Copper-Catalyzed Dehydrogenative C(sp2)–N Bond Formation via

Sep 5, 2017 - A dehydrogenative C(sp2)–N bond-forming strategy via copper-catalyzed intramolecular C–H/N–H coupling has been developed, which sy...
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Copper-Catalyzed Dehydrogenative C(sp2)−N Bond Formation via Direct Oxidative Activation of an Anilidic N−H Bond: Synthesis of Benzoimidazo[1,2‑a]indoles Xiaoxia Wang,†,∥ Na Li,†,∥ Zhongfeng Li,† and Honghua Rao*,†,‡ †

Department of Chemistry, Capital Normal University, Beijing, 100048, P. R. China Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. China

‡

S Supporting Information *

ABSTRACT: A dehydrogenative C(sp2)−N bond-forming strategy via copper-catalyzed intramolecular C−H/N−H coupling has been developed, which systematically unraveled the feasibility and practicality for benzoimdazo[1,2-a]indole formations through oxidative anilidic N−H activation. The merit of this strategy is illustrated by the broad tolerance of functionalities, as well as the utilization of extremely cheap copper catalysis to realize potentially useful indole-fused tetracycles in a step- and atom-economical manner.

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INTRODUCTION Transition-metal-catalyzed C−N bond formations through the coupling of N−H bonds with (pseudo)halocarbon or organometallic reagents are fundamental but powerful tools to access amines and N-heterocycles, common structural features in material- and biology-oriented functional molecules.1,2 These classic C−N bond-forming procedures need preinstallation of reactive groups onto substrates (Figure 1a), which may face

which the key working mode is the generation of N-centered radicals (NCRs) directly from NH groups and the ensuing coupling reactions with C−H bonds to form C−N bonds (Figure 1c), began to draw increasing attention in the synthetic community.8 Several catalytic systems, such as CuI/DTBP,9 CuII/MnO2,10 CuII/Na2S2O8,11 and Ni(acac)2/DTBP,12 were thus applied to produce NCRs directly from sulfonamides or Nalkloxyamides, which can cross-couple with olefinic and aliphatic C−H bonds efficiently. Besides, hypervalent iodine13 and photocatalysis14,15 capacitate the generation of NCRs and the reaction with C(aryl)−H bonds by using phosphamides, sulfonamide, and phthalimides as the NH sources as well. These strategies offer a great potential in C−N bond formations to access amines and N-heterocycles, wherein the utilization of sulfonamidyl and benzamidyl radicals has been the major focuses; in contrast, generation and utilization of other NCRs, such as the much less reactive anilidyl radicals, have remained poorly developed because of their intrinsically lower reactivities.16 Therefore, it is desirable but challenging to develop such reactivities of anilidyl radicals that can enable C− N bond formations and assemble N-heterocycles (particularly the fused N-heterocycles) through C−H/N−H coupling pathway eventually. As is well-known, indole-fused heterocycles, such as the benzoimdazo[1,2-a]indole scaffold, are privileged structural constituents of numerous natural products and pharmacological entities.17 In 2016, Sekar’s group developed an intramolecular nucleophilic addition reaction of sulfonamides to cyclic iodonium ion and subsequent HI-elimination to afford the benzoimidazo[1,2-a]indoles.18 Alternatively, as indicated above,

Figure 1. Strategies for C−N bond formations.

great challenges on account of their low atom-economy and generation of unavoidable byproducts, thus leaving ample opportunities to develop more economical C−N bond-forming protocols.3 In this context, a more direct approach of using C−H bonds instead of (pseudo)halocarbon and organometallic substrates would be an ideal alternative to react with N−H bonds, which can be classified into two mechanistic manifolds according to the proposed intermediates on the reaction pathway.4 The one denoted as “C−H activation catalysis” has been well-developed because it can enable direct metalation of sp,5 sp2,6 or sp3 C−H bonds7 to putatively generate the corresponding organometallic intermediates that easily engage various N−H bonds to eventually forge C−N bonds (Figure 1b). Recently, the other mechanistic manifold involving “N−H activation catalysis”, of © 2017 American Chemical Society

Received: June 29, 2017 Published: September 5, 2017 10158

DOI: 10.1021/acs.joc.7b01617 J. Org. Chem. 2017, 82, 10158−10166

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the dehydrogenative C−H/N−H coupling protocol would provide a distinct but still appealing pathway in atom- and stepeconomic fashion when applied to N-heterocycle constructions. Ir(ppy)2(dtbbpy)PF6 photocatalysis was thereby employed to prove the feasibility of assembling benzoimdazo[1,2-a]indoles, although only one such case via reactive sulfonamidyl radical was given.14 Following this tendency, we herein introduce a cheaper copper catalysis to systematically recognize an intramolecular dehydrogenative C−H/N−H coupling, forming a practical strategy for benzoimidazo[1,2-a]indole installations via direct oxidative activation of anilidic N−H bonds (Scheme 1).

Article

RESULTS AND DISCUSSION

Using 1a as the model substrate,19 Cu2O (10 mol %) as the catalyst, and (tBuO)2 (4.0 equiv) as the oxidant,20 we began our investigations into the proposed intramolecular dehydrogenative coupling between anilidic N−H bonds and indolyl C−H bonds in DCE. Initial results revealed that the utilization of ligands such as dppp is essential to affect this C−H/N−H coupling reaction (Table 1, entries 1 and 2; for the optimization results of other ligands, please refer to section 1 in the Supporting Information). Seeking to improve on this result, a series of copper(I) and copper(II) catalysts, frequently applied in N−H activation strategies,9−11 were evaluated in this reaction, among which Cu2O was more effective in generating the desired product 2a (confirmed by X-ray diffraction; for detailed crystallographic data, please refer to section 4 in the Supporting Information) in 30% yield (entries 2−8). Subsequently, other phosphine ligands, such as dppe, dppb, PCy3, Xphos, and tris(2-methoxyphenyl)phosphine (L1), were

Scheme 1. Copper-Catalyzed Dehydrogenative C−H/N−H Coupling toward Benzoimidazo[1,2-a]indoles

Table 1. Screening of the Reaction Conditionsa,b

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23d 24e 25f 26g 27 28 29h 30i,j

[O] (equiv)

ligand

solvent

% yieldc

( BuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (4.0) (tBuO)2 (3.5) (tBuO)2 (3.0) (tBuO)2 (2.5) (tBuO)2 (2.0) (tBuO)2 (2.5) (tBuO)2 (2.5) (tBuO)2 (2.5) (tBuO)2 (2.5) (tBuO)2 (2.5) (tBuO)2 (2.5) (tBuO)2 (2.5) (tBuO)2 (2.5) (tBuO)2 (2.5) − (tBuO)2 (2.5) (tBuO)2 (2.25) (tBuO)2 (2.5)

− dppp dppp dppp dppp dppp dppp dppp dppe dppb PCy3 Xphos L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1 L1

DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE p-dioxane TCE DCE/TCE (7:1) DCE/p-dioxane (7:1) DCE/p-dioxane (6:2) DCE/p-dioxane (7:1) DCE/p-dioxane (7:1) DCE/p-dioxane (7:1) DCE/p-dioxane (7:1) DCE/p-dioxane (7:1) DCE/p-dioxane (7:1) DCE/p-dioxane (7:1) DCE/p-dioxane (6:2)

trace 30 28 trace 29 26 23 27 14 22 12 trace 37 42 43 43 40 − trace trace 85 68 51 73 61 70 − 16 72 53

cat. Cu2O Cu2O CuOAc CuCl CuBr CuI CuCl2 Cu(OAc)2 Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O Cu2O − Cu2O Cu2O

t

Reaction conditions: 1a (0.40 mmol), [O] (x equiv), ligand (20 mol %), solvent (1.6 mL), 90 °C, under air for 24 h unless otherwise noted. The best systems are highlighted with bold text. bAbbreviations: cat. = catalyst, [O] = oxidant, dppp = 1,3-bis(diphenylphosphino)propane, dppe = 1,2bis(diphenylphosphino)ethane, dppb = 1,4-bis(diphenylphosphino)-butane, Cy = cyclohexyl, Xphos = 2-dicyclohexylphosphino-2′,4′,6′triisopropylbiphenyl, L1 = tris(2-methoxyphenyl)phosphine, DCE = 1,2-dichloroethane, and TCE = 1,1,2-trichloroethane. cDetermined by 1H NMR with mesitylene as the internal standard. dCu2O (15 mol %) or Cu2O (5 mol %) was used. eReaction was conducted under argon. fReaction was conducted under oxygen. gReaction was conducted at 100 °C. hWith N-(2-(5-methoxy-1H-indol-1-yl)phenyl)acetamide as the substrate. iWith N-(2-(5-bromo-1H-indol-1-yl)phenyl)acetamide as the substrate. jWith 12.5 mol % of Cu2O and 25 mol % of L1. a

10159

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examined, and L1 exhibited higher catalytic reactivity to produce 2a in 37% yield (entries 2 and 9−13). Additionally, loading 2.5 equiv of (tBuO)2 slightly increased the coupling efficiency, furnishing 2a in 43% yield (entries 13−17). Remarkably, the reaction efficiency showed a strong dependency on solvent: p-dioxane, TCE, or DCE/TCE (7:1 v/v ratio) as solvent nearly inhibited the reaction completely, while DCE in combination with p-dioxane as cosolvent showed a marked increase in efficiency (entries 18−21); notably, the largest improvement in reaction efficiency was observed when the model reaction was performed in DCE/p-dioxane (7:1 v/v ratio), affording 2a in the highest yield of 85% (entries 21 and 22). Other endeavors to increase the yield of 2a, such as adjusting the catalyst loading by 5 mol % (entry 23), conducting the reaction under argon or oxygen atmosphere (entries 24 and 25), or performing the reaction at a higher temperature (entry 26), were attempted, but none of them afforded a superior result. Finally, control experiments run in the absence of oxidant or copper catalyst provided completely none or only 16% of the desired product, respectively (entries 27 and 28), thus indicating that the combination of Cu2O catalyst and (tBuO)2 oxidant is crucial for the proposed C−H/ N−H coupling reaction as well. However, the above reaction conditions should be further optimized when reacting substrates bearing electron-donating groups, such as 5-methoxy, on the indole ring, and Cu2O (10 mol %) as the catalyst, (tBuO)2 (2.25 equiv) as the oxidant, L1 (20 mol %) as the ligand, and DCE/p-dioxane (7:1 v/v ratio) as the solvent should be employed to produce the desired products in the highest efficiency (entry 29). Likewise, superior results for substrates bearing electron-withdrawing groups, such as 5bromo, on the indole ring can be obtained with the catalytic system consisting of 12.5 mol % of Cu2O, 2.5 equiv of (tBuO)2, 25 mol % of L1, and 1.6 mL of DCE/p-dioxane (6:2 v/v ratio) (entry 30). With optimal reaction conditions in hand, we first probed the generality of this dehydrogenative C−H/N−H coupling reaction with respect to the substrates bearing a monosubstituent on the indole unit. As shown in Scheme 2, unfunctionalized substrate 1a underwent the titled reaction efficiently (2a, 84% yield), while functionalized ones exhibited varied reactivities. For example, substrates bearing electrondonating groups (e.g., Me, OMe) performed smoothly to deliver the desired products in good yields (2b−g, 61−72% yield), while electron-withdrawing groups, such as catalytically reactive halide functionalities (e.g., Cl, Br, F), displayed slightly lower efficiency (2h−l, 45−63% yield). The ester group was tolerated as well, providing an encouraging quantity of product 2m in 57% yield. Notably, substrates containing strong electron-withdrawing groups, such as cyano functionality, showed marked dropoff in efficiency, furnishing the desired product in the poorest yield (2n, 20% yield). The steric limit of substituent on the indole ring was also investigated, and a detrimental effect to coupling efficiency was observed when using 3-methylated substrate 1o as the coupling partner (43% yield; cf. 2o and 2a−d); however, it is noteworthy that substituents at different positions on the phenyl ring of the indole unit do not seem to affect the reaction efficiency obviously (cf. 2b−d, 2e−g, or 2i−l). Subsequently, a range of substituents on the anilide unit were examined under the optimal reaction conditions, and it was found that all of them were viable for this transformation, affording the desired products in moderate to good yields with

General reaction conditions: 1 (0.40 mmol), solvent (1.6 mL), 90 °C, 24 h, under air. Conditions A: Cu2O (10 mol %), (tBuO)2 (2.5 equiv), L1 (20 mol %), DCE/p-dioxane (7:1 v/v ratio). Condtions B: Cu2O (10 mol %), (tBuO)2 (2.25 equiv), L1 (20 mol %), DCE/p-dioxane (7:1 v/v ratio). Conditions C: Cu2O (12.5 mol %), (tBuO)2 (2.5 equiv), L1 (25 mol %), DCE/p-dioxane (6:2 v/v ratio). Isolated yields are given. Reaction conditions are shown in parentheses. a

no significant differences in efficiency when varying their electronic effects (2p−t, 56−67% yield). Finally, substrates bearing multiple substituents were evaluated to further exemplify the generality of this C−H/ N−H coupling paradigm. For instance, indole/anilide units bearing electron-donating/-donating (2u), -donating/-withdrawing (2v,w), -withdrawing/-donating groups (2x) were successfully reacted to deliver the target products in moderate to good yields (55−70% yield). Moreover, the tolerance of various functionalities highlights the potential for downstream modifications of the indole-fused benzoimidazole scaffolds via either transition-metal-catalyzed cross-coupling reactions or traditional functional group transformations. Further investigations were performed to gain some insights into the reaction mechanism (Scheme 3). As either indolyl sp2 C−H or anilidic N−H activation is the mechanistic consideration, 1a was thereby exposed to conditions A for 12 h and, after being stirred with 2.0 equiv of D2O for an additional 10 min, was transformed into non-deuterated products 3 and 4 (by GC−MS) (with 46% of 2a as the expected product) (Scheme 3a), thus suggesting that the 10160

DOI: 10.1021/acs.joc.7b01617 J. Org. Chem. 2017, 82, 10158−10166

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sp2 C−H bonds, which systematically unravels the feasibility and practicality of benzoimidazo[1,2-a]indole formations in a step- and atom-economical fashion. The successful implementation of this C(sp2)−N bond-forming strategy relies on the direct oxidative activation of anilidic N−H bonds to anilidyl radicals by using extremely cheap and easily handled copper catalysis. Moreover, the power of this C−H/N−H coupling paradigm has been fully exemplified by the tolerance of various functionalities that can serve as useful synthetic handles for subsequent chemical manipulation. We believe that this strategy will generate broad applications among practitioners of synthetic and pharmaceutical chemistry. Exploring the utility of anilidyl radicals to construct other fused heterocycles is currently underway in our laboratory.

Scheme 3. Investigation into the Reaction Mechanism

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proposed reaction may not involve the indolyl sp2 C−H activation pathway. Meanwhile, a radical-trapping experiment was carried out by introducing TEMPO into conditions A; however, no desired product 2a but a full recovery of starting material 1a was observed (Scheme 3b). Additionally, the coupling reaction did not occur in the absence of DTBP (Table 1, entry 27). Remarkably, an anilidic N-methylated byproduct 5 from 1l (a moderated reactive substrate) was detected by GC− MS (m/z 283 was found for [M + H]+) (Scheme 3c), which might be formed through radical cross-coupling between anilidyl radical and methyl radical.21 Finally, the slightly negative Hammett slope observed (ρ = −0.1627) for the titled reaction is consistent with a radical-involved mechanism, which favors electron-rich substrates but is not markedly influenced by the electronic effects of substituents on the indolyl ring. (For more information, please refer to section 5 in the Supporting Information.) These results imply that the titled reaction most probably proceeds through N−H activation, specifically, the anilidyl radical-induced dehydrogenative C−N bond formations. On the basis of the above investigations, a plausible mechanism for this reaction is proposed in Scheme 4. Initiation

EXPERIMENTAL SECTION

General Methods. All reactions were carried out under an air atmosphere unless otherwise stated. All workup and purification procedures were carried out with reagent-grade solvents. Flash column chromatography was performed on silica gel (300−400 mesh) with an appropriate solvent system (see details below). Melting points were recorded on an SGW X-4B instrument. 1H and 13C NMR spectra were recorded on Varian 600 MHz and Bruker 400 MHz spectrometers in CDCl3 or DMSO-d6 solutions and chemical shifts (δ, ppm) were determined with internal solvent signal as reference (CDCl3, 7.26 for 1 H NMR and 77.0 for 13C NMR; DMSO-d6, 2.50 for 1H NMR and 39.5 for 13C NMR). NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet of doublets, t = triplet, td = doublet of triplets, q = quartet, m = multiplet, br = broad signal), coupling constant (in hertz), and integration. High-resolution mass spectra were recorded on a Thermo Scientific LTQ Orbitrap Discovery (Bremen, Germany) (mass analyzer type, linear ion trap). Materials were purchased from Alfa-Aesar, Acros, Aldrich, Aladdin, Energy-Chemical, Bide Pharmatech. Ltd., and Ouhe-Chemicals. Unless otherwise noted, commercial reagents were used without further purifications. The structures of all compounds and their 1H and 13C NMR spectra are provided in the Supporting Information. General Procedures for the Synthesis of Substrate 1. To a well-stirred DMSO solution containing indoles (10.0 mmol, 1.0 equiv) and NaOH (1.0 equiv) was added 1-fluoro-2-nitrobenzenes (10.0 mmol, 1.0 equiv) slowly. The reaction mixture was stirred vigorously at room temperature for 12 h. After completion of the reaction, the resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layer was washed with brine (25 mL), dried with anhydrous Na2SO4, and concentrated under vacuum to give the crude product, which was purified by silica gel column with petroleum ether/ethyl acetate (20:1 to 10:1) as the eluent to give the analytically pure 1-(2-nitrophenyl)-1H-indole I-1.22 I-1 (9.93 mmol) was then dissolved in EtOH (30 mL) and water (7.5 mL). After adding concentrated HCl (43 μL) and iron powder (5.5 g) to the above solution, the resulting mixture was stirred vigorously at 100 °C for 3 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3 × 40 mL). The combined organic layer was washed with brine (25 mL), dried with anhydrous Na2SO4, and concentrated under vacuum to give the crude product, which was purified by silica gel column with petroleum ether/ethyl acetate (10:1) as the eluent to give the analytically pure 2-(1H-indol-1-yl)aniline I-2.23 A CH2Cl2 (58 mL) solution of I-2 (5.76 mmol, 1.20 g) was placed into an ice bath, to which was added Et3N (5.7 mmol, 0.8 mL) and acetyl chloride (8.6 mmol, 0.61 mL; in 30 min) under argon sequentially. The resulting mixture was warmed to room temperature and stirred for an additional 8 h, which, after being diluted with water (10 mL), was washed with HCl (1 M aqueous solution, 2 × 60 mL), a saturated aqueous solution of NaHCO3 (2 × 60 mL), and brine (60 mL). The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum to give the crude product, which was

Scheme 4. Plausible Mechanism

occurs by reducing DTBP with Cu(I) to generate CuII(OBut) complex and tert-butoxyl radical. Upon reaction of the anilidic N−H bond with tert-butoxyl radical or CuII(OBut) complex, anilidyl radical A [can be oxidized to intermediate B with Cu(I) catalyst]9a,20 or Cu(II) complex B [may undergo homolysis to generate radical A and Cu(I) catalyst]12 can be generated, respectively. The ensuing intramolecular radical addition of radical A to the very electron rich indolyl CC bond would produce a carbon-centered radical C, which is believed to undergo direct oxidation by either CuII(OBut) complex or tertbutoxyl radical and deprotonation to release the final product 2a. Meanwhile, the low-valent Cu(I) species was regenerated to continue the catalytic cycle. In summary, we have established an intramolecular dehydrogenative coupling between anilidic N−H and indolyl 10161

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The Journal of Organic Chemistry

2.28 Hz, 1 H), 6.84 (br, s, 1 H), 6.68 (dd, J = 3.24, 0.84 Hz, 1 H), 6.52 (d, J = 2.22 Hz, 1 H), 3.75 (s, 3 H), 1.91 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 157.2, 137.4, 134.3, 129.0, 128.7, 127.9, 127.2, 124.7, 122.6, 122.4, 121.8, 111.1, 104.4, 93.4, 55.6, 24.7. HRESI-MS: [M + H]+ m/z calcd for C17H17N2O2 281.1285, found 281.1280. N-(2-(5-Chloro-1H-indol-1-yl)phenyl)acetamide (1h). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.40 (d, J = 8.34 Hz, 1 H), 7.68 (d, J = 1.74 Hz, 1 H), 7.48 (td, J = 7.85, 1.62 Hz, 1 H), 7.29 (dd, J = 7.74, 1.62 Hz, 1 H), 7.24 (td, J = 7.70, 1.26 Hz, 1 H), 7.21 (d, J = 3.24 Hz, 1 H), 7.16 (dd, J = 8.76, 2.04 Hz, 1 H), 6.99 (d, J = 8.70 Hz, 1 H), 6.74 (br, s, 1 H), 6.70 (dd, J = 3.21, 0.90 Hz, 1 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 135.0, 134.3, 129.8, 129.7, 129.3, 128.2, 127.9, 126.5, 124.8, 123.2, 122.5, 120.7, 111.4, 104.0, 24.6. HR-ESI-MS: [M + H]+ m/z calcd for C16H14ClN2O 285.0789, found 285.0784. N-(2-(4-Bromo-1H-indol-1-yl)phenyl)acetamide (1i). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.37 (d, J = 8.10 Hz, 1 H), 7.47 (td, J = 7.83, 1.68 Hz, 1 H), 7.37 (d, J = 7.44 Hz, 1 H), 7.29 (d, J = 1.62 Hz, 1 H), 7.25−7.22 (m, 2 H), 7.07 (t, J = 7.83 Hz, 1 H), 7.02 (d, J = 8.22 Hz, 1 H), 6.83 (br, s, 1 H), 6.81 (dd, J = 3.21, 0.84 Hz, 1 H), 1.88 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 136.9, 134.3, 129.42, 129.38, 129.0, 128.2, 128.0, 124.8, 123.8, 123.7, 122.6, 115.1, 109.6, 104.6, 24.6. HR-ESIMS: [M − H]− m/z calcd for C16H12BrN2O 327.0133, 329.0113; found 327.0138, 329.0117. N-(2-(5-Bromo-1H-indol-1-yl)phenyl)acetamide (1j). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.40 (d, J = 7.74 Hz, 1 H), 7.85 (s, 1 H), 7.48 (t, J = 7.83 Hz, 1 H), 7.29 (t, J = 7.59 Hz, 2 H), 7.24 (t, J = 7.56 Hz, 1 H), 7.19 (d, J = 2.94 Hz, 1 H), 6.95 (d, J = 8.70 Hz, 1 H), 6.73 (br, s, 1 H), 6.70 (dd, J = 2.34, 0.78 Hz, 1 H), 1.91 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 135.3, 134.3, 130.3, 129.6, 129.4, 128.1, 127.9, 125.8, 124.8, 123.8, 122.5, 114.1, 111.8, 103.9, 24.6. HR-ESI-MS: [M + H]+ m/z calcd for C16H14BrN2O 329.0284, 331.0262; found 329.0279, 331.0257. N-(2-(4-Fluoro-1H-indol-1-yl)phenyl)acetamide (1k). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.41 (d, J = 8.40 Hz, 1 H), 7.48 (td, J = 7.88, 1.50 Hz, 1 H), 7.31 (dd, J = 7.77, 1.20 Hz, 1 H), 7.24 (t, J = 7.44 Hz, 1 H), 7.16 (d, J = 3.18 Hz, 1 H), 7.13 (td, J = 8.04, 5.16 Hz, 1 H), 6.87 (dd, J = 7.62, 10.2 Hz, 1 H), 6.850 (d, J = 11.58 Hz, 1 H), 6.847 (s, 1 H), 6.75 (br, s, 1 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 156.4 (d, JC−F = 247.0 Hz), 139.1 (d, JC−F = 10.8 Hz), 134.3, 129.4, 128.4, 128.2, 127.9, 124.7, 123.5 (d, JC−F = 7.9 Hz), 122.5, 117.8 (d, JC−F = 22.5 Hz), 106.4 (d, JC−F = 3.7 Hz), 105.6 (d, JC−F = 18.9 Hz), 100.4, 24.6. HR-ESI-MS: [M + H]+ m/z calcd for C16H14FN2O 269.1085, found 269.1078. N-(2-(5-Fluoro-1H-indol-1-yl)phenyl)acetamide (1l). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.41 (d, J = 7.98 Hz, 1 H), 7.47 (td, J = 7.89, 1.38 Hz, 1 H), 7.36 (dd, J = 9.33, 2.28 Hz, 1 H), 7.30 (d, J = 7.62 Hz, 1 H), 7.24 (d, J = 7.98 Hz, 1 H), 7.22 (d, J = 3.06 Hz, 1 H), 6.99 (dd, J = 8.94, 4.62 Hz, 1 H), 6.96 (td, J = 8.88, 2.40 Hz, 1 H), 6.75 (br, s, 1 H), 6.72 (d, J = 3.18 Hz, 1 H), 1.91 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 158.4 (d, JC−F = 234.9 Hz), 134.3, 133.2, 130.0, 129.2, 129.1 (d, JC−F = 10.1 Hz), 128.4, 127.9, 124.7, 122.4, 111.3 (d, JC−F = 26.0 Hz), 111.1 (d, JC−F = 9.6 Hz), 106.1 (d, JC−F = 23.5 Hz), 104.3 (d, JC−F = 4.6 Hz), 24.6. HR-ESI-MS: [M + H]+ m/z calcd for C16H14FN2O 269.1085, found 269.1078. Methyl 1-(2-Acetamidophenyl)-1H-indole-6-carboxylate (1m). Eluent: petroleum ether/ethyl acetate 3:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.43 (d, J = 8.94 Hz, 1 H), 7.89 (dd, J = 8.37, 1.44 Hz, 1 H), 7.79 (t, J = 1.26 Hz, 1 H), 7.74 (d, J = 8.34 Hz, 1 H), 7.51 (td, J = 7.85, 1.56 Hz, 1 H), 7.34 (d, J = 3.12 Hz, 1 H), 7.31 (d, J = 6.78 Hz, 1 H), 7.26 (t, J = 7.98 Hz, 1 H), 6.80 (dd, J = 3.15, 0.78 Hz, 1 H), 6.76 (br, s, 1 H), 3.88 (s, 3 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 167.6, 136.2, 134.5, 132.2, 131.7, 129.5, 128.1, 128.0, 124.8, 124.7, 122.6, 121.8, 120.9, 112.4, 104.5, 52.0, 24.5. HR-ESI-MS: [M + K]+ m/z calcd for C18H16KN2O3 347.0793, found 347.0786.

purified by silica gel column with petroleum ether/ethyl acetate (20:1 to 10:1) as the eluent to give the analytically pure N-(2-(1H-indol-1yl)phenyl)acetamide derivatives (substrates 1).24 N-(2-(1H-Indol-1-yl)phenyl)acetamide (1a). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.43 (d, J = 8.34 Hz, 1 H), 7.73 (dd, J = 6.39, 3.12 Hz, 1 H), 7.47 (td, J = 7.88, 1.62 Hz, 1 H), 7.31 (d, J = 7.68, 1 H), 7.25−7.21 (m, 3 H), 7.19 (d, J = 3.24, 1 H), 7.109 (dd, J = 8.82, 2.10 Hz, 1 H), 6.84 (s, 1 H), 6.77 (d, J = 3.18 Hz, 1 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 136.6, 134.4, 129.0, 128.7, 128.5, 128.0, 124.6, 122.9, 122.2, 121.3, 120.8, 110.3, 104.5, 104.4, 24.6. HR-ESI-MS: [M + H]+ m/z calcd for C16H15N2O 251.1184, found 251.1176. N-(2-(4-Methyl-1H-indol-1-yl)phenyl)acetamide (1b). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.44 (d, J = 8.28 Hz, 1 H), 7.46 (td, J = 7.86, 1.56 Hz, 1 H), 7.30 (dd, J = 7.83, 1.50 Hz, 1 H), 7.23 (td, J = 7.62, 1.38 Hz, 1 H), 7.18 (d, J = 3.24 Hz, 1 H), 7.13 (td, J = 7.68, 1.08 Hz, 1 H), 7.01 (d, J = 7.20 Hz, 1 H), 6.93 (d, J = 8.22, 1.08 Hz, 1 H), 6.88 (br, s, 1 H), 6.78 (dd, J = 3.30, 0.84 Hz, 1 H), 2.63 (s, 3 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 136.9, 134.4, 129.3, 128.7, 128.6, 127.9, 126.0, 124.4, 122.9, 121.9, 120.1, 119.3, 113.8, 110.3, 24.7, 9.7. HRESI-MS: [M + H]+ m/z calcd for C17H17N2O 265.1335, found 265.1331. N-(2-(5-Methyl-1H-indol-1-yl)phenyl)acetamide (1c). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.44 (d, J = 8.28 Hz, 1 H), 7.50 (s, 1 H), 7.45 (td, J = 7.92, 1.20 Hz, 1 H), 7.29 (d, J = 7.80, 1.62 Hz, 1 H), 7.22 (t, J = 7.95 Hz, 1 H), 7.14 (d, J = 3.12 Hz, 1 H), 7.05 (dd, J = 8.34, 1.62 Hz, 1 H), 6.98 (d, J = 8.34 Hz, 1 H), 6.87 (br, s, 1 H), 6.68 (d, J = 2.28 Hz, 1H), 2.48 (s, 3 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 135.0, 134.4, 130.1, 129.0, 128.9, 128.5, 127.9, 124.5, 122.0, 120.9, 110.0, 104.0, 24.7, 21.4. HR-ESI-MS: [M + H]+ m/z calcd for C17H17N2O 265.1335, found 265.1331. N-(2-(6-Methyl-1H-indol-1-yl)phenyl)acetamide (1d). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.44 (d, J = 8.10 Hz, 1 H), 7.61 (d, J = 8.10 Hz, 1 H), 7.47 (td, J = 7.86, 1.62 Hz, 1 H), 7.31 (d, J = 7.50 Hz, 1 H), 7.24 (t, J = 7.59 Hz, 1 H), 7.12 (d, J = 3.18 Hz, 1 H), 7.05 (d, J = 8.10 Hz, 1 H), 6.94 (br, s, 1 H), 6.90 (s, 1 H), 6.72 (d, J = 3.18 Hz, 1 H), 2.43 (s, 3 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 137.1, 134.5, 132.9, 129.0, 128.6, 128.0, 127.8, 126.5, 124.5, 122.5, 122.1, 120.9, 110.2, 104.3, 24.6, 21.7. HR-ESI-MS: [M + H]+ m/z calcd for C17H17N2O 265.1335, found 265.1330. N-(2-(4-Methoxy-1H-indol-1-yl)phenyl)acetamide (1e). Eluent: petroleum ether/ethyl acetate 10:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.42 (d, J = 8.34 Hz, 1 H), 7.46 (td, J = 7.91, 1.50 Hz, 1 H), 7.30 (dd, J = 7.83, 1.56 Hz, 1 H), 7.22 (td, J = 7.61, 1.44 Hz, 1 H), 7.14 (t, J = 8.01 Hz, 1 H), 7.09 (d, J = 3.18 Hz, 1 H), 6.875 (br, s, 1 H), 6.865 (dd, J = 3.18, 0.90 Hz, 1 H), 6.70 (d, J = 8.28 Hz, 1 H), 6.61 (d, J = 7.98 Hz, 1 H), 4.00 (s, 3 H), 1.88 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 153.5, 138.0, 134.4, 129.0, 128.5, 128.0, 126.9, 124.5, 123.9, 122.1, 119.3, 103.6, 101.7, 100.6, 55.4, 24.7. HRESI-MS: [M + H]+ m/z calcd for C17H17N2O2 281.1285, found 281.1280. N-(2-(5-Methoxy-1H-indol-1-yl)phenyl)acetamide (1f). Eluent: petroleum ether/ethyl acetate 10:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.42 (d, J = 8.28 Hz, 1 H), 7.45 (td, J = 7.86, 1.56 Hz, 1 H), 7.29 (dd, J = 7.80, 1.50 Hz, 1 H), 7.22 (td, J = 7.56, 1.32 Hz, 1 H), 7.17 (dd, J = 2.49, 0.60 Hz, 1 H), 7.15 (dd, J = 3.12, 0.48 Hz, 1 H), 6.97 (d, J = 8.82 Hz, 1 H), 6.87 (dd, J = 8.70, 2.46 Hz, 1 H), 6.85 (br, s, 1 H), 6.68 (dd, J = 3.15, 0.66 Hz, 1 H), 3.88 (s, 3 H), 1.91 (s, 3 H). 13 C NMR (150 MHz, CDCl3, ppm): δ 168.4, 154.9, 134.3, 131.8, 129.2, 129.0, 128.9, 128.6, 127.9, 124.5, 122.1, 113.0, 111.1, 104.1, 102.9, 55.8, 24.7. HR-ESI-MS: [M + H]+ m/z calcd for C17H17N2O2 281.1285, found 281.1280. N-(2-(6-Methoxy-1H-indol-1-yl)phenyl)acetamide (1g). Eluent: petroleum ether/ethyl acetate 10:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.41 (d, J = 8.16 Hz, 1 H), 7.57 (d, J = 8.64 Hz, 1 H), 7.47 (td, J = 7.86, 1.56 Hz, 1 H), 7.31 (dd, J = 7.80, 1.44 Hz, 1 H), 7.24 (td, J = 7.64, 1.20 Hz, 1 H), 7.07 (d, J = 3.18 Hz, 1 H), 6.86 (dd, J = 8.67, 10162

DOI: 10.1021/acs.joc.7b01617 J. Org. Chem. 2017, 82, 10158−10166

Article

The Journal of Organic Chemistry N-(2-(4-Cyano-1H-indol-1-yl)phenyl)acetamide (1n). Eluent: petroleum ether/ethyl acetate 2:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.36 (d, J = 8.34 Hz, 1 H), 7.53 (dd, J = 7.32, 1.02 Hz, 1 H), 7.51 (td, J = 7.56, 2.04 Hz, 1 H), 7.38 (d, J = 3.24 Hz, 1 H), 7.32−7.24 (m, 4 H), 6.95 (dd, J = 3.24, 0.90 Hz, 1 H), 6.77 (br, s, 1 H), 1.92 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.7, 136.4, 134.2, 131.2, 129.9, 129.7, 127.9, 126.0, 125.1, 123.4, 122.5, 118.0, 115.3, 103.6, 103.1, 24.4. HR-ESI-MS: [M − H]− m/z calcd for C17H12N3O 274.0980, found 274.0987. N-(2-(3-Methyl-1H-indol-1-yl)phenyl)acetamide (1o). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.43 (d, J = 8.28 Hz, 1 H), 7.68−7.65 (m, 1 H), 7.43 (td, J = 7.85, 1.56 Hz, 1 H), 7.26 (dd, J = 7.77, 1.62 Hz, 1 H), 7.23−7.19 (m, 3 H), 7.06−7.04 (m, 1 H), 6.96 (d, J = 1.20 Hz, 1 H), 6.92 (br, s, 1 H), 2.41 (d, J = 1.14, 3 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 136.4, 134.4, 130.8, 129.0, 128.62, 128.57, 128.0, 127.8, 124.5, 123.0, 122.1, 121.0, 107.9, 102.9, 24.7, 18.7. HR-ESI-MS: [M + H]+ m/z calcd for C17H17N2O 265.1335, found 265.1329. N-(2-(1H-Indol-1-yl)-5-methylphenyl)acetamide (1p). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.26 (s, 1 H), 7.72−7.71 (m, 1 H), 7.23−7.18 (m, 3 H), 7.16 (d, J = 3.24 Hz, 1 H), 7.09−7.07 (m, 1 H), 7.04 (d, J = 7.26 Hz, 1 H), 6.76 (s, 1 H), 6.74 (dd, J = 3.21, 0.84 Hz, 1 H), 2.46 (s, 3 H), 1.88 (s, 3 H). 13 C NMR (150 MHz, CDCl3, ppm): δ 168.4, 139.3, 136.8, 134.0, 128.65, 128.61, 127.7, 126.0, 125.3, 122.8, 122.6, 121.2, 120.6, 110.3, 104.2, 24.7, 21.6. HR-ESI-MS: [M + H]+ m/z calcd for C17H17N2O 265.1335, found 265.1331. N-(2-(1H-Indol-1-yl)-4-methylphenyl)acetamide (1q). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.26 (d, J = 8.40 Hz, 1 H), 7.72 (dd, J = 6.60, 2.16 Hz, 1 H), 7.27 (dd, J = 8.22, 1.80 Hz, 1 H), 7.23−7.18 (m, 2 H), 7.18 (d, J = 3.18 Hz, 1 H), 7.12 (s, 1 H), 7.09 (dd, J = 7.68, 1.26 Hz, 1 H), 6.76 (br, s, 1 H), 6.74 (d, J = 3.12 Hz, 1 H), 2.37 (s, 3 H), 1.88 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 136.6, 134.7, 131.7, 129.6, 128.7, 128.6, 128.5, 128.3, 122.8, 122.4, 121.2, 120.7, 110.4, 104.2, 24.5, 20.7. HRESI-MS: [M + H]+ m/z calcd for C17H17N2O 265.1335, found 265.1331. N-(5-Fluoro-2-(1H-indol-1-yl)phenyl)acetamide (1r). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.34 (dd, J = 9.24, 1.20 Hz, 1 H), 7.73 (dd, J = 6.45, 1.98 Hz, 1 H), 7.27−7.20 (m, 3 H), 7.15 (d, J = 3.18 Hz, 1 H), 7.05 (d, J = 7.74 Hz, 1 H), 6.92 (td, J = 8.13, 2.88 Hz, 1 H), 6.86 (br, s, 1 H), 6.77 (d, J = 3.18 Hz, 1 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 162.3 (d, JC−F = 245.4 Hz), 136.8, 136.0 (d, JC−F = 12.2 Hz), 129.2 (d, JC−F = 9.8 Hz), 128.7, 128.5, 123.8, 123.1, 121.3, 120.9, 111.0 (d, JC−F = 23.0 Hz), 110.1, 108.9 (d, JC−F = 28.9 Hz), 104.7, 24.7. HR-ESI-MS: [M − H]− m/z calcd for C16H12FN2O 267.0934, found 267.0939. N-(4-Fluoro-2-(1H-indol-1-yl)phenyl)acetamide (1s). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.36 (dd, J = 9.06, 5.70 Hz, 1 H), 7.72 (dd, J = 7.41, 1.32 Hz, 1 H), 7.26−7.20 (m, 3 H), 7.17 (d, J = 3.24 Hz, 1 H), 7.10 (d, J = 8.10 Hz, 1 H), 7.06 (dd, J = 8.49, 3.00 Hz, 1 H), 6.772 (dd, J = 2.97, 0.84 Hz, 1 H), 6.769 (br, s, 1 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.5, 158.8 (d, JC−F = 245.0 Hz), 136.3, 130.5 (d, JC−F = 3.4 Hz), 130.0 (d, JC−F = 9.5 Hz), 128.8, 128.1, 124.1 (d, JC−F = 8.6 Hz), 123.2, 121.4, 121.0, 115.7 (d, JC−F = 21.6 Hz), 114.9 (d, JC−F = 23.7 Hz), 110.2, 105.0, 24.4. HR-ESI-MS: [M + H]+ m/z calcd for C16H14FN2O 269.1085, found 269.1078. N-(5-Bromo-2-(1H-indol-1-yl)phenyl)acetamide (1t). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.71 (s, 1 H), 7.73−7.71 (m, 1 H), 7.35 (dd, J = 8.31, 2.22 Hz, 1 H), 7.25−7.20 (m, 2 H), 7.16 (d, J = 8.34 Hz, 1 H), 7.14 (d, J = 3.24 Hz, 1 H), 7.07−7.05 (m, 1 H), 6.82 (br, s, 1 H), 6.77 (dd, J = 3.21, 0.90 Hz, 1 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.3, 136.5, 135.5, 129.2, 128.8, 128.2, 127.5, 127.1, 124.7, 123.2, 122.6, 121.4, 121.0, 110.2, 105.0, 24.7. HR-ESI-MS: [M − H]− m/z calcd for C16H12BrN2O 327.0133, 329.0113; found 327.0138, 329.0117. N-(2-(5-Methoxy-1H-indol-1-yl)-5-methylphenyl)acetamide (1u). Eluent: petroleum ether/ethyl acetate 10:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.24 (s, 1 H), 7.17−7.16 (m, 2 H), 7.12 (d, J = 3.12

Hz, 1 H), 7.02 (d, J = 7.38 Hz, 1 H), 6.96 (d, J = 8.94 Hz, 1 H), 6.86 (dd, J = 8.88, 2.46 Hz, 1 H), 6.79 (br, s, 1 H), 6.66 (dd, J = 3.15, 0.72 Hz, 1 H), 3.87 (s, 3 H), 2.45 (s, 3 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 154.8, 139.19, 139.17, 134.0, 132.0, 129.1, 127.6, 126.1, 125.3, 122.5, 112.9, 111.1, 103.8, 102.8, 55.8, 24.7, 21.6. HR-ESI-MS: [M + H]+ m/z calcd for C18H19N2O2 295.1441, found 295.1436. N-(4-Fluoro-2-(5-methoxy-1H-indol-1-yl)phenyl)acetamide (1v). Eluent: petroleum ether/ethyl acetate 10:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.35 (dd, J = 9.18, 5.70 Hz, 1 H), 7.18−7.15 (m, 2 H), 7.14 (d, J = 3.18 Hz, 1 H), 7.04 (dd, J = 8.52, 2.94 Hz, 1 H), 6.98 (d, J = 8.82 Hz, 1 H), 6.89 (dd, J = 8.88, 2.40 Hz, 1 H), 6.79 (br, s, 1 H), 6.68 (dd, J = 3.15, 0.84 Hz, 1 H), 3.87 (s, 3 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 158.8 (d, JC−F = 245.0 Hz), 155.0, 131.5, 130.4 (d, JC−F = 3.1 Hz), 130.1 (d, JC−F = 9.5 Hz), 129.3, 128.6, 124.0 (d, JC−F = 8.6 Hz), 115.5 (d, JC−F = 21.7 Hz), 114.8 (d, JC−F = 23.6 Hz), 113.2, 111.0, 104.7, 103.0, 55.8, 24.4. HR-ESI-MS: [M + H]+ m/z calcd for C17H16FN2O2 299.1190, found 299.1186. N-(5-Bromo-2-(5-methoxy-1H-indol-1-yl)phenyl)acetamide (1w). Eluent: petroleum ether/ethyl acetate 10:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.71 (s, 1 H), 7.50 (s, 1 H), 7.34 (dd, J = 8.34, 2.28 Hz, 1 H), 7.14 (d, J = 8.34 Hz, 1 H), 7.10 (d, J = 3.24 Hz, 1 H), 7.06 (dd, J = 8.34, 1.80 Hz, 1 H), 6.95 (d, J = 8.28 Hz, 1 H), 6.85 (br, s, 1 H), 6.68 (dd, J = 3.21, 0.96 Hz, 1 H), 2.47 (s, 3 H), 1.90 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 135.5, 134.9, 130.4, 129.09, 129.05, 128.2, 127.4, 127.2, 124.7, 124.5, 122.5, 121.0, 109.8, 104.5, 24.7, 21.4. HR-ESI-MS: [M + H]+ m/z calcd for C17H16BrN2O 343.0441, 345.0418; found 343.0435, 345.0412. N-(2-(5-Bromo-1H-indol-1-yl)-4-methylphenyl)acetamide (1x). Eluent: petroleum ether/ethyl acetate 15:1. 1H NMR (600 MHz, CDCl3, ppm): δ 8.22 (d, J = 8.34 Hz, 1 H), 7.83 (d, J = 1.74 Hz, 1 H), 7.30−7.27 (m, 2 H), 7.17 (d, J = 3.18 Hz, 1 H), 7.09 (s, 1 H), 6.95 (d, J = 8.64 Hz, 1 H), 6.67 (dd, J = 3.24, 0.84 Hz, 1 H), 6.65 (br, s, 1 H), 2.37 (s, 3 H), 1.89 (s, 3 H). 13C NMR (150 MHz, CDCl3, ppm): δ 168.4, 135.3, 134.9, 131.5, 130.3, 129.9, 129.7, 128.3, 128.2, 125.6, 123.7, 122.7, 114.0, 111.9, 103.7, 24.5, 20.7. HR-ESI-MS: [M + H]+ m/z calcd for C17H16BrN2O 343.0441, 345.0418; found 343.0435, 345.0412. Typical Procedures for Dehydrogenative C−H/N−H Coupling. Procedure A. An oven-dried round-bottom reaction vessel was charged with Cu2O (5.76 mg, 0. 04 mmol, 10.0 mol %), substrate 1a (0.40 mmol), L1 (28.2 mg, 0.08 mmol, 20 mol %), and (tBuO)2 (146.1 mg, 1.0 mmol, 2.5 equiv). DCE/p-dioxane (1.6 mL, 7:1 v/v ratio) was added by syringe and the reaction mixture was stirred at room temperature for 5 min. Then the vessel was sealed, placed into an oil bath, and heated to 90 °C for 24 h. Upon completion of the reaction, the resulting mixture was cooled to room temperature, filtered through a short silica gel pad, and washed with chloroform. The above solution was evaporated under vacuum, and the residue was purified by silica gel column with petroleum ether/ethyl acetate (10:1) as the eluent to give the analytically pure product 2a. Procedure B. An oven-dried round-bottom reaction vessel was charged with Cu2O (5.76 mg, 0. 04 mmol, 10.0 mol %), substrate 1 (0.40 mmol), L1 (28.2 mg, 0.08 mmol, 20 mol %), and (tBuO)2 (131.6 mg, 0.9 mmol, 2.25 equiv). DCE/p-dioxane (1.6 mL, 7:1 v/v ratio) was added by syringe and the reaction mixture was stirred at room temperature for 5 min. Then the vessel was sealed, placed into an oil bath, and heated to 90 °C for 24 h. Upon completion of the reaction, the resulting mixture was cooled to room temperature, filtered through a short silica gel pad, and washed with chloroform. The above solution was evaporated under vacuum, and the residue was purified by silica gel column with petroleum ether/ethyl acetate (10:1 to 9:1) as the eluent to give the analytically pure products 2b−g, 2q−s, and 2u−w. Procedure C. An oven-dried round-bottom reaction vessel was charged with Cu2O (7.10 mg, 0. 05 mmol, 12.5 mol %), substrate 1 (0.40 mmol), L1 (35.3 mg, 0.10 mmol, 25 mol %), and (tBuO)2 (146.1 mg, 1.0 mmol, 2.5 equiv). DCE/p-dioxane (1.6 mL, 6:2 v/v ratio) was added by syringe and the reaction mixture was stirred at room temperature for 5 min. Then the vessel was sealed, placed into an oil bath, and heated to 90 °C for 24 h. Upon completion of the reaction, 10163

DOI: 10.1021/acs.joc.7b01617 J. Org. Chem. 2017, 82, 10158−10166

Article

The Journal of Organic Chemistry the resulting mixture was cooled to room temperature, filtered through a short silica gel pad, and washed with chloroform. The above solution was evaporated under vacuum, and the residue was purified by silica gel column with petroleum ether/ethyl acetate (10:1 to 3:1) as the eluent to give the analytically pure products 2h−n, 2r−t, and 2x. 1-(10H-Benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2a). The title compound was prepared according to procedure A. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 84% (80.4 mg from 100.2 mg of 1a), yellow solid. Mp: 201.1−201.7 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.43 (s, 1 H), 7.72 (dd, J = 6.72, 1.62 Hz, 1 H), 7.65 (dd, J = 6.09, 2.88 Hz, 1 H), 7.61 (d, J = 7.80 Hz, 1 H), 7.33 (t, J = 7.71 Hz, 1 H), 7.29−7.26 (m, 2 H), 7.23 (t, J = 7.83 Hz, 1 H), 6.04 (s, 1 H), 2.66 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.7, 138.5, 133.7, 132.1, 128.9, 126.8, 124.8, 123.1, 121.7, 120.9, 120.8, 117.4, 110.6, 109.8, 82.2, 25.5. HR-ESI-MS: [M + H]+ m/z calcd for C16H13N2O 249.1028, found 249.1022. 1-(1-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2b). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 69% (70.3 mg from 105.7 mg of 1b), white solid. Mp: 144.8−145.6 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.37 (s, 1 H), 7.48 (t, J = 8.70 Hz, 2 H), 7.28 (t, J = 7.68 Hz, 1 H), 7.18 (t, J = 8.79 Hz, 1 H), 7.16 (t, J = 7.80 Hz, 1 H), 7.04 (d, J = 7.20 Hz, 1 H), 5.83 (s, 1 H), 2.58 (s, 3 H), 2.54 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.7, 138.0, 133.6, 131.6, 130.1, 128.9, 126.4, 124.7, 123.0, 122.0, 120.9, 117.3, 109.7, 108.2, 80.6, 25.5, 18.8. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O 263.1184, found 263.1177. 1-(2-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2c). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 61% (62.5 mg from 105.8 mg of 1c), deep orange solid. Mp: 172.4−173.2 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.38 (s, 1 H), 7.51 (d, J = 8.16 Hz, 1 H), 7.48 (dd, J = 7.74, 1.08 Hz, 1 H), 7.37 (s, 1 H), 7.28 (td, J = 7.70, 1.14 Hz, 1 H), 7.18 (td, J = 7.83, 1.14 Hz, 1 H), 7.05 (d, J = 8.16 Hz, 1 H), 5.84 (s, 1 H), 2.57 (s, 3 H), 2.49 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.6, 138.4, 133.5, 132.2, 131.0, 128.8, 124.9, 124.6, 122.7, 122.2, 120.5, 117.2, 110.1, 109.4, 81.7, 25.3, 21.6. HRESI-MS: [M + H]+ m/z calcd for C17H15N2O 263.1184, found 263.1179. 1-(3-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2d). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 64% (65.2 mg from 105.8 mg of 1d), reddish brown solid. Mp: 162.7−163.5 °C. 1 H NMR (600 MHz, CDCl3, ppm): δ 8.43 (s, 1 H), 7.61 (d, J = 7.74 Hz, 1 H), 7.52 (d, J = 7.98 Hz, 1 H), 7.51 (s, 1 H), 7.33 (td, J = 7.71, 1.14 Hz, 1 H), 7.23 (td, J = 7.95, 1.14 Hz, 1 H), 7.09 (d, J = 7.86 Hz, 1 H), 5.96 (s, 1 H), 2.64 (s, 3 H), 2.55 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.7, 138.0, 133.8, 130.8, 129.8, 129.0, 127.2, 124.7, 123.2, 122.9, 120.4, 117.4, 110.8, 109.7, 82.0, 25.4, 21.9. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O 263.1184, found 263.1178. 1-(1-Methoxy-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2e). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 9:1. Isolated yield: 69% (74.8 mg from 112.3 mg of 1e), purple gray solid. Mp: 198.2− 198.6 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.44 (s, 1 H), 7.62 (d, J = 7.80 Hz, 1 H), 7.37 (d, J = 8.10 Hz, 1 H), 7.34 (td, J = 7.74, 1.14 Hz, 1 H), 7.24 (td, J = 7.80, 1.14 Hz, 1 H), 7.20 (t, J = 7.98 Hz, 1 H), 6.70 (d, J = 7.80 Hz, 1 H), 6.14 (s, 1 H), 4.00 (s, 3 H), 2.68 (s, 3 H). 13 C NMR (100 MHz, CDCl3, ppm): δ 167.7, 152.9, 137.1, 133.7, 128.8, 127.6, 124.6, 123.1, 121.9, 121.7, 117.4, 109.7, 103.9, 101.7, 79.2, 55.3, 25.3. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O2 279.1134, found 279.1128. 1-(2-Methoxy-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2f). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 9:1. Isolated yield: 72% (78.4 mg from 112.2 mg of 1f), brown solid. Mp: 162.7−163.2 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.33 (s, 1 H), 7.45 (d, J = 8.70 Hz, 1 H), 7.38 (d, J = 8.16 Hz, 1 H), 7.24 (td, J = 7.68, 1.14 Hz, 1 H), 7.14 (t, J = 7.56 Hz, 1 H), 7.03 (d, J = 2.52 Hz, 1 H), 6.83 (dd, J = 8.73, 2.46 Hz, 1 H), 5.80 (s, 1 H), 3.87 (s, 3 H), 2.53 (s, 3 H). 13C

NMR (100 MHz, CDCl3, ppm): δ 167.6, 155.2, 138.8, 133.3, 132.8, 128.7, 124.6, 122.6, 121.7, 117.2, 111.1, 109.9, 109.2, 103.2, 82.1, 55.7, 25.3. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O2 279.1134, found 279.1128. 1-(3-Methoxy-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2g). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 9:1. Isolated yield: 71% (77.3 mg from 112.0 mg of 1g), reddish brown solid. Mp: 162.7− 163.5 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.43 (s, 1 H), 7.63 (d, J = 8.76 Hz, 1 H), 7.59 (d, J = 7.80 Hz, 1 H), 7.34 (td, J = 7.71, 1.14 Hz, 1 H), 7.22 (td, J = 7.86, 1.14 Hz, 1 H), 7.13 (d, J = 2.46 Hz, 1 H), 6.91 (dd, J = 8.76, 2.46 Hz, 1 H), 6.01 (s, 1 H), 3.89 (s, 3 H), 2.68 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.5, 155.4, 137.7, 133.8, 128.8, 127.2, 126.0, 124.6, 123.0, 121.2, 117.4, 110.5, 109.6, 95.3, 81.8, 55.9, 25.4. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O2 279.1134, found 279.1127. 1-(2-Chloro-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2h). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 59% (65.7 mg from 113.8 mg of 1h), orange solid. Mp: 191.2−191.9 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.37 (s, 1 H), 7.53 (d, J = 1.92 Hz, 1 H), 7.50 (d, J = 8.52 Hz, 1 H), 7.47 (d, J = 7.86 Hz, 1 H), 7.30 (t, J = 7.62 Hz, 1 H), 7.22 (t, J = 7.86 Hz, 1 H), 7.15 (dd, J = 8.52, 2.04 Hz, 1 H), 5.89 (s, 1 H), 2.60 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.6, 139.3, 133.5, 133.1, 128.4, 127.2, 125.0, 124.8, 123.4, 121.0, 120.2, 117.4, 111.3, 109.7, 81.8, 25.4. HR-ESI-MS: [M + H]+ m/z calcd for C16H12ClN2O 283.0638, found 283.0634. 1-(1-Bromo-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2i). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 45% (58.0 mg from 131.5 mg of 1i), light yellow solid. Mp: 199.2−199.5 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.46 (s, 1 H), 7.77 (d, J = 7.14 Hz, 1 H), 7.67 (dd, J = 7.32, 1.92 Hz, 1 H), 7.37 (td, J = 7.74, 1.08 Hz, 1 H), 7.31−7.24 (m, 3 H), 6.10 (s, 1 H), 2.70 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.7, 138.5, 133.8, 132.1, 129.0, 126.8, 124.8, 123.1, 121.7, 120.9, 120.8, 117.5, 110.6, 109.8, 82.2, 25.5. HR-ESI-MS: [M + H]+ m/z calcd for C16H12BrN2O 327.0133, found 327.0128. 1-(2-Bromo-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2j). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 52% (65.6 mg from 131.7 mg of 1j), dark brown solid. Mp: 189.8−190.2 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.37 (s, 1 H), 7.68 (s, 1 H), 7.44 (t, J = 8.31 Hz, 2 H), 7.30 (t, J = 7.08 Hz, 1 H), 7.27 (t, J = 6.72 Hz, 1 H), 7.22 (t, J = 7.80 Hz, 1 H), 5.87 (s, 1 H), 2.59 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.5, 139.1, 133.6, 133.5, 128.4, 125.2, 124.8, 123.6, 123.5, 123.2, 117.4, 114.8, 111.7, 109.8, 81.7, 25.4. HR-ESI-MS: [M + H]+ m/z calcd for C16H12BrN2O 327.0133, 329.0113; found 327.0131, 329.0104. 1-(1-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2k). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 63% (65.6 mg from 107.2 mg of 1k), white solid. Mp: 155.1−156.3 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.40 (s, 1 H), 7.55 (d, J = 7.86 Hz, 1 H), 7.44 (d, J = 8.10 Hz, 1 H), 7.32 (td, J = 7.70, 1.14 Hz, 1 H), 7.24 (td, J = 7.88, 1.38 Hz, 1 H), 7.16 (td, J = 7.98, 4.98 Hz, 1 H), 6.94 (dd, J = 10.26, 7.98 Hz, 1 H), 6.07 (s, 1 H), 2.65 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.5, 155.9 (d, JC−F = 245.0 Hz), 138.1, 133.6, 128.7 (d, JC−F = 11.4 Hz), 128.4, 124.8, 123.5, 121.3 (d, JC−F = 7.6 Hz), 120.6 (d, JC−F = 21.8 Hz), 117.4, 109.8, 106.8 (d, JC−F = 25.8 Hz), 106.7 (d, JC−F = 3.4 Hz), 77.9, 25.4. HR-ESI-MS: [M + H]+ m/z calcd for C16H12FN2O 267.0934, found 267.0926. 1-(2-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2l). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 60% (62.4 mg from 107.3 mg of 1l), light orange solid. Mp: 186.4−187.0 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.42 (s, 1 H), 7.63 (dd, J = 8.82, 4.32 Hz, 1 H), 7.59 (d, J = 7.68 Hz, 1 H), 7.35 (td, J = 7.88, 1.14 Hz, 1 H), 7.30 (dd, J = 9.48, 2.48 Hz, 1 H), 7.25 (td, J = 7.86, 1.20 Hz, 1 H), 7.00 (td, J = 9.02, 2.52 Hz, 1 H), 6.04 (s, 1 H), 2.67 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.6, 158.8 (d, JC−F = 235.5 Hz), 10164

DOI: 10.1021/acs.joc.7b01617 J. Org. Chem. 2017, 82, 10158−10166

Article

The Journal of Organic Chemistry

110.3, 109.5 (d, JC−F = 9.8 Hz), 106.1 (d, JC−F = 30.7 Hz), 82.5, 25.3. HR-ESI-MS: [M + H]+ m/z calcd for C16H12FN2O 267.0934, found 267.0927. 1-(7-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2s). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 56% (58.0 mg from 107.1 mg of 1s), yellow solid. Mp: 194.3−195.4 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.30 (s, 1 H), 7.60−7.59 (m, 1 H), 7.53− 7.52 (m, 1 H), 7.27−7.23 (m, 2 H), 7.15 (dd, J = 8.07, 2.52 Hz, 1 H), 6.86 (td, J = 9.05, 2.58 Hz, 1 H), 5.90 (s, 1 H), 2.55 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.5, 159.9 (d, JC−F = 242.5 Hz), 138.9 (d, JC−F = 6.2 Hz), 132.1, 129.9, 129.4 (d, JC−F = 9.2 Hz), 126.6 (d, JC−F = 3.0 Hz), 122.1, 121.2, 120.9, 118.1, 110.5, 109.2 (d, JC−F = 23.4 Hz), 98.0 (d, JC−F = 29.5 Hz), 82.5, 25.2. HR-ESI-MS: [M + H]+ m/z calcd for C16H12FN2O 267.0934, found 267.0926. 1-(8-Bromo-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2t). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 58% (74.7 mg from 131.6 mg of 1t), light red solid. Mp 178.1−178.7 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.54 (s, 1 H), 7.64−7.62 (m, 1 H), 7.60−7.59 (m, 1 H), 7.38 (dd, J = 8.31, 1.92 Hz, 1 H), 7.33 (d, J = 8.34 Hz, 1 H), 7.28−7.25 (m, 2 H), 5.97 (s, 1 H), 2.57 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.4, 138.1, 134.3, 132.0, 127.6, 127.4, 126.5, 122.0, 121.2, 120.9, 120.3, 115.6, 110.5, 110.2, 82.4, 25.2. HR-ESI-MS: [M + H]+ m/z calcd for C16H12BrN2O 327.0133, found 327.0130. 1-(2-Methoxy-8-methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10yl)ethanone (2u). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 9:1. Isolated yield: 70% (80.1 mg from 117.6 mg of 1u), light yellow solid. Mp: 171.9− 172.4 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.12 (s, 1 H), 7.40 (d, J = 8.70 Hz, 1 H), 7.21 (d, J = 7.92 Hz, 1 H), 7.01 (d, J = 2.34 Hz, 1 H), 6.99 (d, J = 7.98 Hz, 1 H), 6.82 (dd, J = 8.76, 2.46 Hz, 1 H), 5.76 (s, 1 H), 3.87 (s, 3 H), 2.49 (s, 3 H), 2.38 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.7, 155.2, 139.0, 133.5, 132.6, 126.7, 125.1, 121.8, 117.9, 111.1, 109.9, 108.7, 103.2, 82.0, 55.8, 25.4, 21.6. HR-ESIMS: [M + H]+ m/z calcd for C18H17N2O2 293.1290, found 293.1282. 1-(7-Fluoro-2-methoxy-10H-benzo[4,5]imidazo[1,2-a]indol-10yl)ethanone (2v). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 9:1. Isolated yield: 55% (63.2 mg from 119.4 mg of 1v), white solid. Mp: 167.5−168.2 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.33 (s, 1 H), 7.48 (d, J = 8.58 Hz, 1 H), 7.20 (dd, J = 8.10, 1.86 Hz, 1 H), 7.08 (d, J = 1.86 Hz, 1 H), 6.90−6.86 (m, 2 H), 5.92 (s, 1 H), 3.88 (s, 3 H), 2.61 (s, 3 H). 13 C NMR (100 MHz, CDCl3, ppm): δ 167.4, 160.0 (d, JC−F = 242.1 Hz), 155.6, 139.4, 133.0, 129.6, 129.4 (d, JC−F = 12.3 Hz), 121.6, 118.0, 111.1, 110.3, 108.8 (d, JC−F = 23.4 Hz), 103.5, 97.6 (d, JC−F = 28.9 Hz), 82.6, 55.7, 25.2. HR-ESI-MS: [M + H]+ m/z calcd for C17H14FN2O2 297.1039, found 297.1030. 1-(8-Bromo-2-methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2w). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 65% (86.7 mg from 137.3 mg of 1w), brick red solid. Mp: 234.9−235.7 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.57 (s, 1 H), 7.52 (d, J = 8.22 Hz, 1 H), 7.44−7.41 (m, 2 H), 7.38 (d, J = 8.28 Hz, 1 H), 7.08 (d, J = 8.22 Hz, 1 H), 5.94 (s, 1 H), 2.61 (s, 3 H), 2.49 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.6, 138.5, 134.5, 132.3, 131.5, 128.0, 127.5, 125.0, 122.7, 120.8, 120.5, 115.5, 110.3, 110.2, 82.2, 25.3, 21.7. HR-ESI-MS: [M + H]+ m/z calcd for C17H14BrN2O 341.0290, found 341.0287. 1-(2-Bromo-7-methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2x). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 70% (93.9 mg from 137.2 mg of 1x), brick red solid. Mp: 253.7−254.5 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.19 (s, 1 H), 7.65 (d, J = 1.80 Hz, 1 H), 7.38 (d, J = 8.52 Hz, 1 H), 7.25 (dd, J = 8.46, 1.80 Hz, 1 H), 7.17 (s, 1 H), 6.98 (dd, J = 8.28, 0.84 Hz, 1 H), 5.77 (s, 1 H), 2.52 (s, 3 H), 2.44 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.4, 139.3, 135.0, 133.6, 131.4, 128.5, 125.2, 124.0,

139.6, 133.4, 132.8 (d, JC−F = 10.3 Hz), 128.6, 124.8, 123.3, 123.2, 117.4, 111.1 (d, JC−F = 9.9 Hz), 109.4, 108.8 (d, JC−F = 26.1 Hz), 106.1 (d, JC−F = 24.3 Hz), 82.4, 25.4. HR-ESI-MS: [M + H]+ m/z calcd for C16H12FN2O 267.0934, found 267.0927. Methyl 10-Acetyl-10H-benzo[4,5]imidazo[1,2-a]indole-3-carboxylate (2m). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 5:1. Isolated yield: 57% (68.8 mg from 123.2 mg of 1m), light pink solid. Mp: 214.5−215.2 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.37 (s, 1 H), 8.32 (s, 1 H), 7.89 (dd, J = 8.40, 1.44 Hz, 1 H), 7.68 (d, J = 7.74 Hz, 1 H), 7.57 (dd, J = 8.31, 0.66 Hz, 1 H), 7.36 (td, J = 7.71, 1.14 Hz, 1 H), 7.26 (td, J = 7.86, 1.20 Hz, 1 H), 6.06 (s, 1 H), 3.98 (s, 3 H), 2.66 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.6, 167.5, 140.7, 135.8, 133.4, 128.4, 125.9, 125.0, 123.7, 122.8, 122.2, 120.0, 117.3, 112.5, 110.2, 82.8, 52.0, 25.5. HR-ESI-MS: [M + H]+ m/z calcd for C18H15N2O3 307.1083, found 307.1075. 10-Acetyl-10H-benzo[4,5]imidazo[1,2-a]indole-1-carbonitrile (2n). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 3:1. Isolated yield: 20% (18.6 mg from 110.0 mg of 1n), light orange solid. Mp: 228.4−229.3 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.45 (s, 1 H), 7.95 (d, J = 8.22 Hz, 1 H), 7.69 (d, J = 7.98 Hz, 1 H), 7.59 (dd, J = 7.53, 0.84 Hz, 1 H), 7.42 (td, J = 7.73, 1.14 Hz, 1 H), 7.34 (td, J = 7.89, 1.14 Hz, 1 H), 7.30 (t, J = 7.86 Hz, 1 H), 6.34 (s, 1 H), 2.75 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.6, 140.3, 133.8, 133.6, 128.1, 126.5, 126.4, 125.1, 124.3, 120.3, 118.4, 117.7, 114.9, 110.1, 102.8, 81.3, 25.6. HR-ESI-MS: [M + H]+ m/z calcd for C17H12N3O 274.0980, found 274.0973. 1-(11-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2o). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 43% (43.5 mg from 105.7 mg of 1o), light pink solid. Mp: 191.9−192.4 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 7.90 (d, J = 8.16 Hz, 1 H), 7.74− 7.72 (m, 1 H), 7.66−7.65 (m, 1 H), 7.62 (d, J = 7.98 Hz, 1 H), 7.33− 7.28 (m, 3 H), 7.17 (td, J = 7.91, 1.14 Hz, 1 H), 2.72 (s, 3 H), 2.58 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.4, 136.0, 134.4, 133.8, 129.4, 126.7, 124.6, 122.1, 121.2, 121.1, 119.2, 115.8, 110.3, 109.7, 91.9, 25.9, 10.8. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O 263.1184, found 263.1179. 1-(8-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2p). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 60% (61.0 mg from 105.7 mg of 1p), light pink solid. Mp: 197.5−198.3 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.26 (s, 1 H), 7.71 (d, J = 8.10 Hz, 1 H), 7.65 (dd, J = 7.74, 1.32 Hz, 1 H), 7.49 (d, J = 7.92 Hz, 1 H), 7.29−7.24 (m, 2 H), 7.13 (d, J = 7.92 Hz, 1 H), 6.04 (s, 1 H), 2.66 (s, 3 H), 2.46 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.7, 138.5, 133.7, 133.0, 131.9, 126.7, 126.6, 125.1, 121.4, 120.72, 120.68, 117.9, 110.5, 109.2, 82.0, 25.4, 21.7. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O 263.1184, found 263.1178. 1-(7-Methyl-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2q). The title compound was prepared according to procedure B. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 67% (67.9 mg from 105.7 mg of 1q), pink solid. Mp: 165.7−166.2 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.29 (s, 1 H), 7.74 (dd, J = 7.74, 1.92 Hz, 1 H), 7.66 (dd, J = 6.45, 2.58 Hz, 1 H), 7.43 (s, 1 H), 7.29−7.25 (m, 2 H), 7.03 (dd, J = 8.19, 0.90 Hz, 1 H), 6.03 (s, 1 H), 2.65 (s, 3 H), 2.50 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.5, 138.6, 134.8, 132.0, 131.5, 128.9, 126.7, 123.5, 121.5, 120.74, 120.67, 116.9, 110.6, 110.3, 82.0, 25.3, 21.6. HR-ESI-MS: [M + H]+ m/z calcd for C17H15N2O 263.1184, found 263.1179. 1-(8-Fluoro-10H-benzo[4,5]imidazo[1,2-a]indol-10-yl)ethanone (2r). The title compound was prepared according to procedure C. Eluent: petroleum ether/ethyl acetate 10:1. Isolated yield: 66% (68.2 mg from 107.3 mg of 1r), light pink solid. Mp: 209.2−210.1 °C. 1H NMR (600 MHz, CDCl3, ppm): δ 8.21 (s, 1 H), 7.68 (dd, J = 7.62, 1.68 Hz, 1 H), 7.66 (dd, J = 7.77, 1.86 Hz, 1 H), 7.50 (dd, J = 8.58, 4.50 Hz, 1 H), 7.31−7.26 (m, 2 H), 7.05 (td, J = 8.75, 2.58 Hz, 1 H), 6.06 (s, 1 H), 2.65 (s, 3 H). 13C NMR (100 MHz, CDCl3, ppm): δ 167.7, 158.9 (d, JC−F = 239.1 Hz), 138.8, 134.2 (d, JC−F = 13.8 Hz), 131.8, 126.7, 125.4, 121.8, 121.2, 121.0, 111.2 (d, JC−F = 24.4 Hz), 10165

DOI: 10.1021/acs.joc.7b01617 J. Org. Chem. 2017, 82, 10158−10166

Article

The Journal of Organic Chemistry 123.4, 123.1, 117.0, 114.7, 111.8, 110.4, 81.5, 25.3, 21.6. HR-ESI-MS: [M + H]+ m/z calcd for C17H14BrN2O 341.0290, found 341.0285.

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(6) Representative examples: (a) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184. (b) Shrestha, R.; Mukherjee, P.; Tan, Y.; Litman, Z. C.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 8480. (c) Kim, H.; Chang, S. ACS Catal. 2015, 5, 6665. (d) Shang, M.; Shao, Q.; Sun, S.-Z.; Chen, Y.-Q.; Xu, H.; Dai, H.-X.; Yu, J.-Q. Chem. Sci. 2017, 8, 1469. (7) Representative examples: (a) Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7. (b) Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. Angew. Chem., Int. Ed. 2014, 53, 3496. (c) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129. (d) Wu, X.; Yang, K.; Zhao, Y.; Sun, H.; Li, G.; Ge, H. Nat. Commun. 2015, 6, 6462. (8) Stella, L. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 2, pp 407−439. (9) (a) Zeng, H.-T.; Huang, J.-M. Org. Lett. 2015, 17, 4276. (b) Nozawa-Kumada, K.; Kadokawa, J.; Kameyama, T.; Kondo, Y. Org. Lett. 2015, 17, 4479. (10) Liwosz, T. W.; Chemler, S. R. Chem. - Eur. J. 2013, 19, 12771. (11) Hartung, J.; Schwarz, M.; Svoboda, I.; Fuess, H.; Duarte, M. T. Eur. J. Org. Chem. 1999, 1999, 1275. (12) (a) Zhou, L.; Tang, S.; Qi, X.; Lin, C.; Liu, K.; Liu, C.; Lan, Y.; Lei, A. W. Org. Lett. 2014, 16, 3404. (13) Ma, Y.-N.; Cheng, M.-X.; Yang, S.-D. Org. Lett. 2017, 19, 600. (14) Tong, K.; Liu, X.; Zhang, Y.; Yu, S. Chem. - Eur. J. 2016, 22, 15669. (15) Yamaguchi, T.; Yamaguchi, E.; Itoh, A. Org. Lett. 2017, 19, 1282. (16) The kinetic studies on cyclization of amidyl radicals with alkenes by Newcomb and Moeller revealed an up to 3−4 orders of magnitude lower reactivity for anilidyl radicals (N-aryl) vs the standard amidyl (N-alkyl) radical; thus, in certain cases, for anilidyl radicals the Habstraction to give the corresponding amides competes with the radical-initiated cyclizations. See the following: (a) Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M. J. Am. Chem. Soc. 1998, 120, 7738. (b) Martinez, E.; Newcomb, M. J. Org. Chem. 2006, 71, 557. (c) Xu, H.-C.; Campbell, J. M.; Moeller, K. D. J. Org. Chem. 2014, 79, 379. (d) Fuentes, N.; Kong, W.; Fernández-Sánchez, L.; Merino, E.; Nevado, C. J. Am. Chem. Soc. 2015, 137, 964. (17) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996. (b) Wu, Y.-J. In Heterocyclic Scaffolds II: Reactions and Applications of Indoles; Gribble, G. W., Eds.; Springer: Berlin, 2010. (c) Leonard, J. Nat. Prod. Rep. 1999, 16, 319. (d) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (e) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (f) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489. (g) Teguh, S. C.; Klonis, N.; Duffy, S.; Lucantoni, L.; Avery, V. M.; Hutton, C. A.; Baell, J. B.; Tilley, L. J. Med. Chem. 2013, 56, 6200. (h) Yin, L.; Hu, Q.; Emmerich, J.; Lo, M. M.C.; Metzger, E.; Ali, A.; Hartmann, R. W. J. Med. Chem. 2014, 57, 5179. (18) Badigenchala, S.; Rajeshkumar, V.; Sekar, G. Org. Biomol. Chem. 2016, 14, 2297. (19) When TFAc, Piv, Boc, and Bz were used instead of Ac, none of them delivered detectable product 2a. (20) Other oxidants, including DDQ, BQ, tBuOOH, BzOOBut, AcOOBut, hypervalent iodines, persulfates, H2O2, tBuONO, dicumyl peroxide, and cumene hydroperoxide, were examined; however, none of them afforded observable products. (21) Xia, Q.; Liu, X.; Zhang, Y.; Chen, C.; Chen, W. Org. Lett. 2013, 15, 3326. (22) Zhang, Z.; Xie, C.; Tan, X.; Song, G.; Wen, L.; Gao, H.; Ma, C. Org. Chem. Front. 2015, 2, 942. (23) Munoz, L.; Kavanagh, M. E.; Phoa, A. F.; Heng, B.; Dzamko, N.; Chen, E.-J.; Doddareddy, M. R.; Guillemin, G. J.; Kassiou, M. Eur. J. Med. Chem. 2015, 95, 29. (24) Cary, J. M.; Moore, J. S. Org. Lett. 2002, 4, 4663.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01617. Detailed optimization process for the sytheses, X-ray crystallographic data for 2a, and copies of 1H and 13C NMR spectra for the products (PDF) Crystallographic data for 2a in CIF format (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Honghua Rao: 0000-0003-1609-5692 Author Contributions ∥

X.W. and N.L. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from NSFC (21402128), Beijing Natural Science Foundation (2172015, 2144045), Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), and Capital Normal University is greatly appreciated.

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DOI: 10.1021/acs.joc.7b01617 J. Org. Chem. 2017, 82, 10158−10166