HETEROCYCLES

Short Paper | Special issue | Vol. 88, No. 1, 2014, pp. 675-687
Received, 28th May, 2013, Accepted, 24th June, 2013, Published online, 2nd July, 2013.
DOI: 10.3987/COM-13-S(S)21

■ An Approach to the Synthesis of Novel Dihydroindoles Bearing Electron-Withdrawing Groups at C-2 Position

Fumi Okabe, Hiroshi Maruoka,* Masaru Takasu, Eiichi Masumoto, Toshihiro Fujioka, and Kenji Yamagata

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

Abstract

The synthesis of novel dihydroindoles 8a−d and 9a−d bearing electron-withdrawing groups at C-2 position is presented. The key step of this approach is an efficient intramolecular Diels-Alder reaction of N-alkenylated 2-amino-3-furancarbonitriles 4a−d and 5a−d.

Nitrogen-containing heterocyclic ring systems such as indoles1 and dihydroindoles,2 namely indolines, have shown a great potential in pharmaceutical research and serve as versatile scaffolds in experimental drug design. As a consequence, the synthesis and functionalization of indoles3 and indolines4 has been a major area of focus for synthetic organic chemists, and numerous methods for the preparation of them have been developed.

Indoline derivatives, such as pentopril2b and oleracein A,2f are the structural components of several important pharmaceutically active compounds (Figure 1). In their ring system, it is worth noting that a proton is replaced with an electron-withdrawing group in the C-2 position of indoline skeleton. Our general point of interest goes to the synthesis of novel indolines having electron-withdrawing groups at C-2 position. In connection with our current research interests in this area, the construction of the functionalized indoline ring system through an intramolecular Diels-Alder reaction has been shown to be a simple and versatile tool for a rapid assembly of indoline derivatives.5 As 2-amino-3-furancarbonitriles 1a−d are easily available by established synthetic procedures,6 we focused our attention on the development of a new method for the preparation of indoline derivatives using them as starting materials. In this paper, we wish to report the synthesis of novel indoline derivatives.
Initially, we examined the N-H insertion reaction7 of 2-amino-3-furancarbonitriles 1a−d with α-diazocarbonyl compounds such as dimethyl diazomalonate and methyl diazoacetoacetate (Scheme 1). The reaction of 1a with dimethyl diazomalonate was chosen as a model. After different conditions were screened, we were delighted to find that the N-H insertion product 2a was obtained from this reaction with rhodium(II) acetate dimer [Rh2(OAc)4] as catalyst in a suitable solvent at 70 °C for 1 h. After screening solvents, we found fluorobenzene was the best solvent. With the optimized reaction conditions in hand, 1a−d were subjected to react with dimethyl diazomalonate and methyl diazoacetoacetate, and the representative results are summarized in Table 1.

We next tried the C-propenylation reaction of the N-H insertion products 2a−d and 3a−d with 3-bromopropene (Scheme 1). Thus, compounds 2a−d and 3a−d were reacted with 3-bromopropene in the presence of sodium methoxide in DMF at room temperature to provide the corresponding compounds 4a−d and 5a−d in moderate yields (Table 2). In this reaction, although we examined several reaction conditions, for example, substrate/base molar ratio and solvent, our attempts were unacceptable with respect to yield. It seemed that C-propenylation reaction of 2a−d and 3a−d did not proceed readily because of the influence of steric hindrance of the tertiary carbanion with three bulky substituents.

By comparison of the IR spectra, NMR spectra, mass spectra, and elemental analyses of 4a−d and 5a−d, it seems that the structural assignments given to these compounds are correct (see experimental section). For example, the 1H NMR spectrum of 4a in CDCl3 exhibits a two-proton doublet at δ 3.14 assignable to the methylene protons of 2-propene, a two-proton multiplet in the range of δ 5.09−5.18 assignable to the 3-H proton of 2-propene, and a one-proton multiplet in the range of δ 5.60−5.69 assignable to the 2-H proton of 2-propene. The 13C NMR spectrum of 4a in CDCl3 shows a signal at δ 38.2 because of the methylene carbon of 2-propene, a signal at δ 68.0 because of the quaternary C-2 carbon, a signal at δ 120.8 because of the C-3 carbon of 2-propene, and a signal at δ 130.2 because of the C-2 carbon of 2-propene.
Finally, we attempted the intramolecular Diels-Alder reaction of 4a−d and 5a−d (Scheme 1). As a consequence, treatment of 4a−d and 5a−d in boiling acetic acid for 3 h caused an intramolecular Diels-Alder reaction to furnish the desired indolines 8a−d and 9a−d in moderate to good yields (Table 3). In this reaction, the key intermediates 6a−d and 7a−d were not detected at all. These products 8a−d and 9a−d gave satisfactory elemental analyses and spectroscopic data (IR, 1H NMR, 13C NMR, mass) consistent with their assigned structures (see experimental section). For example, the 1H NMR spectrum of 8a in CDCl3 exhibits a two-proton singlet at δ 3.78 assignable to the methylene protons. The 13C NMR spectrum of 8a in CDCl3 shows a signal at δ 36.8 because of the methylene C-3 carbon and a signal at δ 72.8 because of the quaternary C-2 carbon.

Fortunately, we found the reaction condition under which the key intermediate 6a could be isolated (Scheme 1). Indeed, when a solution of 4a in 1,2-dichlorobenzene was refluxed for 24 h, the oxabridged cycloadduct 6a was obtained in 60% yield. Interestingly, in this reaction, the indoline 8a was not detected at all. Thermal treatment of 6a with acetic acid for 1.5 h caused a ring-opening/dehydration to give the desired 8a (77% yield), which was shown to be identical with the sample prepared from 4a with acetic acid on the basis of a mixed melting point determination and a comparison of the IR spectrum.
On the basis of the above experimental results, the formation of 8a−d and 9a−d could be explained by possible mechanism presented in Scheme 1. Thus, these intramolecular Diels-Alder reactions of 4a−d and 5a−d are assumed to proceed through the formation of the oxabridged cycloadducts 6a−d and 7a−d. Subsequently, a ring-opening/dehydration reaction of cycloadducts 6a−d and 7a−d easily occurs in the presence of acetic acid and then indolines 8a−d and 9a−d would be produced.
In conclusion, we have demonstrated the synthesis of novel dihydroindoles bearing electron-withdrawing groups at C-2 position. The key intramolecular Diels-Alder reaction of N-alkenylated 2-amino-3-furancarbonitriles proceeds smoothly to furnish the corresponding dihydroindoles. Functionalized dihydroindole 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 and 125 MHz, respectively. The 1H and 13C chemical shifts (δ) are reported in parts per million (ppm) relative to TMS as internal standard. Positive FAB MS 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.6
General procedure for the preparation of 2a−d and 3a−d from 1a−d and α-diazocarbonyl compounds.
A solution of 1a−d (20 mmol), dimethy diazomalonate (3.79 g, 24 mmol) and/or methyl diazoacetoacetate (3.41 g, 24 mmol) and Rh2(OAc)4 (0.10 g, 0.23 mmol) in C6H5F (80 mL) was stirred at 70 ̊C for 1 h. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel with CH2Cl2 as eluent to afford 2a−d and 3a−d.
2-[(3-Cyano-5-phenyl-2-furanyl)amino]propanedioic acid 1,3-dimethyl ester (2a): Colorless columns (5.65 g, 90%), mp 134−135 ̊C (acetone); IR (KBr): ν 3309 (NH), 2212 (CN), 1750, 1736 cm-1 (CO); 1H NMR (CDCl3): δ 3.88 (s, 6H, 2CO2CH3), 5.18 (d, J = 7.9 Hz, 1H, 2-H), 5.88 (d, J = 7.9 Hz, 1H, NH), 6.55 (s, 1H, furan 4-H), 7.22−7.26 (m, 1H, aryl H), 7.34−7.37 (m, 2H, aryl H), 7.42−7.45 (m, 2H, aryl H); 13C NMR (CDCl3): δ 53.8 (2CO2CH3), 58.9 (C-2), 71.4 (furan C-3), 105.8 (furan C-4), 114.6 (CN), 122.9, 127.6, 128.76, 128.81, 129.0 (C aryl), 145.3 (furan C-5), 159.2 (furan C-2), 166.2 (2CO); MS: m/z 315 [M+H]+. Anal. Calcd for C16H14N2O5: C, 61.14; H, 4.49; N, 8.91. Found: C, 61.09; H, 4.49; N 8.79.
2-{[5-(4-Chlorophenyl)-3-cyano-2-furanyl]amino}propanedioic acid 1,3-dimethyl ester (2b): Colorless columns (5.67 g, 81%), mp 133−135 ̊C (acetone); IR (KBr): ν 3328 (NH), 2210 (CN), 1749, 1734 cm-1 (CO); 1H NMR (CDCl3): δ 3.88 (s, 6H, 2CO2CH3), 5.17 (d, J = 7.9 Hz, 1H, 2-H), 5.94 (d, J = 7.9 Hz, 1H, NH), 6.55 (s, 1H, furan 4-H), 7.31−7.33 (m, 2H, aryl H), 7.35−7.38 (m, 2H, aryl H); 13C NMR (CDCl3): δ 53.8 (2CO2CH3), 58.9 (C-2), 71.5 (furan C-3), 106.4 (furan C-4), 114.2 (CN), 124.1, 127.4, 129.1, 133.2 (C aryl), 144.4 (furan C-5), 159.3 (furan C-2), 166.1 (2CO); MS: m/z 349 [M+H]+. Anal. Calcd for C16H13ClN2O5: C, 55.10; H, 3.76; N, 8.03. Found: C, 54.89; H, 3.80; N, 7.99.
2-{[3-Cyano-5-(4-methylphenyl)-2-furanyl]amino}propanedioic acid 1,3-dimethyl ester (2c): Colorless columns (4.85 g, 74%), mp 137−138 ̊C (acetone); IR (KBr): ν 3304 (NH), 2207 (CN), 1758, 1737 cm-1 (CO); 1H NMR (CDCl3): δ 2.34 (s, 3H, CH3), 3.88 (s, 6H, 2CO2CH3), 5.17 (d, J = 8.1 Hz, 1H, 2-H), 5.86 (d, J = 8.1 Hz, 1H, NH), 6.48 (s, 1H, furan 4-H), 7.14−7.16 (m, 2H, aryl H), 7.32−7.34 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.2 (CH3) 53.8 (2CO2CH3), 58.9 (C-2), 71.2 (furan C-3), 104.9 (furan C-4), 114.6 (CN), 122.9, 126.3, 129.5, 137.5 (C aryl), 145.7 (furan C-5), 159.0 (furan C-2), 166.2 (2CO); MS: m/z 329 [M+H]+. Anal. Calcd for C17H16N2O5: C, 62.19; H, 4.91; N, 8.53. Found: C, 61.98; H, 4.96; N 8.48.
2-{[3-Cyano-5-(4-methoxyphenyl)-2-furanyl]amino}propanedioic acid 1,3-dimethyl ester (2d): Colorless needles (5.85 g, 85%), mp 116−117 ̊C (acetone); IR (KBr): ν 3328 (NH), 2210 (CN), 1749, 1734 cm-1 (CO); 1H NMR (CDCl3): δ 3.82 (s, 3H, OCH3), 3.88 (s, 6H, 2CO2CH3), 5.16 (d, J = 8.2 Hz, 1H, 2-H), 5.84 (d, J = 8.2 Hz, 1H, NH), 6.39 (s, 1H, furan 4-H), 6.88−6.90 (m, 2H, aryl H), 7.36−7.38 (m, 2H, aryl H); 13C NMR (CDCl3): δ 53.8 (2CO2CH3), 55.3 (OCH3), 59.0 (C-2), 71.2 (furan C-3), 103.9 (furan C-4), 114.3 (C aryl), 114.6 (CN), 121.9, 124.5 (C aryl), 145.6 (furan C-5), 158.9 (furan C-2), 159.3 (C aryl), 166.3 (2CO); MS: m/z 345 [M+H]+. Anal. Calcd for C17H16N2O6: C, 59.30; H, 4.68; N, 8.14. Found: C, 59.10; H, 4.84; N 8.12.
2-[(3-Cyano-5-phenyl-2-furanyl)amino]-3-oxobutanoic acid methyl ester (3a): Colorless columns (4.30 g, 72%), mp 107−108 ̊C (acetone); IR (KBr) : ν 3329 (NH), 2204 (CN), 1755, 1726 cm-1 (CO); 1H NMR (CDCl3): δ 2.49 (s, 3H, COCH3), 3.89 (s, 3H, CO2CH3), 5.29 (d, J = 7.0 Hz, 1H, 2-H), 6.14 (d, J = 7.0 Hz, 1H, NH), 6.54 (s, 1H, furan 4-H), 7.22−7.26 (m, 1H, aryl H), 7.33−7.37 (m, 2H, aryl H), 7.42−7.44 (m, 2H, aryl H); 13C NMR (CDCl3): δ 27.3 (COCH3), 53.9 (CO2CH3), 65.7 (C-2), 70.4 (furan C-3), 105.8 (furan C-4), 114.9 (CN), 122.8, 127.5, 128.8 (C aryl), 128.9 (furan C-5), 145.1 (C aryl), 159.5 (furan C-2), 166.2, 196.9 (CO); MS: m/z 299 [M+H]+. Anal. Calcd for C16H14N2O4: C, 64.42; H, 4.73; N 9.39. Found: C, 64.29; H, 4.71; N 9.29.
2-{[5-(4-Chlorophenyl)-3-cyano-2-furanyl]amino}-3-oxobutanoic acid methyl ester (3b): Colorless columns (4.89 g, 74%), mp 134−135 ̊C (acetone); IR (KBr): ν 3310 (NH), 2205 (CN), 1751, 1728 cm-1 (CO); 1H NMR (CDCl3): δ 2.48 (s, 3H, COCH3), 3.89 (s, 3H, CO2CH3), 5.28 (d, J = 7.0 Hz, 1H, 2-H), 6.15 (d, J = 7.0 Hz, 1H, NH), 6.53 (s, 1H, furan 4-H), 7.30−7.37 (m, 4H, aryl H); 13C NMR (CDCl3): δ 27.3 (COCH3), 53.9 (CO2CH3), 65.7 (C-2), 70.7 (furan C-3), 106.4 (furan C-4), 114.6 (CN), 124.1, 127.5, 129.0, 133.2 (C aryl), 144.1 (furan C-5), 159.7 (furan C-2), 166.1, 196.8 (CO); MS: m/z 333 [M+H]+. Anal. Calcd for C16H13ClN2O4 0.15H2O: C, 57.29; H, 4.00; N, 8.35. Found: C, 57.27; H, 4.05; N, 8.36.
2-{[3-Cyano-5-(4-methylphenyl)-2-furanyl]amino}-3-oxobutanoic acid methyl ester (3c): Colorless columns (4.18 g, 67%), mp 136−137 ̊C (acetone); IR (KBr): ν 3322 (NH), 2208 (CN), 1750, 1726 cm-1 (CO); 1H NMR (CDCl3): δ 2.34 (s, 3H, CH3), 2.47 (s, 3H, COCH3), 3.88 (s, 3H, CO2CH3), 5.27 (d, J = 7.3 Hz, 1H, 2-H), 6.07 (d, J = 7.3 Hz, 1H, NH), 6.46 (s, 1H, furan 4-H), 7.15−7.17 (m, 2H, aryl H), 7.31−7.34 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.2 (CH3), 27.3 (COCH3), 53.8 (CO2CH3), 65.8 (C-2), 70.5 (furan C-3), 104.9 (furan C-4), 114.9 (CN), 122.9, 126.3, 129.5, 137.5 (C aryl), 145.5 (furan C-5), 159.4 (furan C-2), 166.2, 197.0 (CO); MS: m/z 313 [M+H]+. Anal. Calcd for C17H16N2O4: C, 65.38; H, 5.16; N, 8.97. Found: C, 65.28; H, 5.21; N 8.96.
2-{[3-Cyano-5-(4-methoxyphenyl)-2-furanyl]amino}-3-oxobutanoic acid methyl ester (3d): Colorless needles (4.38 g, 67%), mp 119−120 ̊C (acetone); IR (KBr): ν 3245 (NH), 2209 (CN), 1728, 1667 cm-1 (CO); 1H NMR (CDCl3): δ 2.18 (s, 3H, COCH3), 3.80 (s, 1H, CO2CH3), 3.82 (s, 3H, OCH3), 5.70 (s, 1H, 2-H), 6.39 (s, 1H, furan 4-H), 6.88−6.90 (m, 2H, aryl H), 7.38−7.40 (m, 2H, aryl H), 12.37 (br s, 1H, NH); 13C NMR (CDCl3): δ 18.0 (COCH3), 52.2 (OCH3), 55.3 (CO2CH3), 70.3 (furan C-3), 101.3 (C-2), 104.1 (furan C-4), 114.3 (C aryl), 114.9 (CN), 122.2, 124.4 (C aryl), 145.2 (furan C-5), 159.2 (CO), 161.3 (furan C-2), 170.7 (C aryl), 177.0 (CO); MS: m/z 329 [M+H]+. Anal. Calcd for C17H16N2O5: C, 62.19; H, 4.91; N, 8.53. Found: C, 61.98; H, 4.97; N 8.57.
General procedure for the preparation of 4a−d and 5a−d from 2a−d and/or 3a−d and 3-bromopropene.
To an ice-cooled and stirred mixture of 2a−d and/or 3a−d (2.5 mmol) and sodium methoxide (0.18 g, 3.25 mmol) in DMF (10 mL), 3-bromopropene (0.61 g, 5 mmol) was added. The mixture was stirred at rt for 3 h. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel with CH2Cl2 as the eluent to give 4a−d and 5a−d.
2-[(3-Cyano-5-phenyl-2-furanyl)amino]-2-(2-propen-1-yl)propanedioic acid 1,3-dimethyl ester (4a): Colorless columns (0.28 g, 32%), mp 121−123 ̊C (Et2O); IR (KBr): ν 3346 (NH), 2218 (CN), 1761, 1741 cm-1 (CO); 1H NMR (CDCl3): δ 3.14 (d, J = 7.3 Hz, 2H, 2-propene 1-H), 3.82 (s, 6H, CO2CH3), 5.09−5.18 (m, 2H, 2-propene 3-H), 5.60−5.69 (m, 1H, 2-propene 2-H), 6.17 (s, 1H, NH), 6.57 (s, 1H, furan 4-H), 7.22−7.26 (s, 1H, aryl H), 7.34−7.42 (s, 4H, aryl H); 13C NMR (CDCl3): δ 38.2 (2-propene C-1), 53.8 (2CO2CH3), 68.0 (C-2), 72.3 (furan C-3), 105.5 (furan C-4), 114.4 (CN), 120.8 (2-propene C-3), 122.7, 127.4, 128.9, 129.0 (C aryl), 130.2 (2-propene C-2), 145.5 (furan C-5), 158.9 (furan C-2), 167.8 (CO); MS: m/z 355 [M+H]+. Anal. Calcd for C19H18N2O5: C, 64.40; H, 5.12; N, 7.91. Found: C, 64.43; H, 5.17; N, 7.93.
2-{[5-(4-Chlorophenyl)-3-cyano-2-furanyl]amino}-2-(2-propen-1-yl)propanedioic acid 1,3-dimethyl ester (4b): Colorless columns (0.45 g, 46%), mp 120−121 ̊C (Et2O); IR (KBr): 3287 (NH), 2215 (CN), 1749 cm-1 (CO); 1H NMR (CDCl3): δ 3.13 (d, J = 7.3 Hz, 2H, 2-propene 1-H), 3.82 (s, 6H, 2CO2CH3), 5.09−5.20 (m, 2H, 2-propene 3-H), 5.59−5.69 (m, 1H, 2-propene 2-H), 6.21 (s, 1H, NH), 6.57 (s, 1H, furan 4-H), 7.33 (s, 4H, aryl H); 13C NMR (CDCl3): δ 38.2 (2-propene C-1), 53.9 (2CO2CH3), 68.0 (C-2), 72.4 (furan C-3), 106.0 (furan C-4), 114.2 (CN), 120.9 (2-propene C-3), 123.9, 127.5, 129.2 (C aryl), 130.0 (2-propene C-2), 133.1 (C aryl), 144.4 (furan C-5), 158.9 (furan C-2), 167.8 (CO); MS: m/z 389 [M+H]+. Anal. Calcd for C19H17ClN2O5: C, 58.69; H, 4.41; N, 7.21. Found: C, 58.72; H, 4.51; N, 7.28.
2-{[3-Cyano-5-(4-methylphenyl)-2-furanyl]amino}-2-(2-propen-1-yl)propanedioic acid 1,3-dimethyl ester (4c): Yellow oil (0.31 g, 34%); IR (neat): ν 3377 (NH), 2216 (CN), 1747 cm-1 (CO); 1H NMR (CDCl3): δ 2.34 (s, 3H, CH3), 3.13 (d, J = 7.3 Hz, 2H, 2-propene 1-H), 3.82 (s, 6H, 2CO2CH3), 5.09−5.18 (m, 2H, 2-propene 3-H), 5.60−5.69 (m, 1H, 2-propene 2-H), 6.13 (s, 1H, NH), 6.50 (s, 1H, furan 4-H), 7.16−7.18 (m, 2H, aryl H), 7.26−7.31 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.2 (CH3), 38.3 (2-propene C-1), 53.8 (2CO2CH3), 68.1 (C-2), 72.3 (furan C-3), 104.5 (furan C-4), 114.5 (CN), 120.8 (2-propene C-3), 122.7, 126.3, 129.6 (C aryl), 130.2 (2-propene C-2), 137.4 (C aryl), 145.9 (furan C-5), 158.6 (furan C-2), 167.9 (CO); MS: m/z 368 [M+H]+. Anal. Calcd for C21H20N2O5: C, 65.21; H, 5.47; N, 7.60. Found: C, 65.34; H, 5.78; N, 7.44.
2-{[3-cyano-5-(4-methoxyphenyl)-2-furanyl]amino}-2-(2-propen-1-yl)propanedioic acid 1,3-dimethyl ester (4d): Colorless columns (0.45 g, 47%), mp 105−106 ̊C (Et2O); IR (KBr): ν 3269 (NH), 2217 (CN), 1749 cm-1 (CO); 1H NMR (CDCl3): δ 3.12 (d, J = 7.3 Hz, 2H, 2-propene 1-H), 3.82 (s, 9H, OCH3 and 2CO2CH3), 5.09−5.18 (m, 2H, 2-propene 3-H), 5.61−5.69 (m, 1H, 2-propene 2-H), 6.10 (s, 1H, NH), 6.41 (s, 1H, furan 4-H), 6.88−6.92 (m, 2H, aryl H), 7.32−7.35 (m, 2H, aryl H); 13C NMR (CDCl3): δ 38.2 (2-propene C-1), 53.8 (2CO2CH3), 55.3 (OCH3), 68.1 (C-2), 72.4 (furan C-3), 103.5 (furan C-4), 114.5 (C aryl), 114.6 (CN), 120.8 (2-propene C-3), 122.0, 124.3 (C aryl), 130.2 (2-propene C-2), 145.8 (furan C-5), 158.5 (furan C-2), 159.2 (C aryl), 167.9 (CO); MS: m/z 385 [M+H]+. Anal. Calcd for C20H20N2O6: C, 62.49; H, 5.24; N, 7.29. Found: C, 62.49; H, 5.33; N, 7.18.
2-Acetyl-2-[(3-cyano-5-phenyl-2-furanyl)amino]-4-pentenoic acid methyl ester (5a): Colorless columns (0.18 g, 21%), mp 91−92 ̊C (Et2O); IR (KBr): ν 3434 (NH), 2212 (CN), 1651, 1613 cm-1 (CO); 1H NMR (CDCl3): δ 2.10 (s, 3H, COCH3), 3.81 (s, 3H, CO2CH3), 4.00−4.05 (m, 1H, 4-pentene 3-H), 4.34−4.39 (m, 1H, 4-pentene 3-H), 5.25−5.34 (m, 2H, 4-pentene 5-H), 5.29−6.00 (m, 1H, 4-pentene 4-H), 6.57 (s, 1H, furan 4-H), 7.21−7.26 (m, 1H, aryl H), 7.34−7.38 (m, 2H, aryl H), 7.46−7.48 (m, 2H, aryl H), 12.49 (br s, 1H, NH); 13C NMR (CDCl3): δ 18.3 (COCH3), 52.2 (CO2CH3), 54.8 (4-pentene C-3), 70.0 (furan C-3), 106.2 (C-2), 107.1 (furan C-4), 115.4 (CN), 119.7 (4-pentene C-5), 122.6, 127.2, 128.8, 129.3 (C aryl), 132.2 (4-pentene C-4), 144.4 (furan C-5), 161.6 (furan C-2), 170.7, 177.9 (CO); MS: m/z 339 [M+H]+. Anal. Calcd for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found: C, 67.23; H, 5.39; N, 8.20.
2-Acetyl-2-{[5-(4-chlorophenyl)-3-cyano-2-furanyl]amino}-4-pentenoic acid methyl ester (5b): Colorless columns (0.38 g, 41%), mp 131−132 ̊C (Et2O); IR (KBr): ν 3343 (NH), 2213 (CN), 1750, 1728 cm-1 (CO); 1H NMR (CDCl3): δ 2.27 (s, 3H, COCH3), 3.02−3.07 (m, 1H, 4-pentene 3-H), 3.15−3.20 (m, 1H, 4-pentene 3-H), 3.82 (s, 3H, CO2CH3), 5.07−5.17 (m, 2H, 4-pentene 5-H), 5.51−5.59 (m, 1H, 4-pentene 4-H), 6.41 (s, 1H, NH), 6.57 (s, 1H, furan 4-H), 7.26−7.35 (m, 4H, aryl H); 13C NMR (CDCl3): δ 24.4 (COCH3), 37.1 (4-pentene C-3), 53.9 (CO2CH3), 72.3 (furan C-3), 73.3 (C-2), 106.0 (furan C-4), 114.2 (CN), 120.8 (4-pentene C-5), 123.9, 127.4, 129.2 (C aryl), 129.8 (4-pentene C-4), 133.2 (C aryl) 144.4 (furan C-5), 159.0 (furan C-2), 168.4, 198.3 (CO); MS: m/z 373 [M+H]+. Anal. Calcd for C19H17ClN2O4: C, 61.21; H, 4.60; N, 7.51. Found: C, 61.19; H, 4.62; N, 7.54.
2-Acetyl-2-{[3-cyano-5-(4-methylphenyl)-2-furanyl]amino}-4-pentenoic acid methyl ester (5c): Yellow oil (0.37 g, 42%); IR (neat): ν 3360 (NH), 2214 (CN), 1748, 1730 cm-1 (CO); 1H NMR (CDCl3): δ 2.27 (s, 3H, COCH3), 2.34 (s, 3H, CH3), 3.02−3.07 (m, 1H, 4-pentene 3-H), 3.15−3.21 (m, 1H, 4-pentene 3-H), 3.81 (s, 3H, CO2CH3), 5.06−5.16 (m, 2H, 4-pentene 5-H), 5.51−5.60 (m, 1H, 4-pentene 3-H), 6.35 (s, 1H, NH), 6.49 (s, 1H, furan 4-H), 7.15−7.17 (m, 2H, aryl H), 7.23−7.27 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.2 (CH3), 24.4 (COCH3), 37.1 (4-pentene C-3), 53.9 (CO2CH3), 72.1 (furan C-3), 73.4 (C-2), 104.5 (furan C-4), 114.5 (CN), 120.7 (4-pentene C-5), 122.7, 124.1, 126.2, 129.6, 129.7 (C aryl), 130.0 (4-pentene C-4), 137.5 (C aryl), 145.8 (furan C-5), 158.7 (furan C-2), 168.5, 198.5 (CO); MS: m/z 353 [M+H]+. Anal. Calcd for C20H20N2O4 0.25H2O: C, 67.31; H, 5.79; N, 7.85. Found: C, 67.39; H, 5.73; N, 7.92.
2-Acetyl-2-{[3-cyano-5-(4-methoxyphenyl)-2-furanyl]amino}-4-pentenoic acid methyl ester (5d): Colorless columns (0.33 g, 36%), mp 112−113 ̊C (Et2O); IR (KBr): ν 3309 (NH), 2213 (CN), 1752, 1727 cm-1 (CO); 1H NMR (CDCl3): δ 2.26 (s, 3H, COCH3), 3.01−3.05 (m, 1H, 4-pentene 3-H), 3.15−3.19 (m, 1H, 4-pentene 3-H), 3.81 (s, 3H, CO2CH3), 3.82 (s, 3H, OCH3), 5.07−5.17 (m, 2H, 4-pentene 5-H), 5.53−5.57 (m, 1H, 4-pentene 4-H), 6.31 (s, 1H, NH), 6.41 (s, 1H, furan 4-H), 6.89−6.92 (m, 2H, aryl H), 7.29−7.32 (m, 2H, aryl H); 13C NMR (CDCl3): δ 24.5 (COCH3), 37.1 (4-pentene C-3), 53.9 (CO2CH3), 55.3 (OCH3), 72.2 (furan C-3), 73.3 (C-2), 103.4 (furan C-4), 114.5 (C aryl), 114.6 (CN), 120.7 (4-pentene C-5), 121.9, 124.3 (C aryl), 130.0 (4-pentene C-4), 145.7 (furan C-5), 158.6 (furan C-2), 159.2 (C aryl), 168.5, 198.6 (CO); MS: m/z 369 [M+H]+. Anal. Calcd for C20H20N2O5: C, 65.21; H, 5.47; N, 7.60. Found: C, 65.14; H, 5.51; N, 7.61.
General procedure for preparation of 8a−d and 9a−d from 4a−d and 5a−d.
A solution of 4a−d and/or 5a−d (1.0 mmol) in AcOH (10 mL) was refluxed for 3 h. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel with CH2Cl2 as eluent to yield 8a−d and 9a−d.
7-Cyano-1,3-dihydro-5-phenyl-2H-indole-2,2-dicarboxylic acid 2,2-dimethyl ester (8a): Colorless columns (0.28 g, 83%), mp 132−133 ̊C (Et2O); IR (KBr): ν 3309 (NH), 2224 (CN), 1744 cm-1 (CO); 1H NMR (CDCl3): δ 3.78 (s, 2H, 3-H), 3.85 (s, 6H, 2CO2CH3), 5.61 (br s, 1H, NH), 7.30−7.33 (m, 1H, aryl H), 7.38−7.46 (m, 6H, aryl H); 13C NMR (CDCl3): δ 36.8 (C-3), 53.7 (2CO2CH3), 72.8 (C-2), 92.3 (C aryl), 116.9 (CN), 126.5, 127.3, 127.6, 127.8, 128.8, 128.9, 133.6, 139.3, 150.6 (C aryl), 169.5 (2CO); MS: m/z 337 [M+H]+. Anal. Calcd for C19H16N2O4 0.3H2O: C, 66.78; H, 4.90; N, 8.20. Found: C, 66.76; H, 4.85; N, 8.13.
5-(4-Chlorophenyl)-7-cyano-1,3-dihydro-2H-indole-2,2-dicarboxylic acid 2,2-dimethyl ester (8b): Colorless columns (0.28 g, 76%), mp 175−176 ̊C (Et2O); IR (KBr): ν 3312 (NH), 2228 (CN), 1740 cm-1 (CO); 1H NMR (CDCl3): δ 3.77 (s, 2H, 3-H), 3.85 (s, 6H, 2CO2CH3), 5.62 (br s, 1H, NH), 7.36 (s, 4H, aryl H), 7.39−7.41 (m, 2H, aryl H); 13C NMR (CDCl3): δ 36.8 (C-3), 53.7 (2CO2CH3), 72.8 (C-2), 92.3 (C aryl), 116.7 (CN), 127.5, 127.7, 127.8, 128.7, 129.1, 132.3, 133.4, 137.8, 150.8 (C aryl), 169.4 (2CO); MS: m/z 371 [M+H]+. Anal. Calcd for C19H15ClN2O4: C, 61.55; H, 4.08; N, 7.56. Found: C, 61.58; H, 4.20; N, 7.62.
7-Cyano-1,3-dihydro-5-(4-methylphenyl)-2H-indole-2,2-dicarboxylic acid 2,2-dimethyl ester (8c): Colorless columns (0.21 g, 60%), mp 170−171 ̊C (Et2O); IR (KBr): 3304 (NH), 2226 (CN), 1742 cm-1 (CO); 1H NMR (CDCl3): δ 2.37 (s, 3H, CH3), 3.77 (s, 2H, 3-H), 3.84 (s, 6H, 2CO2CH3), 5.57 (br s, 1H, NH), 7.19−7.21 (m, 2H, aryl H), 7.31−7.34 (m, 2H, aryl H), 7.41−7.43 (m, 2H, aryl H); 13C NMR (CDCl3): δ 21.0 (CH3), 36.9 (C-3), 53.6 (2CO2CH3), 72.8 (C-2), 92.3 (C aryl), 114.4 (C aryl), 116.9 (CN), 126.3, 127.5, 127.6, 128.5, 129.6, 133.7, 136.5, 137.1, 150.4 (C aryl), 169.5 (2CO); MS: m/z 351 [M+H]+. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.55; H, 5.27; N, 7.90.
7-Cyano-1,3-dihydro-5-(4-methoxyphenyl)-2H-indole-2,2-dicarboxylic acid 2,2-dimethyl ester (8d): Colorless columns (0.19 g, 52%), mp 188−189 ̊C (Et2O); IR (KBr): ν 3307 (NH), 2226 (CN), 1741 cm-1 (CO); 1H NMR (CDCl3): δ 3.76 (s, 2H, 3-H), 3.83 (s, 3H, OCH3), 3.84 (s, 6H, 2CO2CH3), 5.55 (br s, 1H, NH), 6.92−6.94 (m, 2H, aryl H), 7.34−7.40 (m, 4H, aryl H); 13C NMR (CDCl3): δ 36.9 (C-3), 53.6 (2CO2CH3), 55.3 (OCH3), 72.8 (C-2), 92.4, 114.4 (C aryl), 116.9 (CN), 127.46, 127.55, 127.57, 128.3, 132.0, 133.5, 150.2, 159.2 (C aryl), 169.6 (2CO); MS: m/z 367 [M+H]+. Anal. Calcd for C20H18N2O5: C, 65.57; H, 4.95; N, 7.65. Found: C, 65.45; H, 5.07; N, 7.53.
2-Acetyl-7-cyano-2,3-dihydro-5-phenyl-1H-indole-2-carboxylic acid methyl ester (9a): Colorless columns (0.12 g, 38%), mp 160−161 ̊C (Et2O); IR (KBr): ν 3307 (NH), 2221 (CN), 1749, 1735 cm-1 (CO); 1H NMR (DMSO-d6): δ 2.31 (s, 3H, COCH3), 3.54 (d, J = 17.5 Hz, 1H, 3-H), 3.66 (d, J = 17.5 Hz, 1H, 3-H), 3.76 (s, 3H, CO2CH3), 7.28−7.32 (m, 1H, aryl H), 7.39−7.43 (m, 2H, aryl H), 7.57−7.63 (m, 4H, aryl H), 8.22 (s, 1H, NH); 13C NMR (DMSO-d6): δ 25.3 (COCH3), 35.1 (C-3), 53.0 (CO2CH3), 77.3 (C-2), 89.5 (C aryl), 117.3 (CN), 125.9, 126.8, 127.4, 128.3, 128.5, 128.8, 130.7, 138.6 151.3 (C aryl), 170.5, 201.9 (CO); MS: m/z 321 [M+H]+. Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C, 71.31; H, 5.11; N, 8.76.
2-Acetyl-5-(4-chlorophenyl)-7-cyano-2,3-dihydro-1H-indole-2-carboxylic acid methyl ester (9b): Colorless columns (0.23 g, 65%), mp 211−213 ̊C (Et2O); IR (KBr): ν 3305 (NH), 2223 (CN), 1742, 1715 cm-1 (CO); 1H NMR (DMSO-d6): δ 2.31 (s, 3H, COCH3), 3.53 (d, J = 17.5 Hz, 1H, 3-H), 3.65 (d, J = 17.5 Hz, 1H, 3-H), 3.76 (s, 3H, CO2CH3), 7.43−7.46 (m, 2H, aryl H), 7.60−7.63 (m, 4H, aryl H), 8.29 (s, 1H, NH); 13C NMR (DMSO-d6): δ 25.3 (COCH3), 35.1 (C-3), 53.0 (CO2CH3), 77.4 (C-2), 89.4 (C aryl), 117.2 (CN), 127.2, 127.6, 128.4, 128.6, 128.7, 129.2, 131.6, 137.5, 151.6 (C aryl), 170.4, 201.9 (CO); MS: m/z 355 [M+H]+. Anal. Calcd for C19H15ClN2O3: C, 64.32; H, 4.26; N, 7.90. Found: C, 64.19; H, 4.28; N, 7.87.
2-Acetyl-7-cyano-2,3-dihydro-5-(4-methylphenyl)-1H-indole-2-carboxylic acid methyl ester (9c): Colorless columns (0.31 g, 93%), mp 161−163 ̊C (Et2O); IR (KBr): ν 3309 (NH), 2220 (CN), 1748, 1715 cm-1 (CO); 1H NMR (DMSO-d6): δ 2.31 (s, 6H, COCH3, CH3), 3.53 (d, J = 17.7 Hz, 1H, 3-H), 3.65 (d, J = 17.7 Hz, 1H, 3-H), 3.76 (s, 3H, CO2CH3), 7.21 (d, J = 8.2 Hz, 2H, aryl H), 7.47 (d, J = 8.2 Hz, 2H, aryl H), 7.55−7.56 (m, 1H, aryl H), 7.60 (s, 1H, aryl H), 8.17 (s, 1H, NH); 13C NMR (DMSO-d6) : δ 20.5 (CH3), 25.3 (COCH3), 35.2 (C-3), 53.0 (CO2CH3), 77.3 (C-2), 89.5 (C aryl), 117.3 (CN), 125.7, 127.2, 127.8, 128.4, 129.4, 130.7, 135.8, 136.1, 151.1 (C aryl), 170.5, 201.9 (CO); MS: m/z 335 [M+H]+. Anal. Calcd for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.88; H, 5.47; N, 8.39.
2-Acetyl-7-cyano-2,3-dihydro-5-(4-methoxyphenyl)-1H-indole-2-carboxylic acid methyl ester (9d): Colorless columns (0.15 g, 43%), mp 150−151 ̊C (Et2O); IR (KBr): ν 3327 (NH), 2219 (CN), 1749, 1726 cm-1 (CO); 1H NMR (DMSO-d6): δ 2.31 (s, 3H, COCH3), 3.52 (d, J = 17.5 Hz, 1H, 3-H), 3.64 (d, J = 17.5 Hz, 1H, 3-H), 3.76 (s, 3H, CO2CH3), 3.78 (s, 3H, COCH3), 6.96−6.98 (m, 2H, aryl H), 7.51−7.52 (m, 3H, aryl H), 7.57 (s, 1H, aryl H), 8.12 (s, 1H, NH); 13C NMR (DMSO-d6): δ 25.3 (COCH3), 35.2 (C-3), 53.0 (CO2CH3), 55.1 (OCH3), 77.3 (C-2), 89.5, 114.2 (C aryl), 117.4 (CN), 126.99, 127.04, 127.5, 128.4, 130.6, 131.1, 150.8, 158.5 (C aryl), 170.5, 202.0 (CO); MS: m/z 351 [M+H]+. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.56; H, 5.22; N, 7.98.
The preparation of 6a from 4a.
A solution of 4a (0.35 g, 1 mmol) in 1,2-dichlorobenzene (10 mL) was refluxed for 24 h. After removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel with CH2Cl2:acetone (8:1) as eluent to provide 7-cyano-1,3,3a,4,5,7a-hexahydro-5-phenyl-5,7a-epoxy-2H- indole-2,2-dicarboxylic acid dimethyl ether (6a): This compound was obtained as colorless columns (0.21 g, 60%), mp 180−182 ̊C (Et2O); IR (KBr): ν 3462 (NH), 2237 (CN), 1739 cm-1(CO); 1H NMR (CDCl3): δ 1.87 (t, J = 13.1 Hz, 1H, 4-H), 2.08 (dd, J = 10.7, 13.1 Hz, 1H, 3-H), 2.17−2.20 (m, 1H, 4-H), 2.72 (dd, J = 7.9, 13.1 Hz, 1H, 3-H), 3.49−3.52 (m, 1H, 3a-H), 3.73 (s, 3H, CO2CH3), 3.76 (s, 3H, CO2CH3), 6.33 (s, 1H, NH), 7.28−7.44 (m, 6H, 6-H and aryl H); 13C NMR (CDCl3): δ 36.7 (C-3), 42.1 (C-3a), 42.7 (C-4) 52.8, 53.1 (CO2CH3), 71.1 (C-5), 84.8 (C-2), 109.8 (C-7), 114.6 (CN), 124.8, 127.4, 128.2, 145.6 (C aryl), 158.9 (C-6), 168.4, 169.1 (CO), 173.4 (C-7a); MS: m/z 355 [M+H]+. Anal. Calcd for C19H18N2O5: C, 64.40; H, 5.12; N, 7.91. Found: C, 64.15; H, 5.16; N, 7.88.
The preparation of 8a from 6a.
A solution of 6a (0.35 g, 1 mmol) in AcOH (10 mL) was refluxed for 1.5 h. After removal the solvent in vacuo, the residue was purified by column chromatography on silica gel with CH2Cl2 as eluent to give 8a (0.26 g, 77%), which was shown to be identical with the sample prepared from 4a with AcOH on the basis of a mixed melting point determination and a comparison of the IR spectrum.

ACKNOWLEDGEMENTS
The authors thank Hiroshi Hanazono and Yukiko Iwase for obtaining MS and NMR spectra and Junko Honda for her valuable help with elemental analyses.

References

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