HETEROCYCLES

Note | Regular issue | Vol. 81, No. 6, 2010, pp. 1467-1484
Received, 1st March, 2010, Accepted, 15th April, 2010, Published online, 16th April, 2010.
DOI: 10.3987/COM-10-11936

■ Synthesis of Dihydroindoles and Tetrahydroquinolines by the Intramolecular Diels-Alder Reaction of N-Alkenylated 2-Acylamino-3-furancarbonitriles

Hiroshi Maruoka,* Fumi Okabe, Yoshimichi Koutake, Eiichi Masumoto, Toshihiro Fujioka, and Kenji Yamagata

Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

An approach to dihydroindoles and tetrahydroquinolines from N-alkenylated 2-acylamino-3-furancarbonitriles via a [4 + 2] cycloaddition reaction is described. Thermal treatment of N-alkenylated 2-acylamino-3- furancarbonitriles 5a−d, 6a−d, 9a−d, and 10a−d, which were prepared from 2-acylamino-3-furancarbonitriles 3a−d and/or 4a−d and 4-bromo-1-butene and/or 5-bromo-1-pentene, caused an intramolecular Diels-Alder reaction to give the corresponding dihydroindole and tetrahydroquinoline derivatives 7a−d, 8a−d, 11a−d, and 12a−d. This method has the advantage of easier work-up procedure.

Heterocyclic compounds, particularly five- and six-membered ring compounds, have occupied a prominent place among the organic compounds in view of their diverse biological activities. Dihydroindole derivatives, namely indolines, are common structural elements in many biologically active compounds and natural products.1−6 Tetrahydroquinoline derivatives have also attracted considerable interest due to their importance as synthetic intermediates, pesticides, and pharmaceutical products with a broad range of physiological and biological properties.7−11 For the reasons given above, a great number of methods have been developed for synthesis of dihydroindoles12−20 and tetrahydroquinolines.21−24
In connection with our current research interests in the synthesis of heterocyclic compounds,25−29 we recently reported the synthesis of 4-(cyclic amino)-substituted phthalimide derivatives through a Diels-Alder reaction of maleimides with 2-(cyclic amino)-substituted 3-furancarbonitriles as starting materials.30 Because furan derivatives are useful and versatile synthetic intermediates for heterocyclic compounds, the development of methodologies for the synthesis of such compounds are of significant interest. Among the most significant examples in the furan chemistry, Diels-Alder cycloadditions using this heterocycle as the 4π diene are of particular interest. As part of our efforts in developing new routes in heterocyclic synthesis, we herein describe an efficient procedure for the synthesis of dihydroindole and tetrahydroquinoline derivatives 7, 8, 11, and 12 by an intramolecular Diels-Alder reaction of N-alkenylated 2-acylamino-3-furancarbonitriles 5, 6, 9, and 10.
Initially, we examined the synthesis of 2-acylamino-3-furancarbonitriles 3a−d and 4a−d starting from 2-amino-3-furancarbonitriles 1a−d, which were prepared from phenacylmalononitriles and piperidine according to our previous procedure (Scheme 1).31−33 Unfortunately, thermal treatment of 1a−d with acetic anhydride gave 2-(diacetylated amino)-3-furancarbonitriles 2a−d (2a: 49%, 2b: 54%, 2c: 55%, 2d: 67%) together with 3a−d as minor products. On the basis of this result, we tried to synthesize the desired 3a−d from 1a−d and acetic anhydride in a one-pot process, via a deacetylation reaction of 2a−d. Indeed, when a mixture of 1a−d and acetic anhydride was refluxed for 3 h and then the reaction mixture was treated with sodium hydroxide in aqueous ethanol at room temperature for 30 min, the desired 2-acetylamino-3-furancarbonitriles 3a−d were obtained in good yields (3a: 76%, 3b: 68%, 3c: 75%, 3d: 69%). While, the reaction of 1a−d with benzoyl chloride in pyridine at 60 °C for 2 h afforded the desired 2-benzoylamino-3-furancarbonitriles 4a−d (4a: 73%, 31 4b: 76%, 4c: 80%, 4d: 78%). Elemental analyses, mass spectra, 1H and 13C NMR spectra of 3a−d and 4b−d are consistent with the assigned structures (see experimental section).

We next tried to construct dihydroindole derivatives 7a−d and 8a−d from N-3-buten-1-ylated 2-acylamino-3-furancarbonitriles 5a−d and 6a−d (Scheme 2). Thus, compounds 3a−d were reacted with 4-bromo-1-butene in the presence of sodium hydride in DMF at room temperature to provide the corresponding compounds 5a−d in moderate yields (entries 1−4 in Table 1). Under the same conditions, however, the reaction of 4a−d with 4-bromo-1-butene gave the corresponding compounds 6a−d in very low yields (entries 5−8 in Table 1). Although we examined several reaction conditions, e.g. substrate/base molar ratio and solvent, our attempts were unacceptable with respect to yield. In this case, it seemed possible that 4-bromo-1-butene would easily undergo the elimination reaction of hydrogen bromide to afford 1,3-butadiene. Hence, N-alkenylation reaction of 4a−d did not proceed as a major reaction. Treatment of 5a−d and 6a−d in boiling 1,2-dichlorobenzene for 4 h caused an intramolecular Diels-Alder reaction to furnish the desired dihydroindole derivatives 7a−d and 8a−d in good yields (Table 2). By comparison of the IR spectra, NMR spectra, mass spectra and elemental analyses of 5−8, it seems that the structural assignments given to these compounds are correct (see experimental section).

By analogy process given above, we examined the synthesis of tetrahydroquinoline derivatives 11a−d and 12a−d from N-4-penten-1-ylated 2-acylamino-3-furancarbonitriles 9a−d and 10a−d (Scheme 2). As a consequence, N-alkenylation reaction of compounds 3a−d and 4a−d with 5-bromo-1-pentene in the presence of sodium hydride in DMF at 80 °C for 5 h gave the corresponding compounds 9a−d and 10a−d in moderate yields (Table 3). Thermal treatment of 9a−d and 10a−d in 1-methyl-2-pyrrolidinone for 16−20 h caused an intramolecular Diels-Alder reaction to provide the desired tetrahydroquinoline derivatives 11a−d and 12a−d in moderate yields (Table 4). In this reaction, the use of 1-methyl-2-pyrrolidinone as a solvent was better than that of 1,2-dichlorobenzene in the case of the synthesis of dihydroindoles. These products 9−12 gave satisfactory elemental analyses and spectroscopic data (IR, 1H NMR, 13C NMR, mass) consistent with their assigned structures (see experimental section).
These intramolecular Diels-Alder reactions of 5a−d, 6a−d, 9a−d, and 10a−d are assumed to proceed through the formation of the oxabridged cycloadducts A and B. Subsequently, a ring-opening/dehydration reaction of cycloadducts A and B easily occurs and then dihydroindole and tetrahydroquinoline derivatives 7, 8, 11, and 12 would be produced.

During our study of the synthesis of tetrahydroquinoline derivatives, we found that compound 11a reacted with sodium hydroxide in boiling aqueous methanol for 30 min to give the pyrido[3,2,1-ij]quinazoline derivative 13 in 51% yield. The formation of 13 could be explained by possible mechanism presented in Scheme 3. The reaction of 11a with sodium hydroxide probably causes an intramolecular cycloaddition to afford the intermediate C, which undergoes a Dimroth-type rearrangement34−38 to yield the pyrido[3,2,1-ij]quinazoline derivative 13.
In conclusion, the intramolecular Diels-Alder reaction of N-alkenylated 2-acylamino-3-furancarbonitriles proceeds smoothly to furnish the corresponding dihydroindole and tetrahydroquinoline derivatives. Functionalized dihydroindole and tetrahydroquinoline derivatives are important synthons in organic synthesis and for the preparation of biologically active compounds with interest in medicinal chemistry.

EXPERIMENTAL
All melting points are uncorrected. The IR spectra were recorded on a JASCO FT/IR-4100 spectrometer. The 1H and 13C NMR spectra were measured with a JEOL JNM-A500 spectrometer at 500.00 and 125.65 MHz, respectively. The 1H and 13C chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane as internal standard. Positive FAB mass spectra were obtained on a JEOL JMS-700T spectrometer. Elemental analyses were performed on YANACO MT-6 CHN analyzer. The starting compounds, 2-amino-3-furancarbonitriles 1a−d, were prepared in this laboratory according to the procedure reported in literature.31−33
General procedure for the preparation of 3a−d from 1a−d and acetic anhydride.
A mixture of 1a−d (20 mmol) and acetic anhydride (30 mL, 0.317 mol) was refluxed for 3 h. After removal of the solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed with water, and dried. A mixture of the crude product in 5% aqueous NaOH (5 mL) and EtOH (30 mL) was stirred at rt for 30 min. After removal of the solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed with water, dried, and recrystallized from acetone to give 3a−d.
N-(3-Cyano-5-phenyl-2-furanyl)acetamide (3a)
Colorless prisms (3.42 g, 76%), mp 215−216 °C; IR (KBr): 3187, 3120 (NH), 2223 (CN), 1682 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.14 (s, 3H, COCH3), 7.32 (s, 1H, 4-H), 7.34−7.37 (m, 1H, aryl H), 7.44−7.48 (m, 2H, aryl H), 7.64−7.66 (m, 2H, aryl H), 11.38 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 22.7 (COCH3), 84.9 (C-3), 107.3 (C-4), 113.3 (CN), 123.3, 128.26, 128.28, 129.0 (C aryl), 147.4 (C-5), 151.0 (C-2), 167.7 (CO); MS: m/z 227 [M+H]+. Anal. Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C, 69.03; H, 4.53; N, 12.38.
N-[3-Cyano-5-(4-methoxyphenyl)-2-furanyl]acetamide (3b)
Colorless needles (3.48 g, 68%), mp 221−222 °C; IR (KBr): 3258, 3195, 3126 (NH), 2234 (CN), 1704 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.12 (s, 3H, COCH3), 3.80 (s, 3H, OCH3), 7.01−7.04 (m, 2H, aryl H), 7.13 (s, 1H, 4-H), 7.56−7.59 (m, 2H, aryl H), 11.26 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 22.6 (COCH3), 55.2 (OCH3), 85.1 (C-3), 105.3 (C-4), 113.4 (CN), 114.5, 121.0, 125.0 (C aryl), 147.7 (C-5), 150.4 (C-2), 159.3 (C aryl), 167.6 (CO); MS: m/z 257 [M+H]+. Anal. Calcd for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93. Found: C, 65.66; H, 4.75; N, 10.92.
N-[3-Cyano-5-(4-methylphenyl)-2-furanyl]acetamide (3c)
Colorless columns (3.62 g, 75%), mp 192−193 °C; IR (KBr): 3242, 3192, 3124 (NH), 2224 (CN), 1681 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.13 (s, 3H, COCH3), 2.33 (s, 3H, CH3), 7.22 (s, 1H, 4-H), 7.25−7.28 (m, 2H, aryl H), 7.52−7.55 (m, 2H, aryl H), 11.31 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 20.7 (CH3), 22.7 (COCH3), 85.0 (C-3), 106.4 (C-4), 113.3 (CN), 123.3, 125.6, 129.5, 137.9 (C aryl), 147.7 (C-5), 150.7 (C-2), 167.6 (CO); MS: m/z 241 [M+H]+. Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.02; H, 5.13; N, 11.67.
N-[5-(4-Chlorophenyl)-3-cyano-2-furanyl]acetamide (3d)
Pale yellow prisms (3.61 g, 69%), mp 214−215 °C; IR (KBr): 3187, 3120 (NH), 2226 (CN), 1685 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.13 (s, 3H, COCH3), 7.37 (s, 1H, 4-H), 7.51−7.54 (m, 2H, aryl H), 7.64−7.67 (m, 2H, aryl H), 11.41 (br s, 1H, NH); 13C NMR (DMSO-d6): δ 22.7 (COCH3), 84.8 (C-3), 108.1 (C-4), 113.2 (CN), 125.0, 127.1, 129.0, 132.7 (C aryl), 146.1 (C-5), 151.3 (C-2), 167.6 (CO); MS: m/z 261 [M+H]+. Anal. Calcd for C13H9ClN2O2: C, 59.90; H, 3.48; N, 10.75. Found: C, 59.87; H, 3.56; N, 10.76.
General procedure for the preparation of 4b−d from 1b−d and benzoyl chloride.
A mixture of 1b−d (20 mmol) and benzoyl chloride (3.37 g, 24 mmol) in pyridine (20 mL) was stirred at 60 °C for 2 h. After removal of the solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed with water, dried, and recrystallized from acetone to yield 4b−d. 4a was prepared in this laboratory according to the procedure reported in literature.31
N-[3-Cyano-5-(4-methoxyphenyl)-2-furanyl]benzamide (4b)
Pale yellow needles (4.85 g, 76%), mp 208−209 °C; IR (KBr): 3244 (NH), 2231 (CN), 1683 (CO) cm-1; 1H NMR (DMSO-d6): δ 3.81 (s, 3H, OCH3), 7.03−7.07 (m, 2H, aryl H), 7.24 (s, 1H, 4-H), 7.56−7.61 (m, 2H, aryl H), 7.63−7.70 (m, 3H, aryl H), 8.02−8.05 (m, 2H, aryl H), 11.64 (s, 1H, NH); 13C NMR (DMSO-d6): δ 55.2 (OCH3), 87.1 (C-3), 105.4 (C-4), 113.3 (CN), 114.5, 121.0, 125.1, 128.0, 128.6, 132.1, 132.7 (C aryl), 148.6 (C-5), 150.6 (C-2), 159.5 (C aryl), 164.6 (CO); MS: m/z 319 [M+H]+. Anal. Calcd for C19H14N2O3: C, 71.69; H, 4.43; N, 8.80. Found: C, 71.62; H, 4.54; N, 8.78.
N-[3-Cyano-5-(4-methylphenyl)-2-furanyl]benzamide (4c)
Pale yellow needles (4.85 g, 80%), mp 242−243 °C; IR (KBr): 3253 (NH), 2233 (CN), 1690 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.34 (s, 3H, CH3), 7.28−7.30 (m, 2H, aryl H), 7.33 (s, 1H, 4-H), 7.57−7.62 (m, 4H, aryl H), 7.66−7.70 (m, 1H, aryl H), 8.03−8.06 (m, 2H, aryl H), 11.69 (s, 1H, NH); 13C NMR (DMSO-d6): δ 20.7 (CH3), 86.9 (C-3), 106.5 (C-4), 113.3 (CN), 123.4, 125.6, 128.0, 128.6, 129.5, 132.0, 132.7, 138.1 (C aryl), 148.5 (C-5), 150.9 (C-2), 164.6 (CO); MS: m/z 303 [M+H]+. Anal. Calcd for C19H14N2O2: C, 75.48; H, 4.67; N, 9.27. Found: C, 75.54; H, 4.77; N, 9.28.
N-[5-(4-Chlorophenyl)-3-cyano-2-furanyl]benzamide (4d)
Yellow prisms (5.06 g, 78%), mp 241−242 °C; IR (KBr): 3245 (NH), 2236 (CN), 1691 (CO) cm-1; 1H NMR (DMSO-d6): δ 7.47 (s, 1H, 4-H), 7.53−7.61 (m, 4H, aryl H), 7.66−7.74 (m, 3H, aryl H), 8.02−8.06 (m, 2H, aryl H), 11.78 (s, 1H, NH); 13C NMR (DMSO-d6): δ 86.7 (C-3), 108.2 (C-4), 113.1 (CN), 125.1, 127.1, 128.1, 128.6, 129.1, 132.0, 132.76, 132.84 (C aryl), 147.0 (C-5), 151.5 (C-2), 164.5 (CO); MS: m/z 323 [M+H]+. Anal. Calcd for C18H11ClN2O2: C, 66.99; H, 3.44; N, 8.68. Found: C, 66.95; H, 3.51; N, 8.72.
General procedure for the preparation of 5a−d and 6a−d from 3a−d and/or 4a−d and 4-bromo-1-butene.
To an ice-cooled and stirred solution of 3a−d and 4a−d (5 mmol) in DMF (5 mL) was added 60% NaH (0.24 g, 6 mmol). The stirring was continued at rt until evolution of gas ceased. To the obtained mixture was added 4-bromo-1-butene (1.35 g, 10 mmol) with stirring and then the mixture was stirred at rt for 48 h. After removal of the solvent in vacuo, cold water was added to the residue. The resulting mixture was extracted with Et2O (60 mL). The extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with CH2Cl2 as the eluent to afford 5a−d and 6a−d.
N-3-Buten-1-yl-N-(3-cyano-5-phenyl-2-furanyl)acetamide (5a)
Yellow oil (0.84 g, 60%); IR (neat): 2237 (CN), 1698 (CO) cm-1; 1H NMR (CDCl3): δ 2.09 (s, 3H, COCH3), 2.36−2.41 (m, 2H, 3-butene 2-H), 3.85 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 5.04−5.14 (m, 2H, 3-butene 4-H), 5.70−5.80 (m, 1H, 3-butene 3-H), 6.79 (s, 1H, furan 4-H), 7.37−7.47 (m, 3H, aryl H), 7.60−7.63 (m, 2H, aryl H); 13C NMR (CDCl3): δ 22.0 (COCH3), 32.8 (3-butene C-2), 47.7 (3-butene C-1), 94.0 (furan C-3), 105.8 (furan C-4), 112.1 (CN), 117.5 (3-butene C-4), 124.1, 128.2, 129.1, 129.4 (C aryl), 134.0 (3-butene C-3), 152.4 (furan C-5), 154.3 (furan C-2), 169.7 (CO); MS: m/z 281 [M+H]+. Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.88; H, 5.86; N, 9.96.
N-3-Buten-1-yl-N-[3-cyano-5-(4-methoxyphenyl)-2-furanyl]acetamide (5b)
Colorless needles (1.03 g, 66%), mp 91−92 °C (Et2O); IR (KBr): 2231 (CN), 1714 (CO) cm-1; 1H NMR (CDCl3): δ 2.08 (s, 3H, COCH3), 2.35−2.41 (m, 2H, 3-butene 2-H), 3.83 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 3.85 (s, 3H, OCH3), 5.03−5.13 (m, 2H, 3-butene 4-H), 5.70−5.80 (m, 1H, 3-butene 3-H), 6.64 (s, 1H, furan 4-H), 6.94−6.98 (m, 2H, aryl H), 7.53−7.56 (m, 2H, aryl H); 13C NMR (CDCl3): δ 22.0 (COCH3), 32.7 (3-butene C-2), 47.6 (3-butene C-1), 55.4 (OCH3), 94.0 (furan C-3), 104.1 (furan C-4), 112.3 (CN), 114.6 (C aryl), 117.4 (3-butene C-4), 121.0, 125.8 (C aryl), 134.1 (3-butene C-3), 152.4 (furan C-5), 153.7 (furan C-2), 160.6 (C aryl), 169.8 (CO); MS: m/z 311 [M+H]+. Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.64; H, 5.91; N, 9.03.
N-3-Buten-1-yl-N-[3-cyano-5-(4-methylphenyl)-2-furanyl]acetamide (5c)
Colorless columns (0.82 g, 56%), mp 69−70 °C (Et2O); IR (KBr): 2236 (CN), 1693 (CO) cm-1; 1H NMR (CDCl3): δ 2.08 (s, 3H, COCH3), 2.35−2.41 (m, 2H, 3-butene 2-H), 2.39 (s, 3H, CH3), 3.84 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 5.03−5.13 (m, 2H, 3-butene 4-H), 5.70−5.78 (m, 1H, 3-butene 3-H), 6.72 (s, 1H, furan 4-H), 7.23−7.26 (m, 2H, aryl H), 7.49−7.52 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.3 (CH3), 22.0 (COCH3), 32.8 (3-butene C-2), 47.6 (3-butene C-1), 94.0 (furan C-3), 105.1 (furan C-4), 112.2 (CN), 117.4 (3-butene C-4), 124.1, 125.5, 129.5, 129.8 (C aryl), 134.1 (3-butene C-3), 139.7 (C aryl), 152.5 (furan C-5), 153.9 (furan C-2), 169.7 (CO); MS: m/z 295 [M+H]+. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.52; H, 6.27; N, 9.42.
N-3-Buten-1-yl-N-[5-(4-chlorophenyl)-3-cyano-2-furanyl]acetamide (5d)
Colorless columns (0.86 g, 55%), mp 87−88 °C (Et2O); IR (KBr): 2238 (CN), 1693 (CO) cm-1; 1H NMR (CDCl3): δ 2.09 (s, 3H, COCH3), 2.36−2.41 (m, 2H, 3-butene 2-H), 3.85 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 5.04−5.13 (m, 2H, 3-butene 4-H), 5.71−5.77 (m, 1H, 3-butene 3-H), 6.79 (s, 1H, furan 4-H), 7.40−7.44 (m, 2H, aryl H), 7.53−7.57 (m, 2H, aryl H); 13C NMR (CDCl3): δ 22.0 (COCH3), 32.8 (3-butene C-2), 47.7 (3-butene C-1), 94.2 (furan C-3), 106.3 (furan C-4), 111.9 (CN), 117.5 (3-butene C-4), 125.4, 126.6, 129.4 (C aryl), 134.0 (3-butene C-3), 135.4 (C aryl), 151.1 (furan C-5), 154.5 (furan C-2), 169.5 (CO); MS: m/z 315 [M+H]+. Anal. Calcd for C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90. Found: C, 64.84; H, 4.84; N, 8.91.
N-3-Buten-1-yl-N-(3-cyano-5-phenyl-2-furanyl)benzamide (6a)
Colorless prisms (0.11 g, 6%), mp 57−59 °C (Et2O/petroleum ether); IR (KBr): 2234 (CN), 1682 (CO) cm-1; 1H NMR (CDCl3): δ 2.51−2.57 (m, 2H, 3-butene 2-H), 4.04 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 5.08−5.19 (m, 2H, 3-butene 4-H), 5.80−5.87 (m, 1H, 3-butene 3-H), 6.53 (s, 1H, furan 4-H), 7.25−7.30 (m, 2H, aryl H), 7.34−7.45 (m, 6H, aryl H), 7.47−7.51 (m, 2H, aryl H); 13C NMR (CDCl3): δ 32.7 (3-butene C-2), 48.3 (3-butene C-1), 93.5 (furan C-3), 105.8 (furan C-4), 111.9 (CN), 117.6 (3-butene C-4), 124.0, 127.7, 128.2, 129.0, 129.2, 131.1 (C aryl), 134.1 (3-butene C-3), 134.8 (C aryl), 151.3 (furan C-5), 154.6 (furan C-2), 169.6 (CO); MS: m/z 343 [M+H]+. Anal. Calcd for C22H18N2O2: C, 77.17; H, 5.30; N, 8.18. Found: C, 77.26; H, 5.41; N, 8.19.
N-3-Buten-1-yl-N-[3-cyano-5-(4-methoxyphenyl)-2-furanyl]benzamide (6b)
Colorless needles (0.07 g, 4%), mp 86−87 °C (Et2O/petroleum ether); IR (KBr): 2233 (CN), 1681 (CO) cm-1; 1H NMR (CDCl3): δ 2.50−2.56 (m, 2H, 3-butene 2-H), 3.84 (s, 3H, OCH3), 4.02 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 5.08−5.19 (m, 2H, 3-butene 4-H), 5.80−5.89 (m, 1H, 3-butene 3-H), 6.38 (s, 1H, furan 4-H), 6.91−6.95 (m, 2H, aryl H), 7.25−7.30 (m, 2H, aryl H), 7.34−7.38 (m, 1H, aryl H), 7.40−7.44 (m, 4H, aryl H); 13C NMR (CDCl3): δ 32.7 (3-butene C-2), 48.3 (3-butene C-1), 55.4 (OCH3), 93.6 (furan C-3), 104.1 (furan C-4), 112.1 (CN), 114.5 (C aryl), 117.6 (3-butene C-4), 121.1, 125.6, 127.7, 128.2, 131.0 (C aryl), 134.1 (3-butene C-3), 134.9 (C aryl), 151.5 (furan C-5), 154.0 (furan C-2), 160.5 (C aryl), 169.7 (CO); MS: m/z 373 [M+H]+. Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found: C, 74.07; H, 5.49; N, 7.51.
N-3-Buten-1-yl-N-[3-cyano-5-(4-methylphenyl)-2-furanyl]benzamide (6c)
Colorless needles (0.11 g, 6%), mp 109−110 °C (Et2O); IR (KBr): 2233 (CN), 1679 (CO) cm-1; 1H NMR (CDCl3): δ 2.38 (s, 3H, CH3), 2.51−2.56 (m, 2H, 3-butene 2-H), 4.03 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 5.08−5.19 (m, 2H, 3-butene 4-H), 5.79−5.88 (m, 1H, 3-butene 3-H), 6.46 (s, 1H, furan 4-H), 7.20−7.22 (m, 2H, aryl H), 7.25−7.29 (m, 2H, aryl H), 7.33−7.40 (m, 3H, aryl H), 7.41−7.44 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.3 (CH3), 32.7 (3-butene C-2), 48.3 (3-butene C-1), 93.5 (furan C-3), 105.0 (furan C-4), 112.0 (CN), 117.6 (3-butene C-4), 124.0, 125.5, 127.7, 128.2, 129.7, 131.0 (C aryl), 134.1 (3-butene C-3), 134.8, 139.4 (C aryl), 151.6 (furan C-5), 154.3 (furan C-2), 169.6 (CO); MS: m/z 357 [M+H]+. Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.51; H, 5.76; N, 7.87.
N-3-Buten-1-yl-N-[5-(4-chlorophenyl)-3-cyano-2-furanyl]benzamide (6d)
Colorless columns (0.10 g, 5%), mp 118−119 °C (Et2O); IR (KBr): 2236 (CN), 1672 (CO) cm-1; 1H NMR (CDCl3): δ 2.51−2.56 (m, 2H, 3-butene 2-H), 4.04 (t, J = 7.3 Hz, 2H, 3-butene 1-H), 5.08−5.18 (m, 2H, 3-butene 4-H), 5.79−5.88 (m, 1H, 3-butene 3-H), 6.53 (s, 1H, furan 4-H), 7.25−7.30 (m, 2H, aryl H), 7.35−7.44 (m, 7H, aryl H); 13C NMR (CDCl3): δ 32.8 (3-butene C-2), 48.4 (3-butene C-1), 93.4 (furan C-3), 106.2 (furan C-4), 111.7 (CN), 117.7 (3-butene C-4), 125.2, 126.7, 127.7, 128.3, 129.3, 131.1 (C aryl), 134.0 (3-butene C-3), 134.7, 135.1 (C aryl), 150.1 (furan C-5), 154.9 (furan C-2), 169.5 (CO); MS: m/z 377 [M+H]+. Anal. Calcd for C22H17ClN2O2: C, 70.12; H, 4.55; N, 7.43. Found: C, 70.13; H, 4.63; N, 7.46.
General procedure for the preparation of dihydroindoles 7a−d and 8a−d from 5a−d and 6a−d.
A mixture of 5a−d and 6a−d (1 mmol) in 1,2-dichlorobenzene (1 mL) was stirred at 180 °C for 4 h. After removal of the solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed with water, dried, and recrystallized from an appropriate solvent to give 7a−d and 8a−d.
1-Acetyl-2,3-dihydro-5-phenyl-1H-indole-7-carbonitrile (7a)
Colorless columns (0.22 g, 84%), mp 177−178 °C (acetone); IR (KBr): 2224 (CN), 1675 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.26 (s, 3H, COCH3), 3.19 (t, J = 8.2 Hz, 2H, 3-H), 4.20 (t, J = 8.2 Hz, 2H, 2-H), 7.36−7.40 (m, 1H, aryl H), 7.44−7.48 (m, 2H, aryl H), 7.68−7.71 (m, 2H, aryl H), 7.77−7.79 (m, 1H, aryl H), 7.86−7.87 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 23.4 (COCH3), 28.1 (C-3), 49.7 (C-2), 101.5 (C aryl), 117.0 (CN), 126.4, 127.5, 127.7, 128.9, 129.4, 136.3, 136.9, 137.9, 142.2 (C aryl), 168.3 (CO); MS: m/z 263 [M+H]+. Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. Found: C, 77.89; H, 5.49; N, 10.67.
1-Acetyl-2,3-dihydro-5-(4-methoxyphenyl)-1H-indole-7-carbonitrile (7b)
Colorless needles (0.24 g, 82%), mp 188−189 °C (acetone); IR (KBr): 2225 (CN), 1676 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.26 (s, 3H, COCH3), 3.17 (t, J = 8.2 Hz, 2H, 3-H), 3.80 (s, 3H, OCH3), 4.18 (t, J = 8.2 Hz, 2H, 2-H), 7.00−7.03 (m, 2H, aryl H), 7.63−7.65 (m, 2H, aryl H), 7.71−7.72 (m, 1H, aryl H), 7.81−7.82 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 23.3 (COCH3), 28.1 (C-3), 49.7 (C-2), 55.1 (OCH3), 101.5, 114.4 (C aryl), 117.1 (CN), 127.0, 127.6, 128.7, 130.2, 136.0, 136.8, 141.6, 159.1 (C aryl), 168.3 (CO); MS: m/z 293 [M+H]+. Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52; N, 9.58. Found: C, 73.98; H, 5.57; N, 9.55.
1-Acetyl-2,3-dihydro-5-(4-methylphenyl)-1H-indole-7-carbonitrile (7c)
Colorless prisms (0.23 g, 83%), mp 200−201 °C (acetone); IR (KBr): 2221 (CN), 1666 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.26 (s, 3H, COCH3), 2.34 (s, 3H, CH3), 3.18 (t, J = 8.2 Hz, 2H, 3-H), 4.19 (t, J = 8.2 Hz, 2H, 2-H), 7.25−7.28 (m, 2H, aryl H), 7.57−7.61 (m, 2H, aryl H), 7.74−7.75 (m, 1H, aryl H), 7.83−7.85 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 20.5 (CH3), 23.3 (COCH3), 28.1 (C-3), 49.7 (C-2), 101.5 (C aryl), 117.1 (CN), 126.2, 127.3, 129.1, 129.5, 135.0, 136.2, 136.8, 137.1, 141.9 (C aryl), 168.3 (CO); MS: m/z 277 [M+H]+. Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.25; H, 5.90; N, 10.14.
1-Acetyl-5-(4-chlorophenyl)-2,3-dihydro-1H-indole-7-carbonitrile (7d)
Colorless needles (0.22 g, 74%), mp 179−180 °C (acetone); IR (KBr): 2222 (CN), 1678 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.26 (s, 3H, COCH3), 3.19 (t, J = 8.2 Hz, 2H, 3-H), 4.20 (t, J = 8.2 Hz, 2H, 2-H), 7.48−7.52 (m, 2H, aryl H), 7.71−7.75 (m, 2H, aryl H), 7.80−7.81 (m, 1H, aryl H), 7.86−7.87 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 23.4 (COCH3), 28.1 (C-3), 49.7 (C-2), 101.6 (C aryl), 116.9 (CN), 127.4, 128.2, 128.8, 129.5, 132.6, 134.9, 136.7, 136.9, 142.4 (C aryl), 168.4 (CO); MS: m/z 297 [M+H]+. Anal. Calcd for C17H13ClN2O: C, 68.81; H, 4.42; N, 9.44. Found: C, 68.89; H, 4.46; N, 9.47.
1-Benzoyl-2,3-dihydro-5-phenyl-1H-indole-7-carbonitrile (8a)
Colorless prisms (0.25 g, 77%), mp 267−268 °C (CH2Cl2); IR (KBr): 2229 (CN), 1662 (CO) cm-1; 1H NMR (CDCl3): δ 3.16 (t, J = 7.9 Hz, 2H, 3-H), 4.23 (t, J = 7.9 Hz, 2H, 2-H), 7.36−7.40 (m, 1H, aryl H), 7.44−7.49 (m, 4H, aryl H), 7.52−7.55 (m, 3H, aryl H), 7.56−7.65 (m, 1H, aryl H), 7.72−7.73 (m, 1H, aryl H), 7.75−7.77 (m, 2H, aryl H); 13C NMR (CDCl3): δ 29.5 (C-3), 53.3 (C-2), 103.8 (C aryl), 116.8 (CN), 126.9, 127.7, 128.0, 128.5, 128.8, 129.1, 130.5, 131.9, 134.6, 136.2, 138.5, 138.9, 143.6 (C aryl), 169.4 (CO); MS: m/z 325 [M+H]+. Anal. Calcd for C22H16N2O: C, 81.46; H, 4.97; N, 8.64. Found: C, 81.39; H, 5.08; N, 8.69.
1-Benzoyl-2,3-dihydro-5-(4-methoxyphenyl)-1H-indole-7-carbonitrile (8b)
Pale yellow columns (0.28 g, 79%), mp 214−215 °C (acetone); IR (KBr): 2231 (CN), 1660 (CO) cm-1; 1H NMR (DMSO-d6): δ 3.15 (t, J = 7.9 Hz, 2H, 3-H), 3.81 (s, 3H, OCH3), 4.18 (t, J = 7.9 Hz, 2H, 2-H), 7.02−7.05 (m, 2H, aryl H), 7.53−7.57 (m, 2H, aryl H), 7.61−7.63 (m, 1H, aryl H), 7.67−7.70 (m, 2H, aryl H), 7.76−7.79 (m, 2H, aryl H), 7.83−7.84 (m, 1H, aryl H), 7.88−7.89 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 29.0 (C-3), 53.1 (C-2), 55.2 (OCH3), 102.5, 114.4 (C aryl), 116.7 (CN), 127.2, 127.7, 128.3, 128.4, 128.5, 130.3, 131.7, 134.6, 136.8, 137.3, 142.8, 159.2 (C aryl), 168.5 (CO); MS: m/z 355 [M+H]+. Anal. Calcd for C23H18N2O2: C, 77.95; H, 5.12; N, 7.90. Found: C, 78.03; H, 5.23; N, 7.89.
1-Benzoyl-2,3-dihydro-5-(4-methylphenyl)-1H-indole-7-carbonitrile (8c)
Pale brown prisms (0.28 g, 83%), mp 201−202 °C (acetone); IR (KBr): 2231 (CN), 1668 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.35 (s, 3H, CH3), 3.16 (t, J = 7.9 Hz, 2H, 3-H), 4.18 (t, J = 7.9 Hz, 2H, 2-H), 7.28−7.30 (m, 2H, aryl H), 7.53−7.57 (m, 2H, aryl H), 7.61−7.64 (m, 3H, aryl H), 7.77−7.79 (m, 2H, aryl H), 7.86 (s, 1H, aryl H), 7.91 (s, 1H, aryl H); 13C NMR (DMSO-d6): δ 20.6 (CH3), 28.9 (C-3), 53.1 (C-2), 102.5 (C aryl), 116.7 (CN), 126.4, 127.4, 128.4, 128.5, 128.6, 129.5, 131.7, 134.6, 135.0, 136.9, 137.3, 143.1 (C aryl), 168.5 (CO); MS: m/z 339 [M+H]+. Anal. Calcd for C23H18N2O: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.63; H, 5.48; N, 8.26.
1-Benzoyl-5-(4-chlorophenyl)-2,3-dihydro-1H-indole-7-carbonitrile (8d)
Colorless prisms (0.30 g, 85%), mp 235−236 °C (acetone); IR (KBr): 2236 (CN), 1665 (CO) cm-1; 1H NMR (DMSO-d6): δ 3.17 (t, J = 7.9 Hz, 2H, 3-H), 4.20 (t, J = 7.9 Hz, 2H, 2-H), 7.52−7.58 (m, 4H, aryl H), 7.61−7.64 (m, 1H, aryl H), 7.76−7.79 (m, 4H, aryl H), 7.92−7.93 (m, 1H, aryl H), 7.94−7.95 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 28.9 (C-3), 53.1 (C-2), 102.6 (C aryl), 116.6 (CN), 127.7, 128.4, 128.47, 128.52, 128.9, 129.1, 131.8, 132.8, 134.5, 135.6, 136.8, 137.5, 143.7 (C aryl), 168.6 (CO); MS: m/z 359 [M+H]+. Anal. Calcd for C22H15ClN2O: C, 73.64; H, 4.21; N, 7.81. Found: C, 73.67; H, 4.31; N, 7.78.
General procedure for the preparation of 9a−d and 10a−d from 3a−d and/or 4a−d and 5-bromo-1-pentene.
To an ice-cooled and stirred solution of 3a−d and 4a−d (5 mmol) in DMF (5 mL) was added 60% NaH (0.24 g, 6 mmol). The stirring was continued at rt until evolution of gas ceased. To the obtained mixture was added 5-bromo-1-pentene (1.49 g, 10 mmol) with stirring and then the mixture was stirred at 80 °C for 5 h. After removal of the solvent in vacuo, cold water was added to the residue. The resulting mixture was extracted with Et2O (60 mL). The extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with CH2Cl2 as the eluent to afford 9a−d and 10a−d.
N-(3-Cyano-5-phenyl-2-furanyl)-N-4-penten-1-ylacetamide (9a)
Brown oil (1.22 g, 83%); IR (neat): 2236 (CN), 1698 (CO) cm-1; 1H NMR (CDCl3): δ 1.69−1.76 (m, 2H, 4-pentene 2-H), 2.09 (s, 3H, COCH3), 2.10−2.15 (m, 2H, 4-pentene 3-H), 3.78 (t, J = 7.6 Hz, 2H, 4-pentene 1-H), 4.95−5.05 (m, 2H, 4-pentene 5-H), 5.74−5.83 (m, 1H, 4-pentene 4-H), 6.79 (s, 1H, furan 4-H), 7.37−7.47 (m, 3H, aryl H), 7.60−7.63 (m, 2H, aryl H); 13C NMR (CDCl3): δ 22.0 (COCH3), 27.5 (4-pentene C-2), 30.6 (4-pentene C-3), 47.8 (4-pentene C-1), 94.0 (furan C-3), 105.8 (furan C-4), 112.1 (CN), 115.5 (4-pentene C-5), 124.1, 128.2, 129.1, 129.4 (C aryl), 137.2 (4-pentene C-4), 152.2 (furan C-5), 154.4 (furan C-2), 169.7 (CO); MS: m/z 295 [M+H]+. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.48; H, 6.25; N, 9.45.
N-[3-Cyano-5-(4-methoxyphenyl)-2-furanyl]-N-4-penten-1-ylacetamide (9b)
Colorless columns (0.96 g, 59%), mp 56−57 °C (Et2O/petroleum ether); IR (KBr): 2235 (CN), 1691 (CO) cm-1; 1H NMR (CDCl3): δ 1.68−1.75 (m, 2H, 4-pentene 2-H), 2.07 (s, 3H, COCH3), 2.09−2.14 (m, 2H, 4-pentene 3-H), 3.76 (t, J = 7.5 Hz, 2H, 4-pentene 1-H), 3.85 (s, 3H, OCH3), 4.95−5.04 (m, 2H, 4-pentene 5-H), 5.74−5.83 (m, 1H, 4-pentene 4-H), 6.64 (s, 1H, furan 4-H), 6.94−6.98 (m, 2H, aryl H), 7.53−7.56 (m, 2H, aryl H); 13C NMR (CDCl3): δ 22.0 (COCH3), 27.5 (4-pentene C-2), 30.7 (4-pentene C-3), 47.8 (4-pentene C-1), 55.4 (OCH3), 94.0 (furan C-3), 104.1 (furan C-4), 112.3 (CN), 114.6 (C aryl), 115.4 (4-pentene C-5), 121.0, 125.8 (C aryl), 137.2 (4-pentene C-4), 152.4 (furan C-5), 153.8 (furan C-2), 160.6 (C aryl), 169.8 (CO); MS: m/z 325 [M+H]+. Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.39; H, 6.28; N, 8.61.
N-[3-Cyano-5-(4-methylphenyl)-2-furanyl]-N-4-penten-1-ylacetamide (9c)
Colorless columns (0.87 g, 56%), mp 54−55 °C (Et2O/petroleum ether); IR (KBr): 2236 (CN), 1697 (CO) cm-1; 1H NMR (CDCl3): δ 1.68−1.75 (m, 2H, 4-pentene 2-H), 2.07 (s, 3H, COCH3), 2.08−2.14 (m, 2H, 4-pentene 3-H), 2.39 (s, 3H, CH3), 3.77 (t, J = 7.6 Hz, 2H, 4-pentene 1-H), 4.95−5.04 (m, 2H, 4-pentene 5-H), 5.73−5.82 (m, 1H, 4-pentene 4-H), 6.72 (s, 1H, furan 4-H), 7.23−7.26 (m, 2H, aryl H), 7.49−7.52 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.3 (CH3), 22.0 (COCH3), 27.5 (4-pentene C-2), 30.7 (4-pentene C-3), 47.8 (4-pentene C-1), 94.0 (furan C-3), 105.0 (furan C-4), 112.2 (CN), 115.4 (4-pentene C-5), 124.1, 125.5, 129.8 (C aryl), 137.2 (4-pentene C-4), 139.7 (C aryl), 152.5 (furan C-5), 154.1 (furan C-2), 169.8 (CO); MS: m/z 309 [M+H]+. Anal. Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C, 74.06; H, 6.56; N, 9.10.
N-[5-(4-Chlorophenyl)-3-cyano-2-furanyl]-N-4-penten-1-ylacetamide (9d)
Colorless columns (0.98 g, 60%), mp 56−57 °C (Et2O/petroleum ether); IR (KBr): 2238 (CN), 1696 (CO) cm-1; 1H NMR (CDCl3): δ 1.68−1.75 (m, 2H, 4-pentene 2-H), 2.09 (s, 3H, COCH3), 2.09−2.14 (m, 2H, 4-pentene 3-H), 3.77 (t, J = 7.6 Hz, 2H, 4-pentene 1-H), 4.96−5.04 (m, 2H, 4-pentene 5-H), 5.73−5.82 (m, 1H, 4-pentene 4-H), 6.79 (s, 1H, furan 4-H), 7.40−7.44 (m, 2H, aryl H), 7.53−7.57 (m, 2H, aryl H); 13C NMR (CDCl3): δ 22.0 (COCH3), 27.5 (4-pentene C-2), 30.6 (4-pentene C-3), 47.9 (4-pentene C-1), 94.1 (furan C-3), 106.3 (furan C-4), 111.9 (CN), 115.5 (4-pentene C-5), 125.4, 126.6, 129.4, 135.4 (C aryl), 137.1 (4-pentene C-4), 151.1 (furan C-5), 154.6 (furan C-2), 169.5 (CO); MS: m/z 329 [M+H]+. Anal. Calcd for C18H17ClN2O2: C, 65.75; H, 5.21; N, 8.52. Found: C, 65.82; H, 5.29; N, 8.50.
N-(3-Cyano-5-phenyl-2-furanyl)-N-4-penten-1-ylbenzamide (10a)
Colorless prisms (1.03 g, 58%), mp 101−102 °C (Et2O/petroleum ether); IR (KBr): 2237 (CN), 1666 (CO) cm-1; 1H NMR (CDCl3): δ 1.83−1.90 (m, 2H, 4-pentene 2-H), 2.17−2.23 (m, 2H, 4-pentene 3-H), 3.95−3.99 (m, 2H, 4-pentene 1-H), 4.98−5.09 (m, 2H, 4-pentene 5-H), 5.79−5.88 (m, 1H, 4-pentene 4-H), 6.54 (s, 1H, furan 4-H), 7.25−7.30 (m, 2H, aryl H), 7.33−7.45 (m, 6H, aryl H), 7.47−7.50 (m, 2H, aryl H); 13C NMR (CDCl3): δ 27.4 (4-pentene C-2), 30.8 (4-pentene C-3), 48.6 (4-pentene C-1), 93.5 (furan C-3), 105.8 (furan C-4), 111.9 (CN), 115.5 (4-pentene C-5), 124.0, 127.7, 128.2, 129.0, 129.2, 131.0, 134.9 (C aryl), 137.2 (4-pentene C-4), 151.3 (furan C-5), 154.7 (furan C-2), 169.6 (CO); MS: m/z 357 [M+H]+. Anal. Calcd for C23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.57; H, 5.74; N, 7.88.
N-[3-Cyano-5-(4-methoxyphenyl)-2-furanyl]-N-4-penten-1-ylbenzamide (10b)
Colorless columns (0.66 g, 34%), mp 95−96 °C (Et2O); IR (KBr): 2233 (CN), 1679 (CO) cm-1; 1H NMR (CDCl3): δ 1.82−1.89 (m, 2H, 4-pentene 2-H), 2.17−2.23 (m, 2H, 4-pentene 3-H), 3.84 (s, 3H, OCH3), 3.93−3.97 (m, 2H, 4-pentene 1-H), 4.98−5.09 (m, 2H, 4-pentene 5-H), 5.79−5.88 (m, 1H, 4-pentene 4-H), 6.39 (s, 1H, furan 4-H), 6.91−6.95 (m, 2H, aryl H), 7.25−7.30 (m, 2H, aryl H), 7.33−7.38 (m, 1H, aryl H), 7.40−7.45 (m, 4H, aryl H); 13C NMR (CDCl3): δ 27.4 (4-pentene C-2), 30.8 (4-pentene C-3), 48.6 (4-pentene C-1), 55.4 (OCH3), 93.5 (furan C-3), 104.0 (furan C-4), 112.0 (CN), 114.5 (C aryl), 115.5 (4-pentene C-5), 121.1, 125.6, 127.6, 128.2, 130.9, 134.9 (C aryl), 137.2 (4-pentene C-4), 151.6 (furan C-5), 154.1 (furan C-2), 160.4 (C aryl), 169.7 (CO); MS: m/z 387 [M+H]+. Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74; N, 7.25. Found: C, 74.70; H, 5.84; N, 7.25.
N-[3-Cyano-5-(4-methylphenyl)-2-furanyl]-N-4-penten-1-ylbenzamide (10c)
Colorless needles (0.80 g, 43%), mp 95−96 °C (Et2O); IR (KBr): 2232 (CN), 1673 (CO) cm-1; 1H NMR (CDCl3): δ 1.83−1.90 (m, 2H, 4-pentene 2-H), 2.17−2.23 (m, 2H, 4-pentene 3-H), 2.38 (s, 3H, CH3), 3.94−3.98 (m, 2H, 4-pentene 1-H), 4.98−5.09 (m, 2H, 4-pentene 5-H), 5.79−5.88 (m, 1H, 4-pentene 4-H), 6.47 (s, 1H, furan 4-H), 7.19−7.23 (m, 2H, aryl H), 7.25−7.29 (m, 2H, aryl H), 7.33−7.40 (m, 3H, aryl H), 7.41−7.44 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.3 (CH3), 27.4 (4-pentene C-2), 30.8 (4-pentene C-3), 48.6 (4-pentene C-1), 93.5 (furan C-3), 105.0 (furan C-4), 112.0 (CN), 115.5 (4-pentene C-5), 124.0, 125.5, 127.6, 128.2, 129.7, 131.0, 134.9 (C aryl), 137.2 (4-pentene C-4), 139.4 (C aryl), 151.6 (furan C-5), 154.4 (furan C-2), 169.7 (CO); MS: m/z 371 [M+H]+. Anal. Calcd for C24H22N2O2: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.89; H, 6.10; N, 7.59.
N-[5-(4-Chlorophenyl)-3-cyano-2-furanyl]-N-4-penten-1-ylbenzamide (10d)
Pale yellow prisms (0.92 g, 47%), mp 120−121 °C (Et2O); IR (KBr): 2237 (CN), 1673 (CO) cm-1; 1H NMR (CDCl3): δ 1.83−1.89 (m, 2H, 4-pentene 2-H), 2.17−2.23 (m, 2H, 4-pentene 3-H), 3.95−3.99 (m, 2H, 4-pentene 1-H), 4.98−5.08 (m, 2H, 4-pentene 5-H), 5.78−5.87 (m, 1H, 4-pentene 4-H), 6.54 (s, 1H, furan 4-H), 7.25−7.31 (m, 2H, aryl H), 7.35−7.44 (m, 7H, aryl H); 13C NMR (CDCl3): δ 27.4 (4-pentene C-2), 30.8 (4-pentene C-3), 48.6 (4-pentene C-1), 93.4 (furan C-3), 106.2 (furan C-4), 111.7 (CN), 115.6 (4-pentene C-5), 125.2, 126.7, 127.6, 128.3, 129.3, 131.1, 134.8, 135.2 (C aryl), 137.2 (4-pentene C-4), 150.2 (furan C-5), 155.0 (furan C-2), 169.5 (CO); MS: m/z 391 [M+H]+. Anal. Calcd for C23H19ClN2O2: C, 70.68; H, 4.90; N, 7.17. Found: C, 70.72; H, 5.02; N, 7.18.
General procedure for the preparation of tetrahydroquinolines 11a−d and 12a−d from 9a−d and 10a−d.
A mixture of 9a−d and 10a−d (1 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was stirred at 210 °C for 16 h (in the case of the preparation of 11a−d, 12a, and 12d) or for 20 h (in the case of the preparation of 12b,c). After removal of the solvent in vacuo, cold water was added to the residue. Further processing of the resulting mixture is described in the following paragraphs.
(A) The resulting mixture was extracted with CH2Cl2 (30 mL). The extract was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with CH2Cl2-acetone (4:1) as the eluent to afford 11a−d.
(B) The precipitate was isolated by filtration, washed with water, dried, and recrystallized from an appropriate solvent to give 12a−d.
1-Acetyl-1,2,3,4-tetrahydro-6-phenyl-8-quinolinecarbonitrile (11a)
Colorless columns (0.16 g, 58%), mp 136−137 °C (acetone/petroleum ether); IR (KBr): 2231 (CN), 1659 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.97 (br s, 2H, 3-H), 2.23 (br s, 3H, COCH3), 2.85 (br s, 2H, 4-H), 3.78 (br s, 2H, 2-H), 7.38−7.43 (m, 1H, aryl H), 7.46−7.50 (m, 2H, aryl H), 7.72−7.75 (m, 2H, aryl H), 7.85 (br s, 1H, aryl H), 7.93 (br s, 1H, aryl H); 13C NMR (DMSO-d6): δ 22.1 (COCH3), 23.3 (C-3), 25.9 (C-4), 45.0 (C-2), 109.9 (C aryl), 117.2 (CN), 126.6, 128.0, 128.4, 128.9, 131.3, 137.3, 137.7 (C aryl), 169.7 (CO); MS: m/z 277 [M+H]+. Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.31; H, 5.96; N, 10.12.
1-Acetyl-1,2,3,4-tetrahydro-6-(4-methoxyphenyl)-8-quinolinecarbonitrile (11b)
Brown oil (0.16 g, 52%); IR (neat): 2228 (CN), 1670 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.96 (br s, 2H, 3-H), 2.21 (br s, 3H, COCH3), 2.83 (br s, 2H, 4-H), 3.81 (br s, 2H, 2-H), 3.81 (s, 3H, OCH3), 7.01−7.05 (m, 2H, aryl H), 7.67−7.70 (m, 2H, aryl H), 7.80 (br s, 1H, aryl H), 7.88 (br s, 1H, aryl H); 13C NMR (DMSO-d6): δ 22.1 (COCH3), 23.4 (C-3), 25.8 (C-4), 45.0 (C-2), 55.2 (OCH3), 114.4 (C aryl), 117.3 (CN), 127.8, 130.0, 130.7, 159.3 (C aryl), 169.7 (CO); MS: m/z 307 [M+H]+. Anal. Calcd for C19H18N2O2・0.25H2O: C, 73.41; H, 6.00; N, 9.01. Found: C, 73.45; H, 6.08; N, 8.91.
1-Acetyl-1,2,3,4-tetrahydro-6-(4-methylphenyl)-8-quinolinecarbonitrile (11c)
Pale brown prisms (0.15 g, 52%), mp 129−130 °C (acetone/petroleum ether); IR (KBr): 2224 (CN), 1665 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.96 (br s, 2H, 3-H), 2.22 (br s, 3H, COCH3), 2.35 (s, 3H, CH3), 2.83 (br s, 2H, 4-H), 3.78 (br s, 2H, 2-H), 7.27−7.30 (m, 2H, aryl H), 7.61−7.64 (m, 2H, aryl H), 7.82 (br s, 1H, aryl H), 7.90 (br s, 1H, aryl H); 13C NMR (DMSO-d6): δ 20.6 (CH3), 22.1 (COCH3), 23.3 (C-3), 25.8 (C-4), 44.9 (C-2), 117.2 (CN), 126.4, 128.1, 129.5, 130.9, 134.7, 137.1, 137.5 (C aryl), 169.7 (CO); MS: m/z 291 [M+H]+. Anal. Calcd for C19H18N2O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.64; H, 6.31; N, 9.63.
1-Acetyl-6-(4-chlorophenyl)-1,2,3,4-tetrahydro-8-quinolinecarbonitrile (11d)
Colorless prisms (0.14 g, 45%), mp 129−130 °C (Et2O); IR (KBr): 2232 (CN), 1674 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.96 (br s, 2H, 3-H), 2.23 (br s, 3H, COCH3), 2.84 (br s, 2H, 4-H), 3.79 (br s, 2H, 2-H), 7.51−7.55 (m, 2H, aryl H), 7.75−7.79 (m, 2H, aryl H), 7.86 (br s, 1H, aryl H), 7.96 (br s, 1H, aryl H); 13C NMR (DMSO-d6): δ 22.1 (COCH3), 23.3 (C-3), 25.8 (C-4), 45.0 (C-2), 117.1 (CN), 128.4, 128.9, 131.2, 132.9, 136.5 (C aryl), 169.7 (CO); MS: m/z 311 [M+H]+. Anal. Calcd for C18H15ClN2O: C, 69.57; H, 4.86; N, 9.01. Found: C, 69.51; H, 4.94; N, 8.97.
1-Benzoyl-1,2,3,4-tetrahydro-6-phenyl-8-quinolinecarbonitrile (12a)
Colorless prisms (0.24 g, 71%), mp 238−239 °C (CH2Cl2); IR (KBr): 2224 (CN), 1664 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.95 (br s, 2H, 3-H), 2.95 (t, J = 6.7 Hz, 2H, 4-H), 3.80 (br s, 2H, 2-H), 7.38−7.54 (m, 8H, aryl H), 7.73−7.75 (m, 2H, aryl H), 7.86−7.88 (m, 1H, aryl H), 7.91−7.93 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 23.4 (C-3), 25.9 (C-4), 46.1 (C-2), 109.4 (C aryl), 116.9 (CN), 126.6, 128.1, 128.2, 128.5, 129.0, 130.9, 131.4, 134.9, 135.0, 137.2, 137.5, 140.5 (C aryl), 170.5 (CO); MS: m/z 339 [M+H]+. Anal. Calcd for C23H18N2O: C, 81.63; H, 5.36; N, 8.28. Found: C, 81.55; H, 5.43; N, 8.25.
1-Benzoyl-1,2,3,4-tetrahydro-6-(4-methoxyphenyl)-8-quinolinecarbonitrile (12b)
Pale brown prisms (0.21 g, 57%), mp 192−193 °C (acetone); IR (KBr): 2232 (CN), 1661 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.95 (br s, 2H, 3-H), 2.93 (t, J = 6.7 Hz, 2H, 4-H), 3.77−3.81 (m, 3H, 2-H), 3.80 (s, 3H, OCH3), 7.01−7.04 (m, 2H, aryl H), 7.41−7.45 (m, 2H, aryl H), 7.48−7.51 (m, 3H, aryl H), 7.67−7.70 (m, 2H, aryl H), 7.80−7.82 (m, 1H, aryl H), 7.86−7.87 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 23.5 (C-3), 25.9 (C-4), 46.0 (C-2), 55.2 (OCH3), 109.3, 114.4 (C aryl), 116.9 (CN), 127.7, 127.8, 128.2, 128.5, 129.8, 130.7, 130.8, 134.8, 135.1, 137.0, 139.8, 159.4 (C aryl), 170.4 (CO); MS: m/z 369 [M+H]+. Anal. Calcd for C24H20N2O2: C, 78.24; H, 5.47; N, 7.60. Found: C, 78.31; H, 5.61; N, 7.59.
1-Benzoyl-1,2,3,4-tetrahydro-6-(4-methylphenyl)-8-quinolinecarbonitrile (12c)
Colorless columns (0.21 g, 60%), mp 171−172 °C (acetone); IR (KBr): 2227 (CN), 1653 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.95 (br s, 2H, 3-H), 2.35 (s, 3H, CH3), 2.94 (t, J = 6.7 Hz, 2H, 4-H), 3.79 (br s, 2H, 2-H), 7.27−7.29 (m, 2H, aryl H), 7.41−7.45 (m, 2H, aryl H), 7.49−7.53 (m, 3H, aryl H), 7.61−7.64 (m, 2H, aryl H), 7.83−7.84 (m, 1H, aryl H), 7.88−7.90 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 20.6 (CH3), 23.4 (C-3), 25.9 (C-4), 46.1 (C-2), 109.4 (C aryl), 116.9 (CN), 126.4, 128.1, 128.2, 128.5, 129.6, 130.9, 131.1, 134.6, 134.8, 135.0, 137.2, 137.5, 140.2 (C aryl), 170.5 (CO); MS: m/z 353 [M+H]+. Anal. Calcd for C24H20N2O: C, 81.79; H, 5.72; N, 7.95. Found: C, 81.79; H, 5.84; N, 7.93.
1-Benzoyl-6-(4-chlorophenyl)-1,2,3,4-tetrahydro-8-quinolinecarbonitrile (12d)
Colorless columns (0.24 g, 64%), mp 221−222 °C (acetone); IR (KBr): 2229 (CN), 1650 (CO) cm-1; 1H NMR (DMSO-d6): δ 1.95−1.97 (m, 2H, 3-H), 2.95 (t, J = 6.7 Hz, 2H, 4-H), 3.79 (br s, 2H, 2-H), 7.42−7.46 (m, 2H, aryl H), 7.50−7.54 (m, 5H, aryl H), 7.76−7.79 (m, 2H, aryl H), 7.90−7.91 (m, 1H, aryl H), 7.92−7.94 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 23.4 (C-3), 25.9 (C-4), 46.2 (C-2), 109.5 (C aryl), 116.8 (CN), 128.2, 128.4, 128.48, 128.50, 128.9, 130.9, 131.4, 133.0, 134.9, 135.0, 135.8, 136.3, 140.8 (C aryl), 170.5 (CO); MS: m/z 373 [M+H]+. Anal. Calcd for C23H17ClN2O: C, 74.09; H, 4.60; N, 7.51. Found: C, 74.07; H, 4.71; N, 7.48.
Preparation of pyridoquinazoline 13 from 11a.
A mixture of 11a (0.276 g, 1 mmol) in 10% aqueous NaOH (1 mL) and MeOH (5 mL) was refluxed for 30 min. After removal of the solvent in vacuo, cold water was added to the residue. The precipitate was isolated by filtration, washed with water, dried, and recrystallized from acetone to yield 3-methyl-9-phenyl-1H,5H-pyrido[3,2,1-ij]quinazolin-1(6H)-one (13) (0.14 g, 51%) as colorless needles, mp 258−259 °C; IR (KBr): 1632 (CO) cm-1; 1H NMR (DMSO-d6): δ 2.07−2.13 (m, 2H, 6-H), 2.53 (s, 3H, CH3), 3.00 (t, J = 6.1 Hz, 2H, 7-H), 4.14 (t, J = 5.8 Hz, 2H, 5-H), 7.37−7.41 (m, 1H, aryl H), 7.47−7.51 (m, 2H, aryl H), 7.70−7.73 (m, 2H, aryl H), 7.86−7.87 (m, 1H, aryl H), 8.10−8.11 (m, 1H, aryl H); 13C NMR (DMSO-d6): δ 20.6 (C-6), 22.9 (CH3), 25.9 (C-7), 46.7 (C-5), 119.6, 122.0, 126.4, 127.6, 127.8, 129.0, 130.7, 136.2, 137.0, 138.7 (C aryl), 160.8 (C-3), 167.8 (CO); MS: m/z 277 [M+H]+. Anal. Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.16; H, 5.84; N, 10.11.

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