Ruthenium-Catalyzed Decarboxylative C–H Alkenylation in Aqueous

Apr 26, 2018 - ... CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 10...
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Note Cite This: J. Org. Chem. 2018, 83, 7514−7522

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Ruthenium-Catalyzed Decarboxylative C−H Alkenylation in Aqueous Media: Synthesis of Tetrahydropyridoindoles Xiao-Yang Jin,†,‡ Li-Jun Xie,†,‡ Hou-Ping Cheng,†,‡ An-Di Liu,†,‡ Xue-Dong Li,†,‡ Dong Wang,† Liang Cheng,*,†,‡ and Li Liu*,†,‡ †

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Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *

ABSTRACT: We disclose herein a Ru(II)-catalyzed decarboxylative and oxidative coupling of N-substituted indolyl carboxylic acids with broad substrate scope in an aqueous solution. This method provides a sustainable and efficient access to synthesize various indole-fused cyclohexanyl acetic acids under mild conditions.

T

transition-metal-catalyzed cyclization (Fujiwara−Moritani reaction)3 of indole-based precursors (Scheme 1). The C−H

he indole-fused cyclohexanyl acetic acid core, like its parent moleculeindole or pyrrole, is a frequent motif in numerous pharmaceutical candidates and natural products that have been shown to exhibit significant physiological effects (Figure 1).1,2 For example, the natural product Cimicidin

Scheme 1. Transition-Metal-Catalyzed Oxidative C-2 Olefination Protocols of Indoles with Alkenes

Figure 1. Selected natural alkaloid and biological compounds based on indole-fused cyclohexanyl acetic acids.

bond activation is controlled by a directing group at the C-3 position (aldehyde, ketone, amide, etc.)4 or by a protecting group at the nitrogen atom (amide, ketone, heteroaryl, etc.).5 However, the installation and removal of these chelating groups adds additional steps, compromising the step-economical nature of the overall C−H activation strategy. Further

showed considerable inhibition of acetylcholinesterase activity in vitro,2a whereas the carbocycle-fused indole 1 exhibits subnanomolar affinity for the human CRTH2 receptor and thus represents a potent and selective CRTH2 agonist.2b The synthetic cyclohexanyl acetic acid 2 is a potent modulators of the S1P1 receptor.2f Owing to the presence of this indole skeleton in various biologically active compounds, the development of facile methods for the rapid synthesis of this substituted indole-fused acetic acid is strongly desired. Until now, most of the reported synthetic processes for the construction of the desired cyclohexanyl core involved a © 2018 American Chemical Society

Special Issue: Organic and Biocompatible Transformations in Aqueous Media Received: January 25, 2018 Published: April 26, 2018 7514

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

Note

The Journal of Organic Chemistry transformation (other than removal) with the existing directing groups in the final products always encountered problems. Thus, there has been a strong drive from the synthetic community to develop traceless directing groups.6 Apart from substantial improvement of the transition-metal-catalyzed cyclization, the reaction of (hetero)aryl carboxylic acids is of particular interest because of their wide availability as building blocks.7 Furthermore, the carboxylic group can be easily removed during the process, which eliminates additional steps for the decarboxylation and releases the block site for further installation of other desired groups. However, its application to indolyl carboxylic acids was limited.4 In connection with our interest in transition-metal-catalyzed C−C coupling transformations,8 we envisaged that an intramolecular decarboxylative and oxidative alkenylation might be an attractive way to form a cyclohexanyl acetic acid structure, which could be converted into a diversely functionalized indole derivative (Scheme 1). On the other hand, remarkable progress has been achieved in the catalyzed functionalizations of unreactive C−H bonds by the use of water as an environmentally benign, nonflammable, and nontoxic reaction medium; however, the insolubility of starting materials, reagents, or catalysts has been a common challenge to organic reactions.9 As part of our continuous interest in C−H functionalizations and aqueous reactions,10 we describe an efficient, regiospecific, decarboxylative, and general oxidative C−H alkenylation of simple N-alkenylalkyl indoles to generate a wide range of indole-fused cyclohexenyl acrylates in aqueous solution. We also demonstrated that the carboxylic acid group serves as an effective anchor for the ortho-functionalization and can be tracelessly cleaved in decarboxylative coupling for further derivation. The details of these findings are described herein. We worked to establish a practical approach by changing the nature of the directing group from commonly used aldehyde, ketone, amide, etc. to a removable carboxylic acid. Our optimization studies began with the C-3 carboxylic acid derivative of indole 3a as a model substrate, which was subjected to previously developed conditions for C-2 alkenylation with a carboxylic acid directing group4a,c (Table 1). Trace or no product was generated in all cases (entries 1 and 2). Thus, we were compelled to optimize the reaction condition and established an ideal combination for the alkenylation reaction. Through the optimization, an aqueous mixture was proven to be the solvent of choice.11 The Ru(II) catalyst12 was only soluble in water, but the indolyl carboxylic acid was not; thus a high efficiency was ensured by a homogeneous solution with methanol. The intramolecular cyclization was eventually optimized with 5 mol % of Ru(II) catalyst and O2 as a benign oxidant, and the desired product 4a was also confirmed from X-ray analysis of single crystals obtained from the decarboxylation reaction (entry 3). The aerobic oxidative alkenylation in pure organic solvents was viable, but with reduced efficacy (entries 4−6). Direct oxidation in organometallic reactions by molecular oxygen is often kinetically unfavored. It is noteworthy to mention that, in our case, the best result was obtained when molecular oxygen was used as the terminal oxidant, whereas other commonly used oxidants such as Cu(OAc)2 (entry 7) or V2O5 (entry 8) were proven to be unsuccessful. The product was also obtained smoothly under air (entry 9). The use of other bases such as KOAc, but not CsOAc, was less effective (entries 10 and 11). Again, to demonstrate the importance of carboxylic acid as the

Table 1. Screening of Metal Complexes, Additives, and Solventsa

entry

variations from standard condition

1

Pd(OAc)2, Cu(OAc)2·H2O, 4Å MS, LiOAc, DMAc, 140 °C, N2 [RuCl2(p-cymene)]2, Cu(OAc)2·H2O, DMF, 80 °C, N2, 6 h none n-butanol instead of H2O−MeOH THF instead of H2O−MeOH toluene instead of H2O−MeOH Cu(OAc)2 V2O5 under air no CsOAc KOAc instead of CsOAc 5a instead of 3a 5b instead of 3a

2 3 4 5 6 7c 8c 9 10 11 12 13

yield (%) 6 NRb 79 31 12 22 16 41 65 NDd 35e NR NR

a

Standard condition: 3a (0.5 mmol, 144 mg), [RuCl2(p-cymene)]2 (0.025 mmol, 15 mg), and CsOAc (0.5 mmol, 96 mg) in H2O− MeOH (3/7, total 1 mL) at 90 °C for 18 h under oxygen (balloon). Isolated yield for 4a was given. bNR: no reaction. c2 equiv of oxidant was used. dND: not detected. Only decarboxylated starting product (5a) was observed. eReaction conducted in methanol at 60 °C.

directing group, we prepared two analogues, 5a,b, which did not undergo cyclization, and only the starting materials were recovered (entries 12 and 13). With this optimized catalytic system in hand, we explored its scope in the intramolecular oxidative alkenylation of indolyl carboxylic acids 3a−o (Table 2). Thus, the catalytic C−H bond formation in aqueous mixture allowed for a rapid and efficient conversion of a series of substituted tetrahydropyrido[1,2a]indolyl carboxylic acids 4a−o in good to excellent yields. Electron-rich (4f−g,i−l) and electron-poor (4b−e,h) groups were tolerated in the reaction for C-4/5/6/7-substituted indolyl carboxylic acids. Other acrylate derivatives, namely, ethyl (4m), tert-butyl (4n), and benzyl (4o), were found to furnish good to excellent yields. However, simple acrylic acid (4p), phenylvinylsulfone (4q), or terminal alkene without an activating group (4r) gave results inferior to those of their ester counterparts. Interestingly, when methylvinyl ketone was used, a conjugate adduct 4s rather than the coupling product was isolated in 78% yield4g (vide inf ra). It is noteworthy to mention that in all cases only (Z)-4 isomers were detected and isolated. Applying this efficient oxidative coupling led to the formation of the corresponding indole-fused cyclohexanyl acetic acids 1 and 2. Selective hydrogenation of the acrylate 4a followed by sulfenylation, both steps in water, gave the sulfane 7a. Saponification of the resultant sulfane 7a with lithium hydroxide afforded the target molecule 1 as a prostaglandin D2 receptor antagonist (Scheme 2).2a On the other hand, hydrogenation of 4g followed by demethylation provided phenol 5b. Etherification and subsequent saponification of the ester under basic conditions afforded the substituted tricyclic acid derivative 2, which was used as an S1P1 receptor agonist in 7515

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

Note

The Journal of Organic Chemistry Table 2. Substrate Scopea

a

Standard condition: 3a−s (0.5 mmol), [RuCl2(p-cymene)]2 (0.025 mmol, 15 mg), and CsOAc (0.5 mmol, 96 mmol) in H2O−MeOH (3/7, total 1 mL) at 90 °C for 18 h under oxygen (balloon). Isolated yield for 4a−s was given. bBased on recovered starting material yield.

Scheme 2. Synthesis of 3-Sulfenylindole-Fused Cyclohexanyl Acetic Acid 1

Scheme 3. Application of the Decarboxylative Coupling for the Synthesis of Indole-Fused Cyclohexanyl Acetic Acid 2

7516

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

Note

The Journal of Organic Chemistry Scheme 4. Proposed Mechanism

we have shown that the reaction solvent has a strong effect on the cyclization, and an aqueous solution was proven to be optimal for this coupling. Further studies will aim at enlightening our understanding on the detailed mechanism for extending this application in related synthetically versatile processes.

the treatment of autoimmune and inflammatory disorders (Scheme 3). Based on our results and previous mechanistic studies of the other researchers on the decarboxylative C−H functionalizations,13 a tentative mechanism was proposed, as shown in Scheme 4. The reaction was initiated by a base-promoted dissociation of the dinuclear ruthenium catalyst [RuCl2(pcymene)]2. The resulting ruthenium biscarboxylate I underwent a C−H cyclometalation assisted by the carboxyl acid to furnish II. The cyclometalated intermediate II coordinated with the intramolecular acrylate III and proceeded via a migratory alkene insertion to deliver a seven-membered metallacyle IV. A sequential β-elimination and decarboxylation/proto-demetalation afforded the product 4 while releasing CO2 and the Ru intermediate VI, which was later oxidized by molecular oxygen at ambient pressure to regenerate the catalyst I. The reason that an adduct 4s was generated rather than a coupling product may be ascribed to the β-H elimination step, in which the acidity of α-H in the intermediate IV is strong enough for the following proto-demetalation, and thus an addition reaction occurred.4g The excellent stereoselectivity where, in our case, only (Z)-4 was obtained was probably due to the syn-conformation required in the β-elimination (see Figure S1 in the Supporting Information for a detailed conformation analysis of the transition state for the β-elimination). In summary, we have reported a mild and selective Ru(II)catalyzed decarboxylative and oxidative coupling to access substituted indole-fused cyclohexanyl acetic acids in good to excellent yields. Notably, the carboxylic acid group acts as an essential and traceless directing group, which allows for a selective oxidative coupling at the ortho-position. Furthermore,

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EXPERIMENTAL SECTION

General Method for the Synthesis of 3a−s. To a mixture of sodium hydride (60%, 2.285 g, 57.14 mmol) in dry N,Ndimethylformamide (25 mL) was added dropwise a solution of methyl 1H-indole-3-carboxylate (5.0 g, 28.57 mmol in 25 mL of N,Ndimethylformamide). The mixture was stirred for 10 min, and then 5bromobut-1-ene (4.4 mL, 37.14 mmol) was added. The reaction continued stirring for another 2 h at room temperature and was then diluted with ethyl acetate (200 mL). The organic layer was washed with water (200 mL × 2) and brine (200 mL × 2), dried over anhydrous sodium sulfate, evaporated, and purified by silica column chromatography (eluent: petroleum ether/ethyl acetate 10/1) to afford the intermediate methyl 1-(pent-4-en-1-yl)-1H-indole-3-carboxylate as a colorless oil (6.89 g, yield 99%). A mixture of methyl 1(pent-4-en-1-yl)-1H-indole-3-carboxylate (6.89 g, 28.4 mmol) and potassium hydroxide (6.35 g, 113.4 mmol) in methanol (40 mL) and water (30 mL) was heated to reflux for 16 h. The solution was acidified to pH 6 with 1 N hydrochloride, and the intermediate 1-(pent-4-en-1yl)-1H-indole-3-carboxylic acid 3r was filtered as a white solid (5.77 g, yield 88%). To a solution of 1-(pent-4-en-1-yl)-1H-indole-3-carboxylic acid 3r (5.0 g, 21.83 mmol), methyl acrylate (39.5 mL, 436.6 mmol), and second Grubbs catalyst (925 mg, 1.091 mmol) was added dichloromethane (150 mL) under nitrogen. The mixture was stirred for 16 h at room temperature, evaporated, and purified by silica column chromatography (eluent: petroleum ether/ethyl acetate 3/1) 7517

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

Note

The Journal of Organic Chemistry

122.2, 113.6, 110.8, 106.2, 103.2, 55.8, 51.5, 46.4, 29.1, 28.1; IR νmax (KBr, film, cm−1) 2921, 1721, 1657, 1529, 1223, 776; HRMS (ESI, orbitrap) calcd for C17H18O5N [M − H+] 316.1190, found 316.1191. (E)-6-Chloro-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic Acid 3h: Gray solid, 430 mg (from 1.9 mmol), 70% yield, mp 155−157 °C; 1H NMR (300 MHz, CDCl3) δ 8.15−8.12 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.28−7.26 (d, J = 6.9 Hz, 1H), 6.96−6.86 (m, 1H), 5.87−5.82 (d, J = 15.9 Hz, 1H), 4.17−4.12 (m, 2H), 3.73 (s, 3H), 2.27−2.21 (m, 2H), 2.11−2.01 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 169.7, 166.6, 146.5, 136.9, 135.7, 129.2, 125.4, 123.05, 123.02, 122.4, 111.0, 106.9, 51.6, 46.3, 29.1, 28.0; IR νmax (KBr, film, cm−1) 2923, 1719, 1661, 1533, 1274, 815; HRMS (ESI, orbitrap) calcd for C16H15O4NCl [M − H+] 320.0695, found 320.0696. (E)-1-(6-Methoxy-6-oxohex-4-enyl)-6-methyl-1H-indole-3-carboxylic Acid 3i: Gray solid, 486 mg (From 1.64 mmol), 98% yield, mp 143−145 °C; 1H NMR (300 MHz, CDCl3) δ 8.12−8.09 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.14 (s, 2H), 6.97−6.87 (m, 1H), 5.87−5.82 (d, J = 15.6 Hz, 1H), 4.18−4.13 (m, 2H), 3.73 (s, 3H), 2.50 (s, 3H), 2.24−2.20 (m, 2H), 2.10−2.03 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 170.5, 166.7, 146.9, 136.9, 134.7, 133.0, 124.8, 124.0, 122.2, 121.6, 109.9, 106.6, 51.5, 46.1, 29.1, 28.0, 21.8; IR νmax (KBr, film, cm−1) 2924, 1721, 1658, 1533, 1276, 811; HRMS (ESI, orbitrap) calcd for C17H18O4N [M − H+] 300.1241, found 300.1244. (E)-6-Methoxy-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic Acid 3j: Gray solid, 238 mg (from 2.0 mmol), 37% yield, mp 154−156 °C; 1H NMR (300 MHz, CDCl3) δ 8.11−8.08 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 6.97−6.89 (m, 2H), 6.78 (s, 1H), 5.87−5.82 (d, J = 15.6 Hz, 1H), 4.14−4.10 (m, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 2.27−2.20 (m, 2H), 2.09−2.00 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 170.6, 166.8, 157.1, 147.0, 137.5, 134.4, 122.8, 122.3, 121.1, 111.7, 106.8, 93.8, 55.8, 51.6, 46.1, 29.1, 28.0; IR νmax (KBr, film, cm−1) 2949, 1720, 1659, 1533, 1275, 817; HRMS (ESI, orbitrap) calcd for C17H18O5N [M − H+] 316.1190, found 316.1188. (E)-1-(6-Methoxy-6-oxohex-4-enyl)-7-methyl-1H-indole-3-carboxylic Acid 3k: Gray solid, 446 mg (from 1.64 mmol), 90% yield, mp 126−128 °C; 1H NMR (300 MHz, CDCl3) δ 8.15−8.12 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.19−7.15 (m, 1H), 7.03−7.00 (d, J = 6.9 Hz, 1H), 6.97−6.87 (m, 1H), 5.88−5.83 (d, J = 15.9 Hz, 1H), 4.39−4.35 (m, 2H), 3.73 (s, 3H), 2.70 (s, 3H), 2.27−2.23 (m, 2H), 2.04−1.99 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 170.0, 166.6, 146.6, 135.9, 135.2, 128.5, 126.0, 124.6, 122.3, 116.0, 111.4, 106.3, 51.6, 46.4, 29.3, 29.1, 28.0; IR νmax (KBr, film, cm−1) 2949, 1721, 1659, 1541, 1268, 791; HRMS (ESI, orbitrap) calcd for C17H18O4N [M − H+] 300.1241, found 300.1244. (E)-7-Methoxy-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic Acid 3l: Gray solid, 361 mg (from 1.93 mmol), 59% yield, mp 136−137 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.9 (s, 1H), 7.96 (s, 1H), 7.63−7.61(d, J = 7.8 Hz, 1H), 7.10−7.05 (m, 1H), 6.95−6.86 (m, 1H), 6.78−6.75 (d, J = 8.1 Hz, 1H), 5.91−5.86 (d, J = 15.6 Hz, 1H), 4.42−4.37 (m, 2H), 3.90 (s, 3H), 3.64 (s, 3H), 2.22−2.16 (m, 2H), 1.94−1.90 (m, 2H); 13C NMR (500 MHz, DMSO-d6) δ 166.5, 166.0, 149.1, 147.6, 136.4, 129.4, 125.9, 122.5, 121.5, 113.9, 107.0, 104.1, 55.9, 51.6, 49.0, 30.1, 28.9; IR νmax (KBr, film, cm−1) 2950, 1722, 1659, 1538, 1155, 790; HRMS (ESI, orbitrap) calcd for C17H18O5N [M − H+] 316.1190, found 316.1189. (E)-1-(6-Ethoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic Acid 3m: Gray solid, 315 mg (From 1.09 mmol), 96% yield, mp 87−88 °C; 1H NMR (300 MHz, CDCl3) δ 8.27−8.24 (m, 1H), 7.91 (s, 1H), 7.38−7.29 (m, 3H), 6.96−6.86 (m, 1H), 5.86−5.81 (d, J = 15.6 Hz, 1H), 4.22−4.15 (m, 4H), 2.28−2.21 (m, 2H), 2.12−2.03 (m, 2H), 1.31−1.26 (m, 3H); 13C NMR (300 MHz, CDCl3) δ 170.5, 166.4, 146.6, 136.6, 135.3, 127.1, 123.1, 122.8, 122.4, 122.1, 110.0, 106.8, 60.5, 46.3, 29.2, 28.2, 14.3; IR νmax (KBr, film, cm−1) 2927, 1714, 1661, 1532, 1276, 751; HRMS (ESI, orbitrap) calcd for C17H19O4NNa [M + Na+] 324.1206, found 324.1207. (E)-1-(6-tert-Butoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic Acid 3n: Gray solid, 345 mg (from 1.09 mmol), 96% yield, mp 116− 118 °C; 1H NMR (300 MHz, CDCl3) δ 8.27−8.24 (m, 1H), 7.93− 7.91 (d, J = 6.9 Hz, 1H), 7.38−7.29 (m, 3H), 6.86−6.76 (m, 1H),

to afford the product (E)-1-(6-methoxy-6-oxohex-4-en-1-yl)-1Hindole-3-carboxylic acid 3a as a white solid (4.39 g; yield 74%). (E)-1-(6-Methoxy-6-oxohex-4-en-1-yl)-1H-indole-3-carboxylic acid 3a: White solid, mp 132−134 °C; 1H NMR (300 MHz, CDCl3) δ 8.26−8.23 (m, 1H), 7.90 (s, 1H), 7.37−7.29 (m, 3H), 6.96−6.86 (m, 1H), 5.86−5.81 (d, J = 15.6 Hz, 1H), 4.21−4.17 (m, 2H), 3.73 (s, 3H), 2.27−2.20 (m, 2H), 2.11−2.02 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 170.7, 166.8, 147.0, 136.7, 135.4, 127.1, 123.2, 122.5, 122.4, 122.1, 110.1, 106.8, 51.7, 46.3, 29.3, 28.2; IR νmax (KBr, film, cm−1) 2948, 1720, 1659, 1532, 1276, 751; HRMS (ESI, orbitrap) calcd for C16H16O4N [M − H+] 286.1084, found 286.1081. (E)-4-Bromo-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3b: Gray solid, 148 mg (from 0.45 mmol), 89% yield, mp 122−124 °C; 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.52−7.49 (d, J = 7.5 Hz, 1H), 7.31−7.26 (m, 1H), 7.15−7.09 (m, 1H), 6.94− 6.85 (m, 1H), 5.86−5.80 (d, J = 15.6 Hz, 1H), 4.19−4.10 (m, 2H), 3.73 (s, 3H), 2.26−2.19 (m, 2H), 2.09−2.02 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.4, 165.6, 145.5, 137.2, 136.2, 126.8, 124.6, 122.8, 121.3, 113.6, 108.2, 106.4, 50.5, 45.3, 28.0, 26.9; IR νmax (KBr, film, cm−1) 2920, 1720, 1645, 1523, 1167, 763; HRMS (ESI, orbitrap) calcd for C16H16O4NBrNa [M + Na+] 388.0154, found 388.0147. (E)-5-Chloro-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3c: Gray solid, 421 mg (from 1.52 mmol), 86% yield, mp 144−146 °C; 1H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.88 (s, 1H), 7.24 (s, 2H), 6.95−6.85 (m, 1H), 5.86−5.81 (d, J = 15.9 Hz, 1H), 4.19−4.14 (m, 2H), 3.73 (s, 3H), 2.26−2.19 (m, 2H), 2.08−2.03 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 170.3, 166.6, 146.6, 136.1, 134.9, 128.3, 127.9, 123.5, 122.4, 121.6, 111.0, 106.4, 51.6, 46.4, 29.1, 28.1; IR νmax (KBr, film, cm−1) 2926, 1719, 1661, 1533, 1160, 775; HRMS (ESI, orbitrap) calcd for C16H15O4NCl [M − H+] 320.0695, found 320.0698. (E)-5-bromo-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3d. Gray solid, 275 mg (from 0.9 mmol), 83% yield, mp 122−124 °C; 1H NMR (300 MHz, CDCl3) δ 8.40−8.39 (d, J = 1.5 Hz,1H), 7.87 (s, 1H), 7.41−7.38 (dd, J = 1.8, 9.0 Hz, 1H), 7.24−7.21 (d, J = 9.0 Hz, 1H), 6.95−6.85 (m, 1H), 5.87−5.81 (d, J = 15.6 Hz, 1H), 4.20−4.16 (m, 2H), 3.73 (s, 3H), 2.27−2.20 (m, 2H), 2.11−2.02 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 170.1, 166.7, 146.6, 136.0, 135.3, 128.6, 126.1, 124.7, 122.4, 116.1, 111.4, 106.4, 51.7, 46.5, 29.1, 28.1; IR νmax (KBr, film, cm−1) 2923, 1720, 1661, 1532, 1160, 775; HRMS (ESI, orbitrap) calcd for C16H15O4NBr [M − H+] 364.0189, found 364.0196. (E)-5-Iodo-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3e: Gray solid, 421 mg (from 1.3 mmol), 78% yield, mp 148−149 °C; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 7.83 (s, 1H), 7.58−7.55 (d, J = 8.4 Hz, 1H), 7.13−7.10 (d, J = 8.7 Hz, 1H), 6.95−6.85 (m, 1H), 5.86−5.81 (d, J = 15.6 Hz, 1H), 4.19−4.14 (m, 2H), 3.73 (s, 3H), 2.26−2.19 (m, 2H), 2.10−2.03 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 169.9, 166.6, 146.5, 135.7, 135.6, 131.6, 130.8, 129.1, 122.4, 111.8, 106.1, 86.6, 51.6, 46.3, 29.0, 28.0; IR νmax (KBr, film, cm−1) 2923, 1718, 1660, 1532, 1160, 775; HRMS (ESI, orbitrap) calcd for C16H15O4NI [M − H+] 412.0051, found 412.0050. (E)-Methyl 2-(2-methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 3f: Gray solid, 342 mg (from 2.0 mmol), 56% yield, mp 157−159 °C; 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.85 (s, 1H), 7.25−7.22 (d, J = 8.4 Hz, 1H), 7.13−7.10 (d, J = 8.4 Hz, 1H), 6.95−6.85 (m, 1H), 5.86−5.80 (d, J = 15.6 Hz, 1H), 4.17−4.10 (m, 2H), 3.72 (s, 3H), 2.49 (s, 3H), 2.24−2.17 (m, 2H), 2.08−1.99 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 169.9, 165.8, 146.0, 134.4, 134.0, 131.0, 126.3, 123.7, 121.3, 120.8, 108.7, 105.2, 50.6, 45.3, 28.2, 27.2, 20.6; IR νmax (KBr, film, cm−1) 2921, 1721, 1658, 1532, 1163, 778; HRMS (ESI, orbitrap) calcd for C17H18O4N [M − H+] 300.1241, found 300.1241. (E)-5-Methoxy-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic Acid 3g: Gray solid, 600 mg (from 1.93 mmol), 98% yield, mp 110−111 °C; 1H NMR (300 MHz, CDCl3) δ 7.85 (s, 1H), 7.71−7.70 (d, J = 2.1 Hz, 1H), 7.25−7.22 (d, J = 9.6 Hz, 1H), 6.96−6.86 (m, 2H), 5.86−5.81 (d, J = 15.6 Hz, 1H), 4.18−4.13 (m, 2H), 3.92 (s, 3H), 3.73 (s, 3H), 2.26−2.19 (m, 2H), 2.10−2.03 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 170.7, 166.6, 156.1, 146.8, 135.2, 131.5, 127.8, 7518

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

Note

The Journal of Organic Chemistry

2H), 3.75 (s, 3H), 3.31−3.28 (m, 2H), 2.17−2.10 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.4, 147.1, 137.5, 134.7, 127.5, 123.1, 121.4, 120.7, 111.3, 109.4, 99.5, 51.2, 41.8, 25.3, 22.9; IR νmax (KBr, film, cm−1) 2920, 1703, 1619, 1520, 1159, 749; HRMS (ESI, orbitrap) calcd for C15H16O2N [M + H+] 242.1175, found 242.1177. (E)-Methyl 2-(1-Bromo-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4b: Light yellow solid, 32.7 mg, 40% yield, mp 74− 75 °C; 1H NMR (300 MHz, CDCl3) δ 7.29−7.21 (m, 2H), 7.10−7.02 (m, 1H), 6.97 (s, 1H), 6.54 (s, 1H), 4.13−4.07 (m, 2H), 3.76 (s, 3H), 3.31−3.27 (m, 2H), 2.17−2.11 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.2, 146.1, 137.5, 135.2, 128.3, 123.7, 123.4, 115.3, 112.4, 108.5, 99.6, 51.2, 42.2, 25.0, 22.6; IR νmax (KBr, film, cm−1) 2920, 1702, 1618, 1520, 1154, 782; HRMS (ESI, orbitrap) calcd for C15H15O2NBr [M + H+] 320.0280, found 320.0283. (E)-Methyl 2-(2-Chloro-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4c: Light yellow solid, 89.8 mg, 65% yield, mp 144−146 °C; 1H NMR (300 MHz, CDCl3) δ 7.56−7.55 (d, J = 1.2 Hz, 1H), 7.21−7.14 (m, 2H), 6.85 (s, 1H), 6.46 (s, 1H), 4.11−4.07 (m, 2H), 3.75 (s, 3H), 3.30−3.25 (m, 2H), 2.17−2.09 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.2, 146.4, 135.9, 135.8, 128.4, 126.3, 123.4, 120.5, 112.2, 110.4, 98.8, 51.3, 42.0, 25.1, 22.7; IR νmax (KBr, film, cm−1) 2957, 1708, 1617, 1517, 1159, 787; HRMS (ESI, orbitrap) calcd for C15H16O2NCl [M + H+] 276.0785, found 276.0786. (E)-Methyl 2-(2-Bromo-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4d: Light yellow solid, 65.2 mg, 40% yield, mp 138−140 °C; 1H NMR (300 MHz, CDCl3) δ 7.73−7.72 (d, J = 1.5 Hz, 1H), 7.31−7.27 (dd, J = 1.5, 8.7 Hz 1H), 7.17−7.14 (d, J = 8.7 Hz, 1H), 6.85 (s, 1H), 6.47 (s, 1H), 4.12−4.08 (m, 2H), 3.76 (s, 3H), 3.30−3.26 (m, 2H), 2.17−2.09 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 167.1, 146.2, 135.9, 135.6, 128.9, 125.8, 123.5, 113.7, 112.1, 110.7, 98.6, 51.1, 41.8, 24.9, 22.5; IR νmax (KBr, film, cm−1) 2920, 1705, 1622, 1517, 1158, 858; HRMS (ESI, orbitrap) calcd for C15H15O2NBr [M + H+] 320.0280, found 320.0285. (E)-Methyl 2-(2-Iodo-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4e: Gray solid, 47.9 mg, 26% yield, mp 177−179 °C; 1H NMR (400 MHz, CDCl3) δ 7.943−7.940 (d, J = 1.2 Hz, 1H), 7.46−7.44 (dd, J = 1.6, 8.8 Hz 1H), 7.08−7.05 (d, J = 8.8 Hz, 1H), 6.84 (s, 1H), 6.49 (s, 1H), 4.12−4.08 (m, 2H), 3.76 (s, 3H), 3.30− 3.26 (m, 2H), 2.16−2.10 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.2, 146.3, 136.4, 135.4, 131.3, 130.1, 129.9, 112.3, 111.3, 98.4, 84.2, 51.3, 41.9, 25.1, 22.7; IR νmax (KBr, film, cm−1) 2920, 1706, 1698, 1436, 1163, 855; HRMS (ESI, orbitrap) calcd for C15H15O2NI [M + H+] 368.0142, found 368.0148. (E)-Methyl 2-(2-Methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4f: Light yellow solid, 96.3 mg, 75% yield, mp 116−118 °C; 1H NMR (300 MHz, CDCl3) δ 7.37 (s, 1H), 7.18−7.15 (d, J = 8.4 Hz, 1H), 7.06−7.03 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.44 (s, 1H), 4.09−4.06 (m, 2H), 3.74 (s, 3H), 3.29−3.25 (m, 2H), 2.42 (s, 3H), 2.14−2.06 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 167.5, 147.2, 136.0, 134.6, 129.9, 127.7, 125.0, 120.8, 110.9, 109.0, 98.9, 51.1, 41.8, 25.2, 22.8, 21.5; IR νmax (KBr, film, cm−1) 2920, 1702, 1608, 1480, 1160, 787; HRMS (ESI, orbitrap) calcd for C16H18O2N [M + H+] 256.1332, found 256.1334. (E)-Methyl 2-(2-Methoxy-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4g: White solid, 95.4 mg, 70% yield, mp 145−147 °C; 1H NMR (300 MHz, CDCl3) δ 7.20−7.17 (d, J = 8.7 Hz, 1H), 7.03−7.02 (d, J = 2.1 Hz, 1H), 6.92−6.88 (dd, J = 2.4, 11.4 Hz, 1H), 6.86 (s, 1H), 6.44 (s, 1H), 4.11−4.07 (m, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 3.30−3.26 (m, 2H), 2.17−2.09 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 167.3, 154.7, 146.9, 134.9, 132.9, 127.7, 114.3, 110.8, 110.1, 101.7, 98.8, 55.7, 51.0, 41.7, 25.0, 22.7; IR νmax (KBr, film, cm−1) 2920, 1708, 1626, 1480, 1163, 799; HRMS (ESI, orbitrap) calcd for C16H18O3N [M + H+] 272.1281, found 272.1284. (E)-Methyl 2-(3-Chloro-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4h: Light yellow solid, 68 mg, 49% yield, mp 110− 112 °C; 1H NMR (300 MHz, CDCl3) δ 7.51−7.48 (d, J = 8.4 Hz, 1H), 7.27 (s, 1H), 7.08−7.05 (dd, J = 1.5, 8.4 Hz, 1H), 6.89 (s, 1H), 6.45 (s, 1H), 4.08−4.04 (m, 2H), 3.75 (s, 3H), 3.29−3.26 (m, 2H), 2.16−2.08 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 167.1, 146.4, 137.6, 135.3, 128.9, 125.9, 122.1, 121.4, 111.7, 109.2, 99.4, 51.1, 41.8,

5.79−5.73 (d, J = 15.6 Hz, 1H), 4.21−4.17 (m, 2H), 2.24−2.18 (m, 2H), 2.10−2.01 (m, 2H), 1.48 (s, 9H); 13C NMR (300 MHz, CDCl3) δ 170.7, 165.8, 145.3, 136.7, 135.4, 127.1, 124.5, 123.1, 122.4, 122.2, 110.1, 106.8, 80.5, 46.4, 29.1, 28.2; IR νmax (KBr, film, cm−1) 2930, 1708, 1661, 1532, 1158, 751; HRMS (ESI, orbitrap) calcd for C19H23O4NNa [M + Na+] 352.1519, found 352.1519. (E)-1-(6-(Benzyloxy)-6-oxohex-4-enyl)-1H-indole-3-carboxylic Acid 3o: Gray solid, 353 mg (from 1.17 mmol), 82% yield, mp 115− 117 °C; 1H NMR (300 MHz, CDCl3) δ 8.26−8.23 (m, 1H), 7.89 (s, 1H), 7.36−7.28 (m, 8H), 7.00−6.90 (m, 1H), 5.90−5.85 (d, J = 15.6 Hz, 1H), 5.17 (s, 2H), 4.20−4.15 (m, 2H), 2.26−2.19 (m, 2H), 2.10− 2.01 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 170.7, 166.1, 147.3, 136.7, 136.1, 135.4, 128.7, 128.3, 127.1, 123.2, 122.5, 122.4, 122.2, 110.1, 106.9, 66.3, 46.3, 29.3, 29.2, 28.2; IR νmax (KBr, film, cm−1) 2920, 1717, 1658, 1532, 1274, 751; HRMS (ESI, orbitrap) calcd for C22H21O4NNa [M + Na+] 386.1362, found 386.1364. (E)-1-(5-Carboxypent-4-enyl)-1H-indole-3-carboxylic Acid 3p: Gray solid, 230 mg (from 2.18 mmol), 38% yield, mp 181−183 °C; 1 H NMR (300 MHz, DMSO-d6) δ 12.0 (s, 2H), 8.08 (s, 1H), 8.03− 8.01 (d, J = 7.2 Hz, 1H), 7.59−7.56 (d, J = 7.8 Hz, 1H), 7.26−7.16 (m, 2H), 6.87−6.18 (m, 1H), 5.78−5.73 (d, J = 15.6 Hz, 1H), 4.28−4.24 (m, 2H), 2.17−2.15 (m, 2H), 1.98−1.92 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.4, 166.0, 147.9, 136.7, 135.6, 126.9, 122.8, 122.6, 121.7, 121.3, 111.1, 106.9, 45.9, 29.0, 28.3; IR νmax (KBr, film, cm−1) 2922, 1658, 1532, 1276, 1210, 1162, 751; HRMS (ESI, orbitrap) calcd for C15H14O4N [M − H+] 272.0928, found 272.0927. (E)-1-(5-(Phenylsulfonyl)pent-4-enyl)-1H-indole-3-carboxylic Acid 3q: Gray solid, 310 mg (from 2.18 mmol), 38% yield, mp 82−84 °C; 1 H NMR (300 MHz, CDCl3) δ 8.23−8.21 (m, 1H), 7.86−7.84 (m, 3H), 7.63−7.50 (m, 3H), 7.32−7.28 (m. 3H), 6.97−6.88 (m, 1H), 6.34−6.29 (d, J = 15.3 Hz, 1H), 4.19−4.15 (m, 2H), 2.27−2.20 (m, 2H), 2.10−2.01 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 170.3, 144.3, 140.2, 136.4, 135.1, 133.5, 131.9, 129.3, 127.6, 126.9, 123.1, 122.3, 122.0, 109.8, 106.8, 46.0, 28.4, 27.7; IR νmax (KBr, film, cm−1) 2923, 1660, 1533, 1145, 752, 592; HRMS (ESI, orbitrap) calcd for C20H18O4NS [M − H+] 368.0962, found 368.0963. (E)-1-(6-Oxooct-4-enyl)-1H-indole-3-carboxylic Acid 3s: Gray solid, 280 mg (from 1.31 mmol), 75% yield, mp 106−108 °C; 1H NMR (300 MHz, CDCl3) δ 8.26−8.23 (m, 1H), 7.90 (s, 1H), 7.38− 7.29 (m, 3H), 6.79−6.69 (m, 1H), 6.12−6.07 (d, J = 15.9 Hz, 1H), 4.23−4.18 (m, 2H), 2.54−2.46 (m, 2H), 2.27−2.20 (m, 2H), 2.13− 2.03 (m, 2H), 1.10−1.05 (m, 3H); 13C NMR (500 MHz, CDCl3) δ 200.6, 170.4, 144.0, 136.5, 135.3, 130.8, 127.0, 123.0, 122.3, 122.0, 109.9, 106.7, 46.3, 33.6, 29.3, 28.1, 8.0; IR νmax (KBr, film, cm−1) 2923, 1661, 1531, 1207, 1162, 752; HRMS (ESI, orbitrap) calcd for C17H18O3N [M − H+] 284.1292, found 284.1293. 1-(Pent-4-en-1-yl)-1H-indole-3-carboxylic Acid 3r: Intermediate in the preparation of staring materials; white solid, 3.06 g (from 13.66 mmol), 98% yield, mp 122−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.27−8.24 (m, 1H), 7.92 (s, 1H), 7.39−7.36 (m, 1H), 7.32−7.28 (m, 2H), 5.84−5.74 (m, 1H), 5.09−5.07 (d, J = 9.2 Hz, 1H), 5.04 (s, 1H), 4.19−4.15 (m, 2H), 2.13−2.08 (m, 2H), 2.03−1.96 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 170.6, 136.89, 136.80, 135.6, 127.1, 123.0, 122.3, 122.1, 116.3, 110.2, 106.5, 46.4, 30.7, 28.8; IR νmax (KBr, film, cm−1) 2924, 1660, 1532, 1396, 1276, 1232, 750; HRMS (ESI, orbitrap) calcd for C14H16O2N [M + H+] 230.1175, found 230.1177. General Method for the Synthesis of 4a−s. To a solution of (E)-1-(6-methoxy-6-oxohex-4-en-1-yl)-1H-indole-3-carboxylic acid 3a (0.5 mmol, 143 mg) in a mixture of water−methanol (3/7, 1 mL total) were added cesium acetate (0.5 mmol, 96 mg) and [RuCl2(pcymene)]2 (0.025 mmol, 15 mg). The mixture was stirred at 90 °C under O2 for 18 h, evaporated, and purified by silica column chromatography (eluent: petroleum ether/ethyl acetate = 40/1) to afford the product (E)-methyl 2-(7,8-dihydropyrido[1,2-a]indol9(6H)-ylidene)acetate 4a as a light yellow solid (95.4 mg, yield 79%). (E)-Methyl 2-(7,8-Dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4a: Light yellow solid, 95.4 mg, 79% yield, mp 87−89 °C; 1 H NMR (400 MHz, CDCl3) δ 7.62−7.60 (d, J = 8.0 Hz, 1H), 7.30− 7.28 (dd, J = 0.4, 8.4 Hz, 1H), 7.23−7.21 (dd, J = 1.2, 8.4 Hz, 1H), 7.13−7.09 (m, 1H), 6.95 (s, 1H), 6.48−6.47 (m, 1H), 4.14−4.11 (m, 7519

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

Note

The Journal of Organic Chemistry 25.0, 22.5; IR νmax (KBr, film, cm−1) 2920, 1704, 1617, 1348, 1159, 810; HRMS (ESI, orbitrap) calcd for C15H15O2NCl [M + H+] 276.0785, found 276.0791. (E)-Methyl 2-(3-Methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4i: Light yellow solid, 94.3 mg, 74% yield, mp 118−120 °C; 1H NMR (300 MHz, CDCl3) δ 7.49−7.47 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.96−6.93 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.44 (s, 1H), 4.10−4.06 (m, 2H), 3.74 (s, 3H), 3.30−3.26 (m, 2H), 2.47 (s, 3H), 2.15−2.07 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.4, 147.2, 137.8, 134.0, 133.1, 125.3, 122.6, 120.9, 110.5, 109.1, 99.3, 51.0, 41.6, 25.2, 22.7, 22.0; IR νmax (KBr, film, cm−1) 2945, 1703, 1609, 1516, 1151, 810; HRMS (ESI, orbitrap) calcd for C16H18O2N [M + H+] 256.1332, found 256.1334. (E)-Methyl 2-(3-Methoxy-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4j: Light yellow solid, 103 mg, 76% yield, mp 105− 106 °C; 1H NMR (300 MHz, CDCl3) δ 7.48−7.45 (d, J = 8.7 Hz, 1H), 6.89 (s, 1H), 6.80−6.77 (dd, J = 1.5, 8.7 Hz, 1H), 6.69 (s, 1H), 6.39 (s, 1H), 4.07−4.03 (m, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.30− 3.26 (m, 2H), 2.16−2.08 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 167.5, 157.3, 147.1, 138.2, 133.7, 122.1, 121.8, 111.5, 109.6, 99.7, 91.9, 55.5, 51.0, 41.7, 25.1, 22.7; IR νmax (KBr, film, cm−1) 2947, 1701, 1619, 1355, 1152, 814; HRMS (ESI, orbitrap) calcd for C16H18O3N [M + H+] 272.1281, found 272.1284. (E)-Methyl 2-(4-Methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4k: Light yellow solid, 91.9 mg, 72% yield, mp 129−130 °C; 1H NMR (300 MHz, CDCl3) δ 7.43−7.41 (d, J = 7.5 Hz, 1H), 6.98−6.90 (m, 3H), 6.45 (s, 1H), 4.57−4.53 (m, 2H), 3.75 (s, 3H), 3.26−3.22 (m, 2H), 2.74 (s, 3H), 2.13−2.05 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 167.4, 147.5, 136.8, 134.7, 128.1, 126.0, 121.3, 120.5, 119.4, 110.8, 100.4, 51.0, 45.1, 24.9, 23.4, 20.5; IR νmax (KBr, film, cm−1) 2920, 1710, 1617, 1345, 1159, 808; HRMS (ESI, orbitrap) calcd for C16H18O2N [M + H+] 256.1332, found 256.1333. (E)-Methyl 2-(4-Methoxy-7,8-dihydropyrido[1,2-a]indol-9(6H)ylidene)acetate 4l: Light yellow solid, 98.2 mg, 72% yield, mp 91− 92 °C; 1H NMR (300 MHz, CDCl3) δ 7.18−7.15 (d, J = 8.1 Hz, 1H), 6.98−6.93 (m, 1H), 6.89 (s, 1H), 6.60−6.58 (d, J = 7.8 Hz, 1H), 6.43 (s, 1H), 4.60−4.57 (m, 2H), 3.90 (s, 3H), 3.74 (s, 3H), 3.25−3.20 (m, 2H), 2.10−2.02 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 167.4, 147.8, 147.5, 134.6, 129.3, 127.7, 120.6, 113.9, 110.8, 103.3, 99.9, 55.3, 51.0, 45.1, 25.1, 23.3; IR νmax (KBr, film, cm−1) 2946, 1704, 1606, 1256, 1158, 728; HRMS (ESI, orbitrap) calcd for C16H18O3N [M + H+] 272.1281, found 272.1283. (E)-Ethyl 2-(7,8-Dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4m: Light yellow solid, 48.1 mg, 75% yield, mp 84−86 °C; 1H NMR (300 MHz, CDCl3) δ 7.61−7.58 (d, J = 7.5 Hz, 1H), 7.29−7.19 (m, 2H), 7.12−7.08 (m, 1H), 6.93 (s, 1H), 6.47 (s, 1H), 4.24−4.17 (m, 2H), 4.11−4.08 (m, 2H), 3.28 (s, 2H), 2.12−2.09 (m, 2H), 1.34−1.30 (m, 2H); 13C NMR (500 MHz, CDCl3) δ 170.0, 166.6, 146.6, 135.9, 135.2, 128.5, 126.0, 124.6, 122.3, 116.0, 111.4, 106.3, 51.6, 46.4, 29.1, 28.0; IR νmax (KBr, film, cm−1) 2922, 1699, 1618, 1521, 1154, 749; HRMS (ESI, orbitrap) calcd for C16H18O2N [M + H+] 256.1332, found 256.1335. (E)-tert-Butyl 2-(7,8-Dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4n: Light yellow solid, 48.4 mg, 68% yield, mp 87−89; 1H NMR (300 MHz, CDCl3) δ 7.60−7.58 (d, J = 7.8 Hz, 1H), 7.29−7.18 (m, 2H), 7.12−7.07 (m, 1H), 6.92 (s, 1H), 6.40 (s, 1H), 4.12−4.08 (m, 2H), 3.27−3.24 (m, 2H), 2.14−2.09 (m, 2H), 1.52 (s, 9H); 13C NMR (300 MHz, CDCl3) δ 166.6, 145.6, 137.4, 135.0, 127.6, 122.8, 121.3, 120.6, 113.8, 109.3, 99.1, 80.1, 41.9, 28.5, 28.3, 28.2, 25.1, 22.9; IR νmax (KBr, film, cm−1) 2922, 1699, 1618, 1366, 1138, 748; HRMS (ESI, orbitrap) calcd for C18H22O2N [M + H+] 284.1656, found 284.1651. (E)-Benzyl 2-(7,8-Dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4o: Light yellow solid, 32.3 mg, 40% yield, mp 78−80 °C; 1 H NMR (300 MHz, CDCl3) δ 7.60−7.57 (d, J = 8.1 Hz, 1H), 7.40− 7.19 (m, 8H), 7.12−7.07 (m, 1H), 6.93 (s, 1H), 6.52 (s, 1H), 5.19 (s, 2H), 4.11−4.07 (m, 2H), 3.31−3.28 (m, 2H), 2.12−2.08 (m, 2H); 13C NMR (300 MHz, CDCl3) δ 166.7, 147.5, 137.5, 136.5, 134.6, 128.7, 128.4, 128.3, 128.2, 127.5, 123.1, 121.4, 120.7, 111.3, 109.4, 99.6, 65.8, 41.8, 25.3, 22.8; IR νmax (KBr, film, cm−1) 2921, 1701, 1617, 1520,

1147, 748; HRMS (ESI, orbitrap) calcd for C21H20O2N [M + Na+] 318.1488, found 318.1493. (E)-2-(7,8-Dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetic Acid 4p: Yellow soild, 10 mg, 17% yield, 92% brsm, mp 186−189 °C; 1H NMR (300 MHz, CDCl3) δ 7.64−7.61 (d, J = 8.1 Hz, 1H), 7.32−7.22 (m, 2H), 7.15−7.10 (m, 1H), 7.02 (s, 1H), 6.51 (s, 1H), 4.17−4.13 (m, 2H), 3.33−3.30 (m, 2H), 2.18−2.14 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 171.7, 149.2, 137.5, 134.3, 127.4, 123.3, 121.5, 120.7, 110.6, 109.3, 100.2, 41.7, 25.4, 22.7; IR νmax (KBr, film, cm−1) 2923, 1674, 1598, 1517, 1474, 1249, 1227, 1190, 748; HRMS (ESI, orbitrap) calcd for C14H12O2N [M − H+] 226.0873, found 226.0871. (E)-9-(Phenylsulfonylmethylene)-6,7,8,9-tetrahydropyrido[1,2-a]indole 4q: White soild, 30 mg, 18% yield, 89% brsm, mp 132−134 °C; 1 H NMR (300 MHz, CDCl3) δ 7.99−7.96 (m, 2H), 7.61−7.52 (m, 4H), 7.25−7.21 (m, 2H), 7.13−7.08 (m, 1H), 6.89−6.88 (d, J = 3.3 Hz, 2H), 4.11−4.07 (m, 2H), 3.21−3.16 (m, 2H), 2.17−2.09 (m, 2H); 13 C NMR (300 MHz, CDCl3) δ 144.1, 142.5, 137.5, 133.1, 132.2, 129.2, 127.2, 127.1, 123.7, 121.6, 121.2, 120.9, 109.4, 100.7, 41.6, 24.1, 22.4; IR νmax (KBr, film, cm−1) 2922, 1586, 1516, 1445, 1301, 1142, 1082, 749; HRMS (ESI, orbitrap) calcd for C19H17O2NNaS [M + Na+] 346.0872, found 346.0864. 9-Methylene-6,7,8,9-tetrahydropyrido[1,2-a]indole 4r: 14 White soild, 8 mg (from 0.5 mmol), 8% yield. 100% brsm; mp 82−84 °C; 1 H NMR (300 MHz, CDCl3) δ 7.58−7.56 (d, J = 7.8 Hz, 1H), 7.27− 7.24 (m, 1H), 7.18−7.06 (m, 2H), 6.74 (s, 1H), 5.61 (s, 1H), 4.997− 4.995 (d, J = 0.6 Hz 1H), 4.12−4.08 (m, 2H), 2.63−2.59 (m, 2H), 2.16−2.08 (m, 2H); 13C NMR (400 MHz, CDCl3) δ 136.53, 136.52, 136.2, 128.0, 121.5, 120.6, 120.1, 109.2, 109.1, 96.1, 42.2, 30.2, 23.8; IR νmax (KBr, film, cm−1) 2923, 1476, 1329, 1162, 897, 791; HRMS (ESI, orbitrap) calcd for C13H14N [M + H+] 184.1120, found 184.1120. 1-(6,7,8,9-Tetrahydropyrido[1,2-a]indol-9-yl)butan-2-one 4s: Light yellow soild, 90 mg, 74% yield, mp 67−68 °C; 1H NMR (300 MHz, CDCl3) δ 7.52−7.50 (d, J = 7.5 Hz, 1H), 7.25−7.23 (d, J = 7.5 Hz, 1H), 7.16−7.04 (m, 2H), 6.15 (s, 1H), 4.19−4.12 (m, 1H), 3.92− 3.83 (m, 1H), 3.60−3.53 (m, 1H), 3.05−2.98 (dd, J = 17.1, 5.1 Hz,1H), 2.72−2.63 (q, J = 8.7 Hz, 1H), 2.54−2.43 (m, 2H), 2.19− 1.99 (m, 3H), 1.50−1.40 (m, 1H), 1.13−1.08 (t, 3H); 13C NMR (500 MHz, CDCl3) δ 209.9, 140.3, 136.2, 127.9, 120.5, 119.8, 119.7, 108.7, 96.8, 47.9, 42.2, 36.7, 30.6, 27.4, 22.1, 7.8; IR νmax (KBr, film, cm−1) 2924, 1711, 1534, 1457, 1411, 1311, 770, 748; HRMS (ESI, orbitrap) calcd for C16H20ON [M + H+] 242.1539, found 242.1537. General Procedure for the Synthesis of 6a,b. To a solution of (E)-methyl 2-(7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4a (1.2 mmol, 300 mg) in a mixture of tetrahydrofuran (3 mL) and H2O (3 mL) was added Pd/C (60 mg). The mixture was stirred at room temperature for 12 h under H2. Then the mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica column chromatography (eluent: petroleum ether/ ethyl acetate = 30/1) to afford the product methyl 2-(6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetate 6a as a light yellow oil (260 mg, yield 87%). Methyl 2-(6,7,8,9-Tetrahydropyrido[1,2-a]indol-9-yl)acetate 6a: Light yellow oil, 260 mg, 87% yield; 1H NMR (300 MHz, CDCl3) δ 7.53−7.51 (d, J = 7.2 Hz, 1H), 7.24−7.21 (d, J = 7.8 Hz, 1H), 7.16− 7.04 (m, 2H), 6.22 (s, 1H), 4.16−4.09 (m, 1H), 3.89−3.80 (m, 1H), 3.72 (s, 3H), 3.52−3.43 (m, 1H), 2.97−2.90 (dd, J = 5.4, 15.6 Hz,1H), 2.59−2.51 (q, J = 8.7 Hz, 1H), 2.17−2.07 (m, 2H), 2.05−1.96 (m, 1H), 1.60−1.48 (m, 1H); 13C NMR (400 MHz, CDCl3) δ 172.7, 139.6, 136.3, 128.0, 120.7, 119.9, 119.8, 108.8, 97.1, 51.7, 42.2, 39.8, 31.9, 27.3, 22.1; IR νmax (KBr, film, cm−1) 2948, 1738, 1459, 1169, 1012, 775; HRMS (ESI, orbitrap) calcd for C15H18O2N [M + H+] 244.1332, found 244.1335. Methyl 2-(2-Methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6b: White solid, 309 mg, 97% yield, mp 88−90 °C; 1H NMR (300 MHz, CDCl3) δ 7.14−7.11 (d, J = 8.7 Hz, 1H), 7.02−7.01 (d, J = 1.8 Hz, 1H), 6.82−6.78 (dd, J = 1.8, 8.7 Hz, 1H), 6.15 (s, 1H), 4.83 (s, 1H), 4.14−4.06 (m, 1H), 3.88−3.87 (m, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 3.50−3.43 (m, 1H), 2.97−2.90 (dd, J = 5.4, 15.9 Hz,1H), 2.59−2.51 (q, J = 9.0 Hz, 1H), 2.20−2.11 (m, 2H), 2.09−1.97 (m, 1H), 1.61−1.48 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 172.7, 7520

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

Note

The Journal of Organic Chemistry 154.4, 140.3, 131.7, 128.4, 110.8, 109.5, 102.1, 96.9, 56.0, 51.8, 42.3, 39.9, 31.9, 27.3, 22.1; IR νmax (KBr, film, cm−1) 2948, 1737, 1484, 1163, 1034, 794; HRMS (ESI, orbitrap) calcd for C16H20O3N [M + H+] 274.1437, found 274.1441. Procedure for the Synthesis of 6c. To a solution of methyl 2-(2methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6b (100 mg, 0.36 mmol) in dichloromethane (5 mL) was added dropwise boron tribromide (1 M in dichloromethane, 1.44 mL, 1.44 mmol) at 0 °C. The reaction continued stirring overnight at room temperature and was then quenched by saturated sodium bicarbonate and diluted with ethyl acetate (20 mL). The organic layer was washed by water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, evaporated, and purified by silica column chromatography (eluent: petroleum ether/ethyl acetate = 2/1) to afford the intermediate methyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6c as a colorless oil (48.1 mg, yield 48%). Methyl 2-(2-Hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6c: Light yellow oil, 45.1 mg, 48% yield; 1H NMR (300 MHz, CDCl3) δ 7.09−7.07 (d, J = 8.7 Hz, 1H), 6.94−6.93 (d, J = 2.1 Hz, 1H), 6.73−6.69 (dd, J = 2.4, 8.7 Hz, 1H), 6.09 (s, 1H), 4.83 (s, 1H), 4.12−4.06 (m, 1H), 3.87−3.78 (m, 1H), 3.74 (s, 3H), 3.51−3.41 (m, 1H), 2.96−2.89 (dd, J = 5.4, 15.6 Hz,1H), 2.59−2.51 (q, J = 8.7 Hz, 1H), 2.10−2.06 (m, 2H), 2.03−1.94 (m, 1H), 1.60−1.48 (m, 1H); 13 C NMR (400 MHz, CDCl3) δ 172.9, 149.8, 140.6, 131.9, 128.7, 110.4, 109.4, 104.6, 96.5, 51.9, 42.3, 39.8, 32.0, 27.3, 22.1; IR νmax (KBr, film, cm−1) 3366, 2922, 1733, 1451, 1175, 848; HRMS (ESI, orbitrap) calcd for C15H16O3N [M − H+] 258.1135, found 258.1136. Procedure for the Synthesis of 1. To a solution of methyl 2(6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6a (0.37 mmol, 100 mg) in water (2 mL) were added 4-chlorothiophenol (0.37 mmol, 60 mg), iodine (0.037 mmol, 10 mg), and dimethylsulfoxide (1.1 mmol, 0.088 mL). The mixture was stirred at 100 °C for 4 h and then diluted with ethyl acetate (20 mL). The organic layer was washed by water (10 mL), saturated sodium thiosulfate (10 mL × 2) and brine (10 mL), dried over anhydrous sodium sulfate, and evaporated to afford the crude intermediate methyl 2-(10-(4-chlorophenylthio)-6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetate as a light yellow oil. A mixture of the crude intermediate methyl 2-(10-(4-chlorophenylthio)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate and aqueous lithium hydroxide (1 M in water, 1.5 mL) was heated to 60 °C for 4 h and then acidified to pH 6 with 1 N hydrochloride. The solution was diluted with ethyl acetate (20 mL), washed by water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, evaporated, and purified by silica column chromatography (eluent: petroleum ether/ ethyl acetate = 5/1) to afford 2-(10-(4-chlorophenylthio)-6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetic acid 1 as a light yellow solid (37 mg, yield 25%, two steps). 2-(10-(4-Chlorophenylthio)-6,7,8,9-tetrahydropyrido[1,2-a]indol9-yl)acetic acid 1: Light yellow solid, 37 mg, 25% yield; 1H NMR (300 MHz, acetone-d6) δ 10.72 (br, 1H), 7.48−7.41 (m, 2H), 7.24− 7.09 (m, 4H), 7.02−7.00 (d, J = 8.7 Hz, 1H), 4.36−4.31 (m, 1H), 4.06−3.98 (m, 1H), 3.82−3.77 (m, 1H), 2.90−2.69 (m, 2H), 2.31− 2.21 (m, 1H), 2.11−2.04 (m, 3H); 13C NMR (500 MHz, acetone-d6) δ 172.7, 145.7, 139.4, 137.5, 130.7, 130.5, 129.6, 127.5, 122.6, 121.7, 118.7, 110.7, 95.6, 43.4, 38.8, 30.1, 25.4, 19.6; HRMS (ESI, orbitrap) calcd for C20H17O2NClS [M − H+] 370.0674, found 370.0674. Procedure for the Synthesis of 2. To a solution of methyl 2-(2hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6c (0.28 mmol, 75 mg) in dry dimethylformamide (5 mL) were added cesium carbonate (0.58 mmol, 189 mg) and 1-(chloromethyl)-3,5-bis(trifluoromethyl)benzene (0.38 mmol, 48 mg). The mixture was then stirred at 75 °C for 3 h under nitrogen and then diluted with ethyl acetate (50 mL). The organic layer was washed by water (40 mL) and brine (40 mL × 2), dried over anhydrous sodium sulfate, evaporated, and purified by silica column chromatography (eluent: petroleum ether/ethyl acetate = 30/1) to afford the intermediate methyl 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetate as a white solid (90.3 mg, yield 64%). To a solution of methyl 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.1

mmol, 51 mg) in dioxane (2.5 mL) was added aqueous lithium hydroxide (1 M, 0.6 mL, 0.6 mmol). The mixture was stirred at 50 °C for 2 h and then acidified to pH 6 with 1 N hydrochloride. The solution was diluted with ethyl acetate (20 mL), washed by water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, evaporated, and purified by silica column chromatography (eluent: petroleum ether/ethyl acetate = 2/1) to afford 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9yl)acetic acid 2 as a white solid. 2-(2-(3,5-Bis(trifluoromethyl)benzyloxy)-6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetic acid 2: White solid, 31.5 mg, 66% yield; 1H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.16 (s, 2H), 8.06 (s, 1H), 7.27−7.25 (d, J = 6.6 Hz, 1H), 7.10−7.09 (d, J = 1.5 Hz, 1H), 6.86−6.83 (dd, J = 1.8, 6.6 Hz, 1H), 6.18 (s, 1H), 5.30 (s, 2H), 4.16−4.11 (m, 1H), 3.83−3.76 (m, 1H), 3.33−3.28 (m, 1H), 2.88−2.82 (dd, J = 4.2, 12.0 Hz,1H), 2.49−2.43 (q, J = 6.3 Hz, 1H), 2.12−2.01 (m, 2H), 1.99−1.93 (m, 1H), 1.53−1.45 (m, 1H); HRMS (ESI, orbitrap) calcd for C23H18O3NF6 [M − H+] 470.1196, found 470.1195.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00229. 1 H and 13C NMR spectra of all new products and intermediates and X-ray crystallography data (PDF) X-ray data for 4a (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Liang Cheng: 0000-0001-7427-2939 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Key R&D Program of China (2016YFA0602900), National Natural Science Foundation of China (21778057, 21502201, and 21420102003), Beijing Natural Science Foundation (2162049), Young Elite Scientist Sponsorship Program by CAST (2015QNRC001), and Chinese Academy of Sciences.

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REFERENCES

(1) For recent reviews on indole natural products, see: (a) Agarwal, S.; Cammerer, S.; Filali, S.; Frohner, W.; Knoll, J.; Krahl, M. P.; Reddy, K. R.; Knolker, H. J. Curr. Org. Chem. 2005, 9, 1601−1614. (b) de Sá Alves, F. R.; Barreiro, E. J.; Manssour Fraga, C. Mini-Rev. Med. Chem. 2009, 9, 782−793. (c) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620− 6662. (2) (a) Mroue, M. A.; Euler, K. L.; Ghuman, M. A.; Alam, M. J. Nat. Prod. 1996, 59, 890−893. (b) Gervais, F. G.; Morello, J. P.; Beaulieu, C.; Sawyer, N.; Denis, D.; Greig, G.; Malebranche, A. D.; O’Neill, G. P. Mol. Pharmacol. 2005, 67, 1834−1839. (c) Leblanc, Y.; Roy, P.; Dufresne, C.; Lachance, N.; Wang, Z.; O’Neill, G.; Greig, G.; Denis, D.; Mathieu, M. C.; Slipetz, D.; Sawyer, N.; Tsou, N. Bioorg. Med. Chem. Lett. 2009, 19, 2125−2128. (d) Beaulieu, C.; Guay, D.; Wang, Z.; Leblanc, Y.; Roy, P.; Dufresne, C.; Zamboni, R.; Berthelette, C.; Day, S.; Tsou, N.; Denis, D.; Greig, G.; Mathieu, M.-C.; O’Neill, G. Bioorg. Med. Chem. Lett. 2008, 18, 2696−2700. (e) Buzard, D. J.; Han, S.; Lopez, L.; Kawasaki, A.; Moody, J.; Thoresen, L.; Ullman, B.; Lehmann, J.; Calderon, I.; Zhu, X.; Gharbaoui, T.; Sengupta, D.; 7521

DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522

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DOI: 10.1021/acs.joc.8b00229 J. Org. Chem. 2018, 83, 7514−7522