Novel syntheses of pyrrolo[2,1-a]isoquinolines via 1,3-dipolar cycloaddition between Isoquinoliniums and alkynes

Abstract

A straightforward synthesis of pyrrolo[2,1-a]isoquinolines has been achieved from 1,3-dipolar cycloaddition reaction between isoquinoliniums and alkynes in the presence of K₂CO₃, and features with versatility, easy operation and mild reaction conditions. 22 examples were synthesized.

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Introduction

Bridgehead nitrogen heterocycles show potential applications in pharmaceutical, agrochemical, and industrial areas. Among those, pyrrolo[2,1-a]isoquinoline moieties are ubiquitous structural motifs in a myriad of biologically active alkaloid natural products, such as erythrina and lamellarin. ¹ Recently, these compounds have attracted extensive research interest for applications such as anti-tuberculosis agents,² MPtpA/B phosphatases inhibitors,³ 15-lipoxygenase inhibitors,⁴anti-inflammatory,⁵ antidepressant,⁶ anticancer,^7,8 HIV-1 integrase inhibiting reagents,⁹ calcium entry blockers¹⁰ and potential in vitro antioxidants for lipid peroxidation inhibition.¹¹ As a result, there is a continuous interest in the development of efficient methods for the synthesis of pyrrolo[2,1-a] isoquinolines.¹²

Methods available for the synthesis of these types of compounds include Schöltz,¹³ Tschitschibabin,¹⁴ 1,3-dipolar cycloadditions,¹⁵ 1,5-dipolar cyclizations,¹⁶ metal-catalyzed intramolecular cycloadditions and multicomponent reactions.¹⁷ Problems associated with these strategies include limited versatility, requirements of a transition-metal catalyst or high temperatures. Therefore, the development of new synthetic methods for the synthesis of pyrrolo[2,1-a]isoquinolines is highly desirable.

The classic 1,3-dipolar cycloaddition between pyridinium-related heteroaromatic ylides and alkynes is very attractive considering its versatility and efficiency.^18,15c Based on this reaction, we recently have reported an efficient synthesis of indolizines derivatives from N-ylides (Scheme 1).¹⁹ Subsequently, we explored the possible application of this strategy for the preparation of pyrrolo[2,1-a]isoquinolines from isoquinoline and halogenated ketones. Herein, we report a facile and efficient preparation of pyrrolo[2,1-a]isoquinolines in high yields via the 1,3-dipolar cycloaddition between N-ylides 1 and alkyne 2 under mild reaction conditions (Scheme 1).

Scheme 1 Bridgehead N-heterocycles syntheses via the classic 1,3-dipolar cycloaddition between N-ylides and alkynes.

Results and discussion

Initially, our investigation was performed by reacting 1-(2-oxo-2-phenylethyl)isoquinolinium bromide (1a) with phenylacetylene (2a) in the presence of K₂CO₃ in DMF at 120 °C, from which phenyl(1-phenylpyrrolo[2,1-a]isoquinolin-3-yl) methanone (3a) was obtained in 82% yield. As shown in Table 1, solvent, base and temperature were found to have an important effect for this reaction. Among those, base and its amount were found to be critical for this reaction. In comparison with triethylamine (TEA), K₂CO₃ gave better yields, and 1.5 equiv of base was necessary for this reaction (Table 1, entries 1, 2 and 8). Further screening of solvents showed that DMF gave the best result in comparison to other solvents such as CH₃CN, THF, and H₂O (Table 1, entries 4–7). In DMF, at 90 °C or refluxing conditions, this reaction smoothly generates the desired product 3a in 82% yield (Table 1, entries 3 and 4). Thus, the optimal reaction conditions were found to be in DMF at 90 °C with 1.5 equiv of K₂CO₃. To test the versatility of this reaction, these optimized reaction conditions were also applied to isoquinoliniums 1b–f and alkynes 2b–d, 2g, and 2h as summarized in Table 2. In most cases, the desired pyrrolo[2,1-a]isoquinolines were smoothly obtained in high yields. Among those, isoquinoliniums bearing electron-donating groups gave higher yields in comparison to those with electron-withdrawing groups (Table 2, entries 2–4, and 18), while alkynes with strong electron-donating substituents, like methoxyl groups attached on the phenyl ring gave relatively lower yields in comparison to other alkynes studied (Table 2, entries 8–10). The structure of 3d was confirmed by X-ray analysis, the result is shown in Fig. 1.²⁰ To test the versatility of this reaction, the optimized reaction conditions were further applied to the reaction of other alkynes, such as dimethyl acetylenedicarboxylate (2g) and 1-heptyne (2h). In comparison with phenylacetylene, when activated acetylene (2g) was used for this reaction, also 83% 3u was obtained (Table 2, entry 21). To our delight, when alkyl alkyne (2h) was used, the desired product 3v was obtained in 50% yield (Table 2, entry 22), associated with the inert nature of 1-heptyne.

Fig. 1 The X-ray single-crystal structure of 3d.

Table 1 The optimal reaction conditions for the 1,3-dipolar cycloaddition reaction between isoquinolinium and phenylacetylene

Entry	Base^a	Solvent	T/°C	Time (h)	Yield^d (%)
a 1.5 equiv base was used. b 1.0 equiv PTC was used. c 1.0 equiv base was used. d Yields refer to isoquinolinium.
1	K2CO3	DMF	120	2	82
2	Et3N	DMF	90	2	65
3	K2CO3	DMF	90	2	82
4	K2CO3	DMF	reflux	2	82
5	K2CO3	CH3CN	reflux	5	73
6	K2CO3	THF	reflux	5	75
7^b	K2CO3	H2O	90	5	46
8^c	K2CO3	DMF	90	5	60

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Table 2 Syntheses of pyrrolo[2,1-a]isoquinolines 3via the 1,3-dipolar cycloaddition reaction between isoquinoliniums 1 and alkynes 2

Entry	Isoquinolinium	Alkyne	Product	Yield (%)
1	1a	2a	3a	82
2	1b	2a	3b	79
3	1c	2a	3c	80
4	1d	2a	3d	82
5	1a	2b	3e	81
6	1b	2b	3f	80
7	1c	2b	3g	83
8	1a	2c	3h	57
9	1b	2c	3i	61
10	1c	2c	3j	59
11	1a	2d	3k	88
12	1b	2d	3l	90
13	1c	2d	3m	91
14	1a	2e	3n	86
15	1b	2e	3o	84
16	1c	2e	3p	83
17	1e	2e	3q	52
18	1a	2f	3r	86
19	1b	2f	3s	82
20	1c	2f	3t	85
21	1a	2g	3u	83
22	1f	2h	3v	50

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Interestingly, further application of our optimized reaction conditions to internal alkynes 2e and 2f provided the corresponding 1,2,3-trisubstituted pyrrolo[2,1-a]isoquinolines as major products in high yields (Table 2, entries 14, 15, 16, 18, 19 and 20). Unfortunately, when isoquinolinium 1e, which has a strong electron-withdrawing group (–NO₂) on the benzene ring, was used for the reaction, a low yield was observed (Table 2, entry 17). The structure of 3t was confirmed by X-ray analysis results as shown in Fig. 2.²¹ This high regioselectivity might be attributed to the relatively strong electronic negativity on the C₂ and C₃ of 2e and 2f than those on the C₁ and C₄ of 2e and 2f.

Fig. 2 The X-ray single-crystal structure of 3t.

We propose a plausible mechanism for the synthesis of pyrrolo[2,1-a]isoquinoline as shown in Scheme 2. The deprotonation of isoquinolinium by K₂CO₃ generated the corresponding N-ylide, which acted as a dipole to participate in the subsequent reaction with alkynes to generate the desired pyrrolo[2,1-a]isoquinoline via a 1,3-dipolar cycloaddition reaction.

Scheme 2 Proposed mechanism for the 1,3-dipolar cycloaddition between N-ylides and alkynes.

Conclusion

In conclusion, we have reported a novel and efficient general method for the syntheses of pyrrolo[2,1-a]isoquinolines via a classic 1,3-dipolar cycloaddition reaction between isoquinoliniums and alkynes. Further investigation of this reaction and the electronic properties of the resultant compounds are currently under way in our laboratory.

Experimental section

General

All reactions were carried out using standard Schlenk techniques. Solvents like CH₂Cl₂, CH₃CN and EtOAc were distilled from CaH₂. ¹H NMR and ¹³C NMR spectra were recorded at room temperature in CDCl₃ on Bruker AXS-300 MHz instrument with TMS as internal standard. Coupling constants are reported in Hertz (Hz). IR spectra were taken as KBr plates, HRMS was obtained using ESI ionization. Melting points were measured with micro melting point apparatus. Single crystal X-ray diffraction data were collected in Bruker SMART APEX diffractiometers with molybdenum cathodes.

General procedure for the syntheses of 2-(2-oxo-2-phenylethyl)isoquinolin-2-ium bromide 1

The mixture of 2-bromo-1-phenylethanone (10 mmol) and isoquinoline (10 mmol) were stirred in 10 mL dry CH₃CN at room temperature for a period. After reaction, the precipitate was filtered and washed with acetonitrile to get the pure product 1.

General procedure for the syntheses of polypyrrolo[2,1-a]isoquinolines 3

To a stirred mixture of 2-(2-oxo-2-phenylethyl)isoquinolin-2-ium bromide 1 (1 mmol) and K₂CO₃ (1.5 mmol) in DMF was added phenylacetylene 2 (1 mmol) at room temperature. The resulting mixture was heated in an oil bath at 90 °C for 2 h in a sealed reaction flask. Upon completion of this reaction, the mixture was cooled to room temperature, diluted with CH₂Cl₂, and washed with water. Organic layers were combined, dried over Na₂SO₄, filtered, and evaporated in vacuum. The residue was further purified by flash column chromatography on silica gel (PE/EtOAc = 10 : 1, v/v) to afford the corresponding pyrrolo[2,1-a]isoquinolines 3.

Phenyl(1-phenylpyrrolo[2,1-a]isoquinolin-3-yl)methanone (3a). Yellow solid, mp 172–173 °C; ¹HNMR (CDCl₃, 300 MHz) δ 9.68 (d, J = 7.2 Hz, 1H), 9.29 (d, J = 6.9 Hz, 1H), 8.17 (d, J = 6.9 Hz, 1H), 7.94(d, J = 7.8 Hz, 1H), 7.85 (d, J = 6.3 Hz, 2H), 7.45–7.52 (m, 6H), 7.05–7.22 (m, 5H); ¹³C NMR (75 CDCl₃, MHz) δ 185.5, 140.6, 136.8, 132.1, 131.3, 130.1, 130.1, 129.9, 129.7, 129.2, 128.8, 128.3, 127.8, 127.8, 127.6, 127.2, 127.0, 125.7, 125.3, 125.2, 124.2, 123.5, 123.3, 121.0, 113.9, 113.1, 103.7 ppm; IR (KBr) ν 3051, 3024, 1603, 1574, 1404, 1339, 1290, 1178, 910, 877, 792, 758, 721, 694 cm⁻¹; HRMS (ESI) calcd for C₂₅H₁₇NO ([M + H]⁺) 348.1388, found 348.1379.

(1-Phenylpyrrolo[2,1-a]isoquinolin-3-yl)(p-tolyl)methanone (3b). Yellow solid, mp 212–213 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.18 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 5.7 Hz, 1H), 7.69(d, J = 3.9 Hz, 1H), 7.40–7.43(m, 5H), 7.04–7.11 (m, 6H), 6.85(s, 2H), 2.22(s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 185.4, 141.8, 137.8, 136.8, 130.0, 129.9, 129.3, 128.9, 128.7, 128.4, 128.2, 127.7, 127.5, 127.1, 127.0, 125.7, 125.3, 124.2, 123.4, 120.8, 113.6, 103.2, 21.6 ppm; IR (KBr) ν 3032, 2920, 1601, 1568, 1520, 1393, 1366, 1290, 1229, 912, 793, 766, 702, 664, 600 cm⁻¹; HRMS (ESI) calcd for C₂₆H₁₉NO ([M + H]⁺) 362.1545, found 362.1542.

(4-Methoxyphenyl)(1-phenylpyrrolo[2,1-a]isoquinolin-3-yl)methanone (3c). Yellow solid, mp 153–154 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.59 (d, J = 7.2 Hz, 1H), 7.88–7.96 (m, 3H), 7.67 (d, J = 8.1 Hz, 1H), 7.42–7.55 (m, 5H), 7.26 (t, J = 8.1 Hz, 3H), 7.09 (d, J = 7.8 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 184.5, 162.3, 136.9, 133.0, 132.2, 131.4, 130.1, 129.5, 128.7, 127.8, 127.6, 127.5, 127.1, 127.0, 126.9, 125.6, 125.3, 124.1, 123.5, 120.7, 113.5, 112.9, 103.2, 55.5 ppm; IR (KBr) ν 3445, 2922, 2837, 1614, 1591, 1441, 1366, 1339, 1258, 1238, 1171, 1038, 881, 839, 791, 766, 698 cm⁻¹; HRMS (ESI) calcd for C₂₆H₁₉NO₂ ([M + H]⁺) 378.1494, found 378.1489.

(4-Ethylphenyl)(1-phenylpyrrolo[2,1-a]isoquinolin-3-yl)methanone (3d). Yellow solid, mp 174–175 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.58 (d, J = 8.1 Hz, 1H), 7.870 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.34–7.47 (m, 6H), 7.17–7.24 (m, 4H), 7.04 (d, J = 7.2 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 184.2, 146.8, 136.8, 135.6, 130.6, 128.8, 128.4, 128.2, 127.5, 126.5, 126.3, 126.2, 125.9, 125.7, 124.5, 124.0, 122.9, 122.2, 119.5, 112.4, 27.7, 12.2 ppm; IR (KBr) ν 3138, 2965, 2932, 1597, 1558, 1483, 1439, 1423, 1364, 1335, 1236, 1173, 972, 881, 802, 758, 702 cm⁻¹; HRMS (ESI) calcd for C₂₇H₂₁NO ([M + H]⁺) 376.1701, found 376.1692.

Phenyl(1-(p-tolyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3e). Yellow solid, mp 155–156 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.68 (d, J = 7.2 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 7.5 Hz, 1H), 7.40–7.53 (m, 6H), 7.27 (d, J = 7.5 Hz, 3H), 7.21 (s, 1H), 7.13 (d, J = 7.2 Hz, 1H), 2.46 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 184.4, 139.5, 136.2, 132.6, 131.1, 130.1, 129.0, 128.8, 128.6, 128.4, 128.1, 127.1, 126.8, 126.7, 126.1, 125.9, 124.7, 124.3, 123.2, 122.2, 119.9, 112.7, 20.3 ppm; IR (KBr) ν 3125, 3024, 1601, 1572, 1447, 1364, 1335, 1234, 1175, 935, 876, 827, 797, 725, 698 cm⁻¹; HRMS (ESI) calcd for C₂₆H₁₉NO ([M + H]⁺) 362.1545, found 362.1542.

p-Tolyl(1-(p-tolyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3f). Yellow solid, mp 224–225 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.19 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 6.9 Hz, 1H), 7.68 (d, J = 5.7 Hz, 2H), 7.41–7.43 (m, 5H), 7.02–7.09 (m, 4H), 6.85 (d, J = 7.2 Hz, 2H), 2.23 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 186.3, 140.5, 136.5, 135.6, 135.0, 133.3, 131.6, 128.8, 128.7, 128.2, 128.1, 127.6, 127.5, 127.1, 126.9, 126.5, 126.4, 125.6, 124.0, 123.5, 122.2, 111.5, 102.0, 20.2, 19.8 ppm; IR (KBr) ν 3383, 3034, 2972, 2918, 2349, 2308, 1601, 1520, 1420, 1393, 1339, 1049, 912, 826, 793, 764 cm⁻¹; HRMS (ESI) calcd for C₂₇H₂₁NO ([M + H]⁺) 376.1701, found 376.1694.

(4-Methoxyphenyl)(1-(p-tolyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3g). Yellow solid, mp 147–148 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.52 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.33–7.39 (m, 4H), 7.14–7.22 (m, 3H), 7.00 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 2.38 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 183.4, 161.2, 136.1, 132.8, 132.0, 130.6, 130.3, 128.8, 128.4, 126.5, 126.1, 126.0, 125.9, 124.6, 124.3, 123.1, 122.3, 119.6, 112.4, 54.4, 20.3 ppm; IR (KBr) ν 3130, 3046, 2963, 2839, 2380, 2349, 2309, 1614, 1595, 1506, 1443, 1423, 1364, 1256, 1171, 1026, 964, 880, 800, 615 cm⁻¹; HRMS (ESI) calcd for C₂₇H₂₁NO₂ ([M + H]⁺) 392.1650, found 392.1649.

(1-(4-Methoxyphenyl)pyrrolo[2,1-a]isoquinolin-3-yl)(phenyl)methanone (3h). Yellow solid, mp 167–168 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.59 (d, J = 6.9 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 6.9 Hz, 2H), 7.61 (d, J = 7.8 Hz, 1H), 7.33–7.46 (m, 5H), 7.21 (t, J = 7.8 Hz, 2H), 7.12 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.92 (d, J = 7.8 Hz, 2H),3.82 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 184.2, 157.8, 139.4, 129.9, 129.9, 128.4, 127.9, 127.6, 127.0, 126.6, 126.5, 125.9, 125.7, 124.5, 124.1, 122.9, 121.9, 119.4, 112.9, 112.5, 54.2 ppm; IR (KBr) ν 3123, 3053, 2835, 2380, 2347, 2309, 1601, 1557, 1445, 1364, 1244, 1175, 1031, 966, 876, 812, 698 cm⁻¹; HRMS (ESI) calcd for C₂₆H₁₉NO₂ ([M + H]⁺) 378.1494, found 378.1482.

(1-(4-Methoxyphenyl)pyrrolo[2,1-a]isoquinolin-3-yl)(p-tolyl)methanone (3i). Yellow solid, mp 160–161 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.66 (d, J = 7.5 Hz, 1H), 7.98 (d, J = 7.8 hz, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.44–7.51 (m, 3H), 7.29 (d, J = 6.9, 3H), 7.23 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.02 (d, J = 7.5 Hz, 2H),3.92 (s, 3H), 2.46 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 185.3, 159.0, 141.7, 137.8, 132.0, 131.1, 129.6, 129.3, 129.0, 128.9, 127.6, 127.1, 126.9, 125.7, 125.4, 124.1, 123.3, 120.4, 114.1, 113.5, 55.4, 21.6 ppm; IR (KBr) ν 3117, 3005, 2936, 2378, 2309, 1612, 1557, 1445, 1423, 1337, 1246, 1180, 1032, 880, 837, 797, 750 cm⁻¹; HRMS (ESI) calcd for C₂₇H₂₁NO₂ ([M + H]⁺) 392.1650, found 392.1641.

(4-Methoxyphenyl)(1-(4-methoxyphenyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3j). Yellow solid, mp 173–174 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.61 (d, J = 7.2 Hz, 1H), 7.89–7.99 (m, 3H), 7.70 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 9.0 Hz, 3H), 7.28–7.32 (m, 3H), 7.11 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 9.0 Hz, 3 H), 3.92 (s, 3H), 3.91 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 184.5, 162.3, 159.0, 133.1, 131.4, 131.1, 129.5, 129.0, 127.5, 127.1, 127.1, 126.9, 125.7, 125.4, 124.1, 123.3, 120.3, 114.1, 113.5, 113.4, 55.5, 55.4 ppm; IR (KBr) ν 3132, 3009, 2967, 2934, 2839, 2349, 2309, 1607, 1557, 1439, 1364, 1260, 1182, 1171, 1028, 966, 878, 833, 822, 752, 615 cm⁻¹; HRMS (ESI) calcd for C₂₆H₂₁NO₃ ([M + H]⁺) 408.1600, found 408.1602.

(1-(4-Nitrophenyl)pyrrolo[2,1-a]isoquinolin-3-yl)(phenyl)methanone (3k). Yellow solid, mp 185–186 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.66 (d, J = 7.5 Hz, 1H), 8.32 (d, J = 8.7 Hz, 2H), 7.84–7.91 (m, 3H), 7.74 (t, J = 9.0 Hz, 3H), 7.48–7.57 (m, 3H), 7.34 (t, J = 7.2 Hz, 1H), 7.19–7.23 (m, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 184.6, 146.0, 143.0, 139.2, 130.5, 129.6, 128.8, 128.0, 127.3, 126.4, 126.3, 126.1, 124.6, 123.6, 123.0, 122.8, 117.2, 113.2 ppm; IR (KBr) ν 3127, 3055, 2361, 1614, 1597, 1574, 1512, 1443, 1346, 1233, 1179, 876, 795, 700 cm⁻¹; HRMS (ESI) calcd for C₂₅H₁₆N₂O₃ ([M + H]⁺) 393.1239, found 393.1234.

(1-(4-Nitrophenyl)pyrrolo[2,1-a]isoquinolin-3-yl)(p-tolyl)methanone (3l). Yellow solid, mp 177–178 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.63 (d, J = 7.2 Hz, 1H), 8.32 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.77 (q, J = 7.9 Hz, 4H), 7.53 (t, J = 6.9 Hz, 2H), 7.17–7.36 (m, 5H), 2.45 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 184.5, 143.1, 141.1, 136.4, 129.6, 128.8, 128.2, 128.0, 127.2, 126.3, 126.3, 125.9, 124.5, 123.6, 122.9, 122.8, 117.1, 113.1, 20.5 ppm; IR (KBr) ν 3132, 3055, 2920, 1595, 1510, 1443, 1344, 1234, 1179, 880, 804, 745, 698 cm⁻¹; HRMS (ESI) calcd for C₂₆H₁₈N₂O₃ ([M + H]⁺) 407.1396, found 407.1397.

(4-Methoxyphenyl)(1-(4-nitrophenyl)pyrrolo[2,1-a] isoquinolin-3-yl)methanone (3m). Yellow solid, mp 189–190 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.57 (d, J = 7.2 Hz, 1H), 8.32 (d, J = 8.4 Hz, 2H), 7.87–7.91 (m, 3H), 7.72 (d, J = 8.1 Hz, 3H), 7.52 (t, J = 7.2 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.15(d, J = 7.2 Hz, 1H), 6.99(d, J = 8.4 Hz, 2H), 3.89 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 183.5, 161.5, 145.9, 143.1, 131.6, 130.3, 129.6, 128.7, 127.1, 126.3, 125.4, 124.5, 123.7, 123.2, 122.9, 122.7, 117.0, 113.0, 112.6, 54.4 ppm; IR (KBr) ν 3065, 2920, 2843, 1309, 1626, 1589, 1501, 1335, 1254, 1177, 1105, 1230, 964, 934, 881, 839, 799, 754, 700 cm⁻¹; HRMS (ESI) calcd for C₂₆H₁₈N₂O₄ ([M + H]⁺) 423.1345, found 423.1354.

Phenyl(2-phenyl-1-(phenylethynyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3n). Yellow solid, mp 192–193 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.40 (d, J = 7.8 Hz, 1H), 9.12 (d, J = 7.5 Hz,1H), 7.65 (d, J = 6.9 Hz, 2H), 7.50–7.58 (m, 3H), 7.43 (d, J = 7.2 Hz, 2H), 7.35 (d, J = 5.7 Hz, 3H), 7.12–7.17 (m , 7H), 6.98–7.09 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 187.8, 139.0, 133.4, 131.6, 130.9, 129.8, 128.4, 127.9, 127.6, 127.3, 127.2, 126.8, 124.8, 124.3, 121.5, 114.1, 94.8, 85.3 ppm; IR (KBr) ν 3443, 3059, 2202, 1620, 1527, 1491, 1447, 1398, 1375, 1217, 895, 800, 758, 719, 692 cm⁻¹; HRMS (ESI) calcd for C₃₃H₂₁NO ([M + H]⁺) 448.1701, found 448.1707.

(2-Phenyl-1-(phenylethynyl)pyrrolo[2,1-a]isoquinolin-3-yl)(p-tolyl)methanone (3o). Yellow solid, mp 248–249 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.46 (d, J = 7.5 Hz, 1H), 9.10 (d, J = 7.2 Hz,1H), 7.72 (d, J = 6.3 Hz, 2H), 7.62 (t, J = 9.0 Hz, 3H), 7.25–7.44 (m, 8H), 7.09(s, 2 H), 6.84 (d, J = 7.2 Hz, 2 H), 2.21(s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 186.9, 142.3, 137.5, 135.0, 131.2, 131.0, 130.2, 128.7, 128.5, 127.9, 127.8, 127.3, 127.0, 125.0, 114.1, 98.4, 83.6, 21.6 ppm; IR (KBr) ν 3055, 3022, 2207, 1614, 1493, 1396, 1375, 1358, 1251, 1173, 968, 895, 787, 760, 694 cm⁻¹; HRMS (ESI) calcd for C₃₄H₂₃NO ([M + H]⁺) 462.1858, found 462.1869.

(4-Methoxyphenyl)(2-phenyl-1-(phenylethynyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3p). Yellow solid, mp 203–204 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.47 (d, J = 8.1 Hz, 1H), 9.03 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.61–7.66 (m, 5H), 7.46–7.48 (m, 5H), 7.07–7.15 (m, 4H), 6.57 (d, J = 8.1 Hz, 2H), 3.74(s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 185.5, 161.5, 131.1, 130.1, 129.8, 127.5, 127.3, 126.7, 126.6, 126.0, 125.7, 123.6, 123.1, 112.6, 112.2, 111.9, 93.8, 84.5, 54.3 ppm; IR (KBr) ν 3055, 2953, 2926, 1843, 2309, 2206, 1599, 1375, 1360, 1258, 1215, 1165, 1028, 968, 895, 845, 785, 694 cm⁻¹; HRMS (ESI) calcd for C₃₄H₂₃NO₂ ([M + H]⁺) 478.1807, found 478.1807.

(4-Nitrophenyl)(2-phenyl-1-(phenylethynyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3q). Red solid, mp 227–228 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.50 (d, J = 6.3 Hz, 1H), 9.40 (d, J = 8.1 Hz,1H), 7.85 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 6.6 Hz, 2H), 7.56–7.68 (m, 6H), 7.21–7.40 (m, 6H), 7.09 (s, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 185.1, 148.7, 145.0, 140.7, 133.1, 131.2, 130.9, 130.2, 129.0, 128.4, 128.1, 127.7, 126.9, 124.8, 124.5, 122.6, 114.8, 95.3, 84.6 ppm; IR (KBr) ν 3140, 3051, 2309, 2212, 1614, 1593, 1519, 1408, 1377, 1364, 1346, 1213, 1186, 970, 895, 851, 793 cm⁻¹; HRMS (ESI) calcd for C₃₃H₂₀N₂O₃ ([M + H]⁺) 493.1552, found 493.1538.

Phenyl(2-(p-tolyl)-1-(p-tolylethynyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3r). Yellow solid, mp 187–188 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.40 (d, J = 8.1 Hz, 1H), 9.10 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H), 7.56 (q, J = 7.8 Hz, 3H), 7.43 (d, J = 7.2 Hz, 2H), 7.28 (d, J = 7.8 Hz, 2H), 6.95–7.17 (m, 6H), 6.79(d, J = 7.5 Hz, 2H), 2.29(s, 3H),2.14(s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 186.8, 138.1, 136.9, 135.7, 133.1, 130.3, 129.8, 129.3, 128.8, 128.6, 128.1, 127.2, 127.0, 126.6, 126.5, 125.7, 124.5, 123.7, 123.2, 120.9, 119.9, 112.8, 98.3, 93.9, 83.6, 20.5, 20.2 ppm; IR (KBr) ν 3132, 3055, 3021, 2916, 2349, 2309, 2207, 1605, 1574, 1504, 1375, 1215, 970, 895, 812, 791, 735 cm⁻¹; HRMS (ESI) calcd for C₃₅H₂₅NO ([M + H]⁺) 476.2014, found 476.2021.

p-Tolyl(2-(p-tolyl)-1-(p-tolylethynyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3s). Yellow solid, mp 207–208 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.47 (d, J = 7.2 Hz, 1H), 9.09 (d, J = 7.2 Hz, 1H), 7.71(d, J = 6.9 Hz, 2H), 7.60 (t, J = 9.0 Hz, 2H), 7.41 (q, J = 7.4 Hz, 4H), 7.14–7.26 (m, 5H), 7.06 (d, J = 7.2 Hz, 1H), 6.88 (t, J = 9.0 Hz, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ 186.6, 141.1, 136.8, 135.6, 131.1, 129.9, 129.8, 128.9, 128.1, 127.1, 127.1, 126.9, 126.5, 125.6, 123.7, 123.2, 112.6, 111.9, 98.1, 93.8, 83.7, 20.4, 20.4, 20.1 ppm; IR (KBr) ν 3021, 2918, 2855, 2349, 2308, 2208, 2199, 1605, 1504, 1377, 1360, 1252, 1177, 970, 895, 810, 785 cm⁻¹; HRMS (ESI) calcd for C₃₆H₂₇NO ([M + H]⁺) 490.2171, found 490.2186.

(4-Methoxyphenyl)(2-(p-tolyl)-1-(p-tolylethynyl)pyrrolo[2,1-a]isoquinolin-3-yl)methanone (3t). Yellow solid, mp 190–191 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.46 (d, J = 6.9 Hz, 1H), 8.99 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 6.3 Hz, 2H), 7.56 (q, J = 9.0 Hz, 3H), 7.15–7.39 (m, 5H), 7.03 (d, J = 7.2 Hz, 2H), 6.92 (d, J = 6.3 Hz, 2H), 6.56 (d, J = 7.2 Hz, 2H), 3.73 (s, 3H), 2.37 (s, 3H), 2.25 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 185.6, 161.5, 136.8, 135.6, 132.7, 131.1, 129.9, 129.8, 128.1, 127.1, 127.0, 126.5, 125.6, 123.6, 123.1, 121.1, 120.0, 112.5, 111.9, 97.8, 93.9, 83.8, 54.3, 20.5, 20.1 ppm; IR (KBr) ν 3132, 3009, 2967, 2934, 2839, 2349, 2309, 1607, 1557, 1439, 1425, 1364, 1337, 1260, 1244, 1182, 1171, 1028, 966, 878, 833, 822, 752, 619 cm⁻¹; HRMS (ESI) calcd for C₃₆H₂₇NO₂ ([M + H]⁺) 506.2120, found 506.2117.

Dimethyl 3-benzoylpyrrolo[2,1-a]isoquinoline-1,2-dicarboxy-late (3u). ^15f. ¹H NMR (CDCl₃, 300 MHz) δ 8.78 (q, J = 6.9 Hz, 2H), 7.65 (m, 3H), 7.53 (m, 3H), 7.39 (d, J = 7.2 Hz, 2H), 7.08 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.16 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 186.2, 164.9, 163.6, 138.7, 131.6, 128.5, 128.1, 127.9, 127.4, 127.3, 126.2, 124.6, 123.2, 122.6, 114.9, 51.6, 50.9.

(4-nitrophenyl)(1-pentylpyrrolo[2,1-a]isoquinolin-3-yl)metha-none (3v). Yellow solid, mp 175–176 °C; ¹H NMR (CDCl₃, 300 MHz) δ 9.72 (d, J = 8.1 Hz, 1H), 8.43 (d, J = 8.1 Hz, 2H), 8.21 (d, J = 7.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.72–7.84 (m, 3H), 7.64 (s, 1H), 2.95 (t, J = 7.2 Hz, 2H), 1.74–1.79 (s, 2H), 1.38–1.43 (s, 2H), 1.20–1.25 (s, 2H), 0.95 (t, J = 7.1 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 195.8, 148.9, 144.0, 130.0, 129.0, 128.5, 128.3, 128.1, 127.4, 125.7, 124.9, 123.8, 122.9, 119.2, 112.3, 40.7, 30.1, 26.1, 21.5. 13.2; IR (KBr) ν 3126, 3084, 2964, 2951, 2927, 2872, 1680, 1622, 1595, 1519, 1438, 1400, 1350, 1332, 1234, 1201, 1163, 1043, 927, 854, 813, 756, 709 cm⁻¹; HRMS (ESI) calcd for C₂₄H₂₂BrN₂O₃ ([M + H]⁺) 465.0814, found 465.0819.

Acknowledgements

The work was partially supported by the National Natural Science Foundation of China (nos. 20872001, 21172001), and the Program for the NCET (NCET-10-0004) for their financial support.

References

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20. Crystallographic data for 3d: space group P1̄, a = 9.1922(11) Å, b = 10.0794(12) Å, c = 11.4797(13) Å, α = 105.7280(10)°, β = 97.6090(10)°, γ = 99.7730(10)°, V = 990.6(2) ų, T = 293(2)K, Z = 2. Crystallographic data for compound 3d (CCDC 847772) reported in this paper can be found in the ESI†.
21. Crystallographic data for 3t: space group P2₁/c, a = 12.4387(9) Å, b = 18.3179(14) Å, c = 11.7836(9) Å, α = 90°, β = 94.4610(10)°, γ = 90°, V = 2676.8(3) ų, T = 293(2)K, Z = 4. Crystallographic data for compound 3t (CCDC 847773) reported in this paper can be found in the ESI†.

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Footnote

† Electronic supplementary information (ESI) available: General procedure the syntheses of substrates and products, and ¹H and ¹³C NMR spectra data of all products. CCDC reference numbers 847772 and 847773. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21116e

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