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Original article
9 (
6
); 882-890
doi:
10.1016/j.arabjc.2016.07.020

Facile synthetic approach for 5-aryl-9-hydroxypyrano [3,2-f] indole-2(8H)-one

, , , , ,
 School of Pharmacy, Health Science Center, Xi’an Jiaotong University, No. 76, Yanta West Road, Xi’an 710061, Shaanxi Province, People’s Republic of China

⁎Corresponding author. hehuaizhen@mail.xjtu.edu.cn (Huaizhen He)

Received: , Accepted: ,
© The Author(s) 2016
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

An appropriate method for the synthesis of 5-aryl-9-hydroxypyrano[3,2-f]indole-2(8H)-one was described. The targeted compounds were obtained starting from vanillin via nine steps. Interestingly, in the final cyclization step, the intermediate 4-(2-halogeno phenyl)-7-methoxy-1H-indole-6-yl propiolate could convert directly into the final product in one step reaction using PtCl4 or Pd(PPh3)4/trifluoroacetic acid as catalysts. The possible catalytic mechanism for PtCl4 and Pd(PPh3)4/trifluoroacetic acid was discussed.

Keywords

Heterocyclic
Pyrrolocoumarin
Biphenyl
Vanillin
Catalysis
1

1 Introduction

Pyrroles derivatives constitute an important class of heterocyclic compounds, which exhibit a wide range of pharmacological properties (Estévez et al., 2014; Zhuo et al., 2014; Su et al., 2013; Kathirav et al., 2012; AlMourabit et al., 2011; Young et al., 2010). They have been reported to possess significant anti-HIV (Liu et al., 2008), antitumor (Diana et al., 2011; Wang et al., 2012; Parrino et al., 2014; Barraja et al., 2011; Spanò et al., 2014) and antifungal (El-Gaby et al., 2002) activities. Pyrrolocoumarins have received considerable attention for their biological importance (Chen et al., 2008; Sandhu et al., 2014; Kontogiorgis et al., 2008). Some of them were reported as fluorogenic probes for the detection of H2S, which provided an emission signal for a specific enzymatic process in complex biological systems (Zhou et al., 2014). Moreover, they are also able to inhibit NO production (Sinicropi et al., 2009), COX-2 (Kreft et al., 1998), PLA2 and lipoxygenase (Musser et al., 1993) and showed antiproliferative activity (Guiotto et al., 1995; Barraja et al., 2008; Carbone et al., 2013). Recently, hybridization of pyrrolocoumarin with an arene moiety is present in various synthetic antihyperlipidemic and antitumor drugs such as statins, lamellarins and ningalins (Sashidhara et al., 2010; Marco et al., 2005; Chen and Xu, 2009). Furthermore, a number of arene-fused pyrrolocoumarins have been synthesized and extended the applications in biological detection, such as living cell imaging, neuroimaging, protein labeling tag (SNAP-tag) and the detection and treatment of monoamine oxidases (Tietze et al., 2012; Vadola and Sames, 2012; Mei et al., 2011; Gong et al., 2006; Lin and Yang, 2013). Therefore, aromatization of pyrrolocoumarin received more attention.

On the other hand, biphenyl moiety has also attracted the attention of organic and medicinal chemists for its special biological activities. It was considered as one of the privileged substructures and widely used in pharmaceutical research (Hajduk et al., 2000; Horton et al., 2003). Active substances with biphenyl moiety include sartans (Muszalska et al., 2014), vasopressin agonists (Memoli et al., 2006), matrix metalloproteinase inhibitors (Pikul et al., 2001), factor Xa inhibitors (Zhang et al., 2004), β3-adrenergic receptor agonists (Imanishi et al., 2008), and ETA receptor antagonists (Murugesan et al., 2003). In addition, compounds with biphenyl moiety tend to bind with a wide range of proteins and have high specificity (Hajduk et al., 2000). It means that the introduction of biphenyl substructure might enhance the affinity between compounds and receptors. Thus, combining pyrrolocoumarin with biphenyl may have beneficial effects on biological activities. In addition, previous studies have mainly focused on the angular pyrrolocoumarin synthesis, but less about the linear pyrrolocoumarin. For these reasons, we report an appropriate method for the preparation of biphenyl pyrrolocoumarin 5-(2-halogeno phenyl)-9-hydroxypyrano[3,2-f]indole-2(8H)-one, and discuss the possible catalytic mechanism of PtCl4 and Pd(PPh3)4/trifluoroacetic acid.

2

2 Results and discussion

Three main synthetic strategies could be used to construct the biphenyl pyrrolocoumarin skeleton, named indole-ring construction (A), pyrone-ring construction (B) and biphenyl construction (C) (Fig. 1). Initially, strategy B failed to generate the desired pyrone-ring owing to the electrophilic effect of —NO2 in starting materials. Beyond that, the yield and selectivity of reaction were greatly decreased due to the transformation of the multiple functional groups on starting materials. Then, we turned our efforts to strategy A with vanillin as starting material, indole-ring and pyrone-ring have been successfully constructed and brominated, and compound I was obtained. However, the targeted skeleton has not been achieved since compound I and its modified products were easily broken down in Suzuki–Miyaura cross-coupling reaction. Fortunately, prior to pyrone-ring, the structure C of biphenyl was built by altering the sequence of reactions and gave biphenyl compound II. Finally, the targeted biphenyl pyrrolocoumarin was successfully established using condensation reaction with transition metal catalyst. Therefore, the strategy “A → C → B” was an appropriate method for the synthesis of the biphenyl pyrrolocoumarins compared with other paths. The synthetic route is depicted in Scheme 1.

Synthetic strategy of biphenyl pyrrolocoumarin.
Figure 1
Synthetic strategy of biphenyl pyrrolocoumarin.
General synthetic route for 5-(2-halogeno phenyl)-9-hydroxypyrano[3,2-f]indole-2(8H)-one. Reagents and conditions: (a) Ac2O, Et3N, THF, RT, 0.5 h; (b) Br2, KBr, water, RT, 18 h; (c) Fuming HNO3, –20 °C, 5 min; (d) (1) NaOH, RT, 20 min; (2) 2N HCl pH = 3–4; (e) MeNO2, CH3COO−NH4+, CH3COOH, 120 °C, 4 h; (f) iron powder, AcOH, silica gel (100–200 mesh), N2, 110 °C, 1 h; (g) Pd(PPh3)4, arylboronic acids, Na2CO3, glycol dimethyl ether, H2O, 85 °C, 12 h; (h) propiolic acid, DCC, DMAP, CH2Cl2, RT, 2 h; (i) method 1:5 mol%PtCl4, 1,4-dioxane:1,2-dichloroethane = 1:1, N2, 65 °C, 2 h; method 2: Pd(PPh3)4, trifluoroacetic acid, CH2Cl2, RT, 2 h.
Scheme 1
General synthetic route for 5-(2-halogeno phenyl)-9-hydroxypyrano[3,2-f]indole-2(8H)-one. Reagents and conditions: (a) Ac2O, Et3N, THF, RT, 0.5 h; (b) Br2, KBr, water, RT, 18 h; (c) Fuming HNO3, –20 °C, 5 min; (d) (1) NaOH, RT, 20 min; (2) 2N HCl pH = 3–4; (e) MeNO2, CH3COO−NH4+, CH3COOH, 120 °C, 4 h; (f) iron powder, AcOH, silica gel (100–200 mesh), N2, 110 °C, 1 h; (g) Pd(PPh3)4, arylboronic acids, Na2CO3, glycol dimethyl ether, H2O, 85 °C, 12 h; (h) propiolic acid, DCC, DMAP, CH2Cl2, RT, 2 h; (i) method 1:5 mol%PtCl4, 1,4-dioxane:1,2-dichloroethane = 1:1, N2, 65 °C, 2 h; method 2: Pd(PPh3)4, trifluoroacetic acid, CH2Cl2, RT, 2 h.

According to modification of the previously reported procedure (Wang et al., 2015), compounds 1–4 were synthesized and the overall yield was up to 76% in first four steps. With triethylamine as alkaline reagent, vanillin was esterified with Ac2O in anhydrous THF to give 4-formyl-2-methoxyphenyl acetate (1) within 0.5 h with 99% yield. Then, 5-bromo-4-formyl-2-methoxyphenyl acetate (2) was obtained with 99% yield by electrophilic substitution reaction at C-5 of compound 1 with Br2 in water in the presence of KBr. Compound 2 was treated with fuming nitric acid (1:1.7) at −20 °C for 5 min. The desired 5-bromo-4-formyl-2-methoxy-3-nitrophenyl acetate (3) was obtained in 79% yield. However, when the mass-volume ratio of compound 2 with fuming nitric acid was less than 1:1.3, it would result in drastically diminished yield and increase in the by-products of compound 3. It was presumably due to the local overheating in the process of nitration. Compound 3 was hydrolyzed through treatment with 20% aqueous sodium hydroxide solution and 2 M HCl, successively. The corresponding 6-bromo-4-hydroxy-3-methoxy-2-nitrobenzaldehyde (4) was obtained in nearly 100% yield (Grenier et al., 2000; Martin, 1989; Raiford and Davis, 1927).

In order to establish the new C⚌C bond on aldehyde group of compound 4, classical Henry reaction was employed. Firstly, the reaction of aldehyde group with nitromethane in the presence of AcONa/AcOH gave β-nitroethanol group through nucleophilic addition reaction. Later, the elimination of β-nitroethanol group generated double bond-containing linked product 5-bromo-2-methoxy-3-nitro-4-(2-nitrovinyl)phenol (5) at high temperatures. The whole forming process was achieved by using one-pot method. When a sevenfold molar excess of nitromethane or solvent free was used, the reaction provided a higher yield. To prepare indole-ring by compound 5, two types of reaction systems were used: 10% Pd/C-H2 and iron powder/AcOH. Initially, we investigated the reaction with 10% Pd/C under hydrogen in anhydrous methanol. Only a small quantity of target product was obtained, and more quantities of by-products such as debrominated or uncyclized aminates were formed. On the contrary, in iron powder/AcOH system, compound 5 was reduced successfully and produced the single intermediate 4-bromo-7-methoxy-1H-indole-6-ol (6). It was observed that compound 6 is unstable in organic solvents and darkened easily under the light due to the active hydrogens contained in the structure.

Strategies for the Suzuki–Miyaura cross-coupling reaction of the C-4 of indole with phenylboronic acid have been reported recently (Düfert et al., 2013). However, there was less study on the coupling reaction for the indol structure containing other activate hydrogen groups, such as —OH, —COOH, —CHO, —NH2, SH, which might be difficult for synthesis. Fortunately, using Pd(PPh3)4 as catalyst, compound 6 was easily changed into 4-(2-chlorophenyl)-7-methoxy-1H-indole-6-ol (7) or 4-(2-fluorophenyl)-7-methoxy-1H-indole-6-ol (8) with 2-halogenated phenylboronic acid in the presence of Na2CO3 in 1,2-dimethoxyethane/water (2:1). The resulting mixture needed to adjust to neutral using weak acid (e.g. AcOH) before post-processing. Following, compound 7 or 8 was esterified with propiolic acid to form 4-(2-chlorophenyl)-7-hydroxy-1H-indole-6-yl propiolate (9) or 4-(2-fluorophenyl)-7-hydroxy-1H-indole-6-yl propiolate (10) by DCC/DMAP condensation reaction.

In order to establish pyrone-ring, two kinds of catalytic systems were employed, PtCl4 and Pd(PPh3)4/trifluoroacetic acid, respectively. Surprisingly, no matter which method we choose, compound 9 could smoothly transform to 5-(2-fluorophenyl)-9-hydroxypyrano[3,2-f]indole-2(8H)-one (13) by skipping the construction of 5-(2-fluorophenyl)-9-methoxy-5,8-dihydropyrano[3,2-f]indole-2(4aH)-one (11). The phenomenon also exists in transformation from compound 10 to compound 14. The yields of compounds 13 and 14 were 35% and 42% respectively using PtCl4 method, which were somewhat higher than Pd(PPh3)4/trifluoroacetic acid method (24% and 33%). Since there were few reports about PtCl4 and Pd(PPh3)4 on demethylation of methyl ether (Kong et al., 2009; Habashneh et al., 2009), it was speculated that PtCl4 or Pd(PPh3)4/trifluoroacetic acid might play the role of Lewis acid in catalytic processes. A plausible mechanism was shown in Scheme 2. At an early stage, trifluoroacetic acid needs to undergo ligand exchange with Pd(PPh3)4 to generate HPd(OCOCF3)(PPh3)3, which showed a higher reactivity due to the increased electrophilicity (Zudin et al., 1985; Kitamura and Otsubo, 2012; Arcadi et al., 1992). Owing to bonding weakly to trifluoroacetate anions, a highly electrophilic cationic palladium species, [HPd(PPh3)3]+ was formed in situ (Jia et al., 2000). Then, the two catalytic systems might go through a similar process at catalytic stage. In the catalytic path I, PtCl4 firstly coordinates to the alkynyl and methoxyl group of compound 9 or 10 simultaneously to give the intermediate A. Later, intermediate B was obtained through the intramolecular electrophilic aromatic substitution. After deprotonation and re-hybridization of the carbon center as well as re-aromatization, catalyst PtCl4 was removed from intermediate B to give intermediate C (Vadola and Sames, 2012; Pastine et al., 2003). Subsequently, in the post-processing step, water acted as a nucleophile to facilitate the hydration to give intermediate D. Lastly, the intermediate D undergoes a rapid hydrogen transfer from water to the negative-charged oxygen to give the target compounds (Pasquini et al., 2012). Similarly, in the catalytic path II, hydridopalladium complex [HPd(PPh3)3]+ coordinates to the alkynyl and the oxygen of methoxyl group to form a vinylpalladium intermediate A′ (Trost et al., 2003). Then intermediate B′ was obtained through the intramolecular electrophilic addition and deprotonation. After the re-protonation and reductive elimination, [HPd(PPh3)3]+ was removed from intermediate B′ to give intermediate C′. In the next step, through the electron transfer and protolysis, intermediate C′ was converted into intermediate D′. Followed by nucleophilic substitution, the final compound was obtained. And then, the resulting palladium complex [CH3Pd(PPh3)3]+ was protonated by trifluoroacetic acid, and the hydridopalladium complex [HPd(PPh3)3]+ was regenerated.

Possible catalytic mechanism for PtCl4 and Pd(PPh3)4/trifluoroacetic acid in one-step reaction affording target.
Scheme 2
Possible catalytic mechanism for PtCl4 and Pd(PPh3)4/trifluoroacetic acid in one-step reaction affording target.

Besides, the synthesis of indole compounds 6–10, 13 and 14 was distinguished respectively by characteristic signals of their 1H NMR and 13C NMR spectra corresponding to the chemical shifts (Table 1). In 1H NMR spectra, there was no significant difference between the halogenated groups for the signals of C—H proton and N—H proton, which involved in pyrrol ring, pyrano ring, aromatic ring, methyl and alkyne groups. Individually, contrast to compound 6 (δN—H = 11.29 ppm), the signal of N-H proton in compounds 13 and 14 displayed a characteristic of field shifts to δ = 12.74 ppm and δ = 12.75 ppm respectively, due to the deshielding effect of aryl-ring and pyrone-ring. Similarly, contrast to compounds 7 and 8, the signal of N—H proton in compounds 9 and 10 respectively shifted to δ = 8.51 ppm and δ = 8.49 ppm due to the deshielding effect of propargyl ester. It suggested that halogen atoms (R = F or Cl) have a limited impact on the chemical shifts of their overall molecular structure in 1H NMR spectra. However, in 13C NMR spectra of compounds 7, 9 and 13, fluorine atom showed a strong coupling splitting capability on the carbon atoms. For instance, compound 13 showed a signal at δ = 159.1 ppm with coupling constant JC—F = 247.4 Hz corresponding to the effect of fluorine atom on the directly connected carbon atom of aryl-ring, and δ = 116.0 ppm with coupling constants JC—F = 21.7 Hz corresponding to the effect of ortho-carbon atom of aryl-ring. However, meta and para carbon of aryl-ring showed low values for coupling constants JC—F = 2–4 Hz. Moreover, fluorine atom also had remote coupling splitting role. For example, α-H of pyrano-ring for compound 13 showed a coupling signal at δ = 108.2 ppm with coupling constant JC—F = 2.5 Hz. Likewise, C-3 position of pyrrol-ring for compounds 7 and 9 showed coupling signals at δ = 103.4 ppm and δ = 103.4 ppm with coupling constants JC—F = 3.0 Hz and JC—F = 3.2 Hz, respectively.

Table 1 1H NMR and 13C NMR data of compounds 6–10, 13 and 14.

3

3 Experimental

3.1

3.1 Instruments and reagents

NMR spectra were recorded on a Bruker AVANCE 400 MHz spectrometer (Bruker, Germany). IR spectra were recorded on a Shimadzu Fourier transform infrared 440 spectrometer (SHIMADZU, Japan) in the 4000–500 cm−1 range. The molecular weights were recorded on a Shimadzu GCMS-QP2010 spectrometer (SHIMADZU, Japan). High-resolution mass spectra were obtained by Shimadzu HPLC-IT-TOF-MS (Shimadzu, Japan). Melting points were measured on an X-4 microscope melting point apparatus (Henan, China) without corrected. All the solvents and chemicals were obtained from commercial sources and used without further purification unless otherwise stated. The synthetic procedure was controlled by thin-layer chromatography (TLC) on 0.25 mm silica gel plates (60 GF-254, Qindao Ocean Chemical Company, China) and visualized with ultraviolet light (Shanghai, China). The products were purified by recrystallization or flash chromatography. Column chromatography was carried out on silica gel (300–400 mesh, Qindao Ocean Chemical Company, China).

3.2

3.2 Synthesis

3.2.1

3.2.1 Synthesis of 5-bromo-4-formyl-2-methoxyphenyl acetate (2)

4-formyl-2-methoxyphenyl acetate (1.00 g, 5.15 mmol) was fully dispersible in 10 mL KBr (2.00 g, 16.81 mmol) aqueous solution, and Br2 (0.29 mL, 11.32 mmol) was added dropwise. The mixture was stirred vigorously at RT until the reaction completed. Then, the reaction mixture was poured into ice water (50 mL). The precipitate was filtered, washed with ice water and dried to give 2 as a light brown solid, 1.13 g (99%). m.p. 111–112 °C (lit. (Martin, 1989) 109–110 °C); Rf = 0.71 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3101 (ArH), 2926 (—CH3), 2864 (—CHO), 2762 (—CHO), 1759 (—C⚌O), 1688 (—C⚌O), 1595 (—C⚌C—), 1493 (—C⚌C—), 1155 (—C—O—C—); EI-MS (m/z): 272.1 [M]+.

3.2.2

3.2.2 Synthesis of 5-bromo-4-formyl-2-methoxy-3-nitrophenyl acetate (3)

Compound 2 (6.00 g, 22.05 mmol) was slowly added to a solution of fuming nitric acid (10 mL) over 5 min at −20 °C. The resulting mixture was stirred for further 0.5 h. Then, the reaction mixture was poured into ice water (50 mL) and stood for at least 4 h. The precipitate was filtered, washed with ice water and dried to give 3 as a lightly brown solid, 5.49 g (79%). m.p. 83–84 °C; Rf = 0.48 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3090 (ArH), 2951 (—CH3), 2863 (—CHO), 2758 (—CHO), 1782 (—C⚌O), 1701 (—C⚌O), 1593 (—C⚌C—), 1549 (—NO2), 1473 (—C⚌C—), 1363 (—NO2), 1169 (—C—O—C—); 1H NMR (400 MHz, CDCl3): δ 10.19 (s, 1 H, —CHO), 7.64 (s, 1 H, ArH), 3.91 (s, 3 H, —OCH3), 2.41 (s, 3 H, —O(C⚌O)CH3); 13C NMR (101 MHz, CDCl3): δ 187.5, 167.3, 148.9, 145.2, 144.1, 130.6, 122.9, 120.6, 63.2, 20.8; EI-MS (m/z): 317.0 [M]+.

3.2.3

3.2.3 Synthesis of 6-bromo-4-hydroxy-3-methoxy-2-nitrobenzaldehyde (4)

Compound 3 (0.70 g, 2.19 mmol) was slowly added to a stirred solution of 20% aqueous sodium hydroxide solution (2 mL) and the mixture was stirred at RT for 20 min. The reaction mixture was acidified to pH 3–4 with 2 N HCl at 0 °C. The precipitate was filtered, washed with ice water, and dried to give 4 as a light brown solid, 0.60 g (99%). m.p. 165–166 °C (lit. (Raiford and Davis, 1927) 168–170 °C); Rf = 0.10 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3412 (—OH), 3088 (ArH), 2916 (—CH3), 2851 (—CHO), 2768 (—CHO), 1672 (—C⚌O), 1582 (—C⚌C—), 1541 (—NO2), 1493 (—C⚌C—), 1369 (—NO2), 1194 (—C—O—C—); 1H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H, CHO), 9.96 (s, 1H, —OH), 7.36 (s, 1H, ArH), 3.84 (s, 3H, —OCH3); 13C NMR (101 MHz, DMSO-d6): δ 187.9, 157.8, 144.6, 139.3, 122.5, 122.1, 115.1, 61.7; EI-MS (m/z): 275.0 [M]+.

3.2.4

3.2.4 Synthesis of 5-bromo-2-methoxy-3-nitro-4-(2-nitroethenyl) phenol (5)

To a solution of 4 (1.00 g, 3.64 mmol) in acetic acid (100 mL), ammonium acetate (0.74 g, 9.60 mmol) and nitromethane (1.36 mL, 25.45 mmol) were added and stirred at 120 °C under nitrogen for 4 h. The mixture was cooled to 40 °C and poured into ice water (200 mL). The result mixture was extracted with ethyl acetate (6 × 100 mL). The combined organic phase was washed with water (5 × 100 mL) and saturated brine (2 × 50 mL), dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by flash chromatography (silica gel; petroleum ether: ethyl acetate = 2:1) to give 5 as a yellow solid, 0.70 g (60%). m.p. 98–100 °C; Rf = 0.31 (CH2Cl2); IR (KBr, cm−1): 3444 (—OH), 3117 (—CH⚌CH—), 3047 (ArH), 2924 (—CH3), 1597 (—C⚌C—), 1539 (—NO2), 1487 (—C⚌C—), 1348 (—NO2), 1194 (—C—O—C—); 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J = 14.0 Hz, 1H, —CH⚌CHNO2), 7.43 (s, 1H, ArH), 7.27 (d, J = 13.6 Hz, 1H, —CH⚌CHNO2), 3.95 (s, 3H, —OCH3); 13C NMR (101 MHz, CDCl3): δ 152.3, 145.4, 140.6, 139.1, 131.8, 122.9, 120.7, 115.3, 63.3; HR-ESI-MS (m/z): calcd. [M+H]+: 318.9556, found: 318.9310.

3.2.5

3.2.5 Synthesis of 4-bromo-7-methoxy-1H-indole-6-ol (6)

Under nitrogen, to a solution of 5 (2.00 g, 6.29 mmol) in acetic acid (20 mL), silica gel (2.00 g, 100–200 mesh) and iron powder (4.00 g, 71.63 mmol) were added and stirred at 110 °C for 1 h. The mixture was then filtered, and the filtrate was poured into ice water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with water (1 × 100 mL) and saturated brine (2 × 50 mL), dried over anhydrous Na2SO4. Then the solvent was evaporated. The residue was purified by column chromatography (silica gel; petroleum ether: ethyl acetate = 3:1) to give 6 as a brown thick liquid, 1.10 g (73%). Rf = 0.23 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3423 (—OH), 3134 (pyrrole-CH), 3003 (ArH), 2937 (—CH3), 2835 (—CH2—), 1626 (—C⚌C—), 1502 (—C⚌C—), 1165 (—C—O—C—); 1H NMR (400 MHz, DMSO-d6): δ 11.29 (s, 1H, NH), 9.19 (s, 1H, —OH), 7.31–7.17 (m, 1H, H-indole), 6.92 (s, 1H, ArH), 6.32–6.23 (m, 1H, H-indole), 3.90 (s, 3H, —OCH3); 13C NMR (101 MHz, DMSO-d6): δ 144.4, 132.5, 130.7, 124.9, 123.5, 113.5, 106.5, 101.5, 60.0; HR-ESI-MS (m/z): calcd. [M+H]+: 241.9817, found: 241.9790.

3.2.6

3.2.6 General procedure for the coupling reaction

Under nitrogen, a solution of 6 (0.57 g, 2.36 mmol) in glycol dimethyl ether and water (2:1, 15 mL), boronic acid (3.07 mmol), Na2CO3 (0.37 g, 3.49 mmol) and Pd(PPh3)4 (0.54 g, 0.47 mmol) was added. The resulting mixture was heated at 85 °C under nitrogen for 12 h. The reaction was quenched by addition of AcOH and ice water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The organic phase was washed with water (1 × 100 mL) and saturated brine (2 × 50 mL), dried over anhydrous Na2SO4 and then evaporated. The crude product was purified by column chromatography (silica gel; petroleum ether: ethyl acetate = 2:1) to give product.

3.2.6.1
3.2.6.1 4-(2-fluorophenyl)-7-methoxy-1H-indole-6-ol (7)

Light brown solid, yield 23%; m.p. 137–139 °C; Rf = 0.32 (petroleum ether/acetone, 3:1); IR (KBr, cm−1): 3356 (—OH), 3115 (pyrrole-CH), 3051 (ArH), 2941 (—CH3), 1188 (—C—O—C—); 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H, NH), 7.51 (t, J = 7.4 Hz, 1H, ArH), 7.39–7.28 (m, 1H, ArH), 7.25–7.13 (m, 2H, ArH), 7.10 (s, 1H, H-indole), 6.90 (s, 1H, ArH,), 6.42 (s, 1H, H-indole), 5.45 (s, 1H, —OH), 3.99 (s, 3H, —OCH3); 13C NMR (101 MHz, CDCl3): δ 159.9 (JC—F = 248.97 Hz), 143.4, 131.8 (JC—F = 2.02 Hz), 131.8, 129.3, 128.9 (JC—F = 9.09 Hz), 128.0 (JC—F = 15.15 Hz), 124.4, 124.2 (JC—F = 3.03 Hz), 123.7, 123.3, 116.1 (JC—F = 23.23 Hz), 111.7 (JC—F = 2.02 Hz), 103.4 (JC—F = 3.03 Hz), 61.1; HR-ESI-MS (m/z): calcd. [M+H]+: 258.0930, found: 258.0936.

3.2.6.2
3.2.6.2 4-(2-chlorophenyl)-7-methoxy-1H-indole-6-ol (8)

Light brown solid, yield 39%; m.p. 146–148 °C; Rf = 0.39 (petroleum ether/acetone, 3:1); IR (KBr, cm−1): 3344 (—OH), 3053 (ArH), 2937 (—CH3), 1622 (—C⚌C—), 1192 (—C—O—C—); 1H NMR (400 MHz, CDCl3): δ 8.17 (s, 1H, NH), 7.57–7.47 (m, 1H, ArH), 7.46–7.38 (m, 1H, ArH), 7.37–7.28 (m, 2H, ArH), 7.11 (s, 1H, H-indole), 6.83 (s, 1H, ArH), 6.27 (s, 1H, H-indole), 5.30 (s, 1H, —OH), 4.00 (s, 3H, —OCH3); 13C NMR (101 MHz, CDCl3): δ 143.2, 139.1, 133.3, 132.0, 131.7, 130.0, 129.0, 128.6, 128.0, 126.6, 123.5, 123.4, 111.7, 103.5, 61.1; HR-ESI-MS (m/z): calcd. [M+H]+: 274.0635, found: 274.0623.

3.2.7

3.2.7 General procedure for the condensation reaction

A solution of propiolic acid (0.07 mL, 1.14 mmol) in anhydrous CH2Cl2 (30 mL) was stirred at 0 °C for 5 min. Dicyclohexylcarbodiimide (0.24 g, 1.16 mmol) in anhydrous CH2Cl2 (2 mL) was added. When the white precipitate was formed, a solution of 7 or 8 (0.88 mmol) in anhydrous CH2Cl2 (2 mL) was added to the reaction mixture. Lastly, 4-dimethylaminopryidine (0.02 g, 0.16 mmol) in anhydrous CH2Cl2 (2 mL) was added dropwise to the stirring solution. The reaction was stirred at RT until complete consumption of 7 or 8 monitored by TLC (2 h). Then the mixture was filtered, the filtrate was washed with water (6 × 50 mL) and saturated brine (2 × 50 mL), dried over anhydrous Na2SO4 and evaporated. The solid residue was purified by column chromatography (silica gel; petroleum ether: ethyl acetate = 2:1) to give product.

3.2.7.1
3.2.7.1 4-(2-fluorophenyl)-7--methoxy-1H-indole-6-yl propiolate (9)

Light brown solid, yield 22%; m.p. 139–141 °C; Rf = 0.52 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3431 (NH), 3277 (—C≡C—H), 3121 (pyrrole-CH), 3007 (ArH), 2941 (—CH3), 2127 (—C≡C—), 1724 (—C⚌O), 1200 (—C—O—C—); 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H, NH), 7.52 (t, J = 7.0 Hz, 1H, ArH), 7.40–7.29 (m, 1H, ArH), 7.25–7.23 (m, 1H, ArH), 7.22 (s, 1H, H-indole), 7.21–7.13 (m, 1H, ArH), 6.96 (s, 1H, ArH), 6.48 (d, J = 1.6 Hz, 1H, H-indole), 4.03 (s, 3H, —OCH3), 3.09 (s, 1H, C≡CH); 13C NMR (101 MHz, CDCl3): δ 159.8 (JC—F = 249.0 Hz), 151.4, 136.8, 135.9, 131.8 (JC—F = 3.64 Hz), 129.5, 129.2 (JC—F = 8.18 Hz), 127.7, 127.3 (JC—F = 14.95 Hz), 125.5, 124.2 (JC—F = 3.64 Hz), 116.3 (JC—F = 2.12 Hz), 116.3, 116.0, 103.4 (JC—F = 3.23 Hz), 77.3, 74.3, 61.3; HR-ESI-MS (m/z): calcd. [M+H]+: 310.0879, found: 310.0859.

3.2.7.2
3.2.7.2 4-(2-chlorophenyl)-7-methoxy-1H-indole-6-yl propiolate (10)

Light brown thick liquid, yield 21%. Rf = 0.52 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3431 (NH), 3277 (—C≡C—H), 3115 (pyrrole-CH), 3063 (ArH), 2937 (—CH3), 2125 (—C≡C—), 1728 (—C⚌O), 1198 (—C—O—C—) cm−1; 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H, NH), 7.55–7.48 (m, 1H, ArH), 7.47–7.41 (m, 1H, ArH), 7.36–7.28 (m, 2H, ArH), 7.24–7.19 (m, 1H, H-indole), 6.90 (s, 1H, ArH), 6.39–6.28 (m, 1H, H-indole), 4.05 (s, 3H, —OCH3), 3.09 (s, 1H, C≡CH); 13C NMR (101 MHz, CDCl3): δ 151.4, 138.4, 136.7, 135.7, 133.3, 132.1, 130.1, 129.2, 128.8, 127.8, 127.2, 126.7, 125.4, 116.5, 103.4, 77.2, 74.4, 61.3; EI-MS (m/z): 325 [M]+.

3.2.8

3.2.8 General procedure for the reductive cyclization

  • Method 1

To a solution of 9 or 10 (0.15 mmol) in 1, 4-dioxane and 1, 2-dichloroethane (1:1, 5 mL), 5 mol% PtCl4 (0.01 g) was added. The mixture was stirred under nitrogen at 65 °C for 2 h. Then the reaction was filtered, and the combined solvents were evaporated. The crude residue was dissolved with ethyl acetate (50 mL), washed with water (1 × 50 mL) and saturated brine (2 × 50 mL), dried over anhydrous Na2SO4 and then evaporated. The crude product was subjected to column chromatography (silica gel; petroleum ether–acetone, 2:1) to obtain product.

  • Method 2

To a solution of 9 or 10 (0.40 mmol) in dry CH2Cl2 (5 mL), Pd(PPh3)4 (0.03 g, 0.026 mmol) and 5 mL trifluoroacetic acid were added. The reaction was stirred at RT for 2 h. Then the reaction was filtered, the combined solvents were evaporated, and the crude residue was dissolved with ethyl acetate (50 mL), washed with water (1 × 50 mL) and saturated brine (2 × 50 mL), dried over anhydrous Na2SO4 and then evaporated. The crude product was subjected to column chromatography (silica gel; petroleum ether–acetone, 2:1) to obtain product.

3.2.8.1
3.2.8.1 5-(2-fluorophenyl)-9-hydroxypyrano[3,2-f]indole-2(8H)-one (13)

White solid, method 1: yield 35%, method 2: yield 24%; m.p. 210–212 °C; Rf = 0.28 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3514 (-OH), 3229 (NH), 3115 (ArH), 1790 (—C⚌O), 1618 (—C⚌C—), 1485 (—C⚌C—) cm−1; 1H NMR (400 MHz, DMSO-d6): δ 12.75 (s, 1H, NH), 7.81–7.67 (m, 1H, H-pyrrol), 7.57–7.45 (m, 2H, ArH), 7.42 (s, 1H, H-pyrano), 7.39–7.24 (m, 2H, ArH), 6.72–6.47 (m, 1H, H-pyrrol), 6.01 (s, 1H, —OH), 5.89–5.74 (m, 1H, H-pyrano); 13C NMR (101 MHz, DMSO-d6): δ 178.6, 173.6, 159.1 (JC—F = 247.35 Hz), 155.4, 133.1, 131.4, 130.8, 130.7, 130.6 (JC—F = 3.54 Hz), 126.1, 124.8 (JC—F = 3.54 Hz), 124.7, 124.5 (JC—F = 2.63 Hz), 122.2, 116.0 (JC—F = 21.72 Hz), 108.2 (JC—F = 2.53 Hz), 89.3; EI-MS (m/z): 311 [M]+.

3.2.8.2
3.2.8.2 5-(2-chlorophenyl)-9-hydroxypyrano[3,2-f]indole-2(8H)-one (14)

Pale yellow solid, method 1: yield 42%, method 2: yield 33%; m.p. 220–222 °C; Rf = 0.28 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm−1): 3447 (—OH), 3238 (NH), 3078 (ArH), 1769 (—C⚌O), 1653 (—C⚌C—), 1504 (—C⚌C—); 1H NMR (400 MHz, DMSO-d6): δ 12.74 (s, 1H, NH), 7.71 (d, J = 4.8 Hz, 1H, H-pyrrol), 7.60 (d, J = 6.0 Hz, 1H, ArH), 7.45 (s, 3H, ArH), 7.38 (s, 1H, H-pyrano), 6.57 (d, J = 5.2 Hz, 1H, H-pyrrol), 5.81 (s, 1H, —OH), 5.73 (s, 1H, H-pyrano); 13C NMR (101 MHz, DMSO-d6): δ 179.1, 174.0, 155.9, 136.4, 135.0, 133.9, 132.2, 131.3, 131.1, 130.6, 130.2, 128.0, 126.2, 124.8, 122.6, 108.5, 90.0; HR-ESI-MS (m/z): calcd. [M+H]+: 311.0349, found: 311.8483.

4

4 Conclusion

In conclusion, we describe an appropriate method for the synthesis of 5-(2-halogeno phenyl)-9-hydroxypyrano [3,2-f]indole-2(8H)-one. PtCl4 or Pd(PPh3)4/trifluoroacetic acid was suggested as effective catalysts in the final cyclization step. Further synthesis and biological study for derivatives of 5-(2-halogeno phenyl)-9-hydroxypyrano[3,2-f]indole-2(8H)-one are currently in progress.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (No. 81202494, 30730110, 81302737), and Natural Science Basic Research Plan in Shaanxi Province of China (No. 2016JM8076).

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