AlCl3-Catalyzed Intramolecular Cyclization of N-Arylpropynamides

Nov 11, 2017 - Switchable ortho/ipso-cyclization of N-arylpropynamides induced with N-sulfanylsuccinimides as general sulfur reagents is reported. In ...
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AlCl3‑Catalyzed Intramolecular Cyclization of N‑Arylpropynamides with N‑Sulfanylsuccinimides: Divergent Synthesis of 3‑Sulfenyl Quinolin-2-ones and Azaspiro[4,5]trienones Wen-Chao Gao,*,† Tao Liu,† Yu-Fei Cheng,† Hong-Hong Chang,† Xing Li,† Rong Zhou,*,† Wen-Long Wei,† and Yan Qiao‡ †

College of Chemistry and Chemical Engineering, Taiyuan University of Technology, Taiyuan 030024, P. R. China State Key Laboratory of Coal Conversion, Institute of Coal Chemistry, Chinese Academy of Sciences, Taiyuan 030001, P. R. China

‡

S Supporting Information *

ABSTRACT: Switchable ortho/ipso-cyclization of N-arylpropynamides induced with N-sulfanylsuccinimides as general sulfur reagents is reported. In the presence of MeOH, parafluoro N-arylpropynamides exclusively undergo the ipsocyclization to give 3-sulfenyl azaspiro[4,5]trienones. Two kinds of bioactive heterocycles, benzothieno-[3,2-b]quinoline and -[2,3-c]quinolone, have been directly and efficiently prepared from the corresponding sulfenylated products.

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INTRODUCTION Quinolin-2-ones and their derivatives rank among the most important heterocycles in many naturally occurring products, as well as pharmaceutically active molecules in medicinal chemistry.1 Since it has been accepted that the introduction of a sulfenyl group into organic molecules or heterocycles can significantly enhance their activities and change their physical and pharmacological properties,2 some notable molecules bearing a 3-sulfenyl quinolin-2-one structure have been applied as inhibitors of t-BHP-induced cytotoxicity, inhibitors of DNA topoisomerase, and antifungal agents (Figure 1).1c−f Traditionally, the vast majority of efforts to synthesize 3-sulfenylated

quinolinone derivatives focused on the sulfenylation of quinolin-2-ones using sodium sulfide3 or odorous thiols2c,4 as sulfur sources. However, Kim and co-workers recently described a new method for synthesizing 3-sulfenylated 4hydroxyquinolinones by copper(I) bromide-dimethyl sulfidecatalyzed sulfenylation with arylsulfonylhydrazides as sulfur sources (Scheme 1a).5 Unfortunately, this method only functionalized the pre-existing quinolone framework relying on the strong nucleophilicity of its 3-position. Therefore, the preparation of 3-sulfenylated quinolin-2-ones from more readily available starting materials is highly desirable. In recent years, the intramolecular cyclization of Narylpropynamides has become a powerful and fascinating protocol to form new carbon−carbon and carbon−heteroatom bonds in a single step.6 Among the different variants of this protocol, ipso-spiro cyclization exclusively occurred to give 3functionalized azaspiro[4,5]trienone as the sole product, irrespective of whether the cyclization involved a radical or electrophilic process.7 Specifically, the synthesis of 3-sulfenyl azaspiro[4,5]trienones has been well developed using the ipsocyclization of N-arylpropynamides: Li and co-workers developed Cu-catalyzed radical ipso-cyclization of N-(paramethoxyaryl)propynamides with disulfides as sulfur sources;8a Wang and co-workers also described a similar spirocyclization reaction catalyzed by AgCl with thiophenols as sulfur sources, although the transformation had a wider substrate scope (Scheme 1b).8b As for the synthesis of 3-sulfenyl quinolin-2ones through ortho-cyclization of N-arylpropynamides, the only

Figure 1. Natural products and biological molecules containing quinolin-2-one framework and sulfenyl functional group. © 2017 American Chemical Society

Received: October 10, 2017 Published: November 11, 2017 13459

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

Article

The Journal of Organic Chemistry

Table 1. Optimization of Reaction Conditions for orthoCyclization of 1aa,b

Scheme 1. Different Strategies for the Synthesis of 3Sulfenylated Quinolin-2-ones and Azaspiro[4,5]trienones

known example was reported recently by Jiang and co-workers, in which a multicomponent reagent system of ArSO2Na/PCy3/ DMSO was used to promote the cyclization in a mixed solvent of 1,4-dioxane/ionic liquids (Scheme 1c).9 Nevertheless, to the best of our knowledge, the selective access of either 3-sulfenyl quinolin-2-ones or 3-sulfenyl azaspiro[4,5]trienones using a general sulfur-containing reagent has never been reported. Herein, as a continuation of our research on the selective synthesis of different heterocycles,10 we wish to report the efficient ortho-cyclization of N-arylpropynamides for the synthesis of various 3-sulfenylated quinolin-2-ones with Nsulfanylsuccinimides as sulfur sources, and two kinds of medicinal molecules embedded with a benzothiophene structure are thus directly built up from the corresponding sulfenylated products. Furthermore, using the same Nsulfanylsuccinimide reagents, for substrates with a para-fluoro group on the aniline ring, the ipso-cyclization of Narylpropynamides exclusively proceeds to access 3-sulfenyl azaspiro[4,5]trienones, assisted by methanol as a nucleophile (Scheme 1d).

entry

sulfur source

solvent

catalyst

yield (%)c

1 2 3 4 5 6 7 8 9 10d 11 12 13 14f 15 16 17 18 19g

2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 4 5 6 2a

TsOH (0.3) TFA (0.3) TfOH (0.3) BF3·Et2O (0.3) FeCl3 (0.3) AlCl3 (0.3) AlCl3 (0.2) AlCl3 (0.4) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3) AlCl3 (0.3)

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN THF toluene EtOAc CH2Cl2 DMF CH3CN CH3CN CH3CN CH3CN

0 0 0 28 10 trace 90 81 87 59 0 trace 25 56 0 24 0 0 84

a

b

Reaction conditions: 1a (0.15 mmol), sulfenyl reagent (0.225 mmol), and catalyst (0.045 mmol) in solvent (1.0 mL), at 60 °C for 7 h. cIsolated yield. dThe reaction was performed at room temperature for 24 h. fThe reaction was performed at reflux. gThe reaction was run at a scale of 2 mmol.

efficient and only gave 3a in 59% yield. Other solvents such as THF, toluene, ethyl acetate, CH2Cl2, and even more polar DMF were also tested, but none of them gave a better result than CH3CN (entries 11−15). As for other electrophilic sulfenyl reagents, the reaction using 4 only gave the desired product in 24% yield (entry 16), whereas 3a was not detected when 2a was replaced by 5 or 6 (entries 17 and 18). Furthermore, the present transformation was easily scaled up without loss of efficiency (entry 19). With these established conditions, the generality of orthocyclization with a range of N-sulfanylsuccinimides was first surveyed (Scheme 2, 3a−3i). The efficient formation of 3a−g illustrated that either electron-donating or -withdrawing substituents on the phenyl ring of the arylthiol moiety were tolerated. The reaction using N-sulfanylsuccinimide derived from 2-naphthalenethiol could give the desired product 3h in 87% yield. However, the transformation was unsuccessful when N-(ethylthio)succinimide was used as the sulfenyl reagent. Various alkynamides were also examined in the reaction with N-(p-tolylthio)succinimide (3j−3s). The substituents in the phenyl ring of the alkynyl moiety have no significant effects on the reaction efficiency, and the desired products 3j−3l were obtained in good yields. Note that the aliphatic alkynamide 1m

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RESULTS AND DISCUSSION The initial exploration of this reaction was performed by using N-methyl-N,3-diphenylpropiolamide 1a and N-sulfanylsuccinimide 2a as model substrates (Table 1). A series of catalysts including Lewis or Brönsted acids, which previously found application in the activation of 2a,11 were first examined for this reaction (entries 2−6). No cyclization product was detected when p-toluenesulfonic acid (TsOH) or trifluoroacetic acid (TFA) was used as the catalyst (entries 2 and 3). Even the stronger acid trifluoromethanesulfonic acid (TfOH) only gave the desired product 3a in low yield (entry 4). The reaction catalyzed by the Lewis acid BF3·Et2O or FeCl3 also gave inferior results (entries 5 and 6). To our delight, when AlCl3 was used as the catalyst, the yield of 3-sulfenyl quinolin-2-one 3a could be improved to 90% (entry 7). Raising or lowering the amount of AlCl3 did not give a better result (entries 8 and 9). The reaction performed at room temperature was found to be less 13460

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

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The Journal of Organic Chemistry

Scheme 3. Reaction of Free N−H Alkynamides with NSulfanylsuccinimides

Scheme 2. Scope and Limitations for the Synthesis of 3Sulfenyl Quinolin-2-onesa

With the successful development of methods for the formation of 3-sulfenyl quinolin-2-ones, we next investigated the ipso-cyclization of N-arylpropynamides for the synthesis of 3-sulfenyl azaspiro[4,5]trienone based on the reaction of 2a with 1s. Pleasingly, we found that N-arylpropynamides bearing a para-fluoro group could be exclusively converted to 3-sulfenyl azaspiro[4,5]trienone in the presence of methanol (1 equiv) and N-sulfanylsuccinimide (1.5 equiv) with no detection of ortho-cyclic products (for details, see the Supporting Information). Some N-sulfanylsuccinimides and alkynamide derivatives with para-fluoro groups were then prepared and subjected to this transformation (Scheme 4), and the desired Scheme 4. Scope and Limitations for the Synthesis of 3Sulfenyl Azaspiro[4,5]trienonesa

a

Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), and AlCl3 (0.06 mmol) in MeCN (1.5 mL) at 60 °C; isolated yield and reaction time are given. b0.5 equiv of AlCl3 was used.

was also a good substrate for this transformation and delivered 3m in 98% yield. Substrates bearing either electron-donating or -withdrawing groups on the phenyl ring of the aniline moiety were suitable for this transformation, while the substitution position had a major influence on the yield and structure of products. For example, substrates with ortho-substituted groups of the aniline moiety gave their desired products in moderate to high yields (3n and 3o), whereas two isomers, 3p and 3p′, were isolated at a ratio of 5.3:4 when a meta-chloro-substituted aniline derivative was employed. As for the alkynamides with para-substituted groups on the phenyl ring of the aniline moiety, the ortho-cyclization could also proceed, while desired products were only obtained in low to moderate yields (3q− 3s). It was worth noting that the sulfenylation of the aniline moiety proceeded as the major pathway in the reaction of 2a with 1r bearing a para-methoxy on the aniline ring, while 3sulfenyl azaspiro[4,5]trienone 8a derived from ipso-cyclization was detected in the reaction of 2a with 1s bearing a para-fluoro on the aniline moiety. Furthermore, the R2 groups attached to the nitrogen of amides such as N-ethyl and N-benzyl were all well compatible with this transformation, and the desired products 3t and 3u were isolated in good to excellent yields. In addition, with the use of tetrahydroquinolinamide 1v as the substrate, this reaction could deliver a tricyclic product 3v, which was structurally characterized by X-ray crystallography (see the Supporting Information). Interestingly, when the N− H alkynamides were used as substrates, the ortho-cyclization products were not detected at all, whereas the chlorothiolation of a C−C triple bond proceeded to give the noncyclized products 7a−7d instead (Scheme 3).12

a

Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), MeOH (0.2 mmol), and AlCl3 (0.06 mmol) in MeCN (1.5 mL) at 60 °C; isolated yield and reaction time are given.

spiro products 8a−8j could be furnished in good to high yields. Therefore, by this minor modification of reaction conditions and substrates, we can switch on the ipso/ortho-cyclization for the construction of different 3-sulfenyl N-containing heterocycles at will. To understand the reaction mechanism, several experiments were consequently performed (Scheme 5). First, when 1 equiv of radical scavenger TEMPO was added to the reaction system, we observed the formation of 3a in 61% yield and no TEMPObound intermediate was detected (eq 1). This observation ruled out the possibility of a radical pathway. Furthermore, when 4-phenyl quinolin-2-one was employed under standard conditions, the desired product 3a was not detected, and most of the starting materials were recovered (eq 2). This indicated 13461

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

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which deprotonation and defluorination occurred to produce intermediate F. Finally, the methyl group in intermediate F was removed via nucleophilic displacement (path b). After the method enabling switching between the construction of either 3-sulfenyl quinolin-2-ones or spiro[4,5]trienones had been developed, further applications of the obtained products and corresponding methods were explored. Benzothieno[3,2-b]quinoline is an important skeleton in bioactive molecules with antifungal and anticancer effects (Figure 1).1e,f To our delight, the reaction of 7 with POCl3 directly and efficiently gave the tetracyclic product 9 via double cyclization.13 9 has been reported to be easily transformed to the medicinal 3-arylthio quinolinium salts after N-methylation (Scheme 7, eq 1).1e,f Furthermore, the ortho-cyclization of 1w bearing a terminal alkynyl group could also proceed to produce the desired product 3w, which can be converted to the antitumor molecule benzo[b]thieno[2,3-c]quinolone 11 by Pdcatalyzed intramolecular arylation (eq 2).1d

Scheme 5. Control Experiments

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CONCLUSION In conclusion, we have developed a divergent method for the synthesis of both 3-sulfenyl quinolin-2-ones and azaspiro[4,5]trienones with N-sulfanylsuccinimides as general sulfur sources. For the free N−H alkylamide precursors, the chlorothiolation of a C−C triple bond proceeded rather than intramolecular cyclization. In the synthesis of 3-sulfenyl azaspiro[4,5]trienones via ipso-cyclization, N-arylpropynamides bearing a para-fluoro group in the aniline ring were used as substrates and methanol was used as the nucleophile. Mechanistic studies indicated that the MeOH-nucleophilic defluorination process may have been involved in ipso-cyclization. The resulting 3-sulfenyl products have been proved to be versatile intermediates for the alternative synthesis of benzo[b]thieno-[3,2-b]quinolines and -[2,3-c]quinolones. Efforts toward expanding the range of products to construct other fused heterocycles are underway.

that the sulfenylation process did not occur after the ringclosure step, and 4-phenyl quinolin-2-one was not likely to be the intermediate of ortho-cyclization. As for the ipso-cyclization of 1s, we found that the product 8a was not formed in the absence of H2O or MeOH (eq 3). Additionally, MS analysis of the reaction of 1s with 2a under standard conditions gave peaks at 376.11 (intermediate C) and 408.14 (intermediate D or [E +H]+; see the Supporting Information), which suggested that the electrophilic cyclization induced by sulfenium cation was involved and the oxygen atom of the carbonyl group of 8a originated from methanol. In light of these results and previous reports,9 a tentative mechanism was proposed for both the ortho- and the ipsosulfenylcyclization processes (Scheme 6). After the activation of 2a with AlCl3, the sulfenium cation was transferred to the C−C triple bond of 1a to form intermediate A. For the orthocyclization of 1a, intramolecular ortho-nucleophilic cyclization of the aniline ring resulted in intermediate B, which underwent deprotonation to produce 3a (path a). Alternatively, if fluorine was located at the para-position of amide, the neighboring sp2 carbon was prone to be attacked by external nucleophiles such as H2O or MeOH due to its electron deficiency. The nucleophilic attack of MeOH to 1s would induce the intramolecular ipso-cyclization to form intermediate D, in

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EXPERIMENTAL SECTION

General. 1H NMR spectra were recorded at 400 MHz and 13C NMR spectra were measured at 100 MHz using NMR spectrometers with CDCl3 as the solvent. Chemical shifts (δ) were measured in ppm and referenced to the deuterated chloroform (1H: δ = 7.26 ppm, 13C: δ = 77.00 ppm). High-resolution mass spectrometry (HRMS) was performed on a TOF-Q spectrometer instrument with an ESI source. Melting points were measured with a RD-II type melting point

Scheme 6. Proposed Mechanism

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DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

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The Journal of Organic Chemistry Scheme 7. Synthetic Application

apparatus (uncorrected). X-ray structural analysis was obtained with an X-ray single-crystal diffractometer. N-Sulfanylsuccinimides11 and Narylpropynamides14 are prepared following previous reports and the known compounds are identified by the comparison of their NMR spectra with reported data in the literature. Unless otherwise noted, reagents obtained from commercial sources were directly used without further purification; all solvents were obtained from commercial sources and were purified according to standard procedures. Petroleum ether (PE), where used, has the boiling point range of 60−90 °C. Column chromatography was performed on silica gel (200−300 mesh) by using ester acetate and petroleum ether as eluent. Typical Procedure for the Synthesis of 3-Sulfenyl Quinolin2-ones. To a solution of N-methyl-N,3-diphenylpropiolamide (1a, 0.2 mmol, 1.0 equiv) and N-sulfanylsuccinimides (2a, 0.3 mmol, 1.5 equiv) in CH3CN (1.5 mL) was added AlCl3 (0.06 mmol, 0.3 equiv), and the reaction mixture was stirred at 60 °C until the starting material was consumed. The resulting mixture was diluted with H2O, extracted by EtOAc (3 × 10 mL), and dried over anhydrous Na2SO4. After the organic solvent was removed under reduced pressure, the crude product was purified by flash chromatography on silica gel (PE/EtOAc = 4:1) to give 3a. Typical Procedure for the Synthesis of 3-Sulfenyl Azaspiro[4,5]trienones. To a mixture of N-(4-fluorophenyl)-N-methyl-3phenylpropiolamide (1s, 0.2 mmol, 1.0 equiv) and N-sulfanylsuccinimides (2a, 0.3 mmol, 1.5 equiv) in CH3CN (1.5 mL) was added AlCl3 (0.06 mmol, 0.3 equiv) and CH3OH (0.2 mmol, 1.0 equiv), and the reaction vessel was allowed to stir at 60 °C. After completion of the reaction, the mixture was quenched with H2O (10 mL) and extracted with EtOAc (3 × 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE/EtOAc = 3:1) to afford 8a. Typical Procedure for the Synthesis of Benzothieno[3,2b]quinoline. A mixture of 7b (0.2 mmol, 68.6 mg) and phosphorus oxychloride (1 mL) was stirred at 110 °C for 1 h. After being cooled to room temperature, the mixture was poured into cold water (20 mL), alkalized with concentrated ammonia to pH > 10, and extracted with ethyl acetate (3 × 10 mL). The ethyl acetate layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: PE/EtOAc = 50:1) to give the product 9b as yellow solid. Preparation of Benzothieno[3,2-b]quinoline. To a solution of 3-((2-bromophenyl)thio)-1-methylquinolin-2(1H)-one (3w, 0.2 mmol) and KOPiv (56.0 mg, 0.4 mmol, 2 equiv) in N,Ndimethylacetamide (1.5 mL) was added PdCl2(PPh3)2 (14 mg, 0.02 mmol) at room temperature. The mixture was stirred for 24 h at 140 °C and then quenched by adding hydrochloric acid (1M, 10 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL) and washed with H2O (5 × 10 mL). The combined organic layers were

then dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluent: PE/ EtOAc = 7:1) to give the product as a white solid. 1-Methyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3a). Yield: 64.0 mg (90%); time: 7 h; yellow solid; mp 157−159 °C; TLC, Rf = 0.32 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.64−7.58 (m, 1H), 7.51−7.43 (m, 4H), 7.26−7.21 (m, 3H), 7.16 (t, 1H, J = 7.2 Hz), 7.06 (d, 2H, J = 8.4 Hz), 6.98 (d, 2H, J = 8.0 Hz), 3.84 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.9, 155.6, 139.5, 136.7, 136.0, 132.5, 131.2, 129.5, 129.0, 128.8, 128.6, 128.30, 128.28, 126.2, 122.5, 121.6, 114.4, 31.0, 21.0; HRMS (ESI) m/z calcd. for C23H19NOS [M + H]+: 358.1260, found: 358.1265. 1-Methyl-4-phenyl-3-(phenylthio)quinolin-2(1H)-one (3b). Yield: 62.1 mg (90%); time: 8 h; yellow solid; mp 162−164 °C; TLC, Rf = 0.34 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.62−7.56 (m, 1H), 7.48−7.41 (m, 4H), 7.25−7.19 (m, 3H), 7.18−7.06 (m, 6H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.3, 155.4, 139.9, 136.8, 136.5, 131.1, 129.0, 128.7, 128.6, 128.4, 128.3, 128.2, 126.0, 125.9, 122.1, 121.3, 114.2, 30.7; HRMS (ESI) m/z calcd. for C22H18NOS [M + H]+: 344.1104, found: 344.1106. 3-((4-Methoxyphenyl)thio)-1-methyl-4-phenylquinolin-2(1H)-one (3c). Yield: 69.0 mg (92%); time: 9 h; yellow solid; mp 142−144 °C; TLC, Rf = 0.38 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.59−7.53 (m, 1H), 7.51−7.44 (m, 3H), 7.40 (d, 1H, J = 8.4 Hz), 7.24−7.21 (m, 2H), 7.20−7.16 (m, 3H), 7.11 (t, 1H, J = 7.2 Hz), 6.72 (d, 2H, J = 8.8 Hz), 3.79 (s, 3H), 3.74 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.5, 158.6, 154.1, 139.7, 137.0, 132.0, 130.9, 128.9, 128.3, 128.2, 127.5, 126.6, 122.1, 121,5, 114.4, 114.2, 55.3, 30.7; HRMS (ESI) m/z calcd. for C23H20NO2S [M + H]+: 374.1209, found: 374.1207. 3-((4-Chlorophenyl)thio)-1-methyl-4-phenylquinolin-2(1H)-one (3d). Yield: 64.1 mg (85%); time: 10 h; yellow solid; mp 159−161 °C; TLC, Rf = 0.30 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.63−7.57 (m, 1H), 7.50−7.42 (m, 4H), 7.23−7.18 (m, 3H), 7.16− 7.07 (m, 5H), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.2, 155.6, 139.9, 136.7, 135.0, 131.9, 131.3, 129.8, 129.0, 128.8, 128.5, 128.4, 125.6, 122.2, 121.3, 114.3, 30.7; HRMS (ESI) m/z calcd. for C22H17ClNOS [M + H]+: 378.0714, found: 378.0712. 1-Methyl-3-((4-nitrophenyl)thio)-4-phenylquinolin-2(1H)-one (3e). Yield: 65.2 mg (84%); time: 17 h; yellow solid; mp 185−187 °C; TLC, Rf = 0.38 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 8.04 (d, 2H, J = 8.8 Hz), 7.69−7.62 (m, 1H), 7.51−7.45 (m, 4H), 7.25−7.16 (m, 6H), 3.85 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.8, 157.5, 146.9, 145.3, 140.2, 136.3, 132.1, 129.4, 128.8, 128.5, 128.2, 126.6, 123.9, 123.0, 122.6, 121.1, 114.5, 30.9; HRMS (ESI) m/z calcd. for C22H17N2O3S [M + H]+: 389.0954, found: 389.0953. 3-((2-Bromophenyl)thio)-1-methyl-4-phenylquinolin-2(1H)-one (3f). Yield: 64.2 mg (76%); time: 23 h; yellow solid; mp 146−148 °C; TLC, Rf = 0.38 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 13463

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

Article

The Journal of Organic Chemistry

1,8-Dimethyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3o). Yield: 69.1 mg (93%); time: 5 h; yellow solid; mp 172−174 °C; TLC, Rf = 0.37 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.49−7.42 (m, 3H), 7.34 (t, 1H, J = 4.0 Hz), 7.24−7.19 (m, 2H), 7.10 (d, 2H, J = 8.0 Hz), 7.02−6.96 (m, 4H), 3.84 (s, 3H), 2.71 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 162.3, 154.7, 141.3, 137.3, 135.9, 135.2, 132.7, 129.5, 129.1, 128.7, 128.3, 128.1, 126.9, 126.3, 125.0, 123.2, 122.3, 38.4, 23.7, 21.0; HRMS (ESI) m/z calcd. for C24H22NOS [M + H]+: 372.1417, found: 372.1412. 5-Chloro-1-methyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3p). Yield: 41.2 mg (53%); time: 17 h; yellow solid; mp 198−200 °C; TLC, Rf = 0.32 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.48−7.36 (m, 5H), 7.25−7.18 (m, 3H), 7.09 (d, 2H, J = 8.0 Hz), 7.00 (d, 2H, J = 8.0 Hz), 3.78 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.2, 152.5, 141.7, 139.4, 136.0, 133.8, 132.7, 130.4, 130.2, 129.6, 128.9, 128.7, 127.96, 127.94, 126.4, 118.1, 113.6, 31.7, 21.1; HRMS (ESI) m/z calcd. for C23H18ClNOSNa [M + Na]+: 414.0690, found: 414.0689. 7-Chloro-1-methyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3p′). Yield: 31.1 mg (40%); time: 17 h; yellow solid; mp 208−210 °C; TLC, Rf = 0.47 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.50−7.43 (m, 3H), 7.40 (d, 1H, J = 1.6 Hz), 7.24−7.19 (m, 2H), 7.13−7.04 (m, 4H), 6.99 (d, 2H, J = 8.0 Hz), 3.76 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.1, 154.0, 140.5, 137.1, 136.5, 136.1, 132.3, 130.0, 129.5, 129.1, 128.6, 128.41, 128.38, 126.8, 122.4, 119.9, 114.1, 30.8, 21.0; HRMS (ESI) m/z calcd. for C23H18ClNOSNa [M + Na]+: 414.0690, found: 414.0694. 1,6-Dimethyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3q). Yield: 38.6 mg (52%); time: 7 h; yellow solid; mp 180−182 °C; TLC, Rf = 0.29 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.50−7.44 (m, 3H), 7.43−7.39 (m, 1H), 7.33 (d, 1H, J = 8.4 Hz), 7.25−7.20 (m, 2H), 7.07 (d, 2H, J = 8.0 Hz), 6.98 (d, 3H, J = 8.0 Hz), 3.80 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.4, 155.0, 137.8, 137.0, 135.8, 132.8, 132.3, 131.8, 129.5, 128.8, 128.6, 128.5, 128.3, 128.1, 126.3, 121.3, 114.2, 30.8, 21.0, 20.7; HRMS (ESI) m/z calcd. for C24H22NOS [M + H]+: 372.1417, found: 372.1418. 6-Methoxy-1-methyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3r). Yield: 23.2 mg (30%); time: 13 h; yellow solid; mp 170−172 °C; TLC, Rf = 0.21 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.50−7.41 (m, 3H), 7.35 (d, 1H, J = 9.2 Hz), 7.25−7.17 (m, 3H), 7.08 (d, 2 H, J = 8.0 Hz), 6.98 (d, 2H, J = 8.0 Hz), 6.63 (d, 1H, J = 2.8 Hz), 3.78 (s, 3H), 3.65 (s, 3H), 2.25 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.9, 154.4, 154.1, 136.9, 135.8, 134.5, 132.8, 129.5, 128.9, 128.6, 128.4, 128.2, 127.2, 122.1, 119.0, 115.4, 111.3, 55.5, 30.8, 21.0; HRMS (ESI) m/z calcd. for C24H22NO2S [M + H]+: 388.1366, found: 388.1363. 6-Fluoro-1-methyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3s). Yield: 20.8 mg (28%); time: 22 h; yellow solid; mp 102−104 °C; TLC, Rf = 0.33 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.53−7.45 (m, 4H), 7.34 (d, 1H, J = 8.8 Hz), 7.23−7.19 (m, 2H), 7.14 (d, 1H, J = 2.4 Hz), 7.10−7.06 (m, 2H), 6.98 (d, 2H, J = 8.0 Hz), 3.77 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.9, 153.2, 138.3, 136.2 (J = 2.0 Hz), 132.2, 130.8, 129.6, 129.4, 128.7, 128.5, 128.4, 127.8, 127.7, 122.5, 115.6, 30.9, 21.1; HRMS (ESI) m/z calcd. for C23H19FNOS [M + H]+: 376.1166, found: 376.1160. 1-Ethyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3t). Yield: 70.5 mg (95%); time: 6 h; yellow solid; mp 144−146 °C; TLC, Rf = 0.33 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.60−7.54 (m, 1H), 7.51−7.42 (m, 4H), 7.26−7.19 (m, 3H), 7.14−7.07 (m, 3H), 6.99 (d, 2H, J = 8.0 Hz), 4.43 (q, 2H, J = 3.2 Hz), 2.27 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz); 13C NMR (CDCl3, 100 MHz): δ 159.6, 154.5, 138.7, 136.9, 135.8, 132.7, 130.8, 129.5, 129.1, 128.8, 128.7, 128.3, 128.1, 126.5, 121.8, 121.6, 114.0, 38.5, 21.0, 12.6; HRMS (ESI) m/z calcd. for C24H22NOS [M + H]+: 372.1417, found: 372.1429. 1-Benzyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3u). Yield: 91.8 mg (97%); time: 10 h; yellow solid; mp 78−80 °C; TLC, Rf = 0.48 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.41−7.30 (m, 4H), 7.25−7.14 (m, 8H), 7.12−7.08 (dd, 1H, J = 8.0, 1.2 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.97 (t, 1H, J = 7.2 Hz), 6.91 (d, 2H, J = 8.0

7.64−7.58 (m, 1H), 7.47−7.42 (m, 5H), 7.24−7.19 (m, 3H), 7.14 (t, 1H, J = 7.2 Hz), 7.12−7.06 (m, 1H), 6.99−6.92 (m, 2H), 2.82 (s, 3H); 13 C NMR (CDCl3, 100 MHz): δ 159.9, 155.7, 140.0, 137.9, 136.4, 132.8, 131.3, 129.0, 128.4, 128.3, 127.4, 126.7, 125.2, 122.4, 122.2, 121.3, 114.3, 30.8; HRMS (ESI) m/z calcd. for C22H17BrNOS [M + H]+: 422.0209, found: 422.0212. 3-((2-Bromo-4-methylphenyl)thio)-1-methyl-4-phenylquinolin2(1H)-one (3g). Yield: 70.0 mg (81%); time: 9 h; yellow solid; mp 164−166 °C; TLC, Rf = 0.33 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.62−7.56 (m, 1H), 7.47−7.41 (m, 4H), 7.28 (s, 1H), 7.25−7.18 (m, 3H), 7.16−7.11 (m, 1H), 6.89 (s, 2H), 3.81 (s, 3H), 2.24 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.8, 154.9, 139.9, 137.1, 136.5, 134.0, 133.3, 131.1, 128.89, 128.85, 128.5, 128.42, 128.35, 125.9, 122.8, 122.1, 121.4, 114.2, 30.7, 20.6; HRMS (ESI) m/z calcd. for C23H18BrNOS [M + H]+: 436.0365, found: 436.0354. 1-Methyl-3-(naphthalen-2-ylthio)-4-phenylquinolin-2(1H)-one (3h). Yield: 68.1 mg (87%); time: 13 h; yellow solid; mp 157−159 °C; TLC, Rf = 0.31 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.72 (d, 1H, J = 8.0 Hz), 7.66−7.55 (m, 4H), 7.46−7.34 (m, 6H), 7.29−7.21 (m, 4H), 7.14 (t, 1H, J = 7.2 Hz), 3.81 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.4, 155.5, 140.0, 136.7, 134.0, 133.7, 131.8, 131.2, 129.0, 128.6, 128.30, 128.28, 128.2, 127.6, 127.2, 126.66, 126.65, 126.2, 125.9, 125.4, 122.1, 121.4, 114.2, 30.7; HRMS (ESI) m/ z calcd. for C26H20NOS [M + H]+: 394.1260, found: 394.1276. 1-Methyl-4-(p-tolyl)-3-(p-tolylthio)quinolin-2(1H)-one (3j). Yield: 60.1 mg (81%); time: 5 h; yellow solid; mp 142−144 °C; TLC, Rf = 0.35 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.57 (t, 1H, J = 7.2 Hz), 7.41 (d, 1H, J = 8.4 Hz), 7.31−7.22 (m, 3H), 7.18−7.07 (m, 5H), 6.99 (d, 2H, J = 8.0 Hz), 3,79 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.2, 155.0, 139.8, 138.0, 135.8, 134.0, 132.8, 130.9, 129.5, 129.0, 128.7, 128.6, 126.4, 122.0, 121.5, 114.1, 30.6, 21.4, 21.0; HRMS (ESI) m/z calcd. for C24H21NOSNa [M + Na]+: 394.1236, found: 394.1222. 4-(4-Chlorophenyl)-1-methyl-3-(p-tolylthio)quinolin-2(1H)-one (3k). Yield: 50.2 mg (65%); time: 7 h; yellow solid; mp 100−102 °C; TLC, Rf = 0.31 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.61−7.56 (m, 1H), 7.45−7.39 (m, 3H), 7.19−7.11 (m, 4H), 7.08− 7.03 (m, 2H), 6.98 (d, 2H, J = 8.0 Hz), 3.80 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.2, 153.4, 139.8, 136.1, 135.2, 134.3, 132.4, 131.1, 130.2, 129.6, 129.1, 128.6, 128.5, 127.0, 122.2, 121.1, 114.3, 30.7, 21.0; HRMS (ESI) m/z calcd. for C23H18ClNOSNa [M + Na]+: 414.0690, found: 414.0681. 4-(4-Bromophenyl)-1-methyl-3-(p-tolylthio)quinolin-2(1H)-one (3l). Yield: 72.2 mg (77%); time: 4 h; yellow solid; mp 180−182 °C; TLC, Rf = 0.27 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.62−7.55 (m, 3H), 7.42 (d, 1H, J = 8.4 Hz), 7.19−7.03 (m, 6H), 6.98 (d, 2H, J = 8.0 Hz), 3.80 (s, 3H), 2.26 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.2, 153.3, 139.8, 136.1, 135.7, 132.4, 131.5, 131.1, 130.5, 129.6, 129.1, 128.5, 127.0, 122.4, 122.2, 121.0, 114.3, 30.7, 21.0; HRMS (ESI) m/z calcd. for C23H19BrNOS [M + H]+: 436.0365, found: 436.0364. 1,4-Dimethyl-3-(p-tolylthio)quinolin-2(1H)-one (3m). Yield: 57.9 mg (98%); time: 4 h; yellow solid; mp 132−134 °C; TLC, Rf = 0.32 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.82 (d, 1H, J = 8.0 Hz), 7.63−7.57 (m, 1H), 7.38 (d, 1H, J = 8.0 Hz), 7.31−7.26 (m, 1H), 7.15 (d, 2H, J = 8.0 Hz), 7.03 (d, 2H, J = 8.0 Hz), 3.74 (s, 3H), 2.81 (s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.4, 151.4, 139.4, 135.6, 132.9, 131.0, 129.6, 129.0, 128.2, 126.2, 126.1, 122.1, 121.0, 114.4, 30.5, 20.9, 18.3; HRMS (ESI) m/z calcd. for C18H17NOSNa [M + Na]+: 318.0923, found: 318.0918. 8-Chloro-1-methyl-4-phenyl-3-(p-tolylthio)quinolin-2(1H)-one (3n). Yield: 45.1 mg (58%); time: 20 h; yellow solid; mp 156−158 °C; TLC, Rf = 0.26 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.56 (dd, 1H, J = 7.6, 1.6 Hz), 7.50−7.43 (m, 3H), 7.23−7.18 (m, 2H), 7.13−7.05 (m, 3H), 7.01 (t, 3H, J = 8.0 Hz), 3.98 (s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 161.6, 153.4, 138.2, 136.7, 136.3, 133.8, 132.1, 129.5, 128.6, 128.5, 128.3, 128.1, 127.6, 124.8, 122.7, 120.8, 38.5, 21.0 ; HRMS (ESI) m/z calcd. for C23H19ClNOS [M + H]+: 392.0870, found: 392.0860. 13464

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

Article

The Journal of Organic Chemistry

white solid; mp 154−156 °C; TLC, Rf = 0.34 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.29−7.24 (m, 1H), 7.23−7.17 (m, 3H), 7.16−7.11 (m, 3H), 7.08 (d, 2H, J = 8.8 Hz,), 6.48−6.38 (m, 4H), 2.82 (s, 3H); 13C NMR (CDCl3, 100 MHz):δ 183.8, 167.4, 152.8, 144.8, 133.9, 133.3, 132.6, 131.9, 130.5, 129.9, 129.8, 129.1, 128.4, 128.1, 67.7, 26.3. 3-((2-Bromophenyl)thio)-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (8d). Yield: 67.6 mg (77%); time: 12 h; white solid; mp 100−102 °C; TLC, Rf = 0.28 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.44 (dd, 1H, J = 8.0, 1.2 Hz,), 7.31−7.25 (m, 2H), 7.24−7.19 (m, 4H), 7.14−7.08 (m, 1H), 7.04−6.98 (m, 1H), 6.60−6.43 (m, 4H), 2.89 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 183.9, 167.2, 152.2, 145.0, 133.22, 133.17, 133.0, 132.4, 131.3, 130.5, 129.7, 129.0, 128.3, 127.9, 127.6, 126.0, 67.8, 26.3; HRMS (ESI) m/z calcd. for C22H17BrNO2S [M + H]+: 438.0158, found: 438.0146. 3-((2-Bromo-4-methylphenyl)thio)-1-methyl-4-phenyl-1azaspiro[4.5]deca-3,6,9-triene-2,8-dione (8e). Yield: 74.0 mg (82%); time: 14 h; colorless oil; TLC, Rf = 0.31 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.30−7.18 (m, 7H), 6.94−6.89 (m, 1H), 6.58− 6.43 (m, 4H), 2.89 (s, 3H), 2.23 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 183.9, 167.3, 150.7, 145.1, 139.9, 133.8, 133.7, 133.1, 131.7, 130.5, 129.4, 128.4, 128.14, 128.11, 127.9, 126.6, 67.7, 26.2, 20.7; HRMS (ESI) m/z calcd. for C23H19BrNO2S [M + H]+: 452.0314, found: 452.0311. 1-Methyl-3-(naphthalen-2-ylthio)-4-phenyl-1-azaspiro[4.5]deca3,6,9-triene-2,8-dione (8f). Yield: 65.5 mg (80%); time: 14 h; colorless oil; TLC, Rf = 0.29 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.79 (d, 1H, J = 1.6 Hz,), 7.75−7.71 (m, 1H), 7.69−7.65 (m, 1H), 7.64 (d, 1H, J = 8.8 Hz,), 7.47−7.40 (m, 2H), 7.33 (dd, 1H, J = 8.4, 2.0 Hz), 7.24−7.20 (m, 2H), 7.19−7.13 (m, 3H), 6.57−6.44 (m, 4H), 2.89 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 183.9, 167.7, 152.5, 145.1, 133.4, 133.2, 132.41, 132.37, 130.7, 130.5, 129.6, 128.7, 128.6, 128.4, 128.2, 128.1, 127.6, 127.4, 126.5, 126.4, 67.8, 26.3; HRMS (ESI) m/z calcd. for C26H20NO2S [M + H]+: 410.1209, found: 410.1213. 1,6-Dimethyl-4-phenyl-3-(p-tolylthio)-1-azaspiro[4.5]deca-3,6,9triene-2,8-dione (8g).8a Yield: 59.5 mg (77%); time: 6 h; colorless oil; TLC, Rf = 0.27 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.33−7.23 (m, 5H), 7.22−7.18 (m, 2H), 7.00 (d, 2H, J = 8.0 Hz), 6.47 (s, 2H), 6.35 (s, 1H), 2.77 (s, 3H), 2.27 (s, 3H), 1.76 (d, 3H, J = 1.6 Hz,); 13C NMR (CDCl3, 100 MHz): δ 184.7, 168.1, 153.5, 152.0, 145.5, 137.7, 132.9, 132.5, 132.0, 131.4, 130.5, 129.7, 128.4, 128.0, 127.9, 69.6, 25.7, 21.1, 17.8; 6-Fluoro-1-methyl-4-phenyl-3-(p-tolylthio)-1-azaspiro[4.5]deca3,6,9-triene-2,8-dione (8h).8b Yield: 54.7 mg (70%); time: 3 h; colorless oil; TLC, Rf = 0.30 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.35−7.23 (m, 3H), 7.22−7.13 (m, 4H), 6.98 (d, 2H, J = 8.0 Hz), 6.44−6.39 (m, 2H), 6.18 (d, 1H, J = 12.0 Hz), 2.89 (s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 185.8 (J = 15 Hz), 169.4 (J = 288 Hz), 167.9, 148.6, 141.5 (J = 4.0 Hz), 137.9, 134.3, 132.2 (J = 1.0 Hz), 131.7, 129.9, 129.7, 129.6, 128.4, 128.0, 127.2, 113.9, 113.8, 68.2 (d, J = 23.3 Hz), 26.1, 21.1. 1,4-Dimethyl-3-(p-tolylthio)-1-azaspiro[4.5]deca-3,6,9-triene-2,8dione (8i).8a Yield: 55.0 mg (88%); time: 4 h; colorless oil; TLC, Rf = 0.35 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.31−7.27 (m, 2H), 7.10 (d, 2H, J = 8.0 Hz), 6.57−6.52 (m, 2H), 6.38−6.32 (m, 2H), 2.86 (s, 3H), 2.31 (s, 3H), 1.82 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 184.0, 168.2, 153.3, 145.6, 137.6, 133.3, 131.4, 131.1, 129.9, 128.8, 68.1, 26.6, 21.1, 11.8. 1-Benzyl-4-phenyl-3-(p-tolylthio)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (8j). Yield: 70.0 mg (78%); time: 4 h; white solid; mp 112−114 °C; TLC, Rf = 0.35 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.28−7.16 (m, 10H), 7.11−7.07 (m 2H), 6.99 (d, 2H, J = 7.6 Hz), 6.33 (dt, 2H, J = 12.8, 2.8 Hz), 6.22 (dt, 2H, J = 10.8, 2.4 Hz), 4.54 (s, 2H), 2.27 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 184.2, 167.8, 152.0, 145.4, 137.8, 137.4, 132.8, 132.2, 131.7, 130.4, 129.7, 129.4, 128.9, 128.5, 128.2, 128.1, 127.8, 127.6, 68.1, 45.0, 21.1; HRMS (ESI) m/z calcd. for C29H24NO2S [M + H]+: 450.1522, found: 450.1520.

Hz), 5.53 (s, 2H), 2.18 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 160.4, 155.3, 139.2, 136.9, 136.3, 135.9, 132.7, 130.9, 129.5, 129.0, 128.8, 128.72, 128.70, 128.33, 128.26, 127.3, 126.8, 126.6, 122.1, 121.6, 115.0, 47.1, 21.0; HRMS (ESI) m/z calcd. for C29H24NOS [M + H]+: 434.1573, found: 434.1585. 7-Phenyl-6-(p-tolylthio)-2,3-dihydro-1H,5H-pyrido[3,2,1-ij]quinolin-5-one (3v). Yield: 48 mg (55%); time: 7 h; yellow solid; mp 174−176 °C; TLC, Rf = 0.36 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.49−7.42 (m, 3H), 7.33−7.30 (m, 1H), 7.25−7.21 (m, 2H), 7.10 (d, 2H, J = 8.4 Hz), 7.04−6.96 (m, 4H), 4.29−4.23 (m, 2H,), 3.02 (t, 2H, J = 2.4 Hz), 2.26 (s, 3H), 2.19−2.11(m, 2H); 13C NMR (CDCl3, 100 MHz): δ 159.8, 154.8, 137.2, 136.6, 135.7, 132.8, 130.3, 129.4, 128.9, 128.6, 128.2, 128.0, 126.8, 126.0, 124.7, 121.5, 121.2, 43.4, 27.7, 21.0, 20.7; HRMS (ESI) m/z calcd. for C25H22NOS [M + H]+: 384.1417, found: 384.1425. (E)-3-Chloro-N,3-diphenyl-2-(phenylthio)acrylamide (7a). Yield: 55.0 mg (75%); time: 18 h; yellow solid; mp 138−140 °C; TLC, Rf = 0.28 (PE:EtOAc = 9:1); 1H NMR (CDCl3, 400 MHz): δ 7.70 (brs, 1H), 7.59−7.55 (m, 2H), 7.44−7.39 (m, 5H), 7.34 (d, 2H, J = 8.0 Hz), 7.31−7.26 (m, 4H), 7.25−7.23 (m, 1H), 7.12−7.07 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ 162.3, 137.08, 136.97, 132.5, 130.7, 129.8, 129.4, 128.9, 128.8, 128.3, 128.1, 127.9, 124.9, 120.2; FTIR (cm−1): 3458, 3335, 3053, 1676, 1594, 1503, 1428, 1111, 751; HRMS (ESI) m/z calcd. for C21H17ClNOS [M + H]+: 366.0714, found: 366.0717. (E)-3-Chloro-N,3-diphenyl-2-(p-tolylthio)acrylamide (7b). Yield: 50.3 mg (70%); time: 22 h; yellow solid; mp 134−136 °C; TLC, Rf = 0.25 (PE:EtOAc = 9:1); 1H NMR (CDCl3, 400 MHz): δ 7.67 (brs, 1H), 7.61−7.55 (m, 2H), 7.49−7.40 (m, 3H), 7.36−7.25 (m, 6H), 7.14−7.06 (m, 3H), 2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 162.3, 138.5, 137.04, 137.02, 135.4, 133.5, 131.4, 130.1, 130.0, 129.7, 128.89, 128.87, 128.7, 128.5, 128.2, 124.8, 120.2, 21.1.; FTIR (cm−1): 3484, 3278, 3085, 1645, 1607, 1543, 1317, 1137, 816; HRMS (ESI) m/z calcd. for C22H19ClNOS [M + H]+: 380.0870, found: 380.0865. (E)-3-Chloro-2-((4-methoxyphenyl)thio)-N,3-diphenylacrylamide (7c). Yield: 61.0 mg (77%); time: 17 h; yellow solid; mp 120−122 °C; TLC, Rf = 0.23 (PE:EtOAc = 9:1); 1H NMR (CDCl3, 400 MHz): δ 7.62−7.53 (m, 3H), 7.47−7.40 (m, 3H), 7.40−7.35 (m, 2H), 7.33− 7.25 (m, 4H), 7.14−7.07 (m, 1H), 6.82−6.76 (m, 2H), 3.73 (s, 3H); 13 C NMR (CDCl3, 100 MHz): δ 162.3, 160.2, 136.9, 136.8, 134.6, 132.6, 130.1, 129.6, 128.98, 128.90, 128.2, 124.8, 121.9, 120.2, 114.9, 55.3; FTIR (cm−1): 3471, 3272, 3085, 1651, 1600, 1111, 616; HRMS (ESI) m/z calcd. for C22H19ClNO2S [M + H]+: 396.0820, found: 396.0812. (E)-3-chloro-2-((4-chlorophenyl)thio)-N,3-diphenylacrylamide (7d). Yield: 57.5 mg (72%); time: 20 h; yellow solid; mp 158−160 °C; TLC, Rf = 0.24 (PE:EtOAc = 9:1); 1H NMR (CDCl3, 400 MHz): δ 7.71 (brs, 1H), 7.55−7.52 (m, 2H), 7.42 (m, 3H), 7.38−7.28 (m, 6H), 7.26−7.24 (m, 2H), 7.12 (t, 1H, J = 7.2 Hz); 13C NMR (CDCl3, 100 MHz): δ 162.1, 137.5, 136.87, 136.83, 134.3, 132.0, 130.9, 129.9, 129.5, 129.0, 128.7, 128.3, 127.3, 125.0, 120.2; FTIR (cm−1): 3452, 3272, 3085, 1651, 1600, 1111, 751; HRMS (ESI) m/z calcd. for C21H16Cl2NOS [M + H]+: 400.0324, found: 400.0323. 1-Methyl-4-phenyl-3-(p-tolylthio)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (8a).8a Yield: 55.2 mg (74%); time: 7 h; white solid; mp 162−164 °C; TLC, Rf = 0.35 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.33−7.29 (m, 1H), 7.28−7.27 (m, 1H), 7.26− 7.20 (m, 5H), 7.00 (d, 2H, J = 8.0 Hz), 6.56−6.44 (m, 4H), 2.89 (s, 3H), 2.28 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 183.9, 167.7, 151.6, 145.2, 137.8, 133.9, 132.8, 131.7, 130.7, 129.7, 129.5, 128.22, 128.16, 127.6, 67.6, 26.2, 21.1; 1-Methyl-4-phenyl-3-(phenylthio)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (8b).8a Yield: 59.0 mg (84%); time: 14 h; yellow solid; mp 70−72 °C; TLC, Rf = 0.25 (PE:EtOAc = 7:3); 1H NMR (CDCl3, 400 MHz): δ 7.32−7.26 (m, 3H), 7.25−7.20 (m, 4H), 7.19−7.14 (m, 3H), 6.57−6.44 (m, 4H), 2.89 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 183.9, 167.6, 152.7, 145.1, 133.1, 132.1, 131.6, 130.9, 130.6, 129.6, 128.9, 128.2, 127.4, 67.6, 26.2; 3-((4-Chlorophenyl)thio)-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (8c).8a Yield: 67.0 mg (85%); time: 17 h; 13465

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

The Journal of Organic Chemistry

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11-Phenylbenzo[4,5]thieno[3,2-b]quinoline (9a). Yield: 52.2 mg (84%); time: 1 h; yellow solid; mp 168−170 °C; TLC, Rf = 0.32 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 8.72−8.68 (m, 1H), 8.38−8.34 (dd, 1H, J = 8.4, 4.0 Hz), 7.89−7.84 (m, 1H), 7.80− 7.75 (m, 2H), 7.66−7.56 (m, 7H), 7.54−7.49 (m, 1H); 13C NMR (CDCl3, 100 MHz): δ 153.6, 147.2, 141.61, 141.59, 136.7, 134.7, 132.1, 129.8, 129.7, 129.4, 129.0, 128.7, 126.1, 125.3, 125.05, 124.96, 124.1, 122.9; HRMS (ESI) m/z calcd. for C21H14NS [M + H]+: 312.0841, found 312.0847. 7-Methyl-11-phenylbenzo[4,5]thieno[3,2-b]quinoline (9b). Yield: 53.3 mg (82%); time: 1 h; yellow solid; mp 142−144 °C; TLC, Rf = 0.29 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 8.51 (s, 1H), 8.35 (d, 1H, J = 8.4 Hz), 7.87−7.83 (dd, 1H, J = 8.4, 4.0 Hz), 7.79− 7.73 (m, 1H), 7.67−7.54 (m, 6H), 7.53−7.47 (m, 1H), 7.43−7.39 (m, 1H), 2.59 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 153.5, 147.1, 141.5, 138.6, 136.7, 135.0, 134.8, 132.6, 131.2, 129.60, 129.41, 128.9, 128.6, 126.0, 125.3, 124.9, 124.1, 122.5, 21.3; HRMS (ESI) m/z calcd. for C22H16NS [M + H]+: 326.0998, found: 326.0999. 7-Methoxy-11-phenylbenzo[4,5]thieno[3,2-b]quinoline (9c). Yield: 51.8 mg (76%); time: 2 h; yellow solid; mp 174−176 °C; TLC, Rf = 0.25 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 8.35 (d, 1H, J = 8.4 Hz), 8.18 (d, 1H, J = 2.4 Hz), 7.86 (d, 1H, J = 8.4 Hz), 7.79−7.74 (m, 1H), 7.66−7.55 (m, 6H), 7.54−7.49 (m, 1H), 7.24−7.21 (dd, 1H, J = 8.8, 2.4 Hz), 4.04 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 158.1, 153.4, 147.1, 141.7, 136.7, 135.8, 133.4, 130.9, 129.6, 129.4, 129.0, 128.6, 126.1, 125.3, 125.0, 123.6, 119.9, 106.1, 55.9 ; HRMS (ESI) m/z calcd. for C22H16NOS [M + H]+: 342.0947, found: 342.0950. 3-((2-Bromophenyl)thio)-1-methylquinolin-2(1H)-one (3w). Yield: 42.8 mg (62%); time: 8 h; yellow solid; mp 120−122 °C; TLC, Rf = 0.27 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 7.78−7.73 (dd, 1H, J = 8.0, 1.6 Hz), 7.64−7.60 (dd, 1H, J = 7.6, 1.6 Hz), 7.53−7.47 (m, 1H), 7.40−7.27 (m, 4H), 7.21−7.16 (m, 1H), 6.97 (s, 1H), 3.80 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 159.6, 138.1, 136.4, 133.9, 132.62, 132.53, 131.2, 130.5, 129.60, 129.51, 128.5, 127.7, 122.4, 120.7, 114.1, 30.1; HRMS (ESI) m/z calcd. for C16H13BrNOS [M + H]+: 345.9896, found: 345.9902. 5-Methylbenzo[4,5]thieno[2,3-c]quinolin-6(5H)-one (11).15 Yield: 43.0 mg (81%); time: 24 h; white solid; mp 156−158 °C; TLC, Rf = 0.36 (PE:EtOAc = 8:2); 1H NMR (CDCl3, 400 MHz): δ 8.73−8.70 (m, 2H), 8.07−8.02 (m, 1H), 7.63−7.56 (m, 4H), 7.47−7.43 (m, 1H), 3.91 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ 158.6, 142.7, 138.6, 135.9, 135.2, 132.9, 128.7, 127.0, 125.5, 125.4, 124.1, 123.9, 122.6, 119.6, 115.5, 30.0.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 21502135), Natural Science Foundation of Shanxi Province (No. 2015021037), and the China Scholarship Council (No. 201608140185).

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REFERENCES

(1) (a) Nakashima, K.; Oyama, M.; Ito, T.; Akao, Y.; Witono, J. R.; Darnaedi, D.; Tanaka, T.; Murata, J.; Iinuma, M. Tetrahedron 2012, 68, 2421. (b) Kamperdick, C.; Van, N. H.; Sung, T. V.; Adam, G. Phytochemistry 1999, 50, 177. (c) Refouvelet, B.; Guyon, C.; Jacquot, Y.; Girard, C.; Fein, H.; Bévalot, F.; Robert, J.-F.; Heyd, B.; Mantion, G.; Richert, L.; Xicluna, A. Eur. J. Med. Chem. 2004, 39, 931. (d) Aleksić, M.; Bertoša, B.; Nhili, R.; Uzelac, L.; Jarak, I.; Depauw, S.; David-Cordonnier, M.-H.; Kralj, M.; Tomić, S.; Karminski-Zamola, G. J. Med. Chem. 2012, 55, 5044. (e) Zhu, X. Y.; Mardenborough, L. G.; Li, S.; Khan, A.; Zhang, W.; Fan, P.; Jacob, M.; Khan, S.; Walker, L.; Ablordeppey, S. Y. Bioorg. Med. Chem. 2007, 15, 686. (f) Boateng, C. A.; Eyunni, S. V. K.; Zhu, X. Y.; Etukala, J. R.; Bricker, B. A.; Ashfaq, M. K.; Jacob, M. R.; Khan, S. I.; Walker, L. A.; Ablordeppey, S. Y. Bioorg. Med. Chem. 2011, 19, 458. (2) (a) Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596. (b) Dénès, F.; Pichowicz, M.; Povie, G.; Renaud, P. Chem. Rev. 2014, 114, 2587. (c) Lee, C.-F.; Liu, Y.-C.; Badsara, S. S. Chem. - Asian J. 2014, 9, 706. (3) Wang, Z.; Xue, L.; He, Y.; Weng, L.; Fang, L. J. Org. Chem. 2014, 79, 9628. (4) (a) Etukala, J. R.; Yadav, J. S. Heteroat. Chem. 2008, 19, 221. (b) Hewawasam, P.; Fan, W.; Cook, D. A.; Newberry, K. S.; Boissard, C. G.; Gribkoff, V. K.; Starrett, J.; Lodge, N. J. Bioorg. Med. Chem. Lett. 2004, 14, 4479. (5) Paul, S.; Shrestha, R.; Edison, T. N. J. I.; Lee, Y. R.; Kim, S. H. Adv. Synth. Catal. 2016, 358, 3050. (6) (a) Jin, D.-P.; Gao, P.; Chen, D.-Q.; Chen, S.; Wang, J.; Liu, X.Y.; Liang, Y.-M. Org. Lett. 2016, 18, 3486. (b) Wang, L.-J.; Wang, A.Q.; Xia, Y.; Wu, X.-X.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2014, 50, 13998. (c) Yang, X.-H.; Ouyang, X.-H.; Wei, W.-T.; Song, R.-J.; Li, J.-H. Adv. Synth. Catal. 2015, 357, 1161. (d) Wen, J.; Wei, W.; Xue, S.; Yang, D.; Lou, Y.; Gao, C.; Wang, H. J. Org. Chem. 2015, 80, 4966. (e) Wei, W.-T.; Song, R.-J.; Ouyang, X.-H.; Li, Y.; Li, H.-B.; Li, J.-H. Org. Chem. Front. 2014, 1, 484. (f) Ouyang, X.-H.; Song, R.-J.; Li, Y.; Liu, B.; Li, J.-H. J. Org. Chem. 2014, 79, 4582. (g) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230. (7) Reddy, C. R.; Prajapti, S. K.; Warudikar, K.; Ranjan, R.; Rao, B. B. Org. Biomol. Chem. 2017, 15, 3130. (8) (a) Qian, P.-C.; Liu, Y.; Song, R.-J.; Xiang, J.-N.; Li, J.-H. Synlett 2015, 26, 1213. (b) Cui, H.; Wei, W.; Yang, D.; Zhang, J.; Xu, Z.; Wen, J.; Wang, H. RSC Adv. 2015, 5, 84657. (9) Wu, W.; An, Y.; Li, J.; Yang, S.; Zhu, Z.; Jiang, H. Org. Chem. Front. 2017, 4, 1751. (10) (a) Gao, W.-C.; Hu, F.; Tian, J.; Li, X.; Wei, W.-L.; Chang, H.H. Chem. Commun. 2016, 52, 13097. (b) Gao, W.-C.; Hu, F.; Huo, Y.M.; Chang, H.-H.; Li, X.; Wei, W.-L. Org. Lett. 2015, 17, 3914. (c) Gao, W.-C.; Jiang, S.; Wang, R.-L.; Zhang, C. Chem. Commun. 2013, 49, 4890. (11) (a) Wang, X.; Gensch, T.; Glorius, F. Org. Chem. Front. 2016, 3, 1619. (b) Gao, W.-C.; Liu, T.; Zhang, B.; Li, X.; Wei, W.-L.; Liu, Q.; Tian, J.; Chang, H.-H. J. Org. Chem. 2016, 81, 11297. (c) Hostier, T.; Ferey, V.; Ricci, G.; Pardoa, D. G.; Cossy, J. Org. Lett. 2015, 17, 3898. (d) Tian, H.; Zhu, C.; Yang, H.; Fu, H. Chem. Commun. 2014, 50, 8875. (12) Murphy, M.; Lynch, D.; Schaeffer, M.; Kissane, M.; Chopra, J.; O’Brien, E.; Ford, A.; Ferguson, G.; Maguire, A. R. Org. Biomol. Chem. 2007, 5, 1228. (13) This double cyclization may go through the intermediate I in Scheme 7. For the cyclization of amides promoted by POCl3, see: (a) Nowak, M.; Pluta, K.; Suwińska, K. New J. Chem. 2002, 26, 1216. (b) Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279. (c) Fodor,

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Corresponding Authors

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

Wen-Chao Gao: 0000-0002-1382-6210 Rong Zhou: 0000-0002-0322-9199 Notes

The authors declare no competing financial interest. 13466

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467

Article

The Journal of Organic Chemistry G.; Gal, J.; Phillips, B. A. Angew. Chem., Int. Ed. Engl. 1972, 11, 919. For the cyclization of Schiff bases promoted by acids, see: (d) Wu, Y.C.; Liu, L.; Li, H.-J.; Wang, D.; Chen, Y.-J. J. Org. Chem. 2006, 71, 6592. (e) Born, J. L. J. Org. Chem. 1972, 37, 3952. (14) Hua, H.-L.; He, Y.-T.; Qiu, Y.-F.; Li, Y.-X.; Song, B.; Gao, P.; Song, X.-R.; Guo, D.-H.; Liu, X.-Y.; Liang, Y.-M. Chem. - Eur. J. 2015, 21, 1468. (15) Li, X.; Pan, J.; Song, S.; Jiao, N. Chem. Sci. 2016, 7, 5384.

13467

DOI: 10.1021/acs.joc.7b02498 J. Org. Chem. 2017, 82, 13459−13467