Copper-Catalyzed Direct, Regioselective Arylamination of N-Oxides

Aug 7, 2017 - Copper-Catalyzed Direct, Regioselective Arylamination of N-Oxides: Studies To Access Conjugated π-Systems. Aniruddha Biswas, Ujjwal Kar...
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Copper-Catalyzed Direct, Regioselective Arylamination of N‑Oxides: Studies To Access Conjugated π‑Systems Aniruddha Biswas, Ujjwal Karmakar, Shiny Nandi, and Rajarshi Samanta* Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India S Supporting Information *

ABSTRACT: An efficient copper(I)-catalyzed direct regioselective arylamination of various heterocyclic N-oxides was achieved successfully under redox-neutral conditions using anthranils as arylaminating reagents. The developed protocol is simple, straightforward, and economic with a broad range substrate scope. The dual functional groups in the final molecules were utilized to construct structurally and functionally diverse nitrogen-containing organic π-conjugated systems.

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INTRODUCTION Distinguished methods for the efficient synthesis of structurally and functionally diverse nitrogen-containing heterocyclic privileged scaffolds starting from the single scaffold are in high demand.1 Among many nitrogen-containing heterocyclic scaffolds, quinoline and related heterocycles are often present in numerous biologically active natural products, pharmaceuticals, agrochemicals, and functional materials.2 The design of specific quinoline-based molecular scaffolds giving rise to versatile compound classes is an important area. Arguably, one of the best approaches to obtain the desired scaffold is transition-metal-catalyzed direct introduction of the functional groups into the quinoline and related moieties, especially into its N-oxide congeners.3,4 Several transition-metal-catalyzed efficient methods were established for the direct C2 selective arylation,5 heteroarylation,6 alkylation,7 alkenylation,8 and C− O9 or C−S bond formations10 on quinoline N-oxide moieties. Very recently, the transition-metal-free C2 selective functionalization of N-oxides was also discussed in the literature.11 Undoubtedly, C2 selective direct C−N bond formations of these scaffolds become a significant area to get attention.12 For example, Li et al. reported CuII-catalyzed C2 aminations of the quinoline N-oxides using lactams, cyclamines, or O-benzoyl hydroxylamines (Scheme 1a,b).12a,b In another elegant approach, Wu and Cui’s group revealed the CuI-catalyzed C2 selective aminations of these N-oxides used secondary aliphatic amines (Scheme 1c).12c Bolm and co-workers also described CuI-catalyzed sulfoximinations of quinoline N-oxides at its C2 position (Scheme 1d).12d Singh’s group recently published the metal-free, stoichiometric phosphonium salt-mediated sulfoximination of azine N-oxides (Scheme 1e).11b To the best of our knowledge, none of these methods addressed C2 selective aryl aminations. Furthermore, challenging other N-oxide substrates was also not successfully surveyed. To overcome these issues, we categorically concentrated on anthranil for our desired © 2017 American Chemical Society

Scheme 1. C2 Selective C−N Bond Formations of Quinoline N-Oxide

transformation because this bifunctional arylaminating agent was recently admired for its ability in various direct arylaminations of sp2 and sp3 C−H bonds.13,14 Its application was known earlier in coupling reactions with organozinc reagents under nickel catalysis,15 but exclusive properties like Received: May 31, 2017 Published: August 7, 2017 8933

DOI: 10.1021/acs.joc.7b01343 J. Org. Chem. 2017, 82, 8933−8942

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The Journal of Organic Chemistry the (i) generation of the aryl nitrene reactive intermediate, (ii) exclusion of external oxidants, and (iii) construction of products with bifunctionality make this one an attractive arylaminating agent to the current researchers. Notably, Hashmi and co-workers described gold-catalyzed annulation techniques to obtain quinolines and 7-acyl indoles using alkynes and anthranils.13a,b In a seminal work, Li and Lan’s group elegantly described RhIII-catalyzed sp3 and sp2 C−H aminations using this bifunctional arylaminating agent.14a Li’s group further improved their indazole synthesis using cooperative CoIII/CuII catalysis.14b In an independent approach, Jiao and co-workers also successfully provided aryl aminations of sp3 and sp2 C−H bonds under RhIII catalysis.14c,d Recently, Li’s group and Wang’s group separately reported the RhIII-catalyzed amination/annulation strategies on indole and 2-pyridone scaffolds.14e,f Very recently, Kim’s group and Yang and Xu’s group individually developed RhIII-catalyzed C-7 amination of indolines with anthranils.14g,h Despite these significant advancements, these methods were mostly limited with either the use of expensive transition-metal catalysts or harsh reaction conditions. Thus, there is still high demand for straightforward economic access to arylaminated N-oxides, high-valued synthons for nitrogen-containing polyaromatic hydrocarbons using cheap, earth abundant, first row transition-metal catalysts.16 In continuation with our interest in directed C−H bond functionalizations,17 especially on the construction of quinoline N-oxide-based organic conjugated π-systems using earth abundant transition-metal catalysts,18 herein we report the syntheses of the C2-arylaminated quinoline and related heterocyclic N-oxides via their cross couplings with anthranils using the eco-friendly and economical copper catalyst (Scheme 1f).

Table 1. Optimization for the Synthesis of Copper-Catalyzed Arylamination Using Anthranila

entry

catalyst

loading (mol %)

solvent

yield (%)b

1 2 3 4 5 6c 7 8 9 10 11 12 13 14 15

Cu(MeCN)4PF6 CuCN CuCl CuBr CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI Cu(OAc)2

10 10 10 10 10 10 10 10 10 10 10 10 10 2 10

1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane DCE EtOAc CH3CN toluene EtOH DMF DMSO 1,4-dioxane 1,4-dioxane

trace trace 62 66 83 89 10 24 32 44 21 52 57 34 nd

a

Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), Cu catalyst (10 mol %), 100 °C, 24 h, 0.1 M, air. bIsolated yields. DCE = 1,2dichloroethane. nd = not detected. cReaction time: 36 h.

groups at the different positions of N-oxides were well tolerated. Electron-donating groups at the C6 position of the quinoline ring firmly survived (Scheme 2, 3b−3e). Substrates containing halogens at the C6 position were well accommodated by keeping the window open for further modifications (Scheme 2, 3f−3h). Importantly, an electron-withdrawing group like the CF3 group at that position was also well accepted (Scheme 2, 3i). Substitutions at the C5 or C4 positions were proved to be quite successful (Scheme 2, 3j,n) for this reaction. Although alkyl and halogen groups were compatible at the C8 position (Scheme 2, 3l−3m), the sensitive acetal group was cleaved during the operation to provide the corresponding product with double aldehyde groups (Scheme 2, 3k). Next, we wanted to examine the nitrogen-containing polyaromatic hydrocarbons, benzo[f ]quinoline and benzo[h]quinoline Noxides, as the expected products could be more interesting in the light of functional materials. We were pleased to see that these substrates smoothly offered expected polyaromatic products with good yields (Scheme 2, 3o−3p). Quinolines with one more saturated ring also afforded the desired products with impressive yields (Scheme 2, 3q−3r). Gratifyingly, another class of isomeric heterocycles, i.e., isoquinoline Noxides, also offered excellent yields and an admirable degree of regioselectivity (Scheme 2, 3s−3u). To make this protocol more general, we explored another class of challenging substrates, i.e., pyridine N-oxides, under our optimized conditions and we were glad to find that the transformations were carried out with moderate to excellent yields (Scheme 2, 3v−3x). Strikingly, another two imporatant classes of nitrogencontaining heterocycles, quinoxaline and quinazoline N-oxides, were also screened with commendable yields and regioselectivity (Scheme 2, 3y−3z). Finally, the structure of the product was unequivocally confirmed via the single-crystal X-ray analysis of compound 3p (Supporting Information, Table

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RESULTS AND DISCUSSION On the basis of the above assumptions, we initiated our investigations using the reactions of quinoline N-oxide (1a) with anthranil (2a) in the presence of copper catalysts. Initially, we turned our attention toward the screening of CuI salts for the transformation. Cu(MeCN)4PF6 and CuCN were found to be extremely useless for this reaction (Table 1, entries 1 and 2). Among the other CuI salts, we were delighted to find that CuCl afforded a reasonably good yield of the desired product in 62% yield (Table 1, entry 3). Furthermore, the other CuI salts like CuBr or CuI were also screened (Table 1, entries 4 and 5), and satisfyingly, 83% isolated yield of the desired product was obtained under CuI-catalyzed conditions (Table 1, entry 5). The isolated yield was marginally improved to 89% via the extension of reaction duration (Table 1, entry 6). For further improvement, other solvents with different polarities were tested. Among them, 1,2-dichloroethane, EtOAc, MeCN, and toluene offered poor yields (Table 1, entries 7−10). Although applications of polar aprotic solvents like DMF and DMSO offered moderate yields of the desired product (Table 1, entries 12 and 13), the polar protic solvent EtOH provided a poor yield (Table 1, entry 11). Incidentally, lower catalyst loading afforded a reduced isolated yield (Table 1, entry 14). Notably, Cu(OAc)2 did not turn out to be an effective catalyst for this transformation (Table 1, entry 15). With the optimized conditions in hand, we sought to explore the substrate scope (Scheme 2). In general, under standard conditions, electronically and sterically variable functional 8934

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Scheme 3. Scope with Various Anthranil Compoundsb

Scheme 2. C2-Arylamination of Different N-Oxides with Anthranild

Reaction temperature: 120 °C bReaction conditions: 1a (0.1 mmol), 2a (0 2 mmol), CuI (10 mol %), 18−36 h, 80−100 °C. a

4a).12d Herein, we envisioned that the obtained final product 3a and its deoxygenated congener 5 would provide strategic platforms to construct nitrogen-containing polyaromatic hydrocarbons via a series of post synthetic modifications (Scheme 4).19 Accordingly, compound 5 was converted into the important quinolino-quinazolinone motif 6 through a novel TBHPmediated oxidative coupling (Scheme 4b).20 Further, a cascade deoxygenation followed by immediate intramolecular alkylation of 3a provided quinolino-quinazoline moiety 7 in a very good yield (Scheme 4c). Interestingly, under an unprecedented double-defunctionalization strategy, benzimidazo[1,2-a]quinoline scaffold 8 was synthesized from 3a (Scheme 4d). Moreover, the formyl group of 3a could be converted into its α,β-unsaturated ester derivative 9 and alkyne derivative 10 in excellent yields (Scheme 4e,f). Additionally, this ortho-amino carbonyl compound 5 was converted into substituted 2-indolyl quinoline scaffold 11 via a 1,2-aryl migration (Scheme 4g)14c and substituted quinolino 2-quinolone 12 through a condensation with Meldrum’s acid (Scheme 4h).14a To reveal more mechanistic insight of the developed reaction, a series of control experiments were carried out. To identify any free radical intermediate’s involvement in the reaction, it was allowed to proceed in the presence of a known radical quencher (3,5-di-tert-4-butylhydroxytoluene, BHT), but there was no significant decrease in isolated yield (Scheme 5i). This observation ruled out the chances of radical pathways. Next, to understand the electronic preference, substituted quinoline N-oxides 1b and 1i were tested under standard conditions. The result of the competition experiment showed that the rate of the reaction strongly favored the electron-rich N-oxide over the electron-deficient one (Scheme 5ii). Moreover, the result of the H−D exchange experiment under the standard conditions in CD3CO2D without 2a (Scheme 5iii) showed that there was no deuteration at the C2 position of 1a. This explains that the C−H metalation step is irreversible in this reaction and might not be the first step. Importantly, in the absence of 1a, the stoichiometric amount of CuI triggered the decomposition of anthranil (2a). In another control experi-

1a (1 g, 6.9 mmol), 24 h, 80 °C. bThe starting material was 8-(1,3dioxolan-2-yl) quinoline 1-oxide. cReaction temperature: 120 °C, 36 h. d The scope with various N-oxides: reaction conditions = 1 (0.1 mmol), 2a (0.2 mmol), CuI (10 mol %), 18−24 h, 80−100 °C, 1,4dioxane (0.1 M). a

S1). To examine the scalability of the optimized method, quinoline N-oxide (1a) was transformed into the expected arylamine in the gram scale with 70% isolated yield (Scheme 2, 3a). Subsequently, this aryl amination could be extended with substituted anthranils 2 having different electronic and steric properties (Scheme 3) with moderate to very good yields (Scheme 3, 4a−4h). Importantly, the post operative removal of the directing group, i.e., the deoxygenation of compound 3a, preceded smoothly to provide C2-arylaminated quinoline 5 (Scheme 8935

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The Journal of Organic Chemistry Scheme 4. Post Synthetic Modificationsa,b

Post synthetic modifications: (a) PCl3 (1.2 equiv), 25 °C, 30 min. (b) TBHP in decane (4 equiv), dry DCE, 90 °C, 16 h. (c) Saturated NH4Cl solution, Zn dust (40 equiv), THF = H2O (1:1), 25 °C, 18 h. (d) TBHP in decane (4 equiv), dry DCE, 100 °C, 20 h. (e) Ph3PCHCO2Et (1.1 equiv), dry CH2Cl2, 90 °C, 1 h. (f) MeCOC(N2)PO(OEt)2 (1.2 equiv), K2CO3 (2 equiv), MeOH, 25 °C, 24 h. (g) N2CHCO2Et (5 equiv), dry CH2Cl2, BF3·Et2O. (g) Meldrum’s acid (2 equiv), AcOH, ethylenediamine, MeOH, 25 °C. bDCE = 1,2-dichloroethane. TBHP = tert-butyl hydroperoxide solution. a

The results of Scheme 5iv,v showed that this transformation did not exhibit a kinetic isotope effect neither in parallel nor in competitive experiments, thus recommending that the C−H bond cleavage for quinoline N-oxide did not occur during the rate-determining step. Notably, when the reaction was carried out with the CuI catalyst under the strict inert conditions, an equivalent amount of product was isolated in comparison to the aerial conditions (Scheme 5vi). In addition, during the search for optimized reaction conditions, there was no detection of the desired product under the CuII catalytic system (Table 1, entry 15). These results clearly revealed that the probability of the CuII species acting in the catalytic cycle was less. On the basis of the preliminary investigations and earlier related literatures, a plausible mechanistic pathway was proposed (Figure 1). First, CuI salt coordinates with the

Scheme 5. Control Experiments for Mechanistic Studies

Figure 1. Proposed Mechanism.

nitrogen center of anthranil (2a) to form complex A. Subsequent cleavage of the N−O bond leads to afford the copper−nitrenoid species, which provides intermediate B via metal−nitrenoid insertion. Consequently, the migratory insertion of nitrenoid into the Cu III −C bond delivers intermediate C. Finally, the protodemetalation of D offers the

ment, simple aniline was not able to provide an isolable C2arylaminated product with 1a under standard conditions. 8936

DOI: 10.1021/acs.joc.7b01343 J. Org. Chem. 2017, 82, 8933−8942

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The Journal of Organic Chemistry arylaminated N-oxide 3a with the regeneration of the CuI active species. Alternatively, oxygen in N-oxides can bind with the Lewis acidic CuI salt. Then the nitrogen center of anthranil coordinates with the copper center. Further, the migration of the copper center to the C2 position of N-oxides followed by the cleavage of the N−O bond also can provide intermediate B. At this stage, the possibility of this pathway cannot be ruled out. Currently, the detail mechanistic studies are under progress.

reduced pressure. The residue was purified by column chromatography using 15−30% ethyl acetate in hexane as the eluent. General Procedure for Copper-Catalyzed C2 Amidation of Quinoline N-Oxides with Anthranil. A 10 mL screw-cap vial was charged with quinoline N-oxide (0.1 mmol) dissolved in 1 mL of 1,4dioxane. Anthranil (0.2 mmol) and CuI (10 mol %) were added to the reaction mixture at room temperature. It was heated to 100−120 °C and allowed to stir for 12−36 h. After the completion of the reaction, the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and the solution was filtered through Celite. The filtrate was concentrated and purified by flash column chromatography using a 30−70% acetone in hexane solvent mixture as the eluent. Procedure for the Synthesis of Compound 5, Removal of Directing Group.23 To a solution of 2-(2-formylphenylamino)quinoline N-oxide (3a) (26.4 mg, 0.1 mmol) in 1,2-dichloroethane (1.5 mL) was added PCl3 (17 mg, 1.2 mmol). The reaction mixture was stirred for 1 h at room temperature and then diluted with H2O (20 mL), extracted with EtOAc (20 mL × 3), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30−40% ethyl acetate in hexane as the eluent on silica gel to obtain product 5 (82%). Procedure for the Synthesis of 12H-Quinolino[2,1-b]quinazolin-12-one (6).24 To a solution of 2-(quinolin-2-ylamino)benzaldehyde (5) (24.8 mg, 0.1 mmol) in 1,2-dichloroethane (1.5 mL) was added 6 M TBHP (4 equiv) in decane. The reaction mixture was stirred for 12 h at 90 °C. After 12 h, the reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate in hexane as the eluent to obtain product 6 (93%). Procedure for the Synthesis of 12H-Quinolino[2,1-b]quinazoline (7).4a To a solution of (2-formylphenylamino)quinoline N-oxide (3a) (26.4 mg, 0.1 mmol) in THF (1.5 mL) was added 1.5 mL of a saturated aqueous NH4Cl solution. Then 40 equiv of activated Zn powder was added to the reaction mixture. The reaction mixture was stirred for 20 h at room temperature. After 20 h, THF was removed under reduced pressure and the residue was diluted with water and separated between EtOAc and water. The EtOAc layer was collected and dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with 30−40% ethyl acetate in hexane as the eluent to obtain the product 7 (77%). Procedure for the Synthesis of Benzimidazo[1,2-a]quinoline (8).25 To a solution of 2-(2-formylphenylamino)quinoline N-oxide (3a) (26.4 mg, 0.1 mmol) in 1,2-dichloroethane (1.5 mL) was added 6 M TBHP (4 equiv) in decane. The reaction mixture was stirred for 12 h at 100 °C. After 12 h, the reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using 40−50% ethyl acetate in hexane as the eluent to obtain product 8 (74%). Procedure for the Synthesis of (E)-2-(2-(3-Ethoxy-3-oxoprop-1-enyl)phenylamino)quinoline 1-Oxide (9). To a solution of 2-(2-formylphenylamino)quinoline N-oxide (3a) (26.4 mg, 0.1 mmol) in dry CH2Cl2 (2 mL) was added ethyl (triphenylphosphoranylidene)acetate (1.2 equiv). The reaction mixture was stirred for 1 h at room temperature. After 1 h, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using 30−40% ethyl acetate in hexane as the eluent to obtain product 9 (93%) Procedure for the Synthesis of 2-(2-Ethynylphenylamino)quinoline 1-Oxide (10).26 To a solution of 2-(2-formylphenylamino)quinoline N-oxide (3a) (26.4 mg, 0.1 mmol) and diethyl 1diazo-2-oxopropylphosphonate (27 mg, 1.2 mmol) in dry MeOH (3 mL) was added anhydrous K2CO3 (26 mg, 0.2 mmol) at room temperature. The solution was stirred at room temperature for 24 h. Next, the solvent was removed under reduced pressure, diluted with water, and then extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column

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CONCLUSION In summary, we have successfully explored an inexpensive, efficient copper-catalyzed direct arylamination of various heterocyclic N-oxides with high atom efficiency. The reaction proceeded under redox-neutral conditions with an admirable degree of regioselectivity. The post modifications of the final product led to the structurally and functionally diverse nitrogen-doped organic π-conjugated systems.

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EXPERIMENTAL SECTION

General Information. Unless otherwise noted, all commercially available compounds were used as provided without further purification. Solvents for chromatography were technical grade. Analytical thin-layer chromatography (TLC) was performed on Merck precoated silica gel 60 F254. Visualization on TLC was achieved by the use of UV light (254 nm). Solvent mixtures were understood as volume/volume. Column chromatography was undertaken on silica gel (230−400 mesh). Chemical shifts were quoted in parts per million (ppm) referenced to the appropriate solvent peak or 0.0 ppm for tetramethylsilane. The following abbreviations were used to describe peak splitting patterns when appropriate: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, td = triplet of doublet, ddd = doublet of doublet of doublet, m = multiplet. Coupling constants, J, were reported in hertz (Hz). The spectra was fully decoupled by broad-band proton decoupling. Chemical shifts were reported in ppm referenced to the center of a triplet at 77.16 ppm of chloroform-d (CDCl3). Infrared (IR) spectra frequencies are given in reciprocal centimeters (cm−1). Only selected absorbance peaks are reported, and KBr is used as the matrix. HRMS of new compounds was measured through the ESI ionization method with a TOF mass analyzer. Materials were obtained from commercial suppliers or prepared according to standard procedures unless otherwise noted. Substrates which are not commercially available were synthesized according to the reported procedures. General Procedure for the Synthesis of Substituted Quinoline N-Oxides.21 To a solution of the corresponding quinoline substrate (1 mmol) in CH2Cl2 (5 mL) was added m-chloroperbenzoic acid (m-CPBA, 1.5 mmol, 1.5 equiv) at 0 °C. The reaction mixture was allowed to stir at room temperature for 24 h. Next saturated aqueous NaHCO3 solution (20 mL) was added to the reaction mixture and extracted with CH2Cl2 (10 mL × 3). The organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel with 80% ethyl acetate in hexane to 100% ethyl acetate as the eluent. Pure quinoline N-oxides were obtained with 80−90% yields. Other heterocyclic N-oxides were prepared as per the reported literature procedures. General Procedure for the Synthesis of Substituted Anthranils.22 A round-bottom flask equipped with a magnetic stir bar was charged with 2-nitroacylbenzene (1.0 mmol) in EtOAc/ MeOH (1:1; 5 mL). SnCl2·2H2O (3.0 mmol) was added to the reaction mixture, and the resulting mixture was stirred overnight at room temperature. The reaction was partitioned between a CH2Cl2 (30 mL) and NaHCO3 solution (20 mL). The aqueous phase was extracted with CH2Cl2 (10 mL × 3), and the combined organic layers were washed with H2O (10 mL) and saturated brine solution (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under 8937

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The Journal of Organic Chemistry

for 24 h at 100 °C. After the completion of the reaction, the solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2 and filtered through Celite. The filtrate was concentrated under reduced pressure and filtered through silica gel column chromatography using an 80% acetone in hexane mixture as the eluant. The 1H NMR spectrum revealed that there was no H−D exchange at the C2 position of 1a. Kinetic Isotope Effect from an Intermolecular Competition between Quinoline N-Oxide and Quinoline-d1 N-Oxide. Quinoline N-oxide (1a) and quinoline-2-d1 N-oxide (1a′) (1:1) (total 0.2 mmol) were dissolved in 1 mL of 1,4-dioxane. Anthranil (2a) (24 mg, 0.2 mmol) was added. Then CuI (3.8 mg, 10 mol %) was added to the solution and the mixture was stirred for 3 h at 100 °C. The consumption of N-oxide was monitored by TLC. The residual starting materials (mixture of quinoline-2-d1 N-oxide and quinoline N-oxide) were recovered after flash filtration through silica gel (230−400 mesh), and the mixture was characterized by 1H NMR spectroscopy. The kH/ kD = 1.00 was calculated by the 1H NMR spectrum of the crude isolated mixture of the residual N-oxides 1a and 1a′. Kinetic Isotope Effect Determined from Absolute Rates of Two Parallel Reactions between Quinoline N-Oxide and Quinoline-2-d1 N-Oxide. Using the established optimized conditions, intermolecular parallel competition experiments between quinoline N-oxide (1a) and quinoline-2-d1 N-oxide (1a′) were carried out, individually. The kH/kD = 1.2 was calculated on the basis of the isolated yields. Analytical Data. 2-(2-Formylphenylamino)quinoline 1-Oxide (3a): yellow amorphous solid, yield 89% (23.5 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 10.06 (s, 1H), 8.46 (d, J = 8.6 Hz, 1H), 8.00−7.92 (m, 3H), 7.87−7.63 (m, 4H), 7.55 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 193.8, 143.2, 139.7, 139.4, 135.6, 135.5, 130.8, 128.5, 126.7, 125.6, 124.4, 124.3, 122.7, 118.4, 117.5, 110.5; FT-IR (KBr, cm−1) ν̃ = 3045, 2925, 2833, 2752, 1675, 1602, 1572, 1530, 1457, 1356, 1282; HRMS calcd for [M + H]+ C16H13N2O2 265.0972, found 265.0982. 2-(2-Formylphenylamino)-6-methoxyquinoline 1-Oxide (3b): yellow amorphous solid, yield 79% (23.2 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 10.05 (s, 1H), 8.39 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 7.5 Hz, 1H), 7.84 (q, J = 9.2 Hz, 2H), 7.71 (d, J = 4.4 Hz, 2H), 7.53−7.40 (m, 2H), 7.28 (t, J = 6.1 Hz, 1H), 3.90 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 194.5, 157.4, 142.1, 140.6, 136.5, 136.0, 135.5, 126.1, 126.1, 124.2, 122.7, 122.6, 119.8, 118.0, 111.7, 107.9, 56.1; FT-IR (KBr, cm−1) ν̃ = 3066, 2848, 2762, 1671, 1599, 1583, 1531, 1547, 1401, 1357, 1283; HRMS calcd for [M + H]+ C17H15N2O3 295.1077, found 295.1080. 2-(2-Formylphenylamino)-6-methylquinoline 1-Oxide (3c): yellow amorphous solid, yield 84% (23.3 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 10.06 (s, 1H), 8.36 (t, J = 6.4 Hz, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.75 (m, 4H), 7.65 (d, J = 9.1 Hz, 1H), 7.31 (t, J = 6.4 Hz, 1H), 2.50 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 194.4, 143.1, 140.4, 138.4, 136.3, 136.0, 135.7, 133.2, 127.9, 126.67, 124.9, 124.6, 122.9, 118.6, 117.9, 111.1, 21.2; FT-IR (KBr, cm−1) ν̃ = 3046, 2847, 2762, 1665, 1615, 1598, 1577, 1526, 1437, 1396, 1328; HRMS calcd for [M + H]+ C17H15N2O2 279.1128, found 279.1127. 6-Cyclopropyl-2-(2-formylphenylamino)quinoline 1-Oxide (3d): yellow amorphous solid, yield 82% (4.9 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 10.06 (s, 1H), 8.35 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.88−7.81 (m, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.75−7.65 (m, 3H), 7.54 (d, J = 9.0 Hz, 1H), 7.29 (m, 1H), 2.11 (m, 1H), 1.07−1.03 (m, 2H), 0.83−0.80 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 194.4, 142.9, 141.9, 140.34, 138.4, 136.3, 136.0, 129.6, 126.6, 124.9, 124.5, 124.4, 122.9, 118.5, 118.0, 111.2, 15.4, 10.3; FT-IR (KBr, cm−1) ν̃ = 3063, 2846, 2758, 1673, 1610, 1597, 1579, 1527, 1458, 1326, 1279; HRMS calcd for [M + H]+ C19H17N2O2 305.1285, found 305.1301. 2-(2-Formylphenylamino)-6-phenylquinoline 1-Oxide (3e): yellow amorphous solid, yield 87% (29.5 mg); 1H NMR (400 MHz, DMSOd6) δ 11.49 (s, 1H), 10.08 (s, 1H), 8.54 (d, J = 9.0 Hz, 1H), 8.35 (d, J = 2.0 Hz, 1H), 8.16 (dd, J = 9.0, 2.0 Hz, 1H), 8.06−7.95 (m, 2H),

chromatography using 30% acetone in hexane as the eluent to afford 10 as a light yellow solid (91% yield). Procedure for the Synthesis of 1-(Quinolin-2-yl)-1H-indole3-carboxylate (11).14c To a solution of 2-(2-formylphenylamino)quinoline (5) (0.1 mmol, 25 mg) and ethyl diazoacetate (57 mg, 5.0 mmol) in CH2Cl2 (2 mL) at 0 °C was added BF3·OEt2 (13 μL, 0.2 mmol) dropwise. The ice bath was removed upon completion of the addition, and the solution was stirred at room temperature for 4 h. The reaction mixture was poured into a saturated aqueous solution of NaHCO3, and it was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using 40% ethyl acetate in hexane as the eluent to afford 11 as a white solid (46%). Procedure for the Synthesis of 2-Oxo-2H-1,2′-biquinoline-3carboxylic Acid (12).14a 2-(2-formylphenylamino)quinoline (5) (0.1 mmol), AcOH (0.2 mmol), and ethylenediamine (0.1 mmol) were dissolved in MeOH (3 mL) at 0 °C. Meldrum’s acid (0.18 mmol) was added, and the resulting mixture was stirred at 0 °C for 1 h and then at room temperature for 18 h. After that, the solvent was removed in a vacuum and the residue was purified by flash column chromatography using ethyl acetate/methanol (10:1) to afford product 12 as a bright yellow solid in 83% yield. Large-Scale Synthesis. Quinoline N-oxide (1a) (1 g, 6.9 mmol) was taken in a 50 mL round-bottom flask and dissolved in 20 mL of 1,4-dioxane. Anthranil (2a) (1.64 g, 13.8 mmol) and then CuI (131 mg, 0.69 mmol) were added to the reaction mixture at room temperature. The reaction mixture was heated at 100 °C and allowed to stir at the same temperature for 24 h. After completion of the reaction time, the solvent was removed under reduced pressure and the residue was directly loaded into the column and purified with a 50−60% acetone in hexane mixture as the eluent with 70% isolated yield. Control Experiment with Electronically Variable Quinoline N-Oxides. Substituted quinoline N-oxides 1b (17.5 mg, 0.1 mmol) and 1i (21.3 mg, 0.1 mmol) were dissolved in 2 mL of 1,4-dioxane. Anthranil (24 mg, 0.2 mmol) and CuI (3.8 mg, 10 mol %) were added to the reaction mixture, and the mixture was stirred at 100 °C for 8 h. After the mixture cooled to room temperature, the solvent was removed under reduced pressure and the mixture of product was isolated by flash column chromatography. The product ratio was identified by 1H NMR to be 1:4 (3i:3b). Control Experiment under an Inert Atmosphere. Quinoline N-oxide (1a) (14.5 mg, 0.1 mmol) was taken in a 10 mL screw-cap vial equipped with a magnetic stir bar and dissolved in 1 mL of 1,4dioxane. After deoxygenation of the reaction mixture through an argon flow, CuI (1.9 mg, 10 mol %) and anthranil (2a) (24 mg, 0.2 mmol) were added under argon. The reaction was heated at 100 °C, and stirring was continued until complete consumption of N-oxide (monitored by TLC). After 24 h, the reaction mixture was allowed to cool to room temperature and purified by flash column chromatography using a 50−60% acetone in hexane solvent mixture as the eluent. Under an argon atmosphere, the isolated yield of the product was not found to decrease substantially. Radical Inhibition Study. Quinoline N-oxide (1a) (14.5 mg, 0.1 mmol) was taken in a 10 mL screw-cap vial equipped with a magnetic stir bar and dissolved in 1 mL of 1,4-dioxane. Then CuI (1.9 mg, 10 mol %), BHT (2,6-di-tert-butyl-4-methylphenol, 44 mg, 0.2 mmol), and anthranil (2a) (24 mg, 0.2 mmol) were added to the reaction, and the mixture was stirred for 24 h at 100 °C. The consumption of Noxide was monitored by TLC, and after 24 h, the reaction mixture was allowed to cool to room temperature. The mixture was directly loaded into the column and purified by flash column chromatography using a 50−60% acetone in hexane solvent mixture. The yield of the desired product was 82%. Deuterium Exchange Experiment. Quinoline N-oxide (1a) (14.5 mg, 0.1 mmol) was taken in a 10 mL screw-cap vial with 0.5 mL of 1,4-dioxane and 0.5 mL of a deuterated solvent. Anthranil (2a) (24 mg, 0.2 mmol) and then CuI (1.9 mg, 10 mol %) were added to the reaction mixture at room temperature. The mixture was allowed to stir 8938

DOI: 10.1021/acs.joc.7b01343 J. Org. Chem. 2017, 82, 8933−8942

Article

The Journal of Organic Chemistry

2-(2-Formylphenylamino)-8-methylquinoline 1-Oxide (3l). yellow amorphous solid, yield 79% (21.9 mg); 1H NMR (400 MHz, DMSOd6) δ 11.49 (s, 1H), 10.06 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 9.3 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.78−7.68 (m, 3H), 7.48 (d, J = 7.3 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.31 (d, J = 4.8 Hz, 1H), 3.14 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 194.2, 144.8, 140.4, 139.4, 136.2, 135.9, 134.2, 130.7, 127.8, 127.5, 126.4, 125.8, 124.8, 122.9, 118.7, 110.6, 24.8; FT-IR (KBr, cm−1) ν̃ = 3046, 2927, 2832, 2754, 1677, 1600, 1582, 1523, 1398, 1315; HRMS calcd for [M + H]+ C17H15N2O2 279.1128, found 279.1127. 8-Fluoro-2-(2-formylphenylamino)quinoline 1-Oxide (3m): yellow amorphous solid, yield 85% (24 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.54 (s, 1H), 10.11 (s, 1H), 8.03−7.96 (m, 2H), 7.85 (d, J = 7.2 Hz, 2H), 7.77 (d, J = 4.0 Hz, 2H), 7.64−7.48 (m, 2H), 7.39 (dt, J = 8.2, 4.2 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 193.6, 152.4 (d, J = 259.4 Hz), 145.5, 139.5, 135.5, 129.6 (d, J = 1.9 Hz), 127.2, 126.4, 125.6 (d, J = 7.7 Hz), 149.6, 125.0 (d, J = 5.3 Hz), 124.7, 123.3, 118.9, 117.0 (d, J = 21.0 Hz), 111.0; 19F NMR (376 MHz, DMSO-d6) δ −118.8; FT-IR (KBr, cm−1) ν̃ = 3067, 2925, 2839, 2752, 1676, 1603, 1580, 1534, 1460, 1405, 1329, 1289; HRMS calcd for [M + H]+ C16H12FN2O2 283.0877, found 283.0872 2-(2-Formylphenylamino)-4-methylquinoline 1-Oxide (3n): yellow amorphous solid, yield 82% (22.8 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 10.07 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.80−7.69 (m, 2H), 7.67 (s, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 2.66 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 194.2, 143.1, 140.3, 139.5, 136.0, 135.6, 131.1, 125.9, 125.8, 124.9, 124.4, 123.1, 119.1, 118.6, 110.9, 18.6; FT-IR (KBr, cm−1) ν̃ = 3062, 2839, 2762, 1665, 1598, 1573, 1526, 1444, 1362, 1279; HRMS calcd for [M + H]+ C17H15N2O2 279.1128, found 279.1126 3-(2-Formylphenylamino)benzo[f ]quinoline 4-Oxide (3o): yellow amorphous solid, yield 77% (24.2 mg) 1H NMR (600 MHz, DMSOd6) δ 11.56 (s, 1H), 10.08 (s, 1H), 8.80 (d, J = 8.2 Hz, 1H), 8.78 (d, J = 9.4 Hz, 1H), 8.57 (d, J = 9.4 Hz, 1H), 8.23 (d, J = 9.4 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.80 (t, J = 7.7 Hz, 1H), 7.6−7.73 (m, 2H), 7.34 (t, J = 7.7 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 194.0, 143.8, 139.9, 138.8, 135.9, 135.6, 132.3, 130.4, 129.1, 129.0, 128.3, 127.3, 124.2, 123.1, 122.6, 121.8, 120.4, 116.4, 118.1, 109.5; FT-IR (KBr, cm−1) ν̃ = 3054, 2927, 2856, 2749, 1675, 1603, 1578, 1532, 1452, 1400, 1321, 1277, 1209; HRMS calcd for [M + H]+ C20H15N2O2 315.1128, found 315.1127. 2-(2-Formylphenylamino)benzo[h]quinoline 1-Oxide (3p): yellow solid, yield 73% (22.9 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.98 (d, J = 8.6 Hz, 1H), 10.14 (s, 1H), 8.11 (dd, J = 11.7, 8.2 Hz, 2H), 8.03 (dd, J = 11.7, 8.2 Hz, 2H), 7.94 (s, 2H), 7.91−7.83 (m, 2H), 7.79 (q, J = 7.3 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 194.4, 146.2, 140.4, 136.4, 136.3, 136.1, 135.0, 129.2, 128.6, 128.4, 127.4, 126.9, 126.3, 125.6, 124.9, 123.8, 123.1, 118.6, 109.5; FT-IR (KBr, cm−1) ν̃ = 3046, 2929, 2839, 2743, 1678, 1604, 1589, 1537, 1436, 1407, 1329, 1285, 1221; HRMS calcd for [M + H]+ C20H15N2O2 315.1128, found 315.1124. 6-(2-Formylphenylamino)-[1,3]dioxolo[4,5-g]quinoline 5-Oxide (3q): yellow amorphous solid, yield 85% (26.2 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 10.05 (s, 1H), 7.96 (d, J = 7.4 Hz, 1H), 7.82 (s, 1H), 7.77 (d, J = 9.3 Hz, 1H), 7.74−7.61 (m, 3H), 7.45 (s, 1H), 7.28 (t, J = 7.4 Hz, 1H), 6.25 (s, 2H); 13C NMR (150 MHz, DMSO-d6) δ 194.5, 152.1, 147.3, 142.8, 140.6, 137.6, 136.6, 136.1, 126.3, 124.2, 122.5, 121.1, 117.9, 108.7, 104.5, 103.0, 96.0; FT-IR (KBr, cm−1) ν̃ = 3051, 2920, 2845, 2754, 1670, 1591, 1570, 1541, 1475, 1426, 1307; HRMS calcd for [M + H]+ C17H13N2O4 309.0870, found 309.0900. 2-(2-Formylphenylamino)-7,8-dihydro-6H-cyclopenta[g]quinoline 1-Oxide (3r): yellow amorphous solid, yield 85% (25.8 mg); 1 H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.06 (s, 1H), 8.31 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 9.5 Hz, 1H), 7.80 (s, 1H), 7.73−7.69 (m, 3H), 7.30 (t, J = 7.6 Hz, 1H), 3.10 (t, J = 7.6 Hz, 2H), 3.02 (t, J = 7.6 Hz, 2H), 2.14−2.08 (m, 2H); 13C NMR (150 MHz, DMSO-d6) δ 194.4, 149.4, 143.2, 143.0, 140.5, 139.5, 136.3,

7.89−7.81 (m, 3H), 7.81−7.71 (m, 2H), 7.54 (t, J = 7.4 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.33 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 193.9, 143.3, 139.7, 138.8, 138.7, 137.1, 135.7, 135.5, 129.7, 129.1, 127.9, 127.1, 126.9, 125.9, 124.7, 124.4, 122.8, 118.5, 118.3, 111.0; FTIR (KBr, cm−1) ν̃ = 3044, 2932, 2853, 2761, 1679, 1612, 1577, 1522, 1386, 1329; HRMS calcd for [M + H]+ C22H17N2O2 341.1285, found 341.1270. 6-Fluoro-2-(2-formylphenylamino)quinoline 1-Oxide (3f): yellow amorphous solid, yield 83% (23.4 mg); 1H NMR (400 MHz, DMSOd6) δ 11.43 (s, 1H), 10.10 (s, 1H), 8.55 (dd, J = 9.4, 5.2 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.97−7.89 (m, 3H), 7.80−7.68 (m, 3H), 7.37 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 194.3, 159.7 (d, J = 243.7 Hz), 143.5, 140.2, 137.1, 136.0, 136.0, 126.5 (d, J = 4.5 Hz), 125.6 (d, J = 10.2 Hz), 124.9, 123.3, 120.9 (d, J = 9.1 Hz), 120.6 (d, J = 25.8 Hz), 118.9, 112.7 (d, J = 22.8 Hz), 112.4; 19F NMR (376 MHz, DMSO-d6) δ −115.94; FT-IR (KBr, cm−1) ν̃ = 3046, 2919, 2841, 2732, 1677, 1603, 1586, 1537, 1372, 1323, 1283; HRMS calcd for [M + H]+ C16H12FN2O2 283.0877, found 283.0872. 6-Chloro-2-(2-formylphenylamino)quinoline 1-Oxide (3g): yellow amorphous solid, yield 72% (21.5 mg); 1H NMR (400 MHz, DMSOd6) δ 11.40 (s, 1H), 10.06 (s, 1H), 8.45 (d, J = 9.3 Hz, 1H), 8.17 (d, J = 2.7 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 9.3 Hz, 1H), 7.86−7.78 (m, 2H), 7.75−7.55 (m, 2H), 7.35 (m, 1H); 13C NMR (150 MHz, DMSO-d6) δ 193.6, 143.7, 139.5, 138.0, 135.4, 131.0, 130.9, 129.9, 127.2, 125.9, 125.1, 124.7, 123.1, 119.8, 118.9, 111.7; FTIR (KBr, cm−1) ν̃ = 3057, 2922, 2832, 2747, 1673, 1605, 1592, 1539, 1401, 1326; HRMS calcd for [M + H]+ C16H1235ClN2O2 299.0582, found 299.0589. 6-Bromo-2-(2-formylphenylamino)quinoline 1-Oxide (3h): yellow amorphous solid, yield 75% (25.6 mg); 1H NMR (400 MHz, DMSOd6) δ 11.40 (s, 1H), 10.05 (s, 1H), 8.37 (d, J = 9.0 Hz, 1H), 8.30 (s, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.93−7.86 (m, 2H), 7.81 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 4.5 Hz, 2H), 7.33 (d, J = 6.6 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 194.4, 144.4, 140.2, 139.0, 136.2, 136.0, 134.3, 131.0, 126.6, 126.6, 125.4, 123.8, 120.6, 119.7, 118.9, 112.4; FTIR (KBr, cm−1) ν̃ = 3054, 2927, 2835, 2742, 1675, 1598, 1584, 1526, 1390, 1317, 1276; HRMS calcd for [M + H]+ C16H1279BrN2O2 343.0077, found 343.0079. 2-(2-Formylphenylamino)-6-(trifluoromethyl)quinoline 1-Oxide (3i): yellow amorphous solid, yield 71% (23.6 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.49 (s, 1H), 10.09 (s, 1H), 8.62 (d, J = 9.3 Hz, 1H), 8.55 (s, 1H), 8.13−8.06 (m, 2H), 8.00 (d, J = 7.8 Hz, 1H), 7.89 (d, J = 9.3 Hz, 1H), 7.83−7.70 (m, 2H), 7.39 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 193.5, 145.2, 140.6, 139.1, 135.5, 134.9, 127.5, 126.7 (q, J = 4.2 Hz), 126.2 (q, J = 3.1 Hz), 124.1 (q, J = 273 Hz), 125.4 (q, J = 10.1 Hz), 123.7, 123.4, 122.8, 119.8, 119.1, 111.7; 19F NMR (376 MHz, DMSO-d6) δ −60.5; FT-IR (KBr, cm−1) ν̃ = 3064, 2972, 2840, 2761, 1672, 1600, 1576, 1523, 1425, 1334, 1281; HRMS calcd for [M + H]+ C17H12F3N2O2 333.0845, found 333.0856. 2-(2-Formylphenylamino)-5-phenylquinoline 1-Oxide (3j): yellow amorphous solid, yield 85% (28.9 mg); 1H NMR (400 MHz, DMSOd6) δ 11.47 (s, 1H), 10.07 (s, 1H), 8.55 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.78 (d, J = 9.5 Hz, 1H), 7.74−7.61 (m, 3H), 7.61−7.47 (m, 6H), 7.35 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 193.8, 142.9, 140.5, 140.0, 139.7, 138.3, 135.6, 135.5, 130.4, 129.8, 128.6, 128.0, 126.4, 124.4, 122.8, 122.2, 118.4, 117.1, 110.6; FT-IR (KBr, cm−1) ν̃ = 3052, 2953, 2844, 2736, 1672, 1601, 1581, 1529, 1441, 1335, 1289; HRMS calcd for [M + H]+ C22H17N2O2 341.1285, found 341.1270. 8-Formyl-2-(2-formylphenylamino)quinoline 1-Oxide (3k): yellow amorphous solid, yield 69% (20.1 mg); 1H NMR (600 MHz, DMSOd6) δ 11.36 (s, 1H), 11.28 (s, 1H), 10.08 (s, 1H), 8.20 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 7.7 Hz, 1H), 7.82 (t, J = 9.1 Hz, 2H), 7.78−7.72 (m, 2H), 7.62 (t, J = 7.7 Hz, 1H), 7.39 (m, 1H); 13 C NMR (150 MHz, DMSO-d6) δ 194.0, 192.2, 145.3, 139.7, 138.0, 135.9, 135.3, 132.8, 131.5, 131.4, 129.1, 125.9, 125.7, 125.0, 124.2, 120.4, 111.5; FT-IR (KBr, cm−1) ν̃ = 3060, 2925, 2866, 2850, 2754, 1670, 1598, 1577, 1533, 1450, 1370, 1325, 1267; HRMS calcd for [M + H]+ C17H13N2O3 293.0921, found 293.0931. 8939

DOI: 10.1021/acs.joc.7b01343 J. Org. Chem. 2017, 82, 8933−8942

Article

The Journal of Organic Chemistry

123.9, 121.9, 119.9, 119.7, 118.3; FT-IR (KBr, cm−1) ν̃ = 3045, 2849, 2758, 1677, 1583, 1561, 1531, 1457, 1400, 1332; HRMS calcd for [M + H]+ C15H12N3O3 282.0873, found 282.0886. 2-(2-Formylphenylamino)quinazoline 1-Oxide (3z): yellow amorphous solid, yield 64% (16.9 mg); 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 10.08 (s, 1H), 9.12 (s, 1H), 8.92 (d, J = 8.6 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 8.05 (t, J = 7.9 Hz, 1H), 7.99 (dd, J = 7.9, 1.6 Hz, 1H), 7.86−7.73 (m, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 195.0, 147.7, 147.1, 141.6, 139.6, 136.6, 135.6, 135.5, 128.5, 126.2, 122.4, 122.1, 121.0, 118.4, 116.7; FT-IR (KBr, cm−1) ν̃ = 3049, 2844, 2745, 1679, 1579, 1568, 1543, 1467, 1408, 1325; HRMS calcd for [M + H]+ C15H12N3O2 266.0924, found 266.0930. 2-(2-Benzoyl-4-chlorophenylamino)quinoline 1-Oxide (4a): yellow amorphous solid, yield 89% (33.2 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.83−7.71 (m, 5H), 7.65 (t, J = 7.5 Hz, 1H), 7.60−7.47 (m, 5H); 13C NMR (100 MHz, DMSO-d6) δ 194.6, 144.0, 139.1, 136.9, 136.6, 133.4, 132.5, 131.2, 130.8, 130.7, 129.8, 128.6, 128.5, 127.4, 126.8, 125.2, 124.3, 123.9, 117.2, 109.7; FTIR (KBr, cm−1) ν̃ = 3060, 2927, 1659, 1603, 1576, 1521, 1442, 1353, 1301, 1254; HRMS calcd for [M + H]+ C22H1635ClN2O2 375.0895, found 375.0895. 2-(6-Formylbenzo[d][1,3]dioxol-5-ylamino)quinoline 1-Oxide (4b): yellow amorphous solid, yield 57% (17.5 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.18 (s, 1H), 9.86 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 9.3 Hz, 1H), 7.80 (t, J = 7.5 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.31 (s, 1H), 6.21 (s, 2H); 13C NMR (150 MHz, DMSO-d6) δ 190.6, 153.2, 144.0, 143.9, 139.4, 137.6, 130.7, 128.5, 126.8, 125.3, 124.1, 120.2, 117.4, 110.8, 110.3, 102.7, 101.6; FT-IR (KBr, cm−1) ν̃ = 3054, 2961, 2858, 2741, 1643, 1586, 1539, 1459, 1407, 1338, 1276; HRMS calcd for [M + H]+ C17H13N2O4 309.0870, found 309.0872. 2-(5-Bromo-2-formylphenylamino)quinoline 1-Oxide (4c): yellow amorphous solid, yield 66% (22.6 mg); 1H NMR (400 MHz, DMSOd6) δ 11.46 (s, 1H), 10.01 (s, 1H), 8.46 (d, J = 8.7 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.94−7.86 (m, 2H), 7.86− 7.76 (m, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.50 (dd, J = 8.2, 1.7 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 193.7, 143.3, 141.5, 139.8, 137.5, 131.4, 129.9, 129.0, 127.4, 126.4, 126.0, 125.1, 123.8, 121.3, 118.1, 111.3; FT-IR (KBr, cm−1) ν̃ = 3042, 2832, 2754, 1673, 1590, 1541, 1457, 1373, 1319; HRMS calcd for [M + H]+ C16H1279BrN2O2 343.0077, found 343.0094. 2-(5-Chloro-2-formylphenylamino)quinoline 1-Oxide (4d): yellow amorphous solid, yield 79% (23.5 mg); 1H NMR (400 MHz, DMSOd6) δ 11.58 (s, 1H), 10.07 (s, 1H), 8.51 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 8.03 (dd, J = 8.7, 2.7 Hz, 2H), 7.91−7.85 (m, 2H), 7.79 (s, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.41 (dd, J = 8.2, 2.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 193.5, 143.3, 141.6, 140.7, 139.9, 137.6, 131.4, 129.0, 127.4, 126.4, 125.1, 123.4, 123.0, 118.3, 118.1, 111.4; FT-IR (KBr, cm−1) ν̃ = 3089, 2842, 2722, 1666, 1578, 1523, 1489, 1431, 1377, 1298; HRMS calcd for [M + H]+ C16H1235ClN2O2 299.0582, found 299.0589. 2-(5-Fluoro-2-formylphenylamino)quinoline 1-Oxide (4e): yellow amorphous solid, yield 85% (24 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 10.00 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 8.8 Hz, 1H), 8.04 (m, 2H), 7.97 (dd, J = 9.2, 2.1 Hz, 1H), 7.91 (dd, J = 9.2, 2.2 Hz, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.65−7.47 (m, 2H), 7.12 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 193.4, 166.6 (d, J = 253.6 Hz), 143.2, 142.8 (d, J = 12.3 Hz), 139.8, 139.6 (d, J = 12.1 Hz), 131.4, 129.0, 127.3, 126.5, 125.2, 121.4, 118.1, 111.5, 110.1 (d, J = 22.6 Hz), 105.1 (d, J = 26.4 Hz); 19F NMR (376 MHz, DMSO-d6) δ −100.68; FT-IR (KBr, cm−1) ν̃ = 3063, 2927, 2856, 2739, 1679, 1604, 1535, 1486, 1409, 1369, 1292; HRMS calcd for [M + H]+ C16H12FN2O2 283.0877, found 283.0878. 2-(2-Formyl-5-methoxyphenylamino)quinoline 1-Oxide (4f): yellow amorphous solid, yield 72% (21.2 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1H), 10.07 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 7.94 (m, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.79 (m, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54−7.49 (m, 2H), 7.47 (d, J = 9.3 Hz, 1H), 7.34 (dd, J =

136.0, 126.9, 124.5, 124.1, 123.2, 122.8, 118.4, 112.8, 109.8, 33.2, 32.1, 26.0; FT-IR (KBr, cm−1) ν̃ = 3042, 2927, 2837, 2744, 1669, 1597, 1575, 1525, 1457, 1400, 1326; HRMS calcd for [M + H]+ C19H17N2O2 305.1285, found 305.1297. 1-(2-Formylphenylamino)isoquinoline 2-Oxide (3s): yellow amorphous solid, yield 93% (24.5 mg); 1H NMR (600 MHz, DMSO-d6) δ 10.32 (s, 1H), 10.13 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.69−7.57 (m, 3H), 7.42 (t, J = 7.7 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 6.49 (d, J = 8.2 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 194.4, 143.8, 140.9, 135.9, 135.0, 134.9, 129.3, 128.7, 128.4, 127.8, 123.5, 123.0, 122.3, 119.7, 120.5, 116.8; FT-IR (KBr, cm−1) ν̃ = 3048, 2952, 2846, 2757, 1678, 1607, 1578, 1529, 1436, 1398, 1334; HRMS calcd for [M + H]+ C16H13N2O2 265.0972, found 265.0982. 5-Bromo-1-(2-formylphenylamino)isoquinoline 2-Oxide (3t): yellow amorphous solid, yield 87% (29.7 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 10.13 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 8.2 Hz, 1H), 7.46−7.38 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 194.2, 143.5, 141.2, 137.4, 134.8, 134.7, 132.1, 129.5, 127.7, 125.0, 123.3, 122.5, 121.3, 120.8, 118.0, 117.0; FT-IR (KBr, cm−1) ν̃ = 3057, 2923, 2844, 2737, 1679, 1589, 1575, 1525, 1497, 1449, 1307, 1298; HRMS calcd for [M + H]+ C16H1279BrN2O2 343.0077, found 343.0081. 1-(2-Formylphenylamino)-5-phenylisoquinoline 2-Oxide (3u): yellow amorphous solid, yield 90% (30.6 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.15 (s, 1H), 8.26 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 4.2 Hz, 2H), 7.59−7.50 (m, 7H), 7.45 (t, J = 7.8 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 195.2, 144.6, 141.8, 140.5, 138.9, 136.7, 135.8, 135.6, 130.4, 129.8, 129.5, 129.3, 128.8, 127.8, 125.1, 123.4, 122.9, 121.2, 118.2, 117.3; FT-IR (KBr, cm−1) ν̃ = 3052, 2954, 2862, 2734, 1676, 1601, 1586, 1525, 1490, 1431, 1321, 1264; HRMS calcd for [M + H]+ C22H17N2O2 341.1285, found 341.1270. 2-(2-Formylphenylamino)pyridine 1-Oxide (3v): yellow amorphous solid, yield 54% (11.05 mg); 1H NMR (400 MHz, DMSOd6) δ 11.31 (s, 1H), 10.05 (s, 1H), 8.39 (d, J = 6.4 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.76−7.61 (m, 3H), 7.39 (t, J = 7.8 Hz, 1H), 7.30 (dt, J = 7.8, 4.0 Hz, 1H), 7.03 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 194.65, 146.15, 140.48, 138.16, 136.74, 136.12, 127.56, 123.92, 122.37, 117.48, 116.95, 110.91; FT-IR (KBr, cm−1) ν̃ = 3059, 2978, 2837, 2751, 1679, 1591, 1566, 1521, 1476, 1423, 1332, 1296; HRMS calcd for [M + H]+ C12H11N2O2 215.0815, found 215.0818. 2-(2-Formylphenylamino)-6-phenylpyridine 1-Oxide (3w): yellow amorphous solid, yield 81% (23.5 mg); 1H NMR (600 MHz, DMSOd6) δ 11.51 (s, 1H), 10.02 (s, 1H), 7.96 (m, 1H), 7.91−7.84 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.66 (m, 1H), 7.50 (q, J = 7.7, 3H), 7.41 (t, J = 8.1 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.17 (dd, J = 8.1, 1.7 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 194.1, 146.8, 146.2, 140.2, 136.4, 135.7, 133.3, 129.3, 129.2, 128.0, 126.4, 123.6, 121.9, 117.4, 117.2, 109.1; FT-IR (KBr, cm−1) ν̃ = 3064, 2834, 2755, 1671, 1596, 1574, 1516, 1448, 1383, 1300, 1263; HRMS calcd for [M + H]+ C18H15N2O2 291.1128, found 291.1140. 2-(2-Formylphenylamino)-6-phenylpyridine 1-Oxide (3x): yellow amorphous solid, yield 88% (32.2 mg); 1H NMR (400 MHz, DMSOd6) δ 11.47 (s, 1H), 10.03 (s, 1H), 7.96 (d, J = 7.3 Hz, 3H), 7.87 (t, J = 8.8 Hz, 3H), 7.78 (d, J = 2.4 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.54− 7.44 (m, 7H), 7.27 (t, J = 7.3 Hz, 1H); 13C NMR (100 MHz, DMSOd6) δ 194.6, 147.3, 146.7, 140.7, 137.9, 137.3, 136.7, 136.4, 133.7, 130.0, 129.8, 129.6, 129.3, 128.4, 127.6, 124.2, 122.5, 117.9, 115.7, 106.5; FT-IR (KBr, cm−1) ν̃ = 3056, 2841, 2722, 1688, 1589, 1576, 1529, 1467, 1397, 1327, 1283; HRMS calcd for [M + H]+ C24H19N2O2 367.1441, found 367.1439. 2-(2-Formylphenylamino)quinoxaline 1,4-Dioxide (3y): yellow amorphous solid, yield 76% (21.3 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 10.08 (s, 1H), 8.72 (s, 1H), 8.44 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.03−7.86 (m, 2H), 7.79−7.72 (m, 3H), 7.38 (t, J = 6.7 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 193.7, 140.9, 139.0, 135.8, 135.7, 134.5, 133.2, 132.6, 128.3, 125.2, 8940

DOI: 10.1021/acs.joc.7b01343 J. Org. Chem. 2017, 82, 8933−8942

Article

The Journal of Organic Chemistry 8.8, 3.1 Hz, 1H), 3.86 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 192.3, 155.8, 144.6, 139.3, 133.1, 130.7, 128.4, 127.9, 126.9, 124.9, 123.7, 123.6, 121.9, 117.2, 116.2, 109.6, 55.7; FT-IR (KBr, cm−1) ν̃ = 3059, 2936, 2857, 2724, 1677, 1606, 1528, 1501, 1411, 1373, 1286; HRMS calcd for [M + H]+ C17H14N2O3 295.1077, found 295.1080. 2-(2-Formyl-4,5-dimethoxyphenylamino)quinoline 1-Oxide (4g): light yellow amorphous solid, yield 48% (15.5 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.94 (s, 1H), 8.45 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 9.1 Hz, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 191.4, 155.1, 145.7, 144.7, 139.9, 136.0, 131.2, 128.9, 127.4, 125.7, 124.4, 119.5, 117.8, 115.8, 110.7, 104.9, 56.6, 56.4; FT-IR (KBr, cm−1) ν̃ = 3067, 2926, 2845, 2709, 1675, 1600, 1531, 1478, 1405, 1368, 1290; HRMS calcd for [M + H]+ C18H16N2O4 325.1183, found 325.1187. 2-(4′-Fluoro-4-formylbiphenyl-3-ylamino)quinoline 1-Oxide (4h): yellow amorphous solid, yield 81% (29 mg); 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 10.09 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.04 (dd, J = 11.1, 8.0 Hz, 2H), 7.99−7.86 (m, 5H), 7.82 (m, 1H), 7.66−7.52 (m, 2H), 7.36 (t, J = 8.8 Hz, 2H); 13C NMR (150 MHz, DMSO-d6) δ 193.2, 162.7 (d, J = 263 Hz), 145.7, 143.3, 140.4, 139.4, 136.1, 135.1 (d, J = 2.4 Hz), 130.8, 129.6 (d, J = 8.0 Hz), 128.5, 126.9, 125.6, 124.4, 123.3, 121.1, 117.5, 116.5, 115.9 (d, J = 21.7 Hz), 110.9; 19 F NMR (376 MHz, DMSO-d6) δ −113.19; FT-IR (KBr, cm−1) ν̃ = 3060, 2929, 2853, 2732, 1686, 1596, 1542, 1483, 1398, 1377, 1296; HRMS calcd for [M + H]+ C22H15FN2O2 359.1190, found 359.1195. 2-(Quinolin-2-ylamino)benzaldehyde (5): yellow amorphous solid, yield 82% (20.3 mg); 1H NMR (400 MHz, CDCl3) δ 11.16 (s, 1H), 9.96 (s, 1H), 9.46 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.68−7.62 (m, 4H), 7.37 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 195.5, 153.3, 147.3, 144.3, 137.7, 136.6, 136.3, 129.8, 127.7, 127.6, 124.7, 124.2, 120.9, 120.1, 118.7, 115.2; FT-IR (KBr, cm−1) ν̃ = 3047, 2929, 2836, 2751, 1665, 1601, 1572, 1525, 1449, 1398, 1325; HRMS calcd for [M + H]+ C16H13N2O 249.1022, found 249.1028. 12H-Quinolino[2,1-b]quinazolin-12-one (6): light yellow amorphous solid, yield 93% (22.8 mg); 1H NMR (600 MHz, CDCl3) δ 9.60 (dt, J = 9.2, 0.9 Hz, 1H), 8.57−8.36 (m, 1H), 7.83 (m, 1H), 7.76 (m, 1H), 7.69−7.59 (m, 3H), 7.52 (m, 1H), 7.48 (td, J = 7.3, 1.0 Hz, 1H), 7.25 (d, J = 9.4 Hz, 1H).13C NMR (150 MHz, CDCl3) δ 163.3, 148.2, 146.6, 135.7, 135.4, 134.8, 129.7, 128.3, 127.7, 126.6, 126.6, 126.3, 125.2, 124.6, 122.0, 120.2; FT-IR (KBr, cm−1) ν̃ = 3046, 2920, 2850, 1686, 1603, 1545, 1471, 1320, 1275; HRMS calcd for [M + H]+ C16H11N2O 247.0866, found 247.0852. 12H-Quinolino[2,1-b]quinazoline (7): yellow amorphous solid, yield 77% (17.8 mg); 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.34−7.27 (m, 2H), 7.24 (d, J = 7.4 Hz, 1H), 7.03 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.75 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 154.6, 147.2, 139.5, 137.9, 131.5, 129.9, 129.6, 128.9, 127.4, 126.3, 124.1, 123.4, 123.1, 121.5, 112.4, 63.9; FT-IR (KBr, cm−1) ν̃ = 3055, 2922, 1618, 1595, 1533, 1482, 1455, 1400, 1318, 1292; HRMS calcd for [M + H]+ C16H13N2 233.1073, found 233.1054. Benzimidazo[1,2-a]quinoline (8): yellow amorphous solid, yield 74% (16.1 mg); 1H NMR (600 MHz, CDCl3) δ 8.52 (d, J = 8.4 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.80 (dd, J = 8.0, 1.6 Hz, 1H), 7.71 (m, 1H), 7.65 (d, J = 9.4 Hz, 1H), 7.60 (d, J = 9.4 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.50−7.39 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 148.4, 144.8, 135.8, 131.3, 129.8, 129.6, 124.6, 124.3, 123.5, 122.8, 120.6, 117.9, 115.3, 114.1; FT-IR (KBr, cm−1) ν̃ = 3030, 2957, 2917, 1894, 1611, 1541, 1451, 1393, 1328, 1278; HRMS calcd for [M + H]+ C15H11N2 219.0917, found 219.0904. (E)-2-(2-(3-Ethoxy-3-oxoprop-1-enyl)phenylamino)quinoline 1Oxide (9): yellow amorphous solid, yield 95% (31.8 mg); 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.43 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.77 (dt, J = 12.1, 3.8 Hz, 3H), 7.60−7.30 (m, 4H), 6.86 (d, J = 9.2 Hz, 1H), 6.64 (d, J = 16.0 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 1.17 (t, J = 7.1 Hz, 3H); 13C NMR

(100 MHz, DMSO-d6) δ 166.1, 145.9, 139.6, 139.3, 137.3, 131.5, 130.6, 130.6, 128.5, 127.9, 127.2, 126.9, 124.6, 123.3, 119.5, 116.9, 108.9, 60.1, 14.1; FT-IR (KBr, cm−1) ν̃ = 3055, 2922, 1722, 1618, 1595, 1533, 1482, 1455, 1400, 1318, 1293; HRMS calcd for [M + H]+ C20H19N2O3 335.1390, found 335.1385. 2-(2-Ethynylphenylamino)quinoline 1-Oxide (10): light yellow amorphous solid, yield 91% (23.6 mg); 1H NMR (600 MHz, CDCl3) δ 9.63 (s, 1H), 8.63 (d, J = 9.2 Hz, 1H), 7.76 (dd, J = 8.1, 6.4 Hz, 2H), 7.68 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.43−7.38 (m, 2H), 7.16 (t, J = 7.5 Hz, 1H), 3.46 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 144.8, 140.0, 139.9, 134.0, 131.2, 130.0, 128.2, 128.0, 125.3, 124.6, 123.9, 120.6, 118.1, 116.1, 108.8, 84.7, 79.4; FT-IR (KBr, cm−1) ν̃ = 3232, 3077, 2929, 1632, 1619, 1596, 1578, 1529, 1423, 1364; HRMS calcd for [M + H]+ C17H13N2O 261.1022, found 261.1028. Ethyl 1-(Quinolin-2-yl)-1H-indole-3-carboxylate (11): white amorphous solid, yield 46% (14.5 mg); 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.43−7.36 (m, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 165.0, 150.5, 147.3, 139.4, 136.1, 132.4, 130.9, 128.9, 128.0, 127.8, 126.7, 124.4, 123.4, 122.0, 114.5, 114.2, 111.5, 60.3, 14.7; FT-IR (KBr, cm−1) ν̃ = 3066 2928, 1694, 1597, 1551, 1508, 1449, 1328, 1287; HRMS calcd for [M + H]+ C20H17N2O2 317.1285, found 317.1280. 2-Oxo-2H-1,2′-biquinoline-3-carboxylic Acid (12): yellow amorphous solid, yield 83% (26.2 mg); 1H NMR (600 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.34 (d, J = 9.2 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 7.2 Hz, 1H), 7.83 (t, J = 8.5 Hz, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.29−7.31 (m, 2H), 7.21 (dd, J = 15.2, 8.5 Hz, 2H), 7.17 (s, 1H), 7.06 (d, J = 7.8 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 164.2, 148.6, 141.6, 136.5, 132.6, 130.5, 130.1, 128.2, 126.5, 125.9, 125.9, 124.2, 123.6, 117.7, 115.2, 114.7, 100.6, 82.7, 56.0; FT-IR (KBr, cm−1) ν̃ = 3053, 3004, 2929, 2862, 1702, 1616, 1593, 1571, 1507, 1425, 1384, 1260; HRMS calcd for [M + H]+ C19H13N2O3 317.0921, found 317.0928.

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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.7b01343. X-ray data for compound 3p (CIF) Spectra of control experiments, crystal data and ORTEP diagram, and 1H and 13C NMR spectra of new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Rajarshi Samanta: 0000-0002-7925-6601 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported the SERB-DST, India (YSS/2014/ 000383). Fellowships received from CSIR, India (A.B.) and IIT Kharagpur (U.K.) is gratefully acknowledged. Central Research Facility, IIT Kharagpur is thankfully acknowledged for the analytical facility.

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REFERENCES

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