[4+2] Annulation of 3-Nitroindoles with alkylidene Malononitriles: Entry

Sep 19, 2018 - A general and transition-metal free method for the construction of carbazol-4-amine motif via vinylogous Michael ...
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Cite This: J. Org. Chem. 2018, 83, 12568−12574

[4 + 2] Annulation of 3‑Nitroindoles with Alkylidene Malononitriles: Entry to Substituted Carbazol-4-amine Derivatives Dongdong Cao,† Anguo Ying,† Hanjie Mo,† Dingben Chen,† Gang Chen,† Zhiming Wang,‡ and Jianguo Yang*,† †

School of Pharmaceutical and Chemical Engineering, Taizhou University, Taizhou 318000, P.R. China College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 311400, P.R. China

‡

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S Supporting Information *

ABSTRACT: A general and transition-metal-free method for the construction of the carbazol-4-amine motif via a vinylogous Michael addition/cyclization/isomerization/elimination reaction of 3-nitroindoles with alkylidene malononitriles has been developed. This novel methodology allows the facile synthesis of a series of di- and trisubstituted carbazol-4amine derivatives in moderate to good yields. A gram-scale experiment was successfully performed, highlighting the practicability of this method. Moreover, this strategy is also applicable to 3-nitrobenzothiophene, affording the corresponding dibenzo[b,d]thiophen-1-amine derivatives in moderate yields.

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large amount of byproduct carbazole (Scheme 1a).6 Moreover, the preparation of substituted carbazol-4-amine using this method is unknown. The reduction of 4-nitrocarbazole derivatives prepared by late-stage nitration of substituted carbazoles under catalytic hydrogenation has also been developed in the course of synthesis of antiostatins (Scheme 1b).7 This strategy may be encountered by the challenge of precise synthesis of the corresponding 4-nitro-substituted carbazole derivatives. Three monosubstituted carbazol-4amine compounds were obtained via the annulation8 between sulfoxides and terminal electron-deficient alkenes (Scheme 1c).9 However, the lengthy preparation of sulfoxides and making use of smelly thiophenols as starting materials lowered its practicability. Recently, Liao and co-workers have reported Pd-catalyzed intramolecular cyclization via direct C−H addition to nitriles for accessing two 3-substituted carbazol4-amine analogues (Scheme 1d).10a Notably, the majority of methods above do not give access to systems with di- or trisubstitution around the benzene ring. A promising methodology for the construction of the carbazol-4-amine scaffold should meet the following requirements: (1) have readily available starting materials; (2) have good functional group tolerance; (3) be transition-metal-free; and (4) be practical. Generally, indoles 1 bearing electron-withdrawing groups at C3 and N1 positions undergo initial nucleophilic addition to the C2-position and subsequently attack electrophiles at the C3-position, which are used to synthesize heterocyclic compounds with an indole11,12 or an indoline13,14 motif. To

INTRODUCTION Carbazol-4-amine derivatives, an important member of the carbazole1 family, are of high interest due to their occurrence in pharmaceutically active compounds2 and organic functional materials.3 They are also key intermediates for the synthesis of the physiologically naturally occurring products4 exemplified by antiostatins A1−A4 and B2−B5, which exhibit a strong inhibitory activity against free-radical-induced lipid peroxidation (Figure 1).5 In this context, developing efficient methods for the construction of such skeletons is highly desirable.

Figure 1. Representative natural products containing the carbazol-4amine motif.

However, a general synthetic method to directly prepare a carbazol-4-amine motif is still in its infancy. Sporadic examples have been reported. Horaguchi and co-workers have developed one example concerning thermal cyclization of 2,2′-diaminobiphenyl over calcium oxide under harsh conditions to deliver the major carbazol-4-amine with concomitant formation of a © 2018 American Chemical Society

Received: July 22, 2018 Published: September 19, 2018 12568

DOI: 10.1021/acs.joc.8b01876 J. Org. Chem. 2018, 83, 12568−12574

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa

Scheme 1. Synthetic Routes toward a Carbazol-4-amine Motif

entry

base

solvent

yield (%)

1 2 3 4 5 6 7 8 9 10 11b

TEA TEA TEA TEA TEA TEA DABCO DIPEA Na2CO3 K2CO3 Cs2CO3

CH3CN CH2Cl2 PhCH3 THF CHCl3 EtOH CH3CN CH3CN CH3CN CH3CN CH3CN

83 70 51 59 75 79 81 79 60 55

a

Unless otherwise noted, the reaction was performed with 1a (0.1 mmol), 2a (0.12 mmol), and TEA (0.2 mmol) in CH3CN (2 mL) at 50 °C for 24 h under N2 atmosphere. b1a was decomposed. TEA = triethyamine, DABCO = 1,4-diazabicyclo[2.2.2]octane, DIPEA = N,N-diisopropylethylamine.

Interestingly, the reaction promoted by Cs2CO3 did not afford product 3a at all, probably due to the decomposition of substrate 1a (entry 11). Thus, the substrate scope was investigated in the presence of triethylamine in CH3CN at 50 °C. With the optimized reaction conditions for the synthesis of carbazol-4-amine derivatives in hand, we set out to examine the scope of this reaction using a variety of alkylidene malononitriles (Table 2). Electron-withdrawing and -donating substitutes on aromatic rings of substrate 2 were all tolerated, giving the corresponding disubstituted carbazol-4-amines in good yields (68−81%, 3b−3f). Ortho- and meta-substituted substrates 2 had no inferior effect on the yields (3g,3h). Alkylidene malononitriles involving a heteroaromatic or condensed ring also proved to be competent candidates (3i− 3k). The reaction of substrates 2 bearing electron-withdrawing groups finished in shorter reaction times. To our delight, challenging cyclic α-tetralone and 1-indanone, as well as propiophenone-derived alkylidene malononitriles, could proceed smoothly to afford the continuous trisubstituted carbazol4-amine derivatives (3l−3n) in moderate yields. Notably, this protocol was also applicable to nonaromatic ketones, such as acetone- and cyclohexanone-derived alkylidene malononitriles, giving the corresponding products 3o and 3p in 34 and 24% yield, respectively. The structure of product was confirmed by the X-ray analysis of a single crystal of product 3a16 (see Supporting Information). Next, the effect of the group at N-1 of indole 1 was investigated (Table 3). Both N-Boc- and Ac-protected 3nitroindoles reacted smoothly in the reaction, delivering the products 3q and 3r in 64 and 60% yield, respectively. We then switched our attention to the substitutes around the indole ring. Indole 4-(3s) and 5-(3t-u) substitutes were tolerated, including electron-donating and -withdrawing groups. The reaction of 5-bromo-substituted indole finished within shorter times. To our delight, this strategy was applicable to 3nitrodibenzothiophene,17 giving access to corresponding dibenzo[b,d]thiophen-1-amine derivatives 3v and 3w in

our knowledge, efforts toward indole-containing heterocyclic compounds using this strategy are relatively limited. We envisioned that di- or trisubstituted carbazol-4-amine derivatives 3 could be obtained via base-promoted vinylogous Michael addition/cyclization of aforementioned electrophilic indoles 1 and ambiphilic alkylidene malononitriles 215 derived from aryl ketones and malononitrile, followed by isomerization/elimination (Scheme 1e). Herein, we report an efficient, general, and practical method toward the synthesis of substituted carbazol-4-amine derivatives.

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RESULTS AND DISCUSSION Initially, N-Ts-3-nitroindole 1a and acetophenone-derived alkylidene malononitrile 2a were chosen as model substrates to optimize the reaction conditions (Table 1). To our delight, the desired disubstituted carbazol-4-amine 3a was obtained in 83% yield when the reaction was conducted at 50 °C in CH3CN using triethylamine as a base for 24 h (entry 1). The yields were decreased (51−75%) in other solvents (entries 2− 6). A small drop in yield was observed when we employed other organic bases such as 1,4-diazabicyclo[2.2.2]octane or N,N-diisopropylethylamine instead (entries 7 and 8). Inorganic bases further decreased the yield of product (entries 9 and 10). 12569

DOI: 10.1021/acs.joc.8b01876 J. Org. Chem. 2018, 83, 12568−12574

Article

The Journal of Organic Chemistry Table 2. Alkylidene Malononitrile Substrate Scopea

Unless otherwise noted, the reaction was performed with 1a (0.1 mmol), 2a (0.12 mmol), and TEA (0.2 mmol) in CH3CN at 50 °C for 24 h under N2 atmosphere. b6 h; TEA = triethylamine. a

nation of 3-nitroindoles with alkylidene malononitriles. Moreover, this novel strategy can also be applicable to 3nitobenzothiophenes, delivering the corresponding substituted dibenzothiophen-1-amine derivatives. Gram scale-up synthesis and detosylation of the products are successfully performed, demonstrating the synthetic utility of this method. Further exploration of electrophilic indole chemistry to synthesize other useful heterocycles is currently underway in our laboratory.

moderate yields (52−57% yields), which were also intriguing heterocyclic motifs of medicinal18 and organic materials.19 To demonstrate the synthetic utility of this method developed above, we attempted gram-scale synthesis of carbazol-4-amine 3a. To our delight, when starting from 1a (3.5 mmol), the corresponding product 3a was successfully obtained in 75% (Scheme 2). The removal of the tosyl group on the N atom of the product 3a11b,c could be achieved to afford the compound 4 in 83% yield. Based on the experimental results in combination with other investigation, the mechanism of the reaction is proposed (Scheme 3). The reaction commenced with deprotonation15 of the alkylidene malononitriles 2 promoted by triethylamine. The resulting anion A reacted with 3-nitroindoles 1 via vinylogous Michael addition/cyclization to afford the intermediate B. Then, final carbazol-4-amine derivatives 3 were obtained by the isomerization of the formed intermediate B, followed by the elimination of nitrous acid11a,12 mediated by triethylamine.

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EXPERIMENTAL SECTION

General Information. 1H and 13C NMR spectra were recorded in CDCl3 or DMSO-d6 using a 400 MHz NMR spectrometer. 1H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Chemical shifts are reported in parts per million relative to TMS or chloroform (1H, δ 0.00; 13C, δ 77.0 or 39.5). Flash column chromatography was performed using silica gel (300−400 mesh). For thin-layer chromatography (TLC), silica gel plates (HSGF 254) were used, and compounds were visualized by irradiation with UV light. High-resolution mass spectra analysis was performed using ESI (electrospray ionization). 3-Nitroindoles,13d 3nitrobenzothiophene,20 and alkylidene malononitriles21 were prepared using reported procedures. All reactions were carried out employing oven-dried glassware under N2 atmosphere. All reagents and solvents were directly used as received.

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CONCLUSION In summary, we have developed an efficient and general methodology for the construction of substituted carbazol-4amine derivatives in moderate to good yields via one-pot vinylogous Michael addition/cyclization/isomerization/elimi12570

DOI: 10.1021/acs.joc.8b01876 J. Org. Chem. 2018, 83, 12568−12574

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The Journal of Organic Chemistry Table 3. Electrophile Scopea

time. The final reaction system was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1−3:1) to afford the desired products 3. 4-Amino-2-phenyl-9-tosyl-9H-carbazole-3-carbonitrile (3a): Canary solid; 36.4 mg, 83% yield; mp = 262−263 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.66−7.64 (m, 3H), 7.59−7.49 (m, 4H), 7.46 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 6.54 (br s, 2H), 2.25 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 147.6, 146.0, 144.6, 141.0, 139.0, 136.9, 133.6, 130.3, 128.8, 128.7, 126.8, 126.3, 124.6, 124.1, 121.9, 117.4, 114.1, 109.9, 104.1, 90.2, 21.0 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H20N3O2S 438.1276; found 438.1278. 4-Amino-2-(4-bromophenyl)-9-tosyl-9H-carbazole-3-carbonitrile (3b): Canary solid; 35.1 mg, 68% yield; mp = 284−285 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.79−7.75 (m, 4H), 7.62−7.55 (m, 4H), 7.46 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.58 (br s, 2H), 2.26 (s, 3H); 13 C{1H} NMR (100 MHz, DMSO-d6) δ 147.6, 146.1, 143.3, 140.9, 138.2, 136.8, 133.5, 131.6, 130.9, 130.4, 126.9, 126.4, 124.6, 124.0, 122.3, 121.9, 117.3, 114.1, 110.1, 104.0, 89.9, 21.0; HRMS (ESITOF) m/z [M + H]+ calcd for C26H19BrN3O2S 516.0381; found 516.0370. 4-Amino-2-(4-chlorophenyl)-9-tosyl-9H-carbazole-3-carbonitrile (3c): Canary solid; 34.5 mg, 73% yield; mp = 280−282 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.68−7.62 (m, 5H), 7.57 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.58 (br s, 2H), 2.26 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 147.6, 146.1, 143.3, 140.9, 137.8, 136.8, 133.6, 133.5, 130.7, 130.4, 128.7, 126.9, 126.4, 124.6, 124.0, 121.9, 117.3, 114.1, 110.1, 104.3, 90.0, 21.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H19Cl(35Cl)N3O2S 472.0887; found 472.0880. 4-Amino-2-(4-methoxyphenyl)-9-tosyl-9H-carbazole-3-carbonitrile (3d): Canary solid; 36.0 mg, 77% yield; mp = 228−230 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 5.13 (br s, 2H), 3.89 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 146.6, 145.5, 144.5, 141.6, 138.0, 134.6, 131.4, 130.2, 129.9, 126.7, 126.5, 124.5, 124.4, 120.3, 117.8, 115.0, 114.1, 110.3, 106.0, 91.6, 55.4, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H22N3O3S 468.1382, found 468.1377. 4-Amino-2-(p-tolyl)-9-tosyl-9H-carbazole-3-carbonitrile (3e): Canary solid; 32.1 mg, 71% yield; mp = 260−261 °C; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.56−7.50 (m, 3H), 7.44 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.14

a

Unless otherwise noted, the reaction was performed with 1 (0.1 mmol), 2 (0.12 mmol), and TEA (0.2 mmol) in CH3CN (2 mL) at 50 °C for 24 h under N2 atmosphere. b6 h; TEA = triethylamine.

Scheme 2. Scale-up Synthesis and Synthetic Manipulation

General Procedure for the Synthesis of Products 3. To a solution of 1 (0.1 mmol) and 2 (0.12 mmol) in CH3CN (2 mL) under N2 atmosphere was added Et3N (0.2 mmol, 20.2 mg, 28 μL). The resulting red solution continued to stir at 50 °C for the indicated

Scheme 3. Proposed Mechanism of the Reaction

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DOI: 10.1021/acs.joc.8b01876 J. Org. Chem. 2018, 83, 12568−12574

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The Journal of Organic Chemistry

°C; 1H NMR (400 MHz, CDCl3) δ 8.23−8.20 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.45−7.33 (m, 5H), 7.02 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.91 (br s, 2H), 3.33 (t, J = 6.8 Hz, 2H), 2.70 (t, J = 6.8 Hz, 2H), 2.22 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.0, 144.7, 143.5, 141.3, 139.2, 138.3, 132.7, 132.1, 129.0, 128.8, 128.0, 127.5, 127.0, 126.8, 126.7, 126.6, 126.0, 123.3, 120.3, 119.5, 115.3, 92.5, 29.8, 28.5, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C28H22N3O2S 464.1433, found 464.1430. 6-Amino-11-tosyl-11,12-dihydroindeno[2,1-a]carbazole-5-carbonitrile (3m): Yellow solid; 24.3 mg, 54% yield; mp = 284−285 °C; 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 6.8 Hz, 1H), 8.43 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 6.4 Hz, 1H), 7.49− 7.37 (m, 6H), 7.04 (d, J = 8.4 Hz, 2H), 5.04 (br s, 2H), 4.40 (s, 2H), 2.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.8, 145.2, 145.0, 143.5, 140.0, 139.6, 138.7, 134.8, 129.7, 128.2, 127.0, 126.6, 126.2, 125.9, 125.1, 124.5, 121.8, 121.7, 120.1, 117.21, 117.17, 113.0, 87.0, 38.7, 21.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H20N3O2S 450.1276, found 450.1266. 4-Amino-1-methyl-2-phenyl-9-tosyl-9H-carbazole-3-carbonitrile (3n): Canary solid; 21.2 mg, 47% yield; mp = 195−197 °C; 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.55−7.46 (m, 3H), 7.45−7.41 (m, 3H), 7.35 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 4.78 (br s, 2H), 2.42 (s, 3H), 2.25 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.0, 145.3, 144.7, 143.2, 141.2, 138.2, 132.2, 129.6, 128.8, 128.59, 128.55, 128.0, 126.9, 126.5, 126.0, 120.3, 120.2, 119.7, 116.1, 96.3, 21.5, 20.3 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H22N3O2S 452.1433, found 452.1431. 4-Amino-2-methyl-9-tosyl-9H-carbazole-3-carbonitrile (3o): White solid; 12.6 mg, 34% yield; mp > 300 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.38 (br s, 2H), 2.55 (s, 3H), 2.26 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 146.9, 145.9, 141.4, 141.2, 136.6, 133.7, 130.3, 126.3, 124.4, 124.3, 121.5, 117.0, 114.0, 108.8, 104.2, 91.7, 21.4, 21.0 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESITOF) m/z [M-H]+ calcd for C21H16N3O2S 374.0963, found 374.0961. 6-Amino-11-tosyl-2,3,4,11-tetrahydro-1H-benzo[a]carbazole-5carbonitrile (3p): White solid; 10.0 mg, 24% yield; mp = 222−224 °C; 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 4.70 (br s, 2H), 3.21 (t, J = 5.8 Hz, 2H), 3.06 (t, J = 6.6 Hz, 2H), 2.23 (s, 3H), 1.98− 1.92 (m, 2H), 1.70−1.65 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 144.6, 144.5, 143.4, 141.1, 140.9, 132.4, 128.8, 128.1, 126.9, 126.0, 125.8, 122.9, 120.0, 119.6, 116.9, 114.9, 95.7, 29.2, 28.9, 22.8, 22.2, 21.5; HRMS (ESI-TOF) m/z [M-H]+ calcd for C24H20N3O2S 414.1276, found 414.1279. tert-Butyl-4-amino-3-cyano-2-phenyl-9H-carbazole-9-carboxylate (3q): Canary solid; 24.5 mg, 64% yield; mp = 191−193 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 2H), 7.53−7.42 (m, 5H), 5.18 (br s, 2H), 1.74 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.5, 146.4, 144.3, 141.9, 139.5, 138.3, 128.9, 128.6, 128.4, 126.5, 124.0, 123.8, 120.1, 118.0, 116.3, 110.1, 108.3, 90.9, 85.0, 28.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C24H22N3O2 384.1712, found 384.1707. 9-Acetyl-4-amino-2-phenyl-9H-carbazole-3-carbonitrile (3r): Canary solid; 19.5 mg, 60% yield; mp = 246−248 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.64−7.61 (m, 3H), 7.56−7.45 (m, 5H), 6.46 (br s, 2H), 2.90 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 171.1, 147.3, 144.1, 141.5, 139.4, 137.6, 128.8, 128.6, 128.4, 126.4, 123.9, 123.8, 121.5, 117.7, 115.6, 109.5, 106.5, 89.6, 27.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C21H16N3O 326.1293, found 326.1296. 4-Amino-5-methyl-2-phenyl-9-tosyl-9H-carbazole-3-carbonitrile (3s): Canary solid; 38.4 mg, 85% yield; mp = 202−204 °C; 1H NMR

(br s, 2H), 2.45 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.6, 145.5, 144.8, 141.6, 138.7, 138.0, 136.1, 134.7, 129.9, 129.4, 128.8, 126.7, 126.5, 124.5, 124.4, 120.4, 115.0, 110.5, 106.2, 91.7, 21.6, 21.3 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H22N3O2S 452.1433, found 452.1435. 2-([1,1′-Biphenyl]-4-yl)-4-amino-9-tosyl-9H-carbazole-3-carbonitrile (3f): Yellow solid; 41.6 mg, 81% yield; mp = 241−243 °C; 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.77−7.73 (m, 6H), 7.68 (d, J = 7.2 Hz, 2H), 7.56−7.38 (m, 5H), 7.18 (d, J = 8.0 Hz, 2H), 5.18 (br s, 2H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.7, 145.6, 144.3, 141.6, 141.5, 140.4, 138.0, 137.9, 134.7, 129.9, 129.4, 128.9, 127.6, 127.4, 127.2, 126.6, 120.4, 115.1, 110.7, 106.3, 91.6, 21.6 (four peaks for aromatic carbon were not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C32H24N3O2S 514.1589, found 514.1598. 4-Amino-2-(3-chlorophenyl)-9-tosyl-9H-carbazole-3-carbonitrile (3g): Canary solid; 43.9 mg, 93% yield; mp = 259−261 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 7.6 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.69 (s, 1H), 7.63 (s, 1H), 7.61−7.55 (m, 4H), 7.46 (t, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.59 (br s, 2H), 2.26 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 147.6, 146.1, 142.9, 141.1, 140.9, 136.8, 133.5, 133.2, 130.5, 130.4, 128.6, 128.5, 127.7, 126.9, 126.4, 124.6, 123.9, 122.0, 117.2, 114.1, 110.2, 104.1, 90.0, 21.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H19Cl(35Cl)N3O2S 472.0887, found 472.0883. 4-Amino-2-(2-chlorophenyl)-9-tosyl-9H-carbazole-3-carbonitrile (3h): Canary solid; 42.0 mg, 89% yield; mp = 275−276 °C; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.4 Hz, 1H), 7.84−7.81 (m, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.56−7.52 (m, 2H), 7.46−7.40 (m, 4H), 7.15 (d, J = 8.4 Hz, 2H), 5.12 (br s, 2H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.0, 145.6, 141.9, 141.1, 138.0, 137.7, 134.4, 132.9, 131.2, 130.0, 129.90, 129.85, 127.0, 126.9, 126.6, 124.6, 124.4, 120.5, 116.7, 115.1, 111.2, 107.5, 93.1, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H19Cl(35Cl)N3O2S 472.0887, found 472.0883. 4-Amino-2-(naphthalen-2-yl)-9-tosyl-9H-carbazole-3-carbonitrile (3i): Canary solid; 35.1 mg, 72% yield; mp = 248−250 °C; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 8.00−7.91 (m, 4H), 7.84 (d, J = 7.6 Hz, 1H), 7.77−7.73 (m, 3H), 7.57−7.52 (m, 3H), 7.45 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 2H), 5.19 (br s, 2H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.7, 145.5, 144.6, 141.5, 138.0, 136.4, 134.6, 133.1, 129.9, 128.43, 128.37, 128.27, 127.7, 126.8, 126.7, 126.6, 126.5, 124.5, 124.3, 120.4, 117.7, 115.0, 110.6, 106.6, 91.8, 21.6 (two peaks for aromatic carbon were not found probably due to overlapping); HRMS (ESI-TOF) m/ z [M + H]+ calcd for C30H22N3O2S 488.1433, found 488.1436. 4-Amino-2-(naphthalen-1-yl)-9-tosyl-9H-carbazole-3-carbonitrile (3j): Canary solid; 40.5 mg, 83% yield; mp = 247−249 °C; 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.4 Hz, 1H), 7.99−7.96 (m, 2H), 7.89−7.86 (m, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.63−7.53 (m, 5H), 7.51−7.43 (m, 2H), 7.19 (d, J = 8.4 Hz, 2H), 5.16 (br s, 2H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.1, 145.6, 143.3, 141.1, 138.2, 136.6, 134.6, 133.7, 131.6, 129.9, 129.1, 128.5, 127.5, 127.0, 126.7, 126.4, 126.1, 125.4, 125.2, 124.6, 124.5, 120.5, 116.9, 115.2, 111.0, 108.0, 93.9, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H22N3O2S 488.1433, found 488.1431. 4-Amino-2-(thiophen-2-yl)-9-tosyl-9H-carbazole-3-carbonitrile (3k): Canary solid; 32.4 mg, 73% yield; mp = 241−243 °C; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.47−7.42 (m, 2H), 7.20−7.16 (m, 3H), 5.17 (br s, 2H), 2.31 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.9, 145.6, 141.5, 140.6, 138.1, 136.5, 134.6, 129.9, 128.1, 127.5, 127.1, 126.9, 126.6, 124.6, 124.3, 120.4, 115.1, 110.8, 106.1, 90.5, 21.6 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C24H18N3O2S2 444.0840, found 444.0843. 8-Amino-13-tosyl-2,13-dihydro-1H-naphtho[2,1-a]carbazole-7carbonitrile (3l): Canary solid; 22.7 mg, 49% yield; mp = 183−185 12572

DOI: 10.1021/acs.joc.8b01876 J. Org. Chem. 2018, 83, 12568−12574

Article

The Journal of Organic Chemistry (400 MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.68− 7.63 (m, 4H), 7.54−7.45 (m, 3H), 7.36 (t, J = 8.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 3H), 5.43 (br s, 2H), 2.98 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.1, 145.4, 144.7, 142.3, 138.9, 138.8, 134.7, 129.83, 129.76, 128.8, 128.7, 128.6, 128.2, 127.0, 126.6, 124.2, 118.1, 112.9, 111.8, 106.1, 91.9, 25.0, 21.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H22N3O2S 452.1433, found 452.1430. 4-Amino-6-methyl-2-phenyl-9-tosyl-9H-carbazole-3-carbonitrile (3t): Canary solid; 33.4 mg, 74% yield; mp = 227−228 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 6.8 Hz, 2H), 7.59 (s, 1H), 7.54−7.45 (m, 3H), 7.32 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 5.10 (br s, 2H), 2.52 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.6, 145.4, 144.6, 141.8, 139.1, 136.2, 134.7, 134.3, 129.9, 128.9, 128.6, 128.0, 126.5, 124.6, 120.7, 117.6, 114.8, 110.7, 106.5, 91.7, 21.6, 21.5 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H22N3O2S 452.1433, found 452.1436. 4-Amino-6-bromo-2-phenyl-9-tosyl-9H-carbazole-3-carbonitrile (3u): Canary solid 38.2 mg, 74% yield; mp = 247−249 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 1.6 Hz, 1H), 8.20 (d, J = 9.2 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.70 (dd, J = 1.8, 9.0 Hz, 1H), 7.65− 7.62 (m, 2H), 7.59−7.50 (m, 4H), 7.33 (d, J = 8.0 Hz, 2H), 6.67 (br s, 2H), 2.26 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 147.7, 146.3, 145.4, 141.4, 138.9, 135.8, 133.3, 130.4, 129.3, 128.8, 128.7, 126.4, 126.0, 124.1, 117.5, 117.3, 115.8, 108.8, 103.9, 90.4, 21.0 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C26H19BrN3O2S 516.0381, found 516.0385. 1-Amino-3-phenyldibenzo[b,d]thiophene-2-carbonitrile (3v): White solid; 15.6 mg, 52% yield; mp = 237−238 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 7.2 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H), 7.63−7.46 (m, 8H), 6.46 (br s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 148.8, 145.2, 142.6, 138.5, 138.0, 133.7, 128.7, 128.5, 126.1, 125.1, 124.0, 122.9, 119.4, 117.9, 112.5, 91.2 (one peak for aromatic carbon was not found probably due to overlapping); HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H13N2S 301.0799, found 301.0800. 1-Amino-3-(p-tolyl)dibenzo[b,d]thiophene-2-carbonitrile (3w): White solid; 17.9 mg, 57% yield; mp = 220−221 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.58−7.50 (m, 4H), 7.41 (s, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.43 (br s, 2H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 148.8, 145.2, 142.6, 138.0, 137.9, 135.6, 133.8, 129.1, 128.6, 126.0, 125.1, 124.0, 122.9, 119.2, 118.0, 112.4, 91.3, 20.8; HRMS (ESITOF) m/z [M + H]+ calcd for C20H15N2S 315.0956, found 315.0960. Procedure for Scale-up Synthesis of Compound 3a. To a solution of 1 (3.5 mmol, 1.11 g) and 2 (4.2 mmol, 0.71 g) in CH3CN (70 mL) under N2 atmosphere was slowly added Et3N (7.0 mmol, 708.3 mg, 0.98 mL). The resulting red solution continued to stir at 50 °C for 24 h. The final reaction system was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1− 3:1) to afford the desired products 3a. Procedure for Removal of Tosyl Group of Product 3a. To a solution of 3a (0.25 mmol, 109.4 mg) in mixed MeOH/THF (4 mL, 2:1) under N2 atmosphere was added granular NaOH (0.5 mmol, 20.0 mg).11 The resulting mixture was stirred at 60 °C for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure. Water (5 mL) was added. Then the mixture was neutralized using HCl (aq, 1 M) and extracted with EtOAc (5 mL × 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified through flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1−3:1) to deliver the detosylated product 4. 4-Amino-2-phenyl-9H-carbazole-3-carbonitrile (4): Canary solid; 58.7 mg, 83% yield; mp = 227−229 °C; 1H NMR (400 MHz, DMSOd6) δ 11.72 (s, 1H), 8.40 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.2 Hz, 2H), 7.54−7.43 (m, 4H), 7.40 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H),

6.83 (s, 1H), 6.30 (br s, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 148.2, 142.8, 142.4, 139.9, 139.2, 128.8, 128.4, 128.0, 124.8, 121.4, 121.3, 119.7, 119.1, 110.9, 106.8, 102.1, 84.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H14N3 284.1188, found 284.1182.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01876. 1

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H NMR and 13C NMR spectra of all new products (PDF) X-ray crystallographic data for compound 3a (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Zhiming Wang: 0000-0002-6583-3826 Jianguo Yang: 0000-0003-4268-7384 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the Natural Science foundation of Zhejiang Province (Nos. LY18B020002, LQ15B020001), the National Natural Science Foundation of China (21576176), and PhD Start-up Grant, Nurturing Project (2017PY008), from Taizhou University for financial support.

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REFERENCES

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DOI: 10.1021/acs.joc.8b01876 J. Org. Chem. 2018, 83, 12568−12574

Article

The Journal of Organic Chemistry (7) Knott, K. E.; Auschill, S.; Jäger, A.; Knölker, H.-J. First Total Synthesis of the Whole Series of the Antiostatins A and B. Chem. Commun. 2009, 1467. (8) Mal, D.; Pahari, P. Recent Advances in the Hauser Annulation. Chem. Rev. 2007, 107, 1892. (9) Ramesh, N.; Rajeshwaran, G. G.; Mohanakrishnan, A. K. Synthesis of Di-, Tri-, and Tetra-substituted Carbazole Analogs Involving Annulation Methodology. Tetrahedron 2009, 65, 3592. (10) (a) Wang, T.-T.; Zhao, L.; Zhang, Y.-J.; Liao, W.-W. PdCatalyzed Intramolecular Cyclization via Direct C-H Addition to Nitriles: Skeletal Diverse Synthesis of Fused Polycyclic Indoles. Org. Lett. 2016, 18, 5002. (b) For synthesis of one N-tosyl-4tosylaminocarbazole via Pd-catalyzed intramolecular oxidative C−H amination, see: Youn, S. W.; Bihn, J. H.; Kim, B. S. Pd-Catalyzed Intramolecular Oxidative C-H Amination: Synthesis of Carbazole. Org. Lett. 2011, 13, 3738. (11) Racemic examples: (a) Pelkey, E. T.; Chang, L.; Gribble, G. W. An Abnormal Barton-Zard Reaction Leading to the Pyrrolo[2,3b]indole Ring System. Chem. Commun. 1996, 1909. 3-Nitroindoles were used as bis-electrophiles to synthesize indolo[3,2-b]indoles. See: (b) Santhini, P. V.; Babu, S. A.; Krishnan R, A.; Suresh, E.; John, J. Heteroannulation of 3-Nitroindoles and 3-Nitrobenzo[b]thiophenes: A Multicomponent Approach toward Pyrrole-Fused Heterocycles. Org. Lett. 2017, 19, 2458. (c) Santhini, P. V.; Krishnan R, A.; Babu, S. A.; Simethy, B. S.; Das, G.; Praveen, V. K.; Varughese, S.; John, J. One-Pot MCR-Oxidation Approach toward Indole-Fused Heteroacenes. J. Org. Chem. 2017, 82, 10537. (12) Asymmetric example: Li, Y.; Tur, F.; Nielsen, R. P.; Jiang, H.; Jensen, F.; Jørgensen, K. A. Enantioselective Formal [4 + 2] cycloadditions to 3-Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles. Angew. Chem., Int. Ed. 2016, 55, 1020. (13) Selected racemic examples: (a) Roy, S.; Kishbaugh, T. L. S.; Jasinski, J. P.; Gribble, G. W. 1,3-Dipolar Cycloaddition of 2- and 3Nitroindoles with Azomethine Ylides. A New Approach to Pyrrolo[3,4-b]indoles. Tetrahedron Lett. 2007, 48, 1313. (b) Wang, K.-K.; Du, W.; Zhu, J.; Chen, Y.-C. Construction of Polycyclic Spirooxindoles through [3 + 2] Annulations of Morita-Baylis-Hillman Carbonates and 3-Nitro-7-azaindoles. Chin. Chem. Lett. 2017, 28, 512. (c) Liu, X.; Yang, D.; Wang, K.; Zhang, J.; Wang, R. A Catalyst-Free 1,3-Dipolar Cycloaddition of C,N-cyclic Azomethine Imines and 3-Nitroindoles: An Easy Access to Five-ring-Fused Tetrahydroisoquinolines. Green Chem. 2017, 19, 82. (d) Rivinoja, D. J.; Gee, Y. S.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. The Diastereoselective Synthesis of Pyrroloindolines by Pd-Catalyzed Dearomative Cycloaddition of 1Tosyl-2-vinylaziridine to 3-Nitroindoles. ACS Catal. 2017, 7, 1053. (e) Gee, Y. S.; Rivinoja, D. J.; Wales, S. M.; Gardiner, M. G.; Ryan, J. H.; Hyland, C. J. T. Pd-Catalyzed Dearomative [3 + 2] Cycloaddition of 3-Nitroindoles with 2-Vinylcyclopropane-1,1-dicarboxylates. J. Org. Chem. 2017, 82, 13517. (f) Lee, S.; Diab, S.; Queval, P.; Sebban, M.; Chataigner, I.; Piettre, S. R. Aromatic CC Bonds as Dipolarophiles: Facile Reactions of Uncomplexed Electron-Deficient Benzene Derivatives and Other Aromatic Rings with a Non-stabilized Azomethine Ylide. Chem. - Eur. J. 2013, 19, 7181. (14) Selected asymmetric examples: (a) Awata, A.; Arai, T. PyBidine/Copper Catalyst: Asymmetric exo’-Selective [3 + 2] Cycloaddition using Imino Ester and Electrophilic Indole. Angew. Chem., Int. Ed. 2014, 53, 10462. (b) Trost, B. M.; Ehmke, V.; O’Keefe, B. M.; Bringley, D. A. Palladium-Catalyzed Dearomative Trimethylenemethane Cycloaddition Reactions. J. Am. Chem. Soc. 2014, 136, 8213. (c) Zhang, J.-Q.; Tong, F.; Sun, B.-B.; Fan, W.-T.; Chen, J.-B.; Hu, D.; Wang, X.-W. Pd-Catalyzed Asymmetric Dearomative Cycloaddition for Construction of Optically Active Pyrroloindoline and Cyclopentaindoline Derivatives: Access to 3aAminopyrroloindolines. J. Org. Chem. 2018, 83, 2882 and references cited therein . (15) Selected examples: (a) Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G. Efficient Method for the Synthesis of Polysubstituted Benzenes by One-Pot Tandem Reaction of Vinyl Malononitriles with Nitroolefines. J. Org. Chem. 2007, 72, 5443. (b) Rani, M. A.; Kumar, S. V.;

Roja, S. S.; Almansour, A. I.; Kumar, R. S.; Athimoolam, S.; Kumar, R. R. Synthesis of Highly Functionalized 2-Thiaspiro[4.5]deca-6,8dienes via Atom Efficient Tandem Michael Addition/Thorpe-Ziegler Cyclization. RSC Adv. 2016, 6, 40585. (c) Esmaeili, A. A.; Moradi, A.; Mohammadi, H. K. Regioselective Synthesis of Highly-substituted Biaryls by Reaction of Vinyl Malonontriles with Acetylenic Esters. Tetrahedron 2010, 66, 3575. (d) Babu, T. H.; Joseph, A. A.; Muralidharan, D.; Perumal, P. T. A Novel Method for the Synthesis of Functionalized Spirocyclic Oxindoles by One-pot Tandem Reaction of Vinyl Malononitriles with Isatylidene Malononitriles. Tetrahedron Lett. 2010, 51, 994. (e) Huang, X.-F.; Zhang, Y.-F.; Qi, Z.-H.; Li, N.K.; Geng, Z.-C.; Li, K.; Wang, X.-W. Organocatalytic Enantioselective Construction of Multi-finctionalized Spirooxindole dienes. Org. Biomol. Chem. 2014, 12, 4372. (f) Guo, Z.-W.; Li, X.-S.; Zhu, W.D.; Xie, J.-W. Construction of Chiral Multi-Functionalized Polyheterocyclic Benzopyran Derivatives by Using an Asymmetric Organocatalytic Domino Reaction. Eur. J. Org. Chem. 2012, 2012, 6924. (g) Shi, X.-M.; Dong, W.-P.; Zhu, L.-P.; Jiang, X.-X.; Wang, R. Asymmetric Vinylogous Michael Addition/Cyclization Cascade Reaction for the Construction of Diversely Structured Spiro-Oxindole Skeletons. Adv. Synth. Catal. 2013, 355, 3119. (16) CCDC 1852173 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ structures. (17) 3-Nitro-1-tosyl-1H-pyrrole and tert-butyl 4-nitro-1H-imidazole1-carboxylate were also tested under optimized reaction conditions. However, no corresponding desired products were obtained, probably due to the formed nitronates’ lack of stabilization by aromatic rings. (18) Cano, C.; Saravanan, K.; Bailey, C.; Bardos, J.; Curtin, N. J.; Frigerio, M.; Golding, B. T.; Hardcastle, I. R.; Hummersone, M. G.; Menear, K. A.; Newell, D. R.; Richardson, C. J.; Shea, K.; Smith, G. C. M.; Thommes, P.; Ting, A.; Griffin, R. J. 1-Substituted (Dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-ones Endowed with Dual DNA-PK/PI3-K Inhibitory Activity. J. Med. Chem. 2013, 56, 6386. (19) Lee, B. H.; Je, J. T.; Yu, S. J.; Yang, B. S.; Lee, S. J. Preparation of heterocyclic Compounds for Organic Light-emiting Device. JP Patent JP2016135775, 2016. (20) Cheng, Q.; Zhang, H.-J.; Yue, W.-J.; You, S.-L. PalladiumCatalyzed Highly Stereoselective Dearomative [3 + 2] Cycloaddition of Nitrobenzofurans. Chem. 2017, 3, 428. (21) Xue, D.; Chen, Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G. Transfer Hydrogenation of Activated CC Bonds Catalyzed by Ruthenium Amido Complexes: Reaction Scope, Limitation, and Enantioselectivity. J. Org. Chem. 2005, 70, 3584.

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DOI: 10.1021/acs.joc.8b01876 J. Org. Chem. 2018, 83, 12568−12574