Abstract
Synthesis of 3-(t-butylimino or cyclohexylimino)-2-aryl-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitriles was developed through a one-pot four- component high-yield reaction of malononitrile, an aldehyde, isoquinoline and t-butylisocyanide or cyclohexylisocyanide. The simple, mild, and efficient reaction is conducted in dichloromethane at room temperature.
Introduction
The design of multicomponent reactions (MCRs) is an important field of research in combinatorial chemistry [1, 2]. Because they are one-pot reactions, generally MCRs afford good yields and ready operations and are fundamentally different from two-component reactions in several aspects [3]. Therefore, great efforts have been and still are being made to find and develop new MCRs [4–8]. By contrast, the great potential of isocyanides for the development of MCRs lies in the diversity of bond-forming processes available, their functional group tolerance, and the high levels of chemo-, regio-, and stereoselectivity often observed [8]. By deploying such an approach for the preparation of heterocyclic compounds, a wide range of reaction types allow subtle structural modifications [9–11]. The isoquinoline skeleton is found in a large number of naturally occurring and synthetic biologically active heterocyclic compounds [12–16]. In particular, 1,2-dihydroisoquinoline derivatives are part of delivery systems that transport drugs through the otherwise highly impermeable blood-brain barrier [17–20]. These compounds also exhibit sedative [21], antidepressant [22, 23], antitumor, and antimicrobial activities [15, 24, 25].
Herein, we describe the synthesis 3-(t-butyliamino or cyclohexylimino)-2-aryl-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile derivatives through a one-pot four-component reaction of malononitrile, a benzaldehyde, isoquinoline and t-butylisocyanide or cyclohexylisocyanide in dichloromethane at room temperature.
Results and discussion
The reaction of malononitrile (1), a benzaldehyde (2), and isoquinoline (3) in the presence of isocyanide (4) proceeded smoothly in dichloromethane at room temperature and was completed within 2–3 days. The 1H NMR and 13C NMR spectra of the crude products clearly indicated the formation of pyrrolo[2,1-a]isoquinoline 5a–l in high yields (Equation 1, Cy is cyclohexyl).
The mass, IR, 1H NMR, and 13C NMR spectra of pure products are fully consistent with the given structures. For example, the mass spectrum of 5a displays the molecular ion [M+] signal at m/z 392. The IR spectrum of 5a shows absorptions at 2250 and 1668 cm-1, indicating the presence of –CN and –C=N– functional groups, respectively. The 1H NMR spectrum of 5a exhibits multiplet signals arising from five CH2 moieties of the cyclohexyl group at δ 1.01–1.80 and also a multiplet for the NCH moiety of the cyclohexyl group at δ 2.89. In addition, characteristic signals for two additional methine protons are observed at δ 4.59 and 5.28. The olefinic protons show two signals at δ 5.85 (d, J = 9.2 Hz) and δ 6.84 (d, J = 9.2 Hz). All aromatic protons resonate at δ 7.13–8.87. In the 13C NMR spectrum of 5a, six distinct saturated-carbon resonances can be found, and two cyano group signals are observed at δ 111.0 and 112.9. Partial assignments of these resonances are given in the experimental section. A suggested mechanism for formation of 5 is shown in Scheme 1. It can be suggested that the Knoevenagel intermediate product is generated by the reaction of malononitrile (1) with an aldehyde 2. Then the isocyanide 4 undergoes an addition reaction with the Knoevenagel intermediate product to generate another intermediate product A, the addition reaction of which with isoquinoline (3) generates a direct precursor B to the observed product 5. An analogous mechanism has been proposed in the literature for related transformations [26–28].
![Scheme 1 Proposed mechanism for the formation of dihydropyrrolo[2,1-a]isoquinolines 5.](/document/doi/10.1515/hc-2013-0004/asset/graphic/hc-2013-0004_scheme1.jpg)
Proposed mechanism for the formation of dihydropyrrolo[2,1-a]isoquinolines 5.
Conclusion
A four-component synthesis of dihydropyrrolo[1,2-a]isoquinolines via reaction of malononitrile, a benzaldehyde, isoquinoline, and an isocyanide may be of interest in the pharmaceutical chemistry field. The procedure is simple and the products are obtained in high yield.
Experimental
General
Compounds 1–4 were obtained from Fluka, Merck, and Aldrich companies and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 on a Bruker DRX-400 Avance spectrometer. IR spectra were recorded in KBr pellets on a Shimadzu IR-460 spectrometer. Mass spectra were recorded on a Finnigan-Mat 8430 spectrometer operating at an ionization potential of 70 eV.
General procedure for the preparation of dihydropyrrolo[1,2-a]isoquinolines 5a–l
To a magnetically stirred mixture of a benzaldehyde (1 mmol), malonitrile (1 mmol) and isoquinoline (1 mmol) in dichloromethane (10 mL), a solution of t-butyl isocyanide or cyclohexyl isocyanide (1.1 mmol) in dichloromethane (3 mL) was dropwise added over 5 min at room temperature. After completion of the reaction [approx. 48–72 h; TLC (EtOAc/hexane, 1:5) monitoring] at room temperature, the solvent was removed; and the residue was washed with a mixture of dichloromethane/ethyl acetate (1:1, 2 × 3 mL). Product 5 was then collected by filtration.
3-(Cyclohexylimino)-2-phenyl-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5a)
The cream powder was obtained in 92% yield; mp 147–149°C; IR: 2250 (CN), 1668 cm-1 (C=N); 1H NMR: δ 1.01–1.80 (m, 10H), 2.89 (m, 1H), 4.59 (s, 1H), 5.28 (s, 1H), 5.96 (d, 1H, J = 9.2 Hz), 6.84 (d, J = 9.2 Hz), 7.13 (t, 1H, J = 7.4 Hz), 7.21 (d, 1H, J = 7.4 Hz), 7.30 (dd, 1H, J1 = 7.8 Hz, J2 = 6.4 Hz), 7.31–7.46 (m, 5H), 8.87 (d, 1H, J = 8.3 Hz); 13C NMR: δ 151.7, 134.3, 130.3, 129.7, 129.5, 128.6, 128.2, 127.8, 125.2, 125.1, 122.8, 119.1, 118.5, 112.9, 111.0, 63.0, 57.8, 51.4, 42.7, 33.7, 33.1, 24.7, 23.5, 23.3; MS: m/z (%) 392(M+, 8), 368 (43), 339 (16), 282 (30), 264 (43), 236 (53), 129 (32), 83 (56), 69 (57), 57 (100), 43 (80), 41 (39). Anal. Calcd for C26H24N4: C, 79.56; H, 6.16; N, 14.27. Found: C, 79.48; H, 6.08; N, 14.20.
3-(Cyclohexylimino)-2-(p-tolyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5b)
The cream powder was obtained in 84% yield; mp 129–131°C; IR: 2251 (CN), 1668 cm-1 (C=N); 1H NMR: δ 1.00–1.56 (m, 10H), 2.34 (s, 3H), 3.03 (m, 1H), 4.61 (s, 1H), 5.29 (s, 1H), 6.01 (d, 1H, J = 9.2 Hz), 6.51 (d, J = 9.2 Hz), 7.11 (t, 1H, J = 7.6 Hz), 7.13 (d, 1H, J = 7.6), 7.22–7.31 (m, 5H), 8.91 (d, 1H, J = 8.3 Hz); 13C NMR: δ 151.1, 138.3, 136.1, 131.1, 129.9, 128.8, 127.7, 125.4, 123.3, 122.4, 121.0, 117.6, 116.3, 112.6, 11.2, 58.8, 57.3, 49.7, 42.8, 33.5, 33.1, 24.7, 23.3, 23.2, 20.12; MS: m/z (%): 406(M+, 5), 379 (40), 295 (11), 206 (12), 129 (100), 91 (24), 55 (45), 41(21). Anal. Calcd for C27H26N4: C, 79.77; H, 6.45; N, 13.78. Found: C, 79.71; H, 6.51; N, 13.89.
2-(4-Chlorophenyl)-3-(cyclohexylimino)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5c)
The pale powder was obtained in 85% yield; mp 131–133°C; IR: 2241 (CN), 1667 cm-1 (C=N); 1H NMR: δ 1.01–1.80 (m, 10H), 2.91 (m, 1H), 4.96 (s, 1H), 5.26 (s, 1H), 5.91 (d, 1H, J = 9.2 Hz), 6.54 (d, 1H, J = 9.2 Hz), 7.09 (t, 1H, J = 7.6 Hz), 7.16 (d, 1H, J = 7.6 Hz), 7.30–7.35 (m, 3H), 7.51 (d, 2H, J = 8.2 Hz), 8.93 (d, 1H, J=8.2 Hz); 13C NMR: δ 157.7, 141.2, 136.3, 130.3, 129.5, 129.2, 128.9, 128.5, 126.1, 123.0, 122.8, 119.3, 118.1, 112.1, 110.3, 61.2, 58.6, 49.5, 42.9, 33.8, 33.3, 24.6, 23.2, 23.1; MS: m/z (%) 428 (M++2, 4), 426 (M+, 12), 401 (20), 153 (10), 129 (100), 111 (21), 83 (41), 55 (9). Anal. Calcd for C26H23ClN4: C, 73.14; H, 5.43; N, 13.12. Found: C, 73.21; H, 5.59; N, 13.09.
3-(Cyclohexylimino)-2-(4-fluorophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5d)
The pale powder was obtained in 87% yield; mp 156–158°C; IR: 2253 (CN), 1668 cm-1 (C=N); 1H NMR: δ 1.03–1.81 (m, 10H), 2.98 (m, 1H), 4.82 (s, 1H), 5.45 (s, 1H), 5.91 (d, 1H, J = 9.8 Hz), 6.81 (d, 1H, J = 9.8 Hz), 7.11 (t, 1H, J = 7.4 Hz), 7.16–7.31 (m, 6H), 8.91 (d, 1H, J = 8.3 Hz); 13C NMR: δ 163.7, 152.1, 136.0, 130.1, 129.4, 128.7, 126.2, 128.1, 123.3, 122.1, 119.9, 117.1, 116.9, 116.4, 115.3, 113.2, 111.3, 60.8, 60.1, 49.9, 42.9, 33.7, 33.4, 24.4, 23.2, 23.1; MS: m/z (%) 410 (M+, 3), 385 (34), 264 (25), 282 (10), 237 (44), 129 (100), 83 (69), 55 (82). Anal. Calcd for C26H23FN4: C, 76.08; H, 5.65; N, 13.65. Found: C, 76.11; H, 5.60; N, 13.54.
2-(4-Bromophenyl)-3-(cyclohexylimino)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5e)
The pale powder was obtained in 89% yield; mp 147–149°C; IR: 2248 (CN), 1673 cm-1 (C=N); 1H NMR: δ 1.02–1.76 (m, 10H), 2.97 (m, 1H), 4.93 (s, 1H), 5.31 (s, 1H), 5.84 (d, 1H, J = 9.8 Hz), 6.84 (d, 1H, J = 9.8 Hz), 7.18 (t, 1H, J = 7.4 Hz), 7.23 (d, 1H, J = 7.4 Hz), 7.29 (t, 1H, J = 7.8 Hz), 7.31 (d, 2H, J = 8.4 Hz), 7.69 (d, 2H, J = 8.4 Hz), 8.96 (d, 1H, J = 7.8 Hz); 13C NMR: δ 151.2, 134.6, 132.7, 129.8, 129.4, 129.1, 128.8, 127.1, 123.6, 123.2, 122.1, 119.1, 117.6, 112.3, 111.1, 61.6, 59.8, 49.9, 42.8, 33.6, 32.9, 30.3, 23.4, 23.1; MS: m/z (%) 472 (M++2, <1), 470 (M+, 1), 447 (31), 445 (25), 362 (78), 361 (100), 281 (70), 280 (61), 129 (42), 55(35). Anal. Calcd for C26H23BrN4: C, 66.25; H, 4.92; N, 11.89. Found: C, 66.33; H, 4.98; N, 11.81.
3-(Cyclohexylimino)-2-(4-nitrophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5f)
The brown powder was obtained in 81% yield; mp 141–143°C; IR: 2237 (CN), 1665 cm-1 (C=N); 1H NMR: δ 1.05–1.70 (m, 10H), 3.05 (m, 1H), 4.74 (s, 1H), 5.29 (s, 1H), 5.92 (d, 1H, J = 9.8 Hz), 6.81 (d, 1H, J = 9.8 Hz), 7.11 (t, 1H, J = 7.8 Hz), 7.19 (d, 1H, J = 7.8 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.69 (d, 2H, J = 8.6 Hz), 8.32 (d, 2H, J = 8.6 Hz), 8.89 (d, 1H, J = 7.8 Hz); 13C NMR: δ 149.2, 148.1, 137.4, 135.7, 131.0, 129.2, 128.6, 126.5, 123.7, 122.4, 121.3, 119.9, 117.4, 112.3, 110.6, 61.7, 60.3, 50.1, 42.6, 33.5, 33.1, 24.2, 23.1, 22.1; MS: m/z (%) 437(M+, <1), 410 (20), 281 (17), 206 (14), 129 (100), 83 (81), 55 (26). Anal. Calcd for C26H23N5O2: C, 71.38; H, 5.30; N, 16.01. Found: C, 71.40; H, 5.49; N, 16.21.
3-(t-Butylimino)-2-phenyl-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5g)
The cream powder was obtained in 89% yield; mp 141–143°C; IR: 2253 (CN), 1666 cm-1 (C=N); 1H NMR: δ 1.39 (s, 9H), 4.51 (s, 1H), 5.19 (s, 1H), 5.91 (d, 1H, J = 9.2 Hz), 6.73 (d, 1H, J = 9.2 Hz), 7.19 (t, 1H, J = 7.6 Hz), 7.24 (d, 1H, J = 7.6 Hz), 7.29 (dd, 1H, J1 = 7.4 Hz, J2 = 6.5 Hz), 7.35–7.44 (m, 5H), 8.91 (d, 1H, J = 8.2 Hz); 13C NMR: δ 152.3, 134.1, 130.6, 129.7, 129.5, 128.6, 128.2, 127.9, 125.9, 125.0, 123.4, 120.3, 118.9, 112.7, 111.2, 63.3, 56.9, 52.0, 42.5, 29.1; MS: m/z (%) 366(M+, 3), 341 (19), 313 (11), 282 (34), 238 (49), 211 (33), 129 (42), 83 (61), 57 (100), 42 (70), 41 (43). Anal. Calcd for C24H22N4: C, 78.66; H, 6.05; N, 15.29. Found: C, 78.54; H, 6.12; N, 15.34.
3-(t-Butylimino)-2-(p-tolyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5h)
The cream powder was obtained in 92% yield; mp 132–133°C; IR: 2250 (CN), 1666 cm-1 (C=N); 1H NMR: δ 1.38 (s, 9H), 2.36 (s, 3H), 4.66 (s, 1H), 5.21 (s, 1H), 6.01 (d, 1H, J = 8.7 Hz), 6.47 (d, CH, J = 8.7 Hz), 7.14 (t, 1H, J = 7.8 Hz), 7.18 (d, 1H, J = 7.8 Hz), 7.24–7.32 (m, 5H), 8.87 (d, 1H, J = 8.3 Hz); 13C NMR: δ 151.9, 138.3, 136.1, 131.3, 129.4, 128.7, 127.5, 124.7, 124.4, 122.4, 122.1, 116.9, 115.8, 112.4, 111.3, 58.4, 57.7, 51.9, 42.3, 29.1, 20.7; MS: m/z (%) 380(M+, 2), 341 (21), 282 (19), 238 (41), 211 (15), 129 (100), 91 (25), 55 (31), 41(28). Anal. Calcd for C25H24N4: C, 78.92; H, 6.36; N, 14.73. Found: C, 78.79; H, 6.24; N, 14.81.
3-(t-Butylimino)-2-(4-chlorophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5i)
The pale powder was obtained in 87% yield; mp 133–135°C; IR: 2250 (CN), 1666 cm-1 (C=N); 1H NMR: δ 1.38 (s, 9H), 4.94 (s, 1H), 5.29 (s, 1H), 5.89 (d, 1H, J = 9.1 Hz), 6.50 (d, J = 9.1 Hz), 7.11 (t, 1H, J = 7.4 Hz), 7.18 (d, 1H, J = 7.4 Hz), 7.25–7.30 (m, 3H), 7.51 (d, 2H, J = 7.8 Hz), 8.93 (d, 1H, J =7.8 Hz); 13C NMR: δ 158.3, 141.0, 136.7, 130.4, 129.6, 129.5, 128.8, 128.2, 127.0, 123.1, 122.4, 119.8, 118.4, 112.3, 111.4, 61.4, 58.4, 52.0, 41.4, 29.1; MS: m/z (%) 402 (M++2, 3), 400 (M+, 9), 375 (15), 282 (19), 238 (9), 129 (100), 115 (21), 83 (53), 55 (11). Anal. Calcd for C24H21ClN4: C, 73.14; H, 5.43; N, 13.12. Found: C, 73.21; H, 5.57; N, 13.04.
3-(t-Butylimino)-2-(4-fluorophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5j)
The pale powder was obtained in 82% yield; mp 143–145°C; IR: 2250 (CN), 1666 cm-1 (C=N); 1H NMR: δ 1.38 (s, 9H), 4.80 (s, 1H), 5.48 (s, 1H), 5.86 (d, 1H, J = 9.2 Hz), 6.93 (d, 1H, J = 9.2 Hz), 7.11 (t, 1H, J = 7.6 Hz), 7.19–7.30 (m, 6H), 8.87 (d, 1H, J =8.2 Hz); 13C NMR: δ 163.4, 151.7, 136.3, 131.0, 129.7, 128.6, 127.6, 126.4, 123.8, 122.1, 120.3, 117.3, 116.9, 116.7, 115.1, 113.5, 111.4, 60.6, 59.4, 51.9, 42.6, 29.3; MS: m/z (%) 384 (M+, 1), 359 (31), 313 (12), 282 (19), 238 (34), 211 (19), 128 (100), 83 (60), 55 (87), 41 (14). Anal. Calcd for C24H21FN4: C, 74.98; H, 5.51; N, 14.57. Found: C, 74.83; H, 5.63; N, 14.63.
2-(4-Bromophenyl)-3-(t-butylimino)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5k)
The pale powder was obtained in 90% yield; mp 156–158°C; IR: 2251 (CN), 1668 cm-1 (C=N); 1H NMR: δ 1.36 (s, 9H), 4.98 (s, 1H), 5.37 (s, 1H), 5.89 (d, 1H, J = 9.1 Hz), 6.79 (d, 1H, J = 9.1 Hz), 7.16 (t, 1H, J = 7.6 Hz), 7.28 (d, 1H, J = 7.6), 7.33 (d, 2H, J = 8.3 Hz), 7.39 (t, 1H, J = 7.4 Hz), 7.64 (d, 2H, J = 8.3 Hz), 8.96 (d, 1H, J = 7.4 Hz); 13C NMR: δ 151.7, 133.9, 132.6, 129.7, 129.5, 129.2, 128.6, 127.8, 123.1, 123.7, 122.5, 118.6, 117.2, 112.9, 111.4, 60.8, 59.5, 52.3, 42.6, 29.3; MS: m/z (%)446 (M++2, <1), 444 (M+, 1), 392 (28), 313 (29), 283 (56), 238 (68), 211 (49), 129 (100), 55(31). Anal. Calcd for C24H21BrN4: C, 64.73; H, 4.75; N, 12.58. Found: C, 67.59; H, 4.88; N, 12.72.
3-(t-Butylimino)-2-(4-nitrophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,1(10bH)-dicarbonitrile (5l)
The brown powder was obtained in 87% yield; mp 152–154°C; IR: 2250 (CN), 1668 cm-1 (C=N); 1H NMR: δ 1.38 (s, 9H), 4.81 (s, 1H), 5.36 (s, 1H), 5.92 (d, 1H, J = 9.2 Hz), 6.81 (d, 1H, J = 9.2 Hz), 7.14 (t, 1H, J = 7.8 Hz), 7.21 (d, 1H, J = 7.8 Hz), 7.37 (t, 1H, J = 7.8 Hz), 7.64 (d, 2H, J = 8.4 Hz), 8.21 (d, 2H, J = 8.4 Hz), 8.91 (d, 1H, J = 7.8 Hz); 13C NMR: δ 151.1, 146.9, 137.0, 135.4, 131.3, 129.6, 129.1, 126.5, 123.9, 122.6, 121.7, 119.8, 118.0, 112.1, 110.9, 61.3, 60.1, 52.6, 42.3, 29.1; MS: m/z (%) 411(M+, <1), 386 (16), 358 (11), 282 (18), 129 (100), 84 (69), 55 (28), 41 (15). Anal. Calcd for C24H21N5O2: C, 70.06; H, 5.14; N, 17.02. Found: C, 70.19; H, 5.22; N, 16.93.
I gratefully acknowledge financial support from the Research Council of Khoy Branch, Islamic Azad University.
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