Synthesis of Acridines from o-Aminoaryl Ketones and Arylboronic

Sep 20, 2018 - *E-mail: [email protected]., *E-mail: [email protected]. ... using copper(II)-mediated relay reactions that involve intermolecular ...
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Synthesis of Acridines from o‑Aminoaryl Ketones and Arylboronic Acids by Copper Trifluoroacetate-Mediated Relay Reactions Hao Wu, Zhiguo Zhang,* Nana Ma, Qingfeng Liu, Tongxin Liu, and Guisheng Zhang* Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China

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ABSTRACT: An efficient and practical method for the synthesis of medicinally important acridines from readily available o-aminoaryl ketones and arylboronic acids was developed using copper(II)-mediated relay reactions that involve intermolecular Chan−Lam cross-coupling and subsequent intramolecular Friedel−Crafts-type reactions. A sole promoter, i.e., Cu(OTf)2, was used; therefore, strongly acidic and basic conditions, nonreadily available or expensive substrates, additives, and noble-metal catalysts were not needed.

A

derivatives.9a o-Aminoaryl ketones are readily available and have been used as substrates for the synthesis of acridines through coupling with substituted cyclohexanones, hypervalent iodonium salts, and aryne intermediates generated from 2(trimethylsilyl)aryl triflates (Scheme 1). Recently, Wang’s

cridine derivatives and acridine-containing analogues show important biological and photocatalytic activities. As early as 1949, the effects of acridine compounds on respiration of the brain of chick embryos were reported.1 Because of their ability to intercalate into DNA and disrupt unwanted cellular processes, various acridines have been used in many areas of medicine, and significant biological activities toward cancers, viruses, bacteria, parasites, funguses, and Alzheimer’s disease have been reported.2,3 In addition, the 9mesityl-10-methylacridinium ion has been used as an effective electron-transfer photocatalyst for oxygenation of anthracenes and olefins and direct catalytic anti-Markovnikov hydroetherification of alkenols.4 9-Methylacridines and other acridine-containing analogues have also been used in the construction of new fluorescent probes5 and as triplet-state, light-emitting materials for organic light-emitting diodes.6 A great amount of research has therefore focused on the construction of acridine cores and preparation of acridinecontaining compounds.7−11 The Brenthsen reaction, a classical approach to acridine synthesis, needs high temperatures and strongly acidic conditions to achieve electrophilic annulation of carboxylic acids with diarylamines, and this greatly narrows the substrate scope.7 Some effective methods that use noble-metal catalysts have been developed.8 For example, Wang’s group developed a palladium-catalyzed synthesis of acridines from 1,2-dibromoarenes and N-tosylhydrazones of o-aminoaryl ketones, with RuPhos (2-dicyclohexylphosphanyl-2′,6′-diisopropoxybiphenyl) as a ligand.8a Buchwald reported acridine synthesis via a palladium-catalyzed intramolecular Heck reaction,8b and Ellman’s group reported a method that involved Rh(III)-catalyzed annulation of aromatic azides with aromatic imines.8e Recently, Miura’s group reported an unexpected Cu(OAc)2-promoted cyclization of tritylamines through C−H and C−N bond cleavages to produce acridine © 2018 American Chemical Society

Scheme 1. Synthetic Routes from o-Acylanilines

group reported methods that involve the reaction of oaminoaryl ketone substrates with cyclohexanone derivatives in the presence of TFA and TBHP in an O2 atmosphere (Scheme 1a).10 Wu’s group8c and Deng’s group8d almost simultaneously reported annulations of o-aminoaryl ketones and cyclohexanones under O2, which were catalyzed by Pd(TFA)2 and PdCl2(2-toluene)3, respectively (Scheme 1a). Hypervalent iodonium salts have also been used as substrates in reactions with o-aminoaryl ketones to produce acridines, under CuI Received: July 17, 2018 Published: September 20, 2018 12880

DOI: 10.1021/acs.joc.8b01828 J. Org. Chem. 2018, 83, 12880−12886

Note

The Journal of Organic Chemistry Scheme 2. Cu(II)-Mediated Cascade Reactions Consisting of Chan−Lam Cross-Coupling/Friedel−Crafts Reactions

Scheme 3. Aerobic Oxidative Annulation of o-Aminoaryl Ketones and Phenylboronic Acid

Table 1. Survey of Reaction Conditionsa

entry

cat. (equiv)

1 2 3 4 5 6b 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.0) Cu(OTf)2 (0.5) Cu(NO3)2 (1.2) Cu(acac2 (1.2) Cu(OAc)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.0) Cu(OTf)2 (0.5) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) Cu(OTf)2 (1.2) In(OTf)2 (0.5) Sc(OTf)2 (0.5) Fe(OTf)3 (0.5) Zn(OTf)2 (0.5)

additive (equiv)

L-proline (0.2) PPh3 (0.2) 1,10-phen (0.2) pyridine (0.2) PPh3 (0.2)

2a (equiv)

solvent

time (h)

3a yield (%)

4a yield (%)

recovered 1a (%)

1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.0 1.2 2.0 1.5 1.5 1.5 1.5

DMSO DMF PEG-400 DCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE TCE

24 24 24 24 14 24 36 36 24 24 24 14 14 14 14 48 72 72 18 48 48 48 48

0 0 15 75 90 73 75 73 trace 15 0 88 93 79 82 76 77 85 90 0 0 0 0

29 24 10 8 0 5 0 0 0 28 15 33 0 0 0 10 trace trace trace 0 0 0 0

71 70 65 10 0 15 18 21 63 63 58 0 0 0 0 0 8 9 0 85 83 88 78

Unless otherwise indicated, all reactions were performed with 1 (0.3 mmol) and 2 (1.5 equiv) at 100 °C. bReaction performed at 80 °C.

a

catalysis or metal-free conditions (Scheme 1b).9b Another effective method for acridine synthesis has been developed by using o-aminoaryl ketones as substrates in reactions with aryne intermediates generated from 2-(trimethylsilyl)aryl triflates in the presence of excess CsF (Scheme 1c).11 However, some of these methods for synthesizing acridines suffer from drawbacks such as the need for expensive metal catalysts, prefunctionalized/multistep starting materials, hazardous byproducts,

limited substrate scopes, and hazards associated with TBHP, e.g., explosions, fires, and toxicity. The design of general and practical strategies for the preparation of substituted acridones, particularly one-pot methods that use readily available substrates, non-noble-metal promoters, and do not need ligands and additives, is therefore of great interest. Here, we report an efficient and practical method for acridine synthesis through copper(II)-mediated relay reactions from o-aminoaryl 12881

DOI: 10.1021/acs.joc.8b01828 J. Org. Chem. 2018, 83, 12880−12886

Note

The Journal of Organic Chemistry Scheme 4. Reaction Extension

Unless otherwise indicated, all reactions were performed with 1 (0.3 mmol), 2 (1.5 equiv), and Cu(OTf)2 (1.2 equiv) in TCE (3 mL) at 100 °C.

a

annulations of o-aminoacetophenones and arylboronic acids for the synthesis of acridones.13 o-Aminoacetophenone (1b) reacted with phenylboronic acid (2a) to afford acridone (5a) in 90% yield, along with a trace amount of acridine 3b (Scheme 3a). When 2-aminodiphenyl ketone (1a) and 2a were subjected to the same conditions, a trace amount of acridine 3b was observed, and intramolecular C−H functionalization of, and C−N formation from, 1a or the generated intermediate 4a gave acridones 5a and 6a in yields of 15% and 65%, respectively (Scheme 3b). These observations indicate that the reaction must be protected from O2 to avoid oxidation of the α-methyl group of the ketone and C(sp2)−H functionalization of o-aminoacetophenones to favor formation of acridines 3. 2-Aminodiphenyl ketone (1a) was selected as a model substrate for the reaction with phenylboronic acid (2a). The reaction was expected to afford 9-phenylacridine (a precursor of the well-known electron-transfer photocatalyst 9-mesityl-10methylacridinium ion4 ). The reaction conditions were optimized in the absence of O2. Some of the key optimization experimental results are summarized in Table 1. First, Cu(OTf)2 was used to promote the reactions at 100 °C of 1a with 2a in various solvents, namely, DMSO, DMF, poly(ethylene glycol) (PEG-400), DCE, and 1,1,2,2-tetrachloroethane (TCE) (Table 1, entries 1−5). TCE emerged as the best solvent and gave a yield of 90% (Table 1, entry 5). Decreasing the reaction temperature to 80 °C (Table 1, entry 6) and the use of Cu(OTf)2 (Table 1, entries 7 and 8) led to lower yields and longer reaction times. Other Cu(II) salts, i.e., Cu(OAc)2, Cu(NO3)2, and Cu(acac)2, proved to be ineffective

ketones and commercially available arylboronic acids, with Cu(OTf)2 as the sole promoter, and without the use of strongly acidic and basic conditions, nonreadily available or expensive substrates, additives, and noble-metal catalysts (Scheme 1d). The acridine core is important in many areas of chemistry but there are currently a few mild, functionally tolerant methods available for the efficient synthesis of acridines. To circumvent the problems with known methods, the use of a non-noble-metal promoter, nonhazardous agents, and readily available substrates is a high priority. Our efforts to synthesize acridines are outlined in the brief retrosynthetic analysis shown in Scheme 2. Acridines 3 could be constructed by Lewis-acidcatalyzed intramolecular Friedel−Crafts reactions of N-aryl-oacylanilines 4, and the C−N bond of 4 could be formed by Chan−Lam cross-coupling reactions of o-aminoaryl ketones and arylboronic acids, based on the possibility of intermolecular coupling of arylamines with arylboronic acids catalyzed by transition metals.12 Cheap Cu(II) salts are Lewis acids and could also be used in Chan−Lam transformations as catalysts; therefore, we envisaged that acridines could be directly synthesized by reactions of the readily available substrates oaminoaryl ketones and commercially available arylboronic acids, with activation by a single Cu(II) salt. Arylboronic acids are well-known reagents and have a broad range of applications in organic synthesis because of their stability, structural diversity, ready availability, and low toxicity. The proposed strategy would therefore be simple and practical. We have developed copper(II)-catalyzed relay intermolecular couplings and subsequent intramolecular aerobic 12882

DOI: 10.1021/acs.joc.8b01828 J. Org. Chem. 2018, 83, 12880−12886

Note

The Journal of Organic Chemistry (Table 1, entries 9−11). In addition, a series of additives, namely, L-proline, triphenylphosphine, 1,10-phenantholine (1,10-phen), and pyridine, was tested to improve the yields and decrease the use of Cu(OTf)2, but no obvious improvement was observed (Table 1, entries 12−16). The ratio of 1a to 2a was also optimized, and it was found that the yield of 3a could not be further increased, regardless of the increasing or decreasing the amount of compound 2a (entries 17−19). Other trifluoroacetate salts, including In(OTf)2, Sc(OTf)2, Fe(OTf)3, and Zn(OTf)2, were also screened; they showed no catalytic activity than that of Cu(OTf)2, and most of the starting material was recovered (Table 1, entries 20−23). The optimum conditions (Table 1, entry 5) were therefore Cu(OTf)2 (1.2 equiv) as the activator and TCE as the solvent at 100 °C, and these were used in further investigations. With the optimum conditions in hand (Table 1, entry 5), we next investigated the substrate scope of the transformation; the results are summarized in Scheme 4. When the substituent (R1) attached to the carbonyl group of o-aminoaryl ketones 1 was phenyl, methyl, p-chlorophenyl, or o-chlorophenyl, the reactions with phenylboronic acid (2a) proceeded well, to give 3a, 3b, 3c, and 3d in yields of 90%, 86%, 80%, and 51% respectively. o-Aminobenzaldehyde gave a low yield, i.e., 55%, of 3e when subjected to the optimum reaction conditions; this is because of the instability of the aldehyde. Either electrondonating groups (EDGs) or electron-withdrawing groups (EWGs) on the benzene rings of o-aminoaryl ketones 1 gave good results in this transformation, and the corresponding products (3f−3j) were obtained in high yields (77%−85%). Notably, the reactions of chloro-, bromo-, and iodo-substituted o-aminoarylcarbonyl compounds with 2a proceeded well and gave good yields of 3h−3j within 10 h; these products could be used in further transformations. The scope of the Cu(OTf)2mediated tandem reactions was further expanded to a variety of substituted arylboronic acids 2. Compounds with a methyl group at different positions on the benzene ring reacted smoothly with 1a to produce the corresponding products 3k− 3p in high yields (70%−93%). The activity order is meta-3l,n,o > para/ortho-3k,m,p, in terms of yields. It is worth noting that meta-Me-substituted starting materials (2l and 2o) showed interesting regioselectivities and led to a mixture of products, i.e., 3l and 3l′ as well as 3o and 3o′, in total yields of 87% and 93%, respectively. These results indicate that cyclization at the meta position relative to R2 was favored over cyclization at the ortho position, based on the ratio of the isolated regioisomers. Arylboronic acids bearing p-fluoro-, p-phenyl, and a strong EDG (MeO) also reacted well to produce the corresponding products 3q, 3r, and 3s in yields of 88%, 82%, and 74%, respectively. However, arylboronic acids bearing a strong EWG (Ac) at the para position relative to the boronic group gave a lower yield (3t). Next, we investigated the synthesis of some fused polycyclic acridines (Scheme 5). 1-Naphthylboronic acid participated in this reaction to give the corresponding fused four-membered acridines 3u and 3v in reasonable yields, i.e., 43% and 40%, along with mixtures of unidentified products. Similarly, 1aminoanthracene-9,10-dione reacted smoothly with phenylboronic acid or 1-naphthylboronic to afford the desired fused five-membered system 3w and six-membered system 3x in yields of 84% (based on 57% conversion of 1-aminoanthracene-9,10-dione) and 83% (based on 48% conversion of 1-aminoanthracene-9,10-dione), respectively.

Scheme 5. Synthesis of Acridines Containing Fused Four- to Six-Membered Ring Systems

In summary, we have developed efficient Cu(OTf)2promoted tandem reactions involving intermolecular Chan− Lam cross-coupling and intramolecular Friedel−Craft reactions for the synthesis of medicinally important acridines from readily available o-aminoaryl ketones and arylboronic acids. This method avoids the need to use strong acidic and basic conditions, nonreadily available or expensive substrates, additives, and noble-metal catalysts. The protocol uses inexpensive Cu(OTf)2 as the sole promoter and no additives. The corresponding acridines were obtained in moderate to excellent yields. This economical, convenient, and efficient method should attract great attention in academic and industrial research.

■

EXPERIMENTAL SECTION

All reagents were purchased from commercial sources and used without further treatment. Petroleum ether (PE) used refers to the 60−90 °C boiling point fraction of petroleum. 1H NMR and 13C{1H} NMR spectra were recorded on a 400 MHz NMR spectrometer (1H NMR, 400 MHz; 13C{1H} NMR, 100 MHz at 25 °C). Coupling constants are reported in hertz (Hz). All high-resolution mass spectra (HRMS) were measured on a mass spectrometer (ESI-oa-TOF). Melting points were measured on a melting point with a thermometer and were uncorrected. All reactions were monitored by TLC. Flash chromatography was carried out on SiO2 (silica gel 200−300 mesh). General Procedure for the Reaction (3a as an Example). To a sealing tube (15 mL) were added phenylboronic acid 2a (55 mg, 0.45 mmol), Cu(OTf)2 (130 mg, 0.36 mmol), and o-aminodiphenyl ketone 1a (59 mg, 0.3 mmol). The mixture was stirred well for 14 h in TCE (3 mL) at 100 °C. (The whole process was closely monitored by TLC.) After the mixture cooled, a solution of NaHCO3 (10 mL) was added to the mixture, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic layer was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by a short flash silica gel column chromatography (eluent = ethyl acetate/petroleum ether = 1:15) to give 9-phenylacridine 3a as a yellow solid (69 mg, 90%). 12883

DOI: 10.1021/acs.joc.8b01828 J. Org. Chem. 2018, 83, 12880−12886

Note

The Journal of Organic Chemistry 9-Phenylacridine (3a). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (69 mg, 90% yield): mp 182−184 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz, 2H), 7.82−7.74 (m, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.61 (m, 3H), 7.50−7.39 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 148.8, 136.0, 130.4, 130.0, 129.6, 128.5, 128.4, 126.9, 125.6, 125.2; HRMS (ESI) m/z calcd for C19H14N ([M + H]+) 256.1121, found 256.1120. 9-Methylacridine (3b). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (50 mg, 86% yield): mp 90−92 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 (t, J = 8.0 Hz, 4H), 7.72 (t, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 H, 2H), 3.02 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 148.1, 142.3, 129.9, 129.7, 125.4, 125.3, 124.4, 13.5; HRMS (ESI) m/ z calcd for C14H12N ([M + H]+) 194.0964, found 194.0964. 9-(4-Chlorophenyl)acridine (3c). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (69 mg, 90% yield): mp 211−214 °C; 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J = 8.0 Hz, 2H), 7.77 (t, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 148.7, 145.6, 134.6, 134.3, 131.8, 130, 129.7, 128.8, 126.4, 125.9, 124.9; HRMS (ESI) m/z calcd for C19H13ClN ([M + H]+) 290.0731, found 290.0729. 2-Chloro-9-(2-chlorophenyl)acridine (3d). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:10) as a yellow solid (49 mg, 51%); 1H NMR (400 MHz, CDCl3) δ 8.29−8.25 (m, 2H), 7.81−7.77 (m, 1H), 7.71−7.66 (m, 2H), 7.58−7.74 (m, 5H), 7.35−7.33 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 148.8, 147.0, 143.3, 134.3, 134.1, 132.0, 131.9, 131.6, 131.3, 130.4, 130.1, 129.7, 127.1, 126.7, 126.2, 125.2, 125.2, 124.4; HRMS (ESI) m/z calcd for C19H12NCl2 ([M + H]+) 324.0347, found 324.0348. Acridine (3e). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (30 mg, 55% yield): mp 109−110 °C; 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.24 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 7.78− 7.76 (m, 2H), 7.54−7.50 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 149.0, 136.1, 130.3, 129.3, 128.2, 126.5, 125.7; HRMS (ESI) m/z calcd for C13H10N ([M + H]+) 180.0808, found 180.0808. 2-Methyl-9-phenylacridine (3f). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (68 mg, 84% yield): mp 133−135 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.72 (m, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.62−7.55 (m, 4H), 7.45− 7.33 (m, 4H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.1, 147.7, 145.8, 136.1, 135.3, 132.8, 130.3, 129.5, 129.4, 129.2, 128.3, 128.1, 126.6, 125.4, 125.2, 125.0, 124.6, 21.9; HRMS (ESI) m/z calcd for C20H16N ([M + H]+) 270.1277, found 270.1275. 2,3-Dimethoxy-9-methylacridine (3g). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (58 mg, 77% yield): mp 130−133 °C; 1H NMR (400 MHz, CDCl3) δ 8.18−8.12 (m, 2H), 7.72−7.68 (m, 1H), 7.52−7.50 (m, 1H), 7.45 (s, 1H), 7.27 (s, 1H), 4.09 (s, 3H), 4.08 (s, 3H), 3.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 153.9, 150.0, 147.2, 146.8, 139.2, 129.5, 128.8, 125.0, 124.7, 124.2, 122.1, 107.1, 100.9, 56.3, 56.10, 13.9; HRMS (ESI) m/z calcd for C16H16NO2 ([M + H]+) 254.1176, found 254.1171. 2-Bromo-9-methylacridine (3h). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (69 mg, 85% yield): mp 152−153 °C; 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.0 Hz, 1H), 8.12−8.05 (m, 2H), 7.98 (d, J = 8.0 Hz, 1H), 7.73−7.69 (m, 2H), 7.49−7.45 (m, 1H), 2.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.4, 146.6, 141.3, 133.2, 131.9, 130.3, 130.1, 126.7, 126.3, 126.1, 125.6, 124.5, 119.7, 13.7; HRMS (ESI) m/z calcd for C14H11BrN ([M + H]+) 272.0069, found 272.0069. 2-Iodo-9-methylacridine (3i). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (76 mg, 80% yield): mp 162−163 °C; 1H NMR (400

MHz, CDCl3) δ 8.56 (d, J = 1.6 Hz, 1H), 8.17−8.13 (m, 2H), 7.93− 7.85 (m, 2H), 7.77−7.73 (m, 1H), 7.55−7.51 (m, 1H), 2.98 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 148.5, 146.8, 141.1, 138.0, 133.6, 131.6, 130.1, 127.0, 125.9, 125.4, 124.5, 91.4, 13.6; HRMS (ESI) m/z calcd for C14H11IN ([M + H]+) 319.9931, found 319.9930. 2,4-Dibromo-9-methylacridine (3j). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (89 mg, 85% yield): mp 165−167 °C; 1H NMR (400 MHz, CDCl3) δ 8.38−8.22 (m, 2H), 8.19−8.08 (m, 2H), 7.83−7.71 (m, 1H), 7.59−7.50 (m, 1H), 2.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.6, 143.3, 142.2, 135.74, 130.9, 130.4, 126.9, 126.8, 126.6, 126.5, 125.8, 124.3, 118.2, 14.0; HRMS (ESI) m/z calcd for C14H10Br2N ([M + H]+) 349.9175, found 349.9176. 4-Methyl-9-phenylacridine (3k). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (59 mg, 73% yield): mp 122−124 °C; 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.0 Hz, 1H), 7.78−7.74 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.63−7.55 (m, 5H), 7.46−7.42 (m, 3H), 7.34− 7.30 (m, 1H), 3.03 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.4, 148.1, 146.9, 137.3, 136.5, 130.5, 130.2, 129.4, 129.2, 128.4, 128.2, 126.7, 125.5, 125.4, 124.9, 18.7; HRMS (ESI) m/z calcd for C20H16N ([M + H]+) 270.1277, found 270.1277. 1-Methyl-9-phenylacridine (3l) and 3-Methyl-9-phenylacridine (3l′). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (70 mg, 87% yield): mp 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 4.0 Hz, 1H3k′), 8.16 (d, J = 4.0 Hz, 1H3k), 7.72−7.69 (m, 1H), 7.66 (d, J = 4.0 Hz, 1H), 7.58−7.53 (m, 4H3k′), 7.51−7.47 (m, 4H3k), 7.40−7.38 (m, 2H), 7.36−7.33 (m, 3H3k′), 7.32−7.30 (m, 3H3k); 13C NMR (100 MHz, CDCl3) δ 149.1, 148.8, 146.8, 140.3, 136.0, 130.4, 130.1, 129.7, 129.4, 128.4, 128.4, 128.2, 127.8, 126.8, 126.4, 125.1, 124.8, 123.5, 29.7, 22.0; HRMS (ESI) m/z calcd for C20H16N ([M + H]+) 270.1276, found 270.1277. 2-Methyl-9-phenylacridine (3m). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (56 mg, 70% yield): mp 134−135 °C; 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 12 Hz, 1H), 7.74−7.70 (m, 1H), 7.67 (d, J = 8.0, 1H), 7.61−7.56 (m, 4H), 7.43− 7.36 (m, 4H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.2, 147.7, 145.9, 136.1, 135.4, 132.8, 130.4, 129.5, 129.4, 129.3, 128.4, 126.7, 125.4, 125.2, 125.1, 124.7, 22.0; HRMS (ESI) m/z calcd for C20H16N ([M + H]+) 270.1277, found 270.1277. 1,3-Dimethyl-9-phenylacridine (3n). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (64 mg, 90% yield): mp 143−145 °C; 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.53−7.49 (m, 3H), 7.42 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 4.0 Hz, 2H), 7.31 (t, J = 4.0 Hz, 1H), 7.07 (s, 1H), 2.52 (s, 3H), 1.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.5, 147.8, 146.8, 139.9, 139.8, 135.7, 131.9, 130.2, 129.7, 129.0, 128.1, 128.0, 127.4, 127.2, 126.2, 125.1, 123.0, 24.9, 21.9; HRMS (ESI) m/z calcd for C21H18N ([M + H]+) 284.1434, found 284.1432. 1,9-Dimethylacridine (3o) and 3,9-Dimethylacridine (3o′). The product was isolated by flash chromatography (eluent = ethyl acetate/ petroleum ether = 1:15) as a yellow solid (58 mg, 93% yield): mp 72−74 °C; 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.0 Hz, 2H), 8.07 (d, J = 8.0 Hz, 1H), 7.95−7.94 (m, 1H), 7.73−7.69 (m, 1H), 7.59−7.48 (m, 1H), 7.35−7.32 (m, 1H), 3.03 (s, 3H3n′), 2.72 (s, 3H3n), 2.56 (s, 3H); 13C NMR (100 MHz, CDCl3) 148.4, 148.1, 142.2, 140.2, 129.7, 128.2, 128.1, 125.1, 124.9, 124.5, 124.1, 123.8, 21.9, 13.5; HRMS (ESI) m/z calcd for C15H14N ([M + H]+) 208.1121, found 208.1121. 2,9-Dimethylacridine (3p). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (46 mg, 74% yield): mp 89−90 °C; 1 H NMR (400 MHz, CDCl3) δ 8.26−8.19 (m, 2H), 8.12 (d, J = 8.0 Hz, 1H), 7.98 (s, 1H), 7.75−7.71 (m, 1H), 7.62−7.59 (m, 1H), 7.55−7.51 (m, 1H), 3.09 (s, 3H), 2.61 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.9, 147.6, 141.8, 137.8, 130.8, 129.1, 129.0, 125.4, 125.2, 125.1, 124.4, 12884

DOI: 10.1021/acs.joc.8b01828 J. Org. Chem. 2018, 83, 12880−12886

Note

The Journal of Organic Chemistry 122.5, 18.8, 13.7; HRMS (ESI) m/z calcd for C15H14N ([M + H]+) 208.1121, found 208.1121 2-Fluoro-9-methylacridine (3q). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (56 mg, 88% yield): mp 121−123 °C; 1H NMR (400 MHz, CDCl3) δ 8.19−8.12 (m, 3H), 7.72 (t, J = 8.0 Hz, 2H), 7.60− 7.50 (m, 2H), 2.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5 (d, J = 247 Hz), 147.7, 145.5, 141.3 (d, J = 8.0 Hz), 132.73 (d, J = 9.0 Hz), 130.1, 129.5, 125.9, 125.5 (d, J = 9.0 Hz), 125.4, 124.1, 121.2 (d, J = 27.0 Hz), 106.6 (d, J = 22.0 Hz), 13.7; HRMS (ESI) m/z calcd for C14H11FN ([M + H]+) 212.0870, found 212.0880. 2,9-Diphenylacridine (3r). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (81 mg, 82% yield): mp 159−161 °C; 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.08−8.05 (m, 1H), 7.88 (d, J = 4.0 Hz, 1H), 7.79−7.75 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.65−7.59 (m, 5H), 7.53−7.48 (m, 2H), 7.44 (t, J = 4.0 Hz, 3H), 7.35 (t, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 148.8, 148.2, 147.3, 140.5, 138.0, 135.9, 130.5, 130.2, 130.1, 129.9, 129.6, 128.9, 128.5, 128.4, 127.6, 127.3, 126.8, 125.7, 125.5, 125.2, 124.1; HRMS (ESI) m/z calcd for C25H18N ([M + H]+) 332.1434, found 332.1425. 2-Methoxy-9-methylacridine (3s). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (50 mg, 74% yield): mp 111−113 °C; 1H NMR (400 MHz, CDCl3) δ 8.23−8.18 (m, 2H), 8.12 (d, J = 8.0 Hz, 1H), 7.72− 7.68 (m, 1H), 7.51−7.52 (m, 1H), 7.48−7.45 (m, 1H), 7.30 (d, J = 2.8 Hz, 1H), 4.00 (s, 3H), 3.04 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.9, 146.8, 145.4, 139.4, 131.7, 130.1, 128.6, 126.2, 125.7, 124.7, 124.1, 100.1, 55.4, 13.7; HRMS (ESI) m/z calcd for C15H14NO ([M + H]+) 224.1070, found 224.1070. 1-(9-Phenylacridin-2-yl)ethanone (3t). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (40 mg, 45% yield): mp 147−149 °C; 1H NMR (400 MHz, CDCl3) δ 8.36−8.35 (m, 1H), 8.30−8.28 (m, 3H), 7.86−7.81 (m, 1H), 7.76−7.73 (m, 1H), 7.67−7.62 (m, 3H), 7.49− 7.45 (m, 3H), 2.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.4, 150.1, 149.8, 149.8, 135.1, 134.0, 131.2, 130.4, 130.2, 130.0, 129.7, 128.9, 128.6, 127.5, 127.1, 126.2, 125.5, 124.0, 26.4; HRMS (ESI) m/ z calcd for C21H16NO ([M + H]+) 298.1232, found 298.1228. 7-Methylbenzo[c]acridine (3u). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (29 mg, 40% yield): mp 126−127 °C; 1H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 8.0 Hz, 1H), 8.37 (d, J = 12.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 12.0 Hz, 1H), 7.87−7.70 (m, 4H), 7.67 (d, J = 8.0 Hz, 1H), 7.62−7.53 (m, 1H), 3.04 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 147.0, 146.9, 141.0, 133.4, 132.0, 130.6, 129.1, 128.8, 127.6, 127.1, 127.1, 126.2, 125.5, 125.5, 124.2, 123.4, 122..1, 13.6; HRMS (ESI) m/z calcd for C18H14N ([M + H]+) 244.1121, found 244.1122. 7-Phenylbenzo[c]acridine (3v). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:15) as a yellow solid (39 mg, 43% yield): mp 123−124 °C; 1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 8.0 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.89−7.78 (m, 3H), 7.77−7.69 (m, 2H), 7.64−7.56 (m, 4H), 7.53− 7.42 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 147.4, 147.3, 146.1, 136.3, 133.5, 131.6, 130.5, 129.9, 129.3, 129.0, 128.4, 128.2, 127.7, 126.6, 125.8, 125.8, 125.5, 124.1, 123.1; HRMS (ESI) m/z calcd for C23H16N ([M + H]+) 306.1277, found 306.1278. 9H-Naphtho[3,2,1-kl]acridin-9-one (3w). The product was isolated by flash chromatography (eluent = ethyl acetate/petroleum ether = 1:20) as a yellow solid (40 mg, 84% yield, based on the 57% conversion rate of 1v): mp 220−223 °C; 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 12.0 Hz, 1H), 8.72−8.70 (m, 1H), 8.58−8.55 (m, 3H), 8.33 (d, J = 12.0 Hz, 1H), 8.01−7.97 (m, 1H), 7.90−7.77 (m, 2H), 7.72−7.68 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 183.0, 150.8, 147.1, 136.4, 135.3, 134.6, 133.6, 133.3, 132.7, 130.8, 130.6, 130.1, 130.0, 129.7, 128.8, 128.4, 127.6, 126.0, 123.2, 121.1; HRMS (ESI) m/z calcd for C20H12NO ([M + H]+) 282.0913, found 282.0907.

9H-Benzo[c]naphtho[3,2,1-kl]acridin-9-one (3x). The product was isolated in 83% yield (based on the 48% conversion rate of 1w), 39 mg, as a yellow solid: mp 233−234 °C; 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J = 8.0 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.68 (d, J = 8.0 Hz, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.55−8.53 (m, 2H), 8.02 (t, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.86−7.79 (m, 4H), 7.70 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 136.6, 135.4, 133.8, 133.2, 132.6, 132.3, 131.8, 130.8, 129.8, 129.6, 129.4, 129.3, 128.7, 127.9, 127.7, 126.8, 125.8, 125.3, 123.6, 122.3; HRMS (ESI) m/z calcd for C24H14NO ([M + H]+) 332.1075, found 332.1078.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01828. NMR spectra for compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Zhiguo Zhang: 0000-0001-6920-0471 Nana Ma: 0000-0003-3225-9554 Tongxin Liu: 0000-0003-2321-8208 Guisheng Zhang: 0000-0001-9880-950X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NSFC (U1604285, 21772032, and 21702051), PCSIRT (IRT1061), 111 Project (D17007), Science and Technology Innovation Talents in Universities of Henan Province (17HASTIT002), and Outstanding Young Talent Cultivation Project Funding of Henan Normal University (14YR002). We thank Helen McPherson, Ph.D., from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

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REFERENCES

(1) (a) Albert, A.; Marshall, P. B. Absence of Correlation between Respiratory Inhibition of Plasmodia by Acridines and Antimalarial Action. Nature 1948, 161, 1008. (b) O’Connor, R. J. Effect of Acridine Compounds on the Resplration of the Brain of the Six-Day Chick Embryo. Nature 1949, 163, 405. (2) (a) Ma, Z.; Choudhury, J. R.; Wright, M. W.; Day, C. S.; Saluta, G.; Kucera, G. L.; Bierbach, U. A. Non-Cross-Linking PlatinumAcridine Agent with Potent Activity in Non-Small-Cell Lung Cancer. J. Med. Chem. 2008, 51, 7574. (b) Goodell, J. R.; Ougolkov, A. V.; Hiasa, H.; Kaur, H.; Remmel, R.; Billadeau, D. D.; Ferguson, D. M. Acridine-Based Agents with Topoisomerase II Activity Inhibit Pancreatic Cancer Cell Proliferation and Induce Apoptosis. J. Med. Chem. 2008, 51, 179. (c) Delcros, J.-G.; Tomasi, S.; Carrington, S.; Martin, B.; Renault, J.; Blagbrough, I. S.; Uriac, P. Effect of Spermine Conjugation on the Cytotoxicity and Cellular Transport of Acridine. J. Med. Chem. 2002, 45, 5098. (d) Campbell, N. H.; Parkinson, G. N.; Reszka, A. P.; Neidle, S. Structural Basis of DNA Quadruplex Recognition by an Acridine Drug. J. Am. Chem. Soc. 2008, 130, 6722. (e) Cheng, M.-K.; Modi, C. J.; Cookson, C.; Hutchinson, I.; Heald, R. A.; McCarroll, A. J.; Missailidis, S.; Tanious, F.; Wilson, W. D.; Mergny, J.-L.; Laughton, C. A.; Stevens, M. F. G. Antitumor Polycyclic Acridines. 20.1 Search for DNA Quadruplex Binding Selectivity in a Series of 8, 13-Dimethylquino[4,3,2-kl]acridinium Salts: Telomere-Targeted Agents. J. Med. Chem. 2008, 51, 963.

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DOI: 10.1021/acs.joc.8b01828 J. Org. Chem. 2018, 83, 12880−12886

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DOI: 10.1021/acs.joc.8b01828 J. Org. Chem. 2018, 83, 12880−12886