Facile Synthetic Approach for 5-Aryl-9-Hydroxypyrano [3,2-F]

Arabian Journal of Chemistry (2016) xxx, xxx–xxx

King Saud University Arabian Journal of Chemistry

www.ksu.edu.sa www.sciencedirect.com

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

Cheng Wang, Tao Wang, Limin Huang, Yajing Hou, Wen Lu, Huaizhen He *

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

Received 17 March 2016; accepted 27 July 2016

KEYWORDS Abstract An appropriate method for the synthesis of 5-aryl-9-hydroxypyrano[3,2-f]indole-2(8H)- Heterocyclic; one was described. The targeted compounds were obtained starting from vanillin via nine steps. Pyrrolocoumarin; Interestingly, in the final cyclization step, the intermediate 4-(2-halogeno phenyl)-7-methoxy-1H- Biphenyl; indole-6-yl propiolate could convert directly into the final product in one step reaction using PtCl4 Vanillin; or Pd(PPh3)4/trifluoroacetic acid as catalysts. The possible catalytic mechanism for PtCl4 and Pd Catalysis (PPh3)4/trifluoroacetic acid was discussed. Ó 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction 2014). Moreover, they are also able to inhibit NO production (Sinicropi et al., 2009), COX-2 (Kreft et al., 1998), PLA2 and lipoxy- Pyrroles derivatives constitute an important class of heterocyclic com- genase (Musser et al., 1993) and showed antiproliferative activity pounds, which exhibit a wide range of pharmacological properties (Guiotto et al., 1995; Barraja et al., 2008; Carbone et al., 2013). (Este´ vez et al., 2014; Zhuo et al., 2014; Su et al., 2013; Kathirav Recently, hybridization of pyrrolocoumarin with an arene moiety is et al., 2012; AlMourabit et al., 2011; Young et al., 2010). They have present in various synthetic antihyperlipidemic and antitumor drugs been reported to possess significant anti-HIV (Liu et al., 2008), antitu- such as statins, lamellarins and ningalins (Sashidhara et al., 2010; mor (Diana et al., 2011; Wang et al., 2012; Parrino et al., 2014; Barraja Marco et al., 2005; Chen and Xu, 2009). Furthermore, a number of et al., 2011; Spano` et al., 2014) and antifungal (El-Gaby et al., 2002) arene-fused pyrrolocoumarins have been synthesized and extended activities. Pyrrolocoumarins have received considerable attention for the applications in biological detection, such as living cell imaging, their biological importance (Chen et al., 2008; Sandhu et al., 2014; neuroimaging, protein labeling tag (SNAP-tag) and the detection Kontogiorgis et al., 2008). Some of them were reported as fluorogenic and treatment of monoamine oxidases (Tietze et al., 2012; Vadola probes for the detection of H2S, which provided an emission signal for and Sames, 2012; Mei et al., 2011; Gong et al., 2006; Lin and Yang, a specific enzymatic process in complex biological systems (Zhou et al., 2013). Therefore, aromatization of pyrrolocoumarin received more attention. On the other hand, biphenyl moiety has also attracted the attention * Corresponding author. of organic and medicinal chemists for its special biological activities. It E-mail address: [email protected] (H. He). was considered as one of the privileged substructures and widely used Peer review under responsibility of King Saud University. 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 metal- loproteinase inhibitors (Pikul et al., 2001), factor Xa inhibitors (Zhang

Production and hosting by Elsevier et al., 2004), b3-adrenergic receptor agonists (Imanishi et al., 2008), http://dx.doi.org/10.1016/j.arabjc.2016.07.020 1878-5352 Ó 2016 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Wang, C. et al., Facile synthetic approach for 5-aryl-9-hydroxypyrano [3,2-f ] indole-2(8H)-one. Arabian Journal of Chemistry (2016), http://dx.doi.org/10.1016/j.arabjc.2016.07.020 2 C. Wang et al. and ETA receptor antagonists (Murugesan et al., 2003). In addition, of compound 2 with fuming nitric acid was less than 1:1.3, it compounds with biphenyl moiety tend to bind with a wide range of would result in drastically diminished yield and increase in proteins and have high specificity (Hajduk et al., 2000). It means that the by-products of compound 3. It was presumably due to the introduction of biphenyl substructure might enhance the affinity the local overheating in the process of nitration. Compound between compounds and receptors. Thus, combining pyrrolocoumarin 3 was hydrolyzed through treatment with 20% aqueous with biphenyl may have beneficial effects on biological activities. In addition, previous studies have mainly focused on the angular pyrrolo- sodium hydroxide solution and 2 M HCl, successively. The coumarin synthesis, but less about the linear pyrrolocoumarin. For corresponding 6-bromo-4-hydroxy-3-methoxy-2-nitrobenzalde these reasons, we report an appropriate method for the preparation hyde (4) was obtained in nearly 100% yield (Grenier et al., of biphenyl pyrrolocoumarin 5-(2-halogeno phenyl)-9-hydroxypyrano 2000; Martin, 1989; Raiford and Davis, 1927). [3,2-f]indole-2(8H)-one, and discuss the possible catalytic mechanism In order to establish the new C‚C bond on aldehyde group of PtCl4 and Pd(PPh3)4/trifluoroacetic acid. of compound 4, classical Henry reaction was employed. Firstly, the reaction of aldehyde group with nitromethane in 2. Results and discussion the presence of AcONa/AcOH gave b-nitroethanol group through nucleophilic addition reaction. Later, the elimination b Three main synthetic strategies could be used to construct the of -nitroethanol group generated double bond-containing biphenyl pyrrolocoumarin skeleton, named indole-ring con- linked product 5-bromo-2-methoxy-3-nitro-4-(2-nitrovinyl)ph struction (A), pyrone-ring construction (B) and biphenyl con- enol (5) at high temperatures. The whole forming process struction (C)(Fig. 1). Initially, strategy B failed to generate was achieved by using one-pot method. When a sevenfold the desired pyrone-ring owing to the electrophilic effect of molar excess of nitromethane or solvent free was used, the reaction provided a higher yield. To prepare indole-ring by ANO2 in starting materials. Beyond that, the yield and selectivity of reaction were greatly decreased due to the transforma- compound 5, two types of reaction systems were used: 10% tion of the multiple functional groups on starting materials. Pd/C-H2 and iron powder/AcOH. Initially, we investigated Then, we turned our efforts to strategy A with vanillin as start- the reaction with 10% Pd/C under hydrogen in anhydrous ing material, indole-ring and pyrone-ring have been success- methanol. Only a small quantity of target product was fully constructed and brominated, and compound I was obtained, and more quantities of by-products such as debromi- obtained. However, the targeted skeleton has not been nated or uncyclized aminates were formed. On the contrary, in achieved since compound I and its modified products were iron powder/AcOH system, compound 5 was reduced success- easily broken down in Suzuki–Miyaura cross-coupling reac- fully and produced the single intermediate 4-bromo-7- tion. Fortunately, prior to pyrone-ring, the structure C of methoxy-1H-indole-6-ol (6). It was observed that compound biphenyl was built by altering the sequence of reactions and 6 is unstable in organic solvents and darkened easily under gave biphenyl compound II. Finally, the targeted biphenyl the light due to the active hydrogens contained in the structure. pyrrolocoumarin was successfully established using condensa- Strategies for the Suzuki–Miyaura cross-coupling reaction tion reaction with transition metal catalyst. Therefore, the of the C-4 of indole with phenylboronic acid have been strategy ‘‘A ? C ? B” was an appropriate method for the reported recently (Du¨ fert et al., 2013). However, there was less synthesis of the biphenyl pyrrolocoumarins compared with study on the coupling reaction for the indol structure contain- A A other paths. The synthetic route is depicted in Scheme 1. ing other activate hydrogen groups, such as OH, COOH, A A According to modification of the previously reported proce- CHO, NH2, SH, which might be difficult for synthesis. dure (Wang et al., 2015), compounds 1–4 were synthesized and Fortunately, using Pd(PPh3)4 as catalyst, compound 6 was the overall yield was up to 76% in first four steps. With triethy- easily changed into 4-(2-chlorophenyl)-7-methoxy-1H-indole- 6-ol (7) or 4-(2-fluorophenyl)-7-methoxy-1H-indole-6-ol (8) lamine as alkaline reagent, vanillin was esterified with Ac2Oin anhydrous THF to give 4-formyl-2-methoxyphenyl acetate (1) with 2-halogenated phenylboronic acid in the presence of Na2- within 0.5 h with 99% yield. Then, 5-bromo-4-formyl-2- CO3 in 1,2-dimethoxyethane/water (2:1). The resulting mixture methoxyphenyl acetate (2) was obtained with 99% yield by needed to adjust to neutral using weak acid (e.g. AcOH) before electrophilic substitution reaction at C-5 of compound 1 with post-processing. Following, compound 7 or 8 was esterified with propiolic acid to form 4-(2-chlorophenyl)-7-hydroxy- 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 1H-indole-6-yl propiolate (9) or 4-(2-fluorophenyl)-7- 5-bromo-4-formyl-2-methoxy-3-nitrophenyl acetate (3) was hydroxy-1H-indole-6-yl propiolate (10) by DCC/DMAP obtained in 79% yield. However, when the mass-volume ratio condensation reaction.

Figure 1 Synthetic strategy of biphenyl pyrrolocoumarin.

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.

In order to establish pyrone-ring, two kinds of catalytic sys- substitution. After deprotonation and re-hybridization of the tems were employed, PtCl4 and Pd(PPh3)4/trifluoroacetic acid, carbon center as well as re-aromatization, catalyst PtCl4 was respectively. Surprisingly, no matter which method we choose, removed from intermediate B to give intermediate C (Vadola compound 9 could smoothly transform to 5-(2-fluorophenyl)- and Sames, 2012; Pastine et al., 2003). Subsequently, in the 9-hydroxypyrano[3,2-f]indole-2(8H)-one (13) by skipping the post-processing step, water acted as a nucleophile to facilitate construction of 5-(2-fluorophenyl)-9-methoxy-5,8-dihydropyr the hydration to give intermediate D. Lastly, the intermediate ano[3,2-f]indole-2(4aH)-one (11). The phenomenon also exists D undergoes a rapid hydrogen transfer from water to the in transformation from compound 10 to compound 14. The negative-charged oxygen to give the target compounds yields of compounds 13 and 14 were 35% and 42% respec- (Pasquini et al., 2012). Similarly, in the catalytic path II, hydri- + tively using PtCl4 method, which were somewhat higher than dopalladium complex [HPd(PPh3)3] coordinates to the alky- Pd(PPh3)4/trifluoroacetic acid method (24% and 33%). Since nyl and the oxygen of methoxyl group to form a 0 there were few reports about PtCl4 and Pd(PPh3)4 on demethy- vinylpalladium intermediate A (Trost et al., 2003). Then lation of methyl ether (Kong et al., 2009; Habashneh et al., intermediate B0 was obtained through the intramolecular elec- 2009), it was speculated that PtCl4 or Pd(PPh3)4/trifluoroacetic trophilic addition and deprotonation. After the re-protonation + acid might play the role of Lewis acid in catalytic processes. A and reductive elimination, [HPd(PPh3)3] was removed from plausible mechanism was shown in Scheme 2. At an early intermediate B0 to give intermediate C0. In the next step, stage, trifluoroacetic acid needs to undergo ligand exchange through the electron transfer and protolysis, intermediate C0 0 with Pd(PPh3)4 to generate HPd(OCOCF3)(PPh3)3, which was converted into intermediate D . Followed by nucleophilic showed a higher reactivity due to the increased electrophilicity substitution, the final compound was obtained. And then, + (Zudin et al., 1985; Kitamura and Otsubo, 2012; Arcadi et al., the resulting palladium complex [CH3Pd(PPh3)3] was proto- 1992). Owing to bonding weakly to trifluoroacetate anions, a nated by trifluoroacetic acid, and the hydridopalladium com- + highly electrophilic cationic palladium species, [HPd plex [HPd(PPh3)3] was regenerated. + (PPh3)3] was formed in situ (Jia et al., 2000). Then, the two Besides, the synthesis of indole compounds 6–10, 13 and 14 catalytic systems might go through a similar process at cat- was distinguished respectively by characteristic signals of their 1 13 alytic stage. In the catalytic path I, PtCl4 firstly coordinates H NMR and C NMR spectra corresponding to the chemical to the alkynyl and methoxyl group of compound 9 or 10 simul- shifts (Table 1). In 1H NMR spectra, there was no significant taneously to give the intermediate A. Later, intermediate B was difference between the halogenated groups for the signals of obtained through the intramolecular electrophilic aromatic CAH proton and NAH proton, which involved in pyrrol ring,

Scheme 2 Possible catalytic mechanism for PtCl4 and Pd(PPh3)4/trifluoroacetic acid in one-step reaction affording target. pyrano ring, aromatic ring, methyl and alkyne groups. Individ- QP2010 spectrometer (SHIMADZU, Japan). High-resolution ually, contrast to compound 6 (dNAH = 11.29 ppm), the signal mass spectra were obtained by Shimadzu HPLC-IT-TOF-MS of N-H proton in compounds 13 and 14 displayed a character- (Shimadzu, Japan). Melting points were measured on an X-4 istic of field shifts to d = 12.74 ppm and d = 12.75 ppm respec- microscope melting point apparatus (Henan, China) without tively, due to the deshielding effect of aryl-ring and pyrone- corrected. All the solvents and chemicals were obtained from ring. Similarly, contrast to compounds 7 and 8, the signal of commercial sources and used without further purification NAH proton in compounds 9 and 10 respectively shifted to unless otherwise stated. The synthetic procedure was con- d = 8.51 ppm and d = 8.49 ppm due to the deshielding effect trolled by thin-layer chromatography (TLC) on 0.25 mm silica of propargyl ester. It suggested that halogen atoms (R = F gel plates (60 GF-254, Qindao Ocean Chemical Company, or Cl) have a limited impact on the chemical shifts of their over- China) and visualized with ultraviolet light (Shanghai, China). all molecular structure in 1H NMR spectra. However, in 13C The products were purified by recrystallization or flash chro- NMR spectra of compounds 7, 9 and 13, fluorine atom showed matography. Column chromatography was carried out on sil- a strong coupling splitting capability on the carbon atoms. For ica gel (300–400 mesh, Qindao Ocean Chemical Company, instance, compound 13 showed a signal at d = 159.1 ppm with China). coupling constant JCAF = 247.4 Hz corresponding to the effect of fluorine atom on the directly connected carbon atom of aryl- 3.2. Synthesis ring, and d = 116.0 ppm with coupling constants JCAF = 21.7 Hz corresponding to the effect of ortho-carbon 3.2.1. Synthesis of 5-bromo-4-formyl-2-methoxyphenyl acetate atom of aryl-ring. However, meta and para carbon of (2) aryl-ring showed low values for coupling constants JCAF = 4-formyl-2-methoxyphenyl acetate (1.00 g, 5.15 mmol) was 2–4 Hz. Moreover, fluorine atom also had remote coupling fully dispersible in 10 mL KBr (2.00 g, 16.81 mmol) aqueous a splitting role. For example, -H of pyrano-ring for compound solution, and Br (0.29 mL, 11.32 mmol) was added dropwise. d 2 13 showed a coupling signal at = 108.2 ppm with coupling The mixture was stirred vigorously at RT until the reaction constant JCAF = 2.5 Hz. Likewise, C-3 position of pyrrol- completed. Then, the reaction mixture was poured into ice ring for compounds 7 and 9 showed coupling signals at water (50 mL). The precipitate was filtered, washed with ice d d = 103.4 ppm and = 103.4 ppm with coupling constants water and dried to give 2 as a light brown solid, 1.13 g (99%). JCAF = 3.0 Hz and JCAF = 3.2 Hz, respectively. m.p. 111–112 °C (lit. (Martin, 1989) 109–110 °C); Rf = 0.71 (petroleum ether/ethyl acetate, 2:1); IR (KBr, cm1): 3101 3. Experimental (ArH), 2926 (ACH3), 2864 (ACHO), 2762 (ACHO), 1759 (AC‚O), 1688 (AC‚O), 1595 (AC‚CA), 1493 (AC‚CA), 3.1. Instruments and reagents 1155 (ACAOACA); EI-MS (m/z): 272.1 [M]+.

NMR spectra were recorded on a Bruker AVANCE 400 MHz 3.2.2. Synthesis of 5-bromo-4-formyl-2-methoxy-3-nitrophenyl 3 spectrometer (Bruker, Germany). IR spectra were recorded on acetate ( ) a Shimadzu Fourier transform infrared 440 spectrometer Compound 2 (6.00 g, 22.05 mmol) was slowly added to a solu- (SHIMADZU, Japan) in the 4000–500 cm1 range. The tion of fuming nitric acid (10 mL) over 5 min at 20 °C. The molecular weights were recorded on a Shimadzu GCMS- resulting mixture was stirred for further 0.5 h. Then, the reac-

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

tion mixture was poured into ice water (50 mL) and stood for 3.2.3. Synthesis of 6-bromo-4-hydroxy-3-methoxy-2- at least 4 h. The precipitate was filtered, washed with ice water nitrobenzaldehyde (4) and dried to give 3 as a lightly brown solid, 5.49 g (79%). m.p. Compound 3 (0.70 g, 2.19 mmol) was slowly added to a stirred ° 83–84 C; Rf = 0.48 (petroleum ether/ethyl acetate, 2:1); IR solution of 20% aqueous sodium hydroxide solution (2 mL) 1 A A (KBr, cm ): 3090 (ArH), 2951 ( CH3), 2863 ( CHO), 2758 and the mixture was stirred at RT for 20 min. The reaction (ACHO), 1782 (AC‚O), 1701 (AC‚O), 1593 (AC‚CA), mixture was acidified to pH 3–4 with 2 N HCl at 0 °C. The pre- A A ‚ A A 1549 ( NO2), 1473 ( C C ), 1363 ( NO2), 1169 cipitate was filtered, washed with ice water, and dried to give 4 A A A A 1 d ( C O C ); H NMR (400 MHz, CDCl3): 10.19 (s, 1 H, as a light brown solid, 0.60 g (99%). m.p. 165–166 °C (lit. A A CHO), 7.64 (s, 1 H, ArH), 3.91 (s, 3 H, OCH3), 2.41 (s, (Raiford and Davis, 1927) 168–170 °C); Rf = 0.10 (petroleum A ‚ 13 d 1 3H, O(C O)CH3); C NMR (101 MHz, CDCl3): ether/ethyl acetate, 2:1); IR (KBr, cm ): 3412 (AOH), 3088 187.5, 167.3, 148.9, 145.2, 144.1, 130.6, 122.9, 120.6, 63.2, (ArH), 2916 (ACH3), 2851 (ACHO), 2768 (ACHO), 1672 20.8; EI-MS (m/z): 317.0 [M]+. (AC‚O), 1582 (AC‚CA), 1541 (ANO2), 1493 (AC‚CA),

1 1369 (ANO2), 1194 (ACAOACA); H NMR (400 MHz, (2 50 mL), dried over anhydrous Na2SO4 and then evapo- DMSO-d6): d 12.35 (s, 1H, CHO), 9.96 (s, 1H, AOH), 7.36 rated. The crude product was purified by column chromatog- 13 (s, 1H, ArH), 3.84 (s, 3H, AOCH3); C NMR (101 MHz, raphy (silica gel; petroleum ether: ethyl acetate = 2:1) to give DMSO-d6): d 187.9, 157.8, 144.6, 139.3, 122.5, 122.1, 115.1, product. 61.7; EI-MS (m/z): 275.0 [M]+. 3.2.6.1. 4-(2-fluorophenyl)-7-methoxy-1H-indole-6-ol (7). 3.2.4. Synthesis of 5-bromo-2-methoxy-3-nitro-4-(2- Light brown solid, yield 23%; m.p. 137–139 °C; Rf = 0.32 nitroethenyl) phenol (5) (petroleum ether/acetone, 3:1); IR (KBr, cm1): 3356 A A To a solution of 4 (1.00 g, 3.64 mmol) in acetic acid (100 mL), ( OH), 3115 (pyrrole-CH), 3051 (ArH), 2941 ( CH3), 1188 A A A A 1 d ammonium acetate (0.74 g, 9.60 mmol) and nitromethane ( C O C ); H NMR (400 MHz, CDCl3): 8.21 (s, 1H, (1.36 mL, 25.45 mmol) were added and stirred at 120 °C under NH), 7.51 (t, J = 7.4 Hz, 1H, ArH), 7.39–7.28 (m, 1H, nitrogen for 4 h. The mixture was cooled to 40 °C and poured ArH), 7.25–7.13 (m, 2H, ArH), 7.10 (s, 1H, H-indole), 6.90 A into ice water (200 mL). The result mixture was extracted with (s, 1H, ArH,), 6.42 (s, 1H, H-indole), 5.45 (s, 1H, OH), A 13 d ethyl acetate (6 100 mL). The combined organic phase was 3.99 (s, 3H, OCH3); C NMR (101 MHz, CDCl3): 159.9 washed with water (5 100 mL) and saturated brine (JCAF = 248.97 Hz), 143.4, 131.8 (JCAF = 2.02 Hz), 131.8, 129.3, 128.9 (J A = 9.09 Hz), 128.0 (J A = 15.15 Hz), (2 50 mL), dried over anhydrous Na2SO4 and concentrated C F C F in vacuum. The residue was purified by flash chromatography 124.4, 124.2 (JCAF = 3.03 Hz), 123.7, 123.3, 116.1 (silica gel; petroleum ether: ethyl acetate = 2:1) to give 5 as a (JCAF = 23.23 Hz), 111.7 (JCAF = 2.02 Hz), 103.4 + (J A = 3.03 Hz), 61.1; HR-ESI-MS (m/z): calcd. [M+H] : yellow solid, 0.70 g (60%). m.p. 98–100 °C; Rf = 0.31 (CH2- C F 1 258.0930, found: 258.0936. Cl2); IR (KBr, cm ): 3444 (AOH), 3117 (ACH‚CHA), 3047 (ArH), 2924 (ACH3), 1597 (AC‚CA), 1539 (ANO2), 1487 (AC‚CA), 1348 (ANO ), 1194 (ACAOACA); 1H 3.2.6.2. 4-(2-chlorophenyl)-7-methoxy-1H-indole-6-ol (8). 2 ° d Light brown solid, yield 39%; m.p. 146–148 C; Rf = 0.39 NMR (400 MHz, CDCl3): 7.97 (d, J = 14.0 Hz, 1H, 1 A ‚ (petroleum ether/acetone, 3:1); IR (KBr, cm ): 3344 CH CHNO2), 7.43 (s, 1H, ArH), 7.27 (d, J = 13.6 Hz, A A A ‚ A 13 ( OH), 3053 (ArH), 2937 ( CH3), 1622 ( C C ), 1192 1H, ACH‚CHNO2), 3.95 (s, 3H, AOCH3); C NMR 1 (ACAOACA); H NMR (400 MHz, CDCl3): d 8.17 (s, 1H, (101 MHz, CDCl3): d 152.3, 145.4, 140.6, 139.1, 131.8, 122.9, + NH), 7.57–7.47 (m, 1H, ArH), 7.46–7.38 (m, 1H, ArH), 120.7, 115.3, 63.3; HR-ESI-MS (m/z): calcd. [M+H] : 7.37–7.28 (m, 2H, ArH), 7.11 (s, 1H, H-indole), 6.83 (s, 1H, 318.9556, found: 318.9310. ArH), 6.27 (s, 1H, H-indole), 5.30 (s, 1H, AOH), 4.00 (s, 3H, AOCH ); 13C NMR (101 MHz, CDCl ): d 143.2, 139.1, 6 3 3 3.2.5. Synthesis of 4-bromo-7-methoxy-1H-indole-6-ol ( ) 133.3, 132.0, 131.7, 130.0, 129.0, 128.6, 128.0, 126.6, 123.5, Under nitrogen, to a solution of 5 (2.00 g, 6.29 mmol) in acetic 123.4, 111.7, 103.5, 61.1; HR-ESI-MS (m/z): calcd. [M acid (20 mL), silica gel (2.00 g, 100–200 mesh) and iron powder +H]+: 274.0635, found: 274.0623. (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 3.2.7. General procedure for the condensation reaction ice water (50 mL) and extracted with ethyl acetate A solution of propiolic acid (0.07 mL, 1.14 mmol) in anhy- (3 100 mL). The organic phase was washed with water drous CH2Cl2 (30 mL) was stirred at 0 °C for 5 min. Dicyclo- (1 100 mL) and saturated brine (2 50 mL), dried over hexylcarbodiimide (0.24 g, 1.16 mmol) in anhydrous CH2Cl2 anhydrous Na2SO4. Then the solvent was evaporated. The (2 mL) was added. When the white precipitate was formed, a residue was purified by column chromatography (silica gel; solution of 7 or 8 (0.88 mmol) in anhydrous CH2Cl2 (2 mL) petroleum ether: ethyl acetate = 3:1) to give 6 as a brown thick was added to the reaction mixture. Lastly, liquid, 1.10 g (73%). Rf = 0.23 (petroleum ether/ethyl acetate, 4-dimethylaminopryidine (0.02 g, 0.16 mmol) in anhydrous 1 A 2:1); IR (KBr, cm ): 3423 ( OH), 3134 (pyrrole-CH), 3003 CH Cl (2 mL) was added dropwise to the stirring solution. A A A A ‚ A 2 2 (ArH), 2937 ( CH3), 2835 ( CH2 ), 1626 ( C C ), 1502 The reaction was stirred at RT until complete consumption A ‚ A A A A A 1 ( C C ), 1165 ( C O C ); H NMR (400 MHz, of 7 or 8 monitored by TLC (2 h). Then the mixture was fil- d A DMSO-d6): 11.29 (s, 1H, NH), 9.19 (s, 1H, OH), 7.31– tered, the filtrate was washed with water (6 50 mL) and sat- 7.17 (m, 1H, H-indole), 6.92 (s, 1H, ArH), 6.32–6.23 (m, 1H, urated brine (2 50 mL), dried over anhydrous Na2SO4 and A 13 H-indole), 3.90 (s, 3H, OCH3); C NMR (101 MHz, evaporated. The solid residue was purified by column chro- d DMSO-d6): 144.4, 132.5, 130.7, 124.9, 123.5, 113.5, 106.5, matography (silica gel; petroleum ether: ethyl acetate = 2:1) + 101.5, 60.0; HR-ESI-MS (m/z): calcd. [M+H] : 241.9817, to give product. found: 241.9790. 3.2.7.1. 4-(2-fluorophenyl)-7–methoxy-1H-indole-6-yl propio- 3.2.6. General procedure for the coupling reaction late (9). Light brown solid, yield 22%; m.p. 139–141 °C; Under nitrogen, a solution of 6 (0.57 g, 2.36 mmol) in glycol Rf = 0.52 (petroleum ether/ethyl acetate, 2:1); IR (KBr, 1 dimethyl ether and water (2:1, 15 mL), boronic acid cm ): 3431 (NH), 3277 (AC„CAH), 3121 (pyrrole-CH), A A „ A A ‚ (3.07 mmol), Na2CO3 (0.37 g, 3.49 mmol) and Pd(PPh3)4 3007 (ArH), 2941 ( CH3), 2127 ( C C ), 1724 ( C O), A A A A 1 d (0.54 g, 0.47 mmol) was added. The resulting mixture was 1200 ( C O C ); H NMR (400 MHz, CDCl3): 8.51 (s, heated at 85 °C under nitrogen for 12 h. The reaction was 1H, NH), 7.52 (t, J = 7.0 Hz, 1H, ArH), 7.40–7.29 (m, 1H, quenched by addition of AcOH and ice water (50 mL) and ArH), 7.25–7.23 (m, 1H, ArH), 7.22 (s, 1H, H-indole), 7.21– extracted with ethyl acetate (3 100 mL). The organic phase 7.13 (m, 1H, ArH), 6.96 (s, 1H, ArH), 6.48 (d, J = 1.6 Hz, was washed with water (1 100 mL) and saturated brine 1H, H-indole), 4.03 (s, 3H, AOCH3), 3.09 (s, 1H, C„CH);

13 C NMR (101 MHz, CDCl3): d 159.8 (JCAF = 249.0 Hz), 3.2.8.2. 5-(2-chlorophenyl)-9-hydroxypyrano[3,2-f]indole-2 151.4, 136.8, 135.9, 131.8 (JCAF = 3.64 Hz), 129.5, 129.2 (8H)-one (14). Pale yellow solid, method 1: yield 42%, ° (JCAF = 8.18 Hz), 127.7, 127.3 (JCAF = 14.95 Hz), 125.5, method 2: yield 33%; m.p. 220–222 C; Rf = 0.28 (petroleum 1 A 124.2 (JCAF = 3.64 Hz), 116.3 (JCAF = 2.12 Hz), 116.3, ether/ethyl acetate, 2:1); IR (KBr, cm ): 3447 ( OH), 3238 A ‚ A ‚ A 116.0, 103.4 (JCAF = 3.23 Hz), 77.3, 74.3, 61.3; HR-ESI-MS (NH), 3078 (ArH), 1769 ( C O), 1653 ( C C ), 1504 + 1 (m/z): calcd. [M+H] : 310.0879, found: 310.0859. (AC‚CA); H NMR (400 MHz, DMSO-d6): d 12.74 (s, 1H, NH), 7.71 (d, J = 4.8 Hz, 1H, H-pyrrol), 7.60 (d, 3.2.7.2. 4-(2-chlorophenyl)-7-methoxy-1H-indole-6-yl propio- J = 6.0 Hz, 1H, ArH), 7.45 (s, 3H, ArH), 7.38 (s, 1H, H- late (10). Light brown thick liquid, yield 21%. Rf = 0.52 (pet- pyrano), 6.57 (d, J = 5.2 Hz, 1H, H-pyrrol), 5.81 (s, 1H, roleum ether/ethyl acetate, 2:1); IR (KBr, cm1): 3431 (NH), AOH), 5.73 (s, 1H, H-pyrano); 13C NMR (101 MHz, 3277 (AC„CAH), 3115 (pyrrole-CH), 3063 (ArH), 2937 DMSO-d6): d 179.1, 174.0, 155.9, 136.4, 135.0, 133.9, 132.2, (ACH3), 2125 (AC„CA), 1728 (AC‚O), 1198 (ACAOACA) 131.3, 131.1, 130.6, 130.2, 128.0, 126.2, 124.8, 122.6, 108.5, 1 1 + cm ; H NMR (400 MHz, CDCl3): d 8.49 (s, 1H, NH), 7.55– 90.0; HR-ESI-MS (m/z): calcd. [M+H] : 311.0349, found: 7.48 (m, 1H, ArH), 7.47–7.41 (m, 1H, ArH), 7.36–7.28 (m, 2H, 311.8483. 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, AOCH3), 3.09 (s, 1H, 4. Conclusion 13 C„CH); C NMR (101 MHz, CDCl3): d 151.4, 138.4, 136.7, 135.7, 133.3, 132.1, 130.1, 129.2, 128.8, 127.8, 127.2, In conclusion, we describe an appropriate method for the synthesis of 126.7, 125.4, 116.5, 103.4, 77.2, 74.4, 61.3; EI-MS (m/z): 325 5-(2-halogeno phenyl)-9-hydroxypyrano [3,2-f]indole-2(8H)-one. PtCl4 or Pd(PPh ) /triﬂuoroacetic acid was suggested as effective catalysts in [M]+. 3 4 the ﬁnal cyclization step. Further synthesis and biological study for derivatives of 5-(2-halogeno phenyl)-9-hydroxypyrano[3,2-f]indole- 3.2.8. General procedure for the reductive cyclization 2(8H)-one are currently in progress.

Method 1 Acknowledgments To a solution of 9 or 10 (0.15 mmol) in 1, 4-dioxane and 1, This work was financially supported by the National Natural 2-dichloroethane (1:1, 5 mL), 5 mol% PtCl4 (0.01 g) was added. The mixture was stirred under nitrogen at 65 °C for Science Foundation of China (No. 81202494, 30730110, 2 h. Then the reaction was filtered, and the combined solvents 81302737), and Natural Science Basic Research Plan in were evaporated. The crude residue was dissolved with ethyl Shaanxi Province of China (No. 2016JM8076). acetate (50 mL), washed with water (1 50 mL) and saturated brine (2 50 mL), dried over anhydrous Na2SO4 and then References evaporated. The crude product was subjected to column chromatography (silica gel; petroleum ether–acetone, 2:1) to obtain AlMourabit, A., Zancanella, M.A., Tilvic, S., Romo, D., 2011. product. Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids. Nat. Prod. Rep. 28, 1229. Method 2 Arcadi, A., Burini, A., Cacchi, S., Delmastro, M., Marinelli, F., To a solution of 9 or 10 (0.40 mmol) in dry CH2Cl2 (5 mL), Pietroni, B.R., 1992. Palladium-catalyzed reaction of vinyl triflates Pd(PPh3)4 (0.03 g, 0.026 mmol) and 5 mL trifluoroacetic acid and vinyl/aryl halides with 4-alkynoic acids: regio- and stereose- were added. The reaction was stirred at RT for 2 h. Then the lective synthesis of (E)-.delta.-vinyl/aryl-.gamma.-methylene-. reaction was filtered, the combined solvents were evaporated, gamma.-butyrolactones. J. Org. Chem. 57, 976. and the crude residue was dissolved with ethyl acetate Barraja, P., Diana, P., Montalbano, A., Carbone, A., Cirrincione, G., (50 mL), washed with water (1 50 mL) and saturated brine Viola, G., Salvador, A., Vedaldi, D., Dall’acqua, F., 2008. Thiopyrano[2,3-e]indol-2-ones: angelicin heteroanalogues with (2 50 mL), dried over anhydrous Na2SO4 and then evaporated. The crude product was subjected to column chromatogra- potent photoantiproliferative activity. Med. Chem. 16, 9668. phy (silica gel; petroleum ether–acetone, 2:1) to obtain product. Barraja, P., Diana, P., Montalbano, A., Carbone, A., Viola, G., Basso, G., Salvador, A., Vedaldi, D., Dall’Acqua, F., Cirrincione, G., 2011. Pyrrolo[3,4-h]quinolinones a new class of photochemother- 3.2.8.1. 5-(2-fluorophenyl)-9-hydroxypyrano[3,2-f]indole-2 apeutic agents. Bioorg. Med. Chem. 7, 2326. (8H)-one (13). White solid, method 1: yield 35%, method 2: Carbone, A., Parrino, B., Barraja, P., Spano` , V., Cirrincione, G., ° yield 24%; m.p. 210–212 C; Rf = 0.28 (petroleum ether/ethyl Diana, P., Maier, A., Kelter, G., Fiebig, H.H., 2013. Synthesis and 1 acetate, 2:1); IR (KBr, cm ): 3514 (-OH), 3229 (NH), 3115 antiproliferative activity of 2,5-bis(30-indolyl)pyrroles, analogues of (ArH), 1790 (AC‚O), 1618 (AC‚CA), 1485 (AC‚CA) the marine alkaloid nortopsentin. Mar. Drugs 11, 643. 1 1 cm ; H NMR (400 MHz, DMSO-d6): d 12.75 (s, 1H, NH), Chen, L., Hu, T., Yao, Z., 2008. Development of new pyrrolo- 7.81–7.67 (m, 1H, H-pyrrol), 7.57–7.45 (m, 2H, ArH), 7.42 (s, coumarin derivatives with satisfactory fluorescent properties and 1H, H-pyrano), 7.39–7.24 (m, 2H, ArH), 6.72–6.47 (m, 1H, notably large stokes shifts. Eur. J. Org. Chem. 2008, 6175. H-pyrrol), 6.01 (s, 1H, AOH), 5.89–5.74 (m, 1H, H-pyrano); Chen, L., Xu, M., 2009. A new approach to pyrrolocoumarin derivatives by Palladium-Catalyzed reactions: expedient construc- 13C NMR (101 MHz, DMSO-d ): d 178.6, 173.6, 159.1 6 tion of polycyclic lamellarin scaffold. Adv. Synth. Catal. 351, 2005. (JCAF = 247.35 Hz), 155.4, 133.1, 131.4, 130.8, 130.7, 130.6 Diana, P., Stagno, A., Barraja, P., Carbone, A., Parrino, B., (JCAF = 3.54 Hz), 126.1, 124.8 (JCAF = 3.54 Hz), 124.7, Dall’Acqua, F., Vedaldi, D., Salvador, A., Brun, P., Castagliuolo, 124.5 (JCAF = 2.63 Hz), 122.2, 116.0 (JCAF = 21.72 Hz), I., Issinger, O.G., Cirrincione, G., 2011. Synthesis of triazenoazain- + 108.2 (JCAF = 2.53 Hz), 89.3; EI-MS (m/z): 311 [M] . doles: a new class of triazenes with antitumor activity. ChemMed- Chem 6, 1291.

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