Synthesis of dihydroindeno[1,2-c]isochromene via cascade cyclization and Friedel–Crafts reaction

Abstract

Dihydroindeno[1,2-c]isochromene can be efficiently prepared from alkynol and aldehydes via cascade cyclization and Friedel–Crafts reaction. The reaction is highly regioselective.

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Introduction

The isochromene skeleton has attracted enormous attention in synthetic chemistry due to its ubiquitous nature in a vast array of natural products and pharmaceuticals.¹ For example, methyl 1,5,8-trimethoxy-1H-isochromene-3-carboxylate (1), and naphtho[2,3-c]pyran-5,10-diones (2–4) exhibit a broad range of biological activities (Fig. 1).² Over the last few years, innumerable synthetic approaches have been proposed and used for the preparation of functionalized 1H-isochromene frameworks since they are encountered in many bioactive molecules. Among various available methods, cyclizations of ortho-arylethylnylphenylmethanol promoted by transition metal catalysts viz. palladium,³ gold⁴ and Fe⁵ have been well explored. In addition methodologies involving three step synthesis starting from 2-allylbenzaldehyde,⁶ silver,⁷ gold,⁸ iodine,⁹ catalyzed cyclization of ortho-alkynylbenzaldehyde, sequential isocyanide-based multicomponent/Wittig reaction,¹⁰ palladium catalyzed reaction of pinacolone with (tert-butyldimethyl(3-bromophenyl)allyloxy)silane,¹¹ copper catalyzed allenic alcohols,¹² and silver catalyzed ortho-alkynylaryl ketones are also described.¹³ Literature reports revealed that cascade reaction is one of the best methods for achieving such goals.¹⁴ These reactions involve careful design of a multistep reaction in a one-pot sequence, making this approach economical and environmentally friendly. Recently, Liu and coworkers have reported the synthesis of four membered complex indeno[1,2-c]isochromene via Lewis acid catalyzed tandem polycyclization of ortho-arylethylnylphenylmethanol and vinyl azides (Scheme 1).¹⁵ In continuation of our interest in oxygen heterocycles,¹⁶ herein, we report a novel Lewis acid mediated intermolecular cascade reaction starting from alkynol and commercially available aromatic aldehydes leading to four membered dihydroindeno[1,2-c]isochromene in a good to excellent yields (Scheme 2). It may be noted that cascade¹⁴ and Friedel–Crafts¹⁷ reactions play a major role in organic synthesis due to their stereoselectivity and C–C bond forming ability in a single step.

Fig. 1 Some biologically active isochromene molecules.

Scheme 1 Liu and coworkers work.

Scheme 2 Present work.

Results and discussion

To start with (2-(phenylethynyl)phenyl)methanol 1a (1.0 equiv.) was treated with benzaldehyde 2a in presence of borontrifluoride etherate (1.0 equiv.) in dichloromethane at room temperature for 12 h and 11-phenyl-5,11-dihydroindeno[1,2-c]isochromene 3a was obtained in 65% yield. Increasing the Lewis acid loading upto 1.5 equivalents resulted in 87% yield of the desired product under the same reaction conditions. In order to optimize the reaction conditions, other parameters such as Lewis and Brønsted acids, solvents, reaction time were studied. Survey of the various solvents revealed that dichloromethane is the best solvent over 1,2-dichloroethane and toluene. Therefore, dichloromethane (DCM) was chosen as a solvent for further investigations (Table 1). From the Table 1, it was observed that other Lewis and Brønsted acids were found to be inefficient. InCl₃ gave 20% yield while In(OTf)₃ gave only 15% yield. Likewise, Cu(OTf)₂, Zn(OTf)₂ and FeCl₃ produced 22, 20, and 25% yield respectively. However, among the Brønsted acids, TfOH yielded 30% whereas, camphor sulfonic acid (CSA) failed to give the desired product.

Table 1 Optimization of the reaction^a

Entry	Lewis/Bronsted acid (equiv.)	Time/h	Solvent	(%) yield^a
a Yields refer to isolated yield. Compound is characterized by ^1H, ^13C NMR, IR and mass spectrometry.
1	BF3·Et2O (1)	12	CH2Cl2	65
2	BF3·Et2O (1.5)	12	CH2Cl2	87
3	BF3·Et2O (1.5)	12	DCE	80
4	BF3·Et2O (1.5)	12	Toluene	35
5	InCl3 (1)	24	CH2Cl2	20
6	In(OTf)3 (1)	24	CH2Cl2	15
7	Cu(OTf)2 (1)	24	CH2Cl2	22
8	Zn(OTf)2 (1)	24	CH2Cl2	20
9	FeCl3 (1)	24	CH2Cl2	25
10	TfOH (1)	24	CH2Cl2	30
11	CSA (1)	24	CH2Cl2	—

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With this optimized conditions in hand, a variety of alkyne alcohols and aldehydes were evaluated as substrates and the results are summarized in Scheme 3. It was observed from Scheme 3 that there is no role of electron-withdrawing and electron-donating groups on the aromatic ring of the aldehydes. Both electron withdrawing and electron donating groups on the aromatic ring of the aldehydes gave good to high yields. This is due to the resonance stabilization of carbocation B both by aryl group as well as isochromene oxygen (Scheme 4). The low yield for the 2,6-dichlorobenzaldehyde may be attributed to steric hindrance. The electronic effect of substituents on the aromatic side chain of the substrates was also studied considering electron donating methyl and electron withdrawing nitro groups. It was observed that as usual the aromatic group with methyl substituent facilitates the Friedel–Crafts reaction and gave product 3p (Scheme 3) with 90% yield, whereas substrate with electron-withdrawing nitro group failed to give desired product (3q 0%, Scheme 3). Aliphatic aldehyde such as isovaleraldehyde gave tricyclic compound 6,6-dimethyl-3-phenyl-1,4,5,6-tetrahydrobenzo[de]isochromene 3r in 85% yield. The structure of the compounds was determined by ¹H, ¹³NMR, IR and HRMS analysis. Finally it was confirmed by the X-ray crystallographic analysis of 3b (Fig. 2).¹⁸

Scheme 3 Synthesis of dihydroindeno[1,2-c]isochromene.

Scheme 4 Mechanism of the reaction.

Fig. 2 X-ray crystallographic structure of 3b.

The mechanism of the reaction can be explained as follows. Lewis acid activates the aldehydes 2 for the nucleophilic attack by the alkyne group of 1 and subsequent cascade type attack by benzylic alcohol to form intermediate A, which after elimination of BF₃OH⁻ gives carbocation B. The carbocation B, after Friedel–Crafts reaction produces final compound 3 (Scheme 4).¹⁹ The mechanism for the formation of 3r can be depicted as follows.

The intermediate B rearranges to more stable carbocation C, which after Friedel–Crafts cyclization gives 3r (Scheme 4).

Conclusion

In conclusion, we have developed a mild and efficient method for the synthesis of dihydroindeno[1,2-c]isochromene from alkynol and aldehydes via cascade cyclization and Friedel–Crafts reaction mediated by boron trifluoride etherate in good yields. The reaction is compatible with a wide range of functional groups such as halo, ether, ester, nitro, amine and nitrile. The aspect of this reaction is that it produces dihydroindeno[1,2-c]isochromene regioselectively.

Experimental section

General information

All the reagents were of reagent grade (AR grade) and were used as purchased without further purification. Silica gel (60–120 mesh size) was used for column chromatography. Reactions were monitored by TLC on silica gel GF₂₅₄ (0.25 mm). Melting points were recorded in an open capillary tube and are uncorrected. Fourier transform-infra red (FT-IR) spectra were recorded as neat liquid or KBr pellets. NMR spectra were recorded in CDCl₃ with tetramethylsilane as the internal standard for ¹H (600 MHz, 400 MHz) or ¹³C (150 MHz, 100 MHz) NMR. Chemical shifts (δ) are reported in ppm and spin–spin coupling constants (J) are given in Hz. HRMS spectra were recorded using Q-TOF mass spectrometer. The starting material alkynol was prepared from known literature method.²⁰

General procedure for the formation of isochromene

To a stirred solution of aldehyde (1.0 equiv.) and alkynol (1.5 equiv.) in dry dichloromethane (5.0 mL) was added BF₃·OEt₂ (1.5 equiv.) dropwise at 0 °C. The reaction mixture was brought to room temperature and stirred for a specific time. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluents. After completion of the reaction, the reaction mixture was treated with saturated sodium bicarbonate solution (5.0 mL). The product was extracted with CH₂Cl₂ (2 × 10.0 mL) and washed with brine. Organic layer was separated and dried over anhydrous Na₂SO₄ and evaporated using rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate and hexane as eluents to afford the cyclic compounds.

Synthesis of 11-phenyl-5,11-dihydroindeno[1,2-c]isochromene (3a). To a stirred solution of benzaldehyde (0.1 mL, 1 mmol) and (2-(2-phenylethynyl)phenyl)methanol (312 mg, 1.5 mmol) in CH₂Cl₂ (5 mL) was added BF₃·OEt₂ (0.18 mL, 1.5 mmol) dropwise at 0 °C. The reaction mixture was brought to room temperature and stirred for 12 h. The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluents. After completion of the reaction, CH₂Cl₂ (10 mL) was added and the reaction mixture was washed with saturated sodium bicarbonate solution and brine solution. The organic layer was separated and dried over anhydrous Na₂SO₄ and evaporated using rotary evaporator to leave the crude product which was purified by column chromatography over silica gel using ethyl acetate and hexane as eluents to give 11-phenyl-5,11-dihydroindeno[1,2-c]isochromene (3a) as a colourless solid. Mp 118–120 °C; R_f (hexane/EtOAc 49 : 1) 0.20; yield 257 mg, 87%; ¹H NMR (600 MHz, CDCl₃) δ 4.79 (s, 1H), 5.40 (d, J = 4.5 Hz, 2H), 6.75 (d, J = 7.2 Hz, 1H), 7.05 (s, 3H), 7.17 (d, J = 7.2 Hz, 2H), 7.21–7.30 (m, 6H), 7.41 (d, J = 7.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 50.7, 70.7, 118.4, 118.9, 120.9, 124.2, 124.4, 126.1, 127.1, 127.2, 127.21, 128.1, 128.5, 129.0, 130.0, 130.8, 136.9, 140.0, 148.2, 156.1; IR (KBr, neat) 3060, 2849, 1605, 1492, 1451, 1142, 1086, 1029, 972, 753 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₇O (M + H)⁺ 297.1274, found 297.1279.

11-(2-Chlorophenyl)-5,11-dihydroindeno[1,2-c]isochromene (3b). Pale yellow solid, mp 130–132 °C; R_f (hexane/EtOAc 49 : 1) 0.20; yield 294 mg, 89%; ¹H NMR (400 MHz, CDCl₃) δ 5.40–5.49 (m, 3H), 6.70 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.99 (t, J = 7.2 Hz, 1H), 7.06–7.20 (m, 5H), 7.30 (t, J = 7.6 Hz, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 46.2, 70.7, 118.5, 120.9, 124.2, 124.4, 126.2, 127.2, 127.4, 127.6, 127.8, 128.4, 128.6, 129.9, 134.4, 136.9, 137.6, 147.7, 156.4; IR (KBr, neat) 2925, 2851, 1615, 1491, 1261, 1145, 1086, 1034, 750 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₆ClO (M + H)⁺ 331.0884, found 331.0879.

11-(3-Chlorophenyl)-5,11-dihydroindeno[1,2-c]isochromene (3c). Colourless oil; R_f (hexane/EtOAc 49 : 1) 0.20; yield 290 mg, 88%; ¹H NMR (600 MHz, CDCl₃) δ 4.72 (s, 1H), 5.41 (d, J = 4.4 Hz, 2H), 6.73 (d, J = 7.2 Hz, 1H), 7.05–7.10 (m, 3H), 7.12–7.21 (m, 5H), 7.23 (s, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 50.1, 70.7, 118.3, 118.5, 120.7, 124.2, 124.5, 126.3, 126.4, 127.2, 127.7, 128.0, 128.5, 130.3, 130.5, 134.7, 136.8, 142.2, 147.5, 156.3; IR (KBr, neat) 2924, 2852, 1604, 1491, 1406, 1281, 1117, 1034, 750 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₆ClO (M + H)⁺ 331.0884, found 331.0888.

11-(4-Chlorophenyl)-5,11-dihydroindeno[1,2-c]isochromene (3d). Colourless oil; R_f (hexane/EtOAc 49 : 1) 0.20; yield 280 mg, 85%; ¹H NMR (400 MHz, CDCl₃) δ 4.75 (s, 1H), 5.41 (d, J = 4.4 Hz, 2H), 6.72–6.74 (m, 1H), 7.07–7.11 (m, 3H), 7.15–7.22 (m, 4H), 7.24 (t, J = 7.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 49.9, 70.8, 118.4, 118.5, 120.7, 124.2, 124.5, 126.3, 127.2, 127.4, 127.8, 128.5, 129.2, 129.5, 130.5, 132.8, 136.8, 138.6, 147.7, 156.2; IR (KBr, neat) 2924, 2852, 1604, 1440, 1407, 1261, 1117, 1034, 750 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₆ClO (M + H)⁺ 331.0884, found 331.0853.

11-(2,6-Dichlorophenyl)-5,11-dihydroindeno[1,2-c] isochromene (3e). Colourless oil; R_f (hexane/EtOAc 49 : 1) 0.20; yield 236 mg, 65%; ¹H NMR (600 MHz, CDCl₃) δ 5.39 (d, J = 4.4 Hz, 2H), 5.73 (s, 1H), 6.72 (d, J = 7.2 Hz, 1H), 7.07–7.12 (m, 4H), 7.15 (d, J = 7.2 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 46.8, 70.7, 117.4, 118.6, 120.1, 123.2, 124.5, 126.1, 127.0, 127.4, 127.9, 128.0, 128.4, 128.6, 128.7, 128.9, 130.3, 140.0, 144.5, 156.3; IR (KBr, neat) 2925, 2853, 1615, 1471, 1218, 1117, 1087, 973, 772 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₅Cl₂O (M + H)⁺ 365.0494, found 365.0424.

11-(3-Bromophenyl)-5,11-dihydroindeno[1,2-c]isochromene (3f). Yellow solid, mp 146–148 °C; R_f (hexane/EtOAc 49 : 1) 0.19; yield 310 mg, 83%; ¹H NMR (400 MHz, CDCl₃) δ 4.84 (s, 1H), 5.44 (d, J = 4.4 Hz, 2H), 6.71 (d, J = 7.2 Hz, 1H), 7.08–7.12 (m, 3H), 7.15–7.22 (m, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 50.2, 70.7, 118.3, 118.6, 120.6, 124.2, 124.5, 125.9, 125.99, 126.0, 126.3, 127.3, 127.6, 127.7, 128.4, 128.5, 128.53, 130.3, 136.9, 144.4, 147.3, 156.4; IR (KBr, neat) 2925, 2853, 1619, 1466, 1324, 1121, 1066, 755 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₆BrO (M + H)⁺ 377.0359, found 377.0319.

11-(4-Fluorophenyl)-5,11-dihydroindeno[1,2-c]isochromene (3g). Yellow solid, mp 125–127 °C; R_f (hexane/EtOAc 50 : 1) 0.18; yield 251 mg, 80%; ¹H NMR (400 MHz, CDCl₃) δ 4.77 (s, 1H), 5.42 (d, J = 4.4 Hz, 2H), 6.74 (t, J = 7.2 Hz, 1H), 6.97 (t, J = 8.0 Hz, 2H), 7.06–7.11 (m, 3H), 7.15–7.24 (m, 4H), 7.30 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 49.8, 70.7, 115.9 (d, J = 21.3 Hz), 118.4, 118.6, 120.7, 124.1, 124.4, 126.2, 127.1, 127.3, 127.8, 128.5, 129.5 (d, J = 8.0 Hz), 130.6, 135.5, 135.6 (d, J = 3.5 Hz), 136.8, 148.0, 156.1, 162.1 (d, J = 243.2 Hz); ¹⁹F NMR (376 MHz, C₆F₆/CDCl₃) δ 45.92 (s, –F); IR (KBr, neat) 2924, 2853, 1600, 1489, 1220, 1150, 1066, 1016, 772 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₆FO (M + H)⁺ 315.1180, found 315.1189.

Methyl 4-(5,11-dihydroindeno[1,2-c]isochromen-11-yl)benzoate (3h). White solid, mp 121–123 °C; R_f (hexane/EtOAc 49 : 1) 0.25; yield 304 mg, 86%; ¹H NMR (600 MHz, CDCl₃) δ 3.86 (s, 3H), 4.80 (s, 1H), 5.41 (d, J = 4.4 Hz, 2H), 6.68–6.70 (m, 1H), 7.04–7.08 (m, 3H), 7.13–7.18 (m, 2H), 7.29 (t, J = 7.2 Hz, 1H), 7.31–7.33 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 50.4, 52.2, 70.7, 118.4, 118.6, 120.6, 124.2, 124.4, 126.3, 127.2, 127.5, 127.7, 128.1, 128.5, 129.2, 130.0, 130.4, 136.9, 145.7, 147.3, 156.3, 167.1; IR (KBr, neat) 2950, 2847, 1721, 1610, 1435, 1281, 1112, 1019, 970, 758 cm⁻¹; HRMS (ESI) calcd for C₂₄H₁₉O₃ (M + H)⁺ 355.1329, found 355.1293.

4-(5,11-Dihydroindeno[1,2-c]isochromen-11-yl)benzonitrile (3i). Colourless oil; R_f (hexane/EtOAc 49 : 1) 0.28; yield 225 mg, 70%; ¹H NMR (400 MHz, CDCl₃) δ 4.80 (s, 1H), 5.42 (d, J = 2.0 Hz, 2H), 6.74–6.76 (m, 1H), 7.07–7.11 (m, 3H), 7.13 (d, J = 7.2 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 7.32 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.44 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 2.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 50.3, 70.7, 111.0, 118.7, 120.4, 124.1, 124.6, 126.5, 127.4, 127.7, 128.4, 128.6, 128.8, 128.9, 129.2, 132.9, 136.8, 146.1, 146.7, 156.6; IR (KBr, neat) 2924, 2853, 2227, 1606, 1489, 1408, 1260, 1142, 1085, 970, 757 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₆NO (M + H)⁺ 322.1226, found 322.1190.

11-(4-(Trifluoromethyl)phenyl)-5,11-dihydroindeno[1,2-c] isochromene (3j). Yellow oil; R_f (hexane/EtOAc 49 : 1) 0.20; yield 273 mg, 75%; ¹H NMR (600 MHz, CDCl₃) δ 4.76 (s, 1H), 5.38 (d, J = 3.0 Hz, 2H), 6.67–6.69 (m, 1H), 7.00–7.10 (m, 3H), 7.12 (d, J = 7.2 Hz, 1H), 7.14–7.17 (m, 1H), 7.28 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.8 Hz, 2H), 7.42 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.8 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 50.2, 70.7, 118.3, 118.6, 120.6, 122.3, 123.5, 124.2 (q, J = 270.0 Hz), 124.5, 126.0 (q, J = 3.0 Hz), 126.4, 127.3, 127.6, 127.8, 128.4, 128.6, 130.4, 136.9, 144.5, 147.3, 156.5; ¹⁹F NMR (376 MHz, C₆F₆/CDCl₃) δ 99.33 (s, –F); IR (KBr, neat) 3068, 2845, 1617, 1491, 1325, 1123, 1066, 857, 752 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₆F₃O (M + H)⁺ 365.1148, found 365.1136.

11-(4-Nitrophenyl)-5,11-dihydroindeno[1,2-c]isochromene (3k). Yellow oil; R_f (hexane/EtOAc 49 : 1) 0.30; yield 286 mg, 84%; ¹H NMR (600 MHz, CDCl₃) δ 4.87 (s, 1H), 5.45 (d, J = 2.0 Hz, 2H), 6.69–6.70 (m, 1H), 7.08–7.10 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.43–7.47 (m, 2H), 7.56 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 8.17 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 49.8, 70.7, 117.9, 118.7, 120.3, 122.4, 123.0, 124.1, 124.6, 126.4, 127.4, 127.6, 127.8, 128.5, 129.2, 130.0, 134.2, 136.8, 142.5, 146.8, 148.7, 156.6; IR (KBr, neat) 2926, 2853, 1604, 1529, 1490, 1351, 1281, 1145, 1087, 972, 753 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₆NO₃ (M + H)⁺ 342.1125, found 342.1097.

11-(p-Tolyl)-5,11-dihydroindeno[1,2-c]isochromene (3l). Yellow oil; R_f (hexane/EtOAc 49 : 1) 0.23; yield 242 mg, 78%; ¹H NMR (600 MHz, CDCl₃) δ 2.29 (s, 3H), 4.74 (s, 1H), 5.40 (d, J = 4.0 Hz, 2H), 6.78 (d, J = 7.2 Hz, 1H), 7.04–7.09 (m, 5H), 7.13–7.18 (m, 4H), 7.27 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 7.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 21.3, 50.3, 70.7, 118.3, 118.9, 120.9, 124.2, 124.3, 126.0, 127.0, 127.1, 127.8, 127.9, 128.5, 129.7, 130.8, 136.6, 136.7, 136.8, 148.4, 155.9; IR (KBr, neat) 2922, 2853, 1604, 1490, 1405, 1259, 1142, 1085, 973, 757 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₉O (M + H)⁺ 311.1430, found 311.1391.

4-(5,11-Dihydroindeno[1,2-c]isochromen-11-yl)-N,N-dimethylaniline (3m). Colourless oil; R_f (hexane/EtOAc 49 : 1) 0.27; yield 241 mg, 71%; ¹H NMR (400 MHz, CDCl₃) δ 2.90 (s, 6H), 4.72 (s, 1H), 5.40 (d, J = 2.4 Hz, 2H), 6.66 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 7.2 Hz, 1H), 7.06–7.11 (m, 2H), 6.12 (d, J = 7.2 Hz, 2H), 7.16–7.22 (m, 2H), 7.25–7.29 (m, 2H), 7.40 (d, J = 7.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 29.9, 40.9, 49.9, 70.7, 113.3, 118.2, 119.2, 121.0, 124.2, 124.3, 125.9, 127.0, 127.3, 127.9, 128.5, 128.8 (2C), 131.1, 136.8, 149.0, 149.8, 155.7; IR (KBr, neat) 2923, 2852, 1604, 1460, 1349, 1219, 1198, 1085, 974, 773 cm⁻¹; HRMS (ESI) calcd for C₂₄H₂₂NO (M + H)⁺ 340.1696, found 340.1710.

11-(4-Chlorophenyl)-3-nitro-5,11-dihydroindeno[1,2-c]isochromene (3n). Yellow oil; R_f (hexane/EtOAc 49 : 1) 0.29; yield 274 mg, 73%; ¹H NMR (400 MHz, CDCl₃) δ 4.80 (s, 1H), 5.50 (dd, J = 13.2 and 12.4 Hz, 2H), 6.77 (d, J = 8.4 Hz, 1H), 7.16–7.21 (m, 3H), 7.27–7.31 (m, 3H), 7.36 (t, J = 7.2 Hz, 1H), 7.49–7.53 (m, 1H), 7.97–8.0 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 49.9, 70.3, 117.1, 119.7, 120.1, 120.2, 124.5, 124.8, 127.8, 127.9, 129.0, 129.3, 129.3, 129.7, 131.1, 133.4, 135.5, 137.1, 137.5, 145.4, 148.4, 160.5; IR (KBr, neat) 2925, 2854, 1603, 1583, 1507, 1489, 1329, 1219, 1126, 1087, 894, 772 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₅ClNO₃ (M + H)⁺ 376.0735, found 376.0753.

11-(4-Methoxyphenyl)-5,11-dihydroindeno[1,2-c]isochromene (3o). Colourless oil; R_f (hexane/EtOAc 49 : 1) 0.21; yield 235 mg, 72%; ¹H NMR (400 MHz, CDCl₃) δ 3.89 (s, 3H), 5.11 (s, 1H), 5.14 (dd, J = 15.2 and 14.8 Hz, 2H), 7.00–7.06 (m, 4H), 7.10 (d, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.24–7.31 (m, 3H), 7.37 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ 55.5, 69.9, 82.0, 114.6, 120.7, 123.8, 124.7, 125.8, 126.0, 126.8, 127.3, 127.8, 129.1, 129.8, 130.4, 134.6, 136.8, 136.81, 141.2, 146.6, 159.5; IR (KBr, neat) 2926, 2835, 1605, 1569, 1461, 1247, 1195, 1033, 852, 759 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₉O₂ (M + H)⁺ 327.1380, found 327.1382.

Methyl 4-(9-methyl-5,11-dihydroindeno[1,2-c]isochromen-11-yl)benzoate (3p). Colourless solid, mp 140–142 °C; R_f (hexane/EtOAc 49 : 1) 0.21; yield 331 mg, 90%; ¹H NMR (600 MHz, CDCl₃) δ 2.30 (s, 3H), 3.87 (s, 3H), 4.78 (s, 1H), 5.40 (dd, J = 16.2 and 13.2 Hz, 2H), 6.65–6.67 (m, 1H), 6.96 (s, 1H), 7.04–7.05 (m, 3H), 7.11 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.30–7.36 (m, 3H), 7.96 (d, J = 8.4 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 21.8, 50.3, 52.2, 53.6, 70.7, 117.5, 118.3, 120.4, 124.4, 125.1, 126.0, 127.6, 128.1, 128.2, 128.5, 129.1, 130.4, 130.6, 134.2, 137.3, 146.0, 147.7, 156.5, 167.1; IR (KBr, neat) 2951, 2853, 1722, 1610, 1492, 1435, 1280, 1111, 1048, 813, 779 cm⁻¹; HRMS (ESI) calcd for C₂₅H₂₁O₃ (M + H)⁺ 369.1485, found 369.1509.

6,6-Dimethyl-3-phenyl-1,4,5,6-tetrahydrobenzo[de]iso-chromene (3r). Colourless oil; R_f (hexane/EtOAc 49 : 1) 0.21; yield 234 mg, 85%; ¹H NMR (400 MHz, CDCl₃) δ 0.66 (s, 3H), 1.25 (d, J = 10.6 Hz, 1H, shielded), 1.31 (s, 3H), 2.31 (d, J = 16.0 Hz, 1H), 2.48 (d, J = 16.0 Hz, 1H), 3.75 (s, 1H, deshielded), 5.22 (s, 2H), 6.42–6.45 (m, 1H), 6.97–6.99 (m, 2H), 7.16–7.23 (m, 3H), 7.25–7.32 (m, 2H); ¹³C NMR (150 MHz, CDCl₃) δ 26.5, 31.5, 40.7, 45.6, 57.9, 70.1, 112.4, 120.4, 123.8, 125.3, 126.5, 127.3, 127.4, 128.0, 128.1, 128.3, 128.4, 128.6, 128.7, 131.4, 141.2, 157.0; IR (KBr, neat) 2955, 2837, 1649, 1492, 1452, 1365, 1170, 1080, 756 cm⁻¹; HRMS (ESI) calcd for C₂₀H₂₁O (M + H)⁺ 277.1587, found 277.1591.

Acknowledgements

PG gratefully acknowledges Council of Scientific and Industrial Research (CSIR), New Delhi for her fellowship. Authors are grateful to Council of Scientific and Industrial Research (CSIR), New Delhi, for financial support (Grant No. 02/0159/13/EMR-II). Authors are also thankful to Central Instrument Facility (CIF) of IIT Guwahati for NMR and XRD facilities.

Notes and references

1. (a) M. G. Moloney, Nat. Prod. Rep., 2002, 19, 597; (b) Y. L. Lin, C.-C. Shen, Y.-J. Huang and Y.-Y. Chang, J. Nat. Prod., 2005, 68, 381; (c) Y. Wang, X. Shang, S. Wang, S. Mo, S. Li, Y. Yang, F. Ye, J. Shi and L. He, J. Nat. Prod., 2007, 70, 296; (d) K. Trisuwan, N. Khamyhong, V. Rukachaisirikul, S. Phongpaichit, S. Preedanon and J. Sakayaroj, J. Nat. Prod., 2010, 73, 1507; (e) J.-M. Gao, S.-X. Yang and J. C. Qin, Chem. Rev., 2013, 113, 4755; (f) C. W. Brown, S. Liu, J. Klucik, K. D. Berlin, P. J. Brennan, D. Kaur and D. M. Benbrook, J. Med. Chem., 2004, 47, 1008.
2. (a) J. Sperry, P. Bachu and M. A. Brimble, Nat. Prod. Rep., 2008, 25, 376; (b) P. N. Solis, C. Lang'at, M. P. Gupta, G. C. Kirby, D. C. Warhurst and J. D. Phillipson, Planta Med., 1995, 61, 62; (c) T. Hayachi, F. T. Smith and K. H. Lee, J. Med. Chem., 1987, 30, 2005; (d) M. A. Brimble, M. R. Nairn and H. Prabaharan, Tetrahedron, 2000, 56, 1937.
3. B. Gabriele, G. Salerno, A. Fagio and R. Pittelli, Tetrahedron, 2003, 59, 6251.
4. A. S. K. Hashmi, S. Schafer, M. Wolfle, C. Diez Gil, P. Fischer, A. Laguna, M. C. Blanco and M. Gimeno, Angew. Chem., Int. Ed., 2010, 46, 6184.
5. M. Asthana, J. B. Singh and R. M. Singh, Tetrahedron Lett., 2016, 57, 615.
6. C.-K. Chan, Y.-L. Chan and M.-Y. Chang, Tetrahedron, 2016, 72, 547.
7. G. Mariaule, G. Newsome, P. Y. Toullec, P. Belmont and V. Michelet, Org. Lett., 2014, 16, 4570.
8. E. Tomás-Mendivil, J. Starck, J.-C. Ortuno and V. Michelet, Org. Lett., 2015, 17, 6126.
9. D. Yue, N. Della Cá and R. C. Larock, J. Org. Chem., 2006, 71, 3381.
10. L. Wang, Z.-R. Guan and M.-W. Ding, Org. Biomol. Chem., 2016, 14, 2413.
11. R. Mutter, I. B. Campbell, E. M. M. de la Nava, A. T. Merritt and M. Wills, J. Org. Chem., 2001, 66, 3284.
12. J. Kawai, P. K. Chikkade, Y. Shimizu and M. Kanai, Angew. Chem., Int. Ed., 2013, 52, 7177.
13. M. Terada, F. Li and Y. Toda, Angew. Chem., Int. Ed., 2014, 53, 235.
14. (a) For review see K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem., Int. Ed., 2006, 45, 7134; (b) P. H. Poulsen, S. Vergura, A. Monleón, D. K. B. Jørgensen and K. A. Jørgensen, J. Am. Chem. Soc., 2016, 138, 6412; (c) G. C. Senadi, B. S. Gore, W.-P. Hu and J.-J. Wang, Org. Lett., 2016, 18, 2890; (d) H. Wang, C. Wang, K. Huang, L. Liu, W. Chang and J. Li, Org. Lett., 2016, 18, 2367.
15. H. X. Siyang, X. Y. Ji, X. R. Wu, X. Y. Wu and P. N. Liu, Org. Lett., 2015, 17, 5220.
16. (a) P. Gogoi, V. K. Das and A. K. Saikia, J. Org. Chem., 2014, 79, 8592; (b) S. Sultana, N. R. Devi and A. K. Saikia, Asian J. Org. Chem., 2015, 4, 1281; (c) P. Ghosh, P. Saha, S. Bondalapati, K. Indukuri and A. K. Saikia, J. Org. Chem., 2014, 79, 4119; (d) S. Sarkar, S. Sultana, K. Indukuri, R. Unnava and A. K. Saikia, Synthesis, 2016, 48, 1727.
17. (a) M. Rueping and B. J. Nachtsheim, Beilstein J. Org. Chem., 2010, 6, 6; (b) B. Gabriele, R. Mancuso and L. Veltri, Chem.–Eur. J., 2016, 22, 5056; (c) N. D. Smith, J. Hayashida and V. H. Rawal, Org. Lett., 2005, 7, 4309; (d) A. K. Saikia, S. Sultana, N. R. Devi, M. J. Deka, K. Tiwari and V. K. Dubey, Org. Biomol. Chem., 2016, 14, 970 and references cited therein.
18. The crystallographic data for compound 3b has been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-1483531.†.
19. U. Borthakur, M. Borah, M. J. Deka and A. K. Saikia, J. Org. Chem., 2016, 81, 8736.
20. M. Ackermann, J. Bucher, M. Rappold, K. Graf, F. Rominger and A. S. K. Hashmi, Asian J. Org. Chem., 2013, 8, 1786.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, ¹H, ¹³C and HRMS spectra of all new compounds. CCDC 1483531. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra22329j

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