 Hz, 2H), 4.46 (q, J = 7.5 Hz, 2H), 3.21 (t, J = 6.5 Hz, 2H), 1.49 (t, J = 7.5 Hz, 3H); IR ν/cm⁻¹ (KBr) 1761, 1713, 1524, 1384, 1321, 1277, 1194, 1138, 1109, 1040, 1011, 893, 853, 817, 777; GC-MS m/z 432.5 [M + 1]⁺, 400.2, 333.8, 263.9, 200.9, 184.5, 85.1.

Ethyl 10-(4-trifluoromethylphenyl)-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo-[3′,4′:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3f)^19s. White solid, yield 83% (0.377 g), mp 203–204 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.49–8.47 (m, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.36–7.34 (m, 2H), 7.25 (t, J = 4.5 Hz, 1H), 4.70 (t, J = 7.0 Hz, 2H), 4.39 (q, J = 7.0 Hz, 2H), 3.13 (t, J = 7.0 Hz, 2H), 1.47 (t, J = 7.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 162.2, 160.6, 159.1, 135.8, 134.2, 133.5, 132.3, 130.3, 127.7, 127.6, 127.5, 126.8, 125.7, 125.6, 125.5, 125.1, 124.5, 122.8, 118.8, 115.6, 61.5, 43.2, 27.9, 13.9; IR ν/cm⁻¹ (KBr) 1762, 1712, 1477, 1417, 1385, 1325, 1277, 1196, 1162, 1117, 1068, 1019, 947, 895, 845, 815; GC-MS m/z 454.7 [M + 1]⁺, 453.8, 371.0, 408.8, 381.8, 338.0, 139.0; HRMS (ESI-TOF) m/z calcd for C₂₄H₁₈F₃N₂O₄ [M + H]⁺ 455.1219, found 455.1216.

Ethyl 10-benzyl-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo-[3′,4′:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3g)¹⁹ⁿ. White solid, yield 88% (0.352 g), mp 200–201 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.49 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.0 Hz, 2H), 7.38–7.30 (m, 3H), 7.27–7.23 (m, 1H), 7.20 (d, J = 7.0 Hz, 1H), 4.77 (s, 2H), 4.68 (t, J = 7.0 Hz, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.10 (t, J = 7.0 Hz, 2H), 1.49 (t, J = 7.0 Hz, 3H); GC-MS m/z 401.0 [M + 1]⁺, 400.0, 371.0, 353.9, 325.9, 224.2, 195.1.

Ethyl 10-propyl-9,11-dioxo-6,9,10,11-tetrahydro-5H-pyrrolo[3′,4′:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3h)^19s. White solid, yield 91% (0.321 g), mp 188–189 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.53 (d, J = 8.5 Hz, 1H), 7.42–7.39 (m, 1H), 7.38–7.34 (m, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.72 (t, J = 7.0 Hz, 2H), 4.43 (q, J = 7.0 Hz, 2H), 3.59 (t, J = 7.0 Hz, 2H), 3.15 (t, J = 7.0 Hz, 2H), 1.72–1.67 (m, 2H), 1.49 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 164.2, 162.7, 159.7, 132.8, 132.4, 130.1, 127.9, 127.9, 127.6, 125.9, 125.7, 118.1, 116.7, 61.5, 43.3, 39.9, 28.4, 22.0, 14.2, 11.4; IR ν/cm⁻¹ (KBr) 1752, 1700, 1471, 1385, 1330, 1280, 1199, 1123, 1012, 779, 746; GC-MS m/z 353.0 [M + 1]⁺, 352.0, 323.1, 278.1, 266.2, 222.2, 139.2, 103.0; HRMS (ESI-TOF) m/z calcd for C₂₀H₂₁N₂O₄ [M + H]⁺ 353.1501, found 353.1498.

3-Ethyl 1,2-diethyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-1,2,3-tricarboxylate (3i)^19s. White solid, yield 78% (0.301 g), mp 112–113 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.20–8.18 (m, 1H), 7.32–7.30 (m, 2H), 7.25–7.24 (m, 1H), 4.54 (t, J = 7.0 Hz, 2H), 4.38 (q, J = 7.0 Hz, 2H), 4.34–4.30 (m, 4H), 3.00 (t, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H), 1.37–1.32 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 166.0, 163.4, 159.9, 136.6, 134.3, 129.2, 128.5, 127.3, 126.9, 126.9, 126.5, 119.0, 110.8, 61.4, 61.0, 60.7, 42.6, 29.4, 14.12, 14.09, 14.05; IR ν/cm⁻¹ (KBr) 1673, 1581, 1431, 1366, 1155, 1043, 886; GC-MS m/z 385.5 [M]⁺, 384.7, 339.7, 312.8, 265.7, 221.9, 139.0, 129.9; HRMS (ESI-TOF) m/z calcd for C₂₁H₂₄NO₆ [M + H]⁺ 386.1604, found 386.1598.

Diethyl 5,6-dihydropyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate (3j)¹⁹ⁿ. Yellow solid, yield 50% (0.157 g), mp 100–101 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.45 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.36–7.30 (m, 2H), 7.25 (d, J = 6.0 Hz, 1H), 4.61 (t, J = 6.5 Hz, 2H), 4.37–4.32 (m, 4H), 3.03 (t, J = 6.5 Hz, 2H), 1.41–1.38 (m, 6H); GC-MS m/z 314.2 [M + 1]⁺, 312.9, 283.5, 155.9, 73.5.

Ethyl 2,3-dimethoxy-9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3k)^19s. Orange solid, yield 90% (0.388 g), mp 194–195 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.88 (s, 1H), 8.23 (t, J = 2.0 Hz, 1H), 8.12–8.10 (m, 1H), 7.66–7.60 (m, 2H), 6.67 (s, 1H), 4.51 (q, J = 7.0 Hz, 2H), 4.21 (t, J = 7.0 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 3H), 3.01 (t, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 179.5, 179.4, 161.5, 150.2, 147.6, 136.2, 135.8, 134.6, 133.1, 132.7, 127.3, 126.9, 126.4, 125.9, 122.9, 119.1, 116.3, 112.4, 110.2, 62.4, 54.3, 55.9, 43.3, 28.5, 14.0; IR ν/cm⁻¹ (KBr) 1718, 1657, 1479, 1385, 1282, 1257, 1217, 1152, 1132, 1045, 1015, 705; HRMS (ESI-TOF) m/z calcd for C₂₅H₂₂NO₆ [M + H]⁺ 432.1447, found 432.1444.

Ethyl 2,3-dimethoxy-9,16-dioxo-5,6,9,16-tetrahydronaphtho[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3l)^19s. Orange solid, yield 80% (0.433 g), mp 271–272 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.98 (s, 1H), 8.80 (s, 1H), 8.68 (s, 1H), 8.04–8.00 (m, 2H), 7.63–7.61 (m, 2H), 6.73 (s, 1H), 4.57 (q, J = 7.5 Hz, 2H), 4.26 (t, J = 7.0 Hz, 2H), 4.13 (s, 3H), 3.93 (s, 3H), 3.06 (t, J = 7.0 Hz, 2H), 1.54 (t, J = 7.5 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 179.6, 179.4, 161.8, 150.2, 147.7, 136.3, 134.9, 134.6, 132.4, 131.3, 129.83, 129.77, 129.3, 128.82, 128.76, 128.4, 127.0, 126.1, 123.8, 119.3, 117.2, 112.6, 110.2, 62.5, 56.3, 56.0, 43.3, 28.6, 14.1; IR ν/cm⁻¹ (KBr) 1719, 1659, 1479, 1384, 1271, 1240, 1222, 1186, 1133, 1038, 914, 763; HRMS (ESI-TOF) m/z calcd for C₂₉H₂₄NO₆ [M + H]⁺ 482.1604, found 482.1600.

Ethyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-pyrrolo[3′,4′:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate (3m)¹⁹ⁿ. Orange solid, yield 80% (0.357 g), mp 230–231 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.24 (s, 1H), 7.49–7.47 (m, 2H), 7.40–7.36 (m, 3H), 6.75 (s, 1H), 4.73 (t, J = 7.0 Hz, 2H), 4.41 (q, J = 7.0 Hz, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.11 (t, J = 7.0 Hz, 2H), 1.46 (t, J = 7.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 163.46, 161.59, 159.59, 150.67, 148.57, 134.01, 132.60, 128.97 (2C), 127.84, 127.28 (2C), 125.55, 125.03, 118.29, 118.08, 114.75, 110.48, 110.26, 61.48, 56.14, 55.97, 43.42, 27.81, 14.12; GC-MS m/z 447.1 [M + 1]⁺, 445.0, 411.3, 385.4, 301.9, 254.3, 100.1, 56.4.

Methyl 2,3-dimethoxy-9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3n)^19s. Orange solid, yield 92% (0.329 g), mp 205–206 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.95 (s, J = 8.0 Hz, 1H), 8.27–8.25 (m, 1H), 8.17–8.16 (m, 1H), 7.71–7.65 (m, 2H), 7.42 (t, J = 6.5 Hz, 1H), 7.36–7.33 (m, 1H), 7.23 (s, J = 7.0 Hz, 1H), 4.26 (t, J = 6.5 Hz, 2H), 4.06 (s, 3H), 3.08 (t, J = 6.5 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 179.51, 179.47, 161.8, 135.8, 135.6, 134.6, 133.7, 133.3, 132.9, 130.1, 128.9, 127.4 (2C), 127.2, 126.5, 126.3, 125.4, 123.4, 117.5, 53.0, 43.2, 29.0; IR ν/cm⁻¹ (KBr) 1712, 1656, 1466, 1412, 1385, 1314, 1269, 1224, 1140, 1113, 1060, 1012, 799, 734; GC-MS m/z 358.1 [M + 1]⁺, 356.8, 333.6, 276.5, 139.8, 73.9; HRMS (ESI-TOF) m/z calcd for C₂₂H₁₆NO₄ [M + H]⁺ 358.1079, found 358.1077.

Methyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-pyrrolo[3′,4′:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate (3o)^19s. Orange solid, yield 71% (0.264 g), mp 217–218 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.58–8.57 (m, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.43–7.36 (m, 5H), 7.29–7.28 (m, 1H), 4.77 (t, J = 7.0 Hz, 2H), 3.98 (s, 3H), 3.18 (t, J = 7.0 Hz, 3H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 163.0, 161.5, 160.0, 133.6, 132.6, 132.4, 130.4, 128.8 (2C), 128.0, 127.9, 127.70, 127.65, 127.0 (2C), 125.5, 125.3, 118.2, 116.3, 52.3, 43.4, 28.3; IR ν/cm⁻¹ (KBr) 1497, 1385, 1199, 756, 694, 620; GC-MS m/z 373.6 [M + 1]⁺, 372.1, 348.6, 303.2, 256.4, 202.1, 154.1, 54.6; HRMS (ESI-TOF) m/z calcd for C₂₂H₁₇N₂O₄ [M + H]⁺ 373.1188, found 373.1184.

tert-Butyl 2,3-dimethoxy-9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo[1,2-a]isoquinoline-8-carboxylate (3p)^19s. Orange solid, yield 61% (0.244 g), mp 170–171 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 9.02 (d, J = 7.5 Hz, 1H), 8.30 (dd, J₁ = 2.0 Hz, J₂ = 6.5 Hz, 1H), 8.23 (dd, J₁ = 2.0 Hz, J₂ = 6.5 Hz, 1H), 7.72–7.69 (m, 2H), 7.45 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.27 (t, J = 7.0 Hz, 2H), 3.11 (t, J = 7.0 Hz, 2H), 1.72 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 179.8, 179.3, 160.6, 135.8, 135.0, 134.9, 133.5, 133.1, 132.9 (2C), 129.9, 128.8, 127.7, 127.4, 127.4, 127.2, 126.5, 122.4, 117.2, 84.1, 43.0, 29.1, 28.1 (3C); IR ν/cm⁻¹ (KBr) 1660, 1467, 1385, 1266, 1229, 1141, 1010, 714; HRMS (ESI-TOF) m/z calcd for C₂₅H₂₁NO₄Na [M + Na]⁺ 422.1369, found 422.1365.

tert-Butyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-pyrrolo [3′,4′:3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate (3q)^19s. Orange solid, yield 58% (0.240 g), mp 234–235 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 8.59 (dd, J₁ = 1.5 Hz, J₂ = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.43–7.35 (m, 5H), 7.28 (t, J = 6.5 Hz, 1H), 4.75 (t, J = 6.5 Hz, 2H), 3.16 (t, J = 6.5 Hz, 2H), 1.68 (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 163.2, 161.6, 159.0, 133.0, 132.8, 132.4, 130.1, 128.9 (2C), 127.9, 127.9, 127.7, 127.6, 127.3 (2C), 125.7, 124.7, 120.2, 116.0, 83.4, 43.3, 28.4, 28.3 (3C); IR ν/cm⁻¹ (KBr) 1759, 1703, 1481, 1415, 1385, 1349, 1305, 1289, 1154, 1135, 1112, 1089, 1051, 950, 889, 843, 762; HRMS (ESI-TOF) m/z calcd for C₂₅H₂₂N₂O₄Na [M + Na]⁺ 437.1478, found 437.1475.

Benzyl 2,3-dimethoxy-9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-pyrrolo[3′,4′:3,4] pyrrolo[2,1-a]isoquinoline-8-carboxylate (3r)^19s. Orange solid, yield 90% (0.390 g), mp 198–199 °C; ¹H NMR (500 MHz, CDCl₃): δ (ppm) 9.00 (d, J = 7.5 Hz, 1H), 8.30 (dd, J₁ = 2.5 Hz, J₂ = 6.0 Hz, 1H), 8.24 (dd, J₁ = 3.0 Hz, J₂ = 6.5 Hz, 1H), 7.74–7.70 (m, 2H), 7.57 (d, J = 6.5 Hz, 2H), 7.47–7.36 (m, 5H), 7.27 (d, J = 8.5 Hz, 1H), 5.53 (s, 2H), 4.26 (t, J = 6.5 Hz, 2H), 3.08 (t, J = 6.5 Hz, 2H); ¹³C NMR (CDCl₃, 125 MHz): δ (ppm) 179.8, 179.5, 161.4, 135.9, 135.8, 135.2, 134.9, 133.7, 133.4, 133.1, 130.2, 129.0, 128.8 (2C), 128.7 (2C), 128.7, 127.5, 127.5, 127.3, 126.7, 126.4, 125.5, 123.7, 117.7, 68.4, 43.3, 29.2; IR ν/cm⁻¹ (KBr) 1642, 1384, 1262, 1097, 802; HRMS (ESI-TOF) m/z calcd for C₂₈H₂₀NO₄ [M + H]⁺ 434.1392, found 434.1390.

Acknowledgements

This work was supported by the Natural Science Foundation of China (Grant no. 21176223), the National Natural Science Foundation of Zhejiang (Grant no. LY13B020016), and the Key Innovation Team of Science and Technology in Zhejiang Province (Grant no. 2010R50018).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Images of ¹H and ¹³C NMR of all products. See DOI: 10.1039/c4ra03455d

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