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Copper Catalyzed Direct, Regioselective Arylamination of N-Oxides: Studies to Access Conjugated #-Systems Aniruddha Biswas, Ujjwal Karmakar, Shiny Nandi, and Rajarshi Samanta J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01343 • Publication Date (Web): 07 Aug 2017 Downloaded from http://pubs.acs.org on August 7, 2017

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The Journal of Organic Chemistry

Copper Catalyzed Direct, Regioselective Arylamination of NOxides: Studies to Access Conjugated π-Systems Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.

Aniruddha Biswas, Ujjwal Karmakar, Shiny Nandi, and Rajarshi Samanta*

Supporting Information Placeholder

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 reagent. The developed protocol is simple, straightforward, and economic with broad range of substrate scope. The dual functional groups in the final molecules were utilized to construct structurally and functionally diverse nitrogen containing organic π-conjugated systems.

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 Designing of specific quinoline based molecular scaffold giving rise to versatile compound classes is an important area. Arguably, one of the best approach 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 arylation5, heteroarylation6, alkylation7, alkenylation8, C-O9 or C-S bond formations10 on quinoline N-oxide moieties. Very recently, transition metal free C-2 selective functionalization of N-oxides were also discussed in the literature.11 Undoubtedly, C2

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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 and 1b).12a,b In another elegant approach, Wu and Cui group revealed the CuI catalyzed C2 selective aminations of these N-oxides using 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 group recently published metal-free, stoichiometric phosphonium salt-mediated sulfoximination of azine N-oxides (Scheme 1e).11bAt per our best of knowledge, none of these methods addressed about 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 transformation, as 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 i) generation of aryl nitrene reactive intermediate, ii) exclusion of external oxidants, iii) construction of products with bifunctionality, make this one as an attractive arylaminating agent towards 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

Scheme 1: C2-Selective C-N bond formations of quinoline N-oxide:

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In a seminal work, Li and Lan group elegantly described Rh(III) catalyzed sp3 and sp2 C-H aminations using this bifunctional arylaminating agent.14a Li group further improved their indazole synthesis using cooperative Co(III)/Cu(II) catalysis.14b In an independent approach, Jiao and co-workers also successfully provided aryl aminations of sp3 and sp2 C-H bonds under Rh(III) catalysis.14c, d Recently, Li group and Wang group separately reported the Rh(III) catalyzed amination/annulations strategies on indole and 2-pyridone scaffolds.14e, f Very recently, Kim group, Yang and Xu group individually developed Rh(III) catalyzed C7 amination of indolines with anthranils.14g, h Despite these significant advancements, these methods were mostly limited either with the use of expensive transition metal catalysts or harsh reaction conditions. Thus there is still high demand for straightforward economic access to arylaminated Noxides, high valued synthons for nitrogen containing poly aromatic 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 construction of quinoline N-oxides based organic conjugated π-systems using earth abundant transition metal catalysts,18 here in we report the syntheses of the C2arylaminated quinoline and related heterocyclic N-oxides via their cross couplings with anthranils using the eco-friendly and economical copper catalyst (Scheme 1f). RESULTS AND DISCUSSION: Based on 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 towards the screening of CuI salts for the transformation. Cu(MeCN)4PF6 and CuCN were found to be extremely un-useful for this reaction (Table 1, entries 1-2). Among the other CuI salts, we were delighted to find that CuCl afforded reasonably good yield of the desired product in 62% (Table 1, entry 3). Furthermore, the other CuI salts like CuBr or CuI were also screened (Table 1, entries 4-5) 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). Table 1. Optimization for the synthesis of copper catalyzed arylamination using anthranila

Entry

Catalyst

1 2

Cu(MeCN)4PF6 CuCN

Loading (mol%) 10 10

solvent

Yield(%)b

1,4dioxane 1,4dioxane

trace traces.

3



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

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 02 10

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

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62 66 83 89 10 24 32 44 21 52 57 34 n.d.

a Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), Cu catalyst (10 mol%), 100 °C, 24 h, 0.1 M, air. b Isolated yields. DCE= 1,2 dicholoroethane. n.d. = not detected. c Reaction time: 36 h.

For further improvement, other solvents with different polarity were tested. Among them, 1,2 dichloroethane, EtOAc, MeCN and toluene offered poor yields (Table 1, entry 7-10). Although applications of polar aprotic solvents like DMF, DMSO offered moderate yields of the desired product (Table 1, entries 12-13), polar protic solvent EtOH provided poor yield (Table 1, entry 11). Incidentally, lower catalyst loading afforded reduced isolated yield (Table 1, entry 14). Notably, Cu(OAc)2 did not turned to be a 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 groups at the different positions of N-oxides were well tolerated. Electron donating groups at the C6 position of quinoline ring were firmly survived (Scheme 2, 3b-3e). Substrates containing halogens at C6 position were well accommodated keeping the window open for further modifications (Scheme 2, 3f-3h). Importantly, electron withdrawing group like CF3 group at that position was also well accepted (Scheme 2, 3i). Substitutions at C5 or C4 positions were proved to be quite successful (Scheme 2, 3j, 3n) for this reaction.

Scheme 2: C2-Arylamination of different N-Oxides with anthranil:

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Scheme 2. Scope with various N-oxides: Reaction Conditions: 1 (0. 1 mmol), 2a (0. 2 mmol), CuI (10 mol%), 18-24 h, 80100 °C, 1,4dioxane (0.1 M). a 1a (1 gm, 6.9 mmol), 24 h, 80 °C. b Starting material was 8-(1,3-dioxolan-2-yl) quinoline 1-oxide. c Reaction temperature: 120 °C, 36 h Although, alkyl and halogen groups were compatible at the C8 position (Scheme 2, 3l-3m), 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 N-oxides, 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

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heterocycle i.e. isoquinoline N-oxides also offered excellent yields and 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 nitrogen containing 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 S1). To examine the scalability of the optimized method, quinoline N-oxide (1a) was transformed into the expected arylamine in gram scale with 70% isolated yield (Scheme 2, 3a).

O N O

+ R1 2

1a O N

Ph H N

O

Cl

H N

4d, 79% O N

H N

N

CHO

CHO

R1 4

H N

O N

CHO

H N

CHO

O 4b, 57%a O

4c, 66%

Br

O N

O N

CHO

H N

4e, 85%

Cl

CHO

H N

1,4-dioxane, O N

4a, 76%a O N

O N

CuI (10 mol%)

O N

CHO

H N

4f, 72%

F

O

F H N

O 4g, 48%a

O

O

4h, 81%

Scheme 3. Scope with various anthranil compounds. Reaction Conditions: 1a (0. 1 mmol), 2a (0. 2 mmol), CuI (10 mol%), 18-36 h, 80-100 °C. a Reaction Temperature: 120 °C

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, post operative removal of the directing group i.e. the deoxygenation of compound 3a preceded smoothly to provide C2-arylaminated quinoline 5 (Scheme 4a).12d Here in, we envisaged 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

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Scheme 4. 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:H20 (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; h) Meldrum’s acid (2 equiv), AcOH, ethylenediamine, MeOH, 25 °C; DCE=1,2 dicholoroethane; TBHP = t-Butyl hydroperoxide solution.

Accordingly, compound 5 was converted into important quinolino-quinazolinone motif 6 through a novel TBHP mediated 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 doubledefunctionalisation 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 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 favoured towards electron rich N-oxide over electron deficient one (Scheme 5ii). Moreover, the result of H-D exchange experiment under the standard conditions in CD3CO2D without 2a (Scheme 5iii) showed that there was no

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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 absence of 1a stoichiometric amount of CuI triggered the decomposition of anthranil (2a). In another control experiment simple aniline was not able to provide isolable C2-arylaminated product with 1a under standard conditions.

Scheme 5. Control experiments for mechanistic studies

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 CuI catalyst under the strict inert conditions, 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 desired product under CuII catalytic system (Table 1, entry 15). These results clearly revealed that the probability of acting CuII species in catalytic cycle was less.

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Figure 1. Proposed Mechanism

Based on the preliminary investigations and earlier related literatures, a plausible mechanistic pathway was proposed (Figure 1). First, CuI salt coordinates with the nitrogen centre of anthranil (2a) to form the complex A. Subsequent cleavage of N-O bond leads to afford the copper nitrenoid species which provides intermediate B via metal nitrenoid insertion. Consequently, migratory insertion of nitrenoid into the CuIII-C bond delivers the intermediate C. Finally, the protodemetalation of D offers the arylaminated N-oxide 3a with the regeneration of CuI active species. Alternatively, oxygen of N-oxides can bind with the Lewis acidic CuI salt. Then the nitrogen center of anthranil coordinates with the the copper center. Further, migration of copper center to the C2 position of N-oxides followed by cleavage of N-O bond also can provide the intermediate B. At this stage, the possibility of this pathway cannot be ruled out. Currently, the detail mechanistic studies are under progress.

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 admirable degree of regioselectivity. The post modifications of the final product led to the structurally and functionally diverse nitrogen doped organic π-conjugated systems.

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 pre-coated silica gel 60 F254. Visualization on TLC was achieved by the use of UV light (254 nm). Solvents mixtures were understood as volume/ volume. Column chromatography was undertaken on silica gel (230-400 mesh). Chemical shifts

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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 unit (Hz). The spectra was fully decoupled by broad band proton decoupling. Chemical shifts were reported in ppm referenced to the centre of a triplet at 77.16 ppm of chloroform-d (CDCl3). In case of Infrared (IR) spectra frequencies are given in reciprocal centimetres (cm-1), only selected absorbance peaks are reported and KBr is used as the matrix. HRMS of new compounds were measured through ESI ionization method with 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 synthesised 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), m-chloroperbenzoic acid (m-CPBA, 1.5 mmol, 1.5 equiv.) was added at 0 °C. The reaction mixture was allowed to stir at room temperature for 24 h. Next saturated aq. NaHCO3 solution (20 mL) was added to the reaction mixture and extracted with CH2Cl2 (10 mL x 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 ethyl acetate as eluent. Pure quinoline N-oxides were obtained with (80-90% yield). Other heterocyclic Noxides 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 stirring bar was charged with the 2-nitroacylbenzene (1.0 mmol) in EtOAc:MeOH (1:1; 5 mL), SnCl2. 2H2O (3.0 mmol) was added to the reaction mixture and stirred overnight at room temperature. The reaction was partitioned between CH2Cl2 (30 mL) and NaHCO3 solution (20 mL). The aqueous phase was extracted with CH2Cl2 (10 mL × 3) and combined organic layers were washed with H2O (10 mL), saturated brine solution (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 15-30% ethyl acetate in hexane as eluent. General procedure for copper catalyzed C-2 amidation of quinoline N-oxides with anthranil: 10 mL screw cap vial was charged with quinoline N-oxide (0.1 mmol) dissolved in 1 mL of 1, 4-dioxane. Anthranil (0.2 mmol) and CuI (10 mol%) were added to the reaction mixture at the room temperature. It was heated to 100-120 C and allowed to stir for 12-36 h. After the completion of the reaction, solvent was removed under reduced pressure. Residue was dissolved in CH2Cl2 and filtered through celite. Filtrate was concentrated and purified by flash column chromatography using 30-70% acetone in hexane solvent mixture as the eluent.

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Procedure for the synthesis of compound 5, Removal of directing group:23 To a solution of 2-(2formylphenylamino)quinoline N-oxide (3a) (26.4mg, 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 x 3), dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography using 30-40% ethyl acetae in hexane as 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-2ylamino)benzaldehyde (5) (24.8 mg, 0.1 mmol) in 1,2-dichloroethane (1.5 mL) was added TBHP (4 equiv.) 6 M in decane was added. The reaction mixture was stirred for 12 h at 90 °C temperature. After 12 h reaction mixture was allowed to cool to room temperature and solvent was removed under reduced pressure. The residue was purified by column chromatography using 30% ethyl acetate in hexane as 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) (26.4mg, 0.1 mmol) in THF (1.5 mL) was added 1.5 mL saturated aq. NH4Cl solution. Then 40 equiv. 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 residue was diluted with water and separated between EtOAc and water. EtOAc layer was collected and drier over anhydrous Na2SO4, and solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel with 30-40% ethyl acetate in hexane as 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 Noxide (3a) (26.4mg, 0.1 mmol) in 1,2-dichloroethane (1.5 mL) TBHP (4 equiv.) 6 M in decane was added. The reaction mixture was stirred for 12 h at 100 °C temperature. After 12 h reaction mixture was allowed to cool to room temperature and solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using 40-50% ethyl acetate in hexane as 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)

(26.4mg,

0.1

mmol)

in

dry

CH2Cl2

(2

mL)

ethyl

(triphenylphosphoranylidene)acetate (1.2 equiv) was added. The reaction mixture was stirred for 1 h at room temperature. After 1 h solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel using 30-40% ethyl acetate in hexane as eluent to obtain product 9 (93%) Procedure for the synthesis of 2-(2-ethynylphenylamino)quinoline 1-oxide (10)26: To a solution of 2-(2formylphenylamino)quinoline N-oxide (3a) (26.4 mg, 0.1 mmol) and diethyl 1-diazo-2-oxopropylphosphonate (27 mg, 1.2

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mmol) in dry MeOH (3 mL) anhydrous K2CO3 (26 mg, 0.2 mmol) was added at room temperature. The solution was stirred at room temperature for 24h. Next, solvent was removed under reduced pressure and was diluted with water then extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered, concentrated under reduced pressure and purified by flash column chromatography (eluent: 30% acetone in hexane) to afford 10 as a light yellow solid. (91% yield). Procedure for the synthesis of 1-(quinolin-2-yl)-1H-indole-3-carboxylate (11):14c To a solution of 2-(2formylphenylamino)quinoline 5 (0.1 mmol, 25 mg) and ethyl diazoacetate (57 mg, 1.0 mmol) in CH2Cl2 (2 mL) at 0 °C was added BF3.OEt2 (13 μL, 0.2 mmol) drop wise. 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, concentrated under reduced pressure and purified by flash chromatography (eluent: 40% ethyl acetate in hexane) to afford 11 as a white solid (46%). Procedure for the synthesis of 2-oxo-2H-1,2'-biquinoline-3-carboxylic acid (12):14a 2-(2-formylphenylamino)quinolines (5) (0.1 mmol), AcOH (0.2 mmol), and ethylenediamine (0.1 mmol) were dissolved in MeOH (3 mL) at 0 °C, to which was added Meldrum's acid (0.18 mmol) 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 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 1,4dioxane. Anthranil 2a (1.64 g, 13.8 mmol) and followed by 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 same temperature for 24 h. After completion of the reaction time, solvent was removed under reduced pressure and the residue was directly loaded to the column and purified with 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 2mL of 1,4dioxane. Anthranil (24 mg, 0.2 mmol) and CuI (3.8 mg, 10 mol%) were added to the reaction mixture and stirred at 100 °C for 8h. After cooling it to room temperature, solvent was removed under reduced pressure and mixture of product was isolated by flash column chromatography and the product ratio was identified by 1H NMR to be 1:4 (3i:3b). Control experiment under 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 stirrer and dissolved in 1 mL 1,4-dioxane. After deoxygenation of the reaction mixture through 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

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100 °C and stirring was continued until complete consumption of N-oxide (monitored by TLC). After 24 h, reaction mixture was allowed to cool to room temperature and purified by flash column chromatography using 50-60% acetone in hexane solvent mixture as eluent. Under 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 magnetic stirring bar and dissolved in 1 mL of 1, 4-dioxane. Then CuI (1.9 mg, 10 mol%), BHT (2,6-di-tert-butyl-4methylphenol, 44 mg, 0.2 mmol) and anthranil 2a (24 mg, 0.2 mmol) were added to the reaction and it was stirred for 24 h at 100 °C. Consumption of N-oxide was monitored by TLC and after 24 h reaction mixture was allowed to cool to room temperature and directly loaded to the column and purified by flash column chromatography using 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 1,4dioxane and 0.5 mL of deuterated solvent. Anthranil 2a (24 mg, 0.2 mmol) and followed by CuI (1.9 mg, 10 mol%) was added to the reaction mixture at room temperature. It was allowed to stir for 24 h at 100 C. After the completion of the reaction, solvent was removed under reduced pressure, residue was dissolved in CH2Cl2 and filtered through celite. Filtrate was concentrated under reduced pressure and filtered through silica gel column chromatography using 80% acetone in hexane mixture as the eluant. The 1H NMR spectrum revealed that there was no H-D exchange at C-2 position of 1a. Kinetic isotope effect from an intermolecular competition between quinoline N‐oxide and d1‐quinoline N‐oxide: Quinoline N‐oxide 1a and 2‐D1‐quinoline N‐oxide 1a’ (1:1) (totally 0.2 mmol), were dissolved in 1mL of 1,4dioxane. Anthranil 2a (24 mg, 0.2 mmol) was added and stirred for 3 h at 100 °C. Then CuI (3.8 mg, 10 mol%) was added to the solution. Consumption of N‐oxide was monitored by TLC. Residual starting materials (mixture of 2‐D1‐quinoline N‐oxide and quinoline N‐oxide) were recovered after flash filtration through silica gel (230‐400 mesh), and it was characterized by 1

H NMR spectrum. The kH/kD = 1.00 was calculated by 1H NMR spectrum of the crude isolated mixture of residual N‐oxides

1a and 1a´. Kinetic isotope effect determined from absolute rates of two parallel reactions between quinoline N‐oxide and 2‐D1‐quinoline N‐oxide: Using the established optimized conditions, intermolecular parallel competition experiments between quinoline N‐oxide 1a and 2‐D1‐quinoline N‐oxide 1a’ were carried out, individually. The kH/kD= 1.2 was calculated based on the isolated yields. Analytical Data:

13



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Page 14 of 26

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): 3045, 2925, 2833, 2752, 1675, 1602, 1572, 1530, 1457, 1356, 1282; HRMS Calculated 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): 3066, 2848, 2762, 1671, 1599, 1583, 1531, 1547, 1401, 1357, 1283; HRMS Calculated 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): 3046, 2847, 2762, 1665, 1615, 1598, 1577, 1526, 1437, 1396, 1328; HRMS Calculated for [M+H]+ : C17H15N2O2: 279.1128; found: 279.1127. 6-Cyclopropyl-2-(2-formylphenylamino)quinoline 1-oxide (3d): Yellow amorphous solid, Yield 82% 2(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): 3063, 2846, 2758, 1673, 1610, 1597, 1579, 1527, 1458, 1326, 1279; HRMS Calculated 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, DMSO-d6) 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), 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,

14


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~

126.9, 125.9, 124.7, 124.4, 122.8, 118.5, 118.3, 111.0; FT-IR:  = (KBr, cm‐1): 3044, 2932, 2853, 2761, 1679, 1612, 1577, 1522, 1386, 1329; HRMS Calculated 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, DMSO-d6) 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): 3046, 2919, 2841, 2732, 1677, 1603, 1586, 1537, 1372, 1323, 1283; HRMS Calculated 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, DMSO-d6) 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; FT-IR:  = (KBr, cm‐1): 3057, 2922, 2832, 2747, 1673, 1605, 1592, 1539, 1401, 1326; HRMS Calculated 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, DMSO-d6) 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; FT-IR:  = (KBr, cm‐1): 3054, 2927, 2835, 2742, 1675, 1598, 1584, 1526, 1390, 1317, 1276; HRMS Calculated 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): 3064, 2972, 2840, 2761, 1672, 1600, 1576, 1523, 1425, 1334, 1281; HRMS Calculated for [M+H]+: C17H12F3N2O2: 333.0845; found: 333.0856

15



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Page 16 of 26

2-(2-Formylphenylamino)-5-phenylquinoline 1-oxide (3j): Yellow amorphous solid, Yield 85% (28.9 mg); 1H NMR (400 MHz, DMSO-d6) 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): 3052, 2953, 2844, 2736, 1672, 1601, 1581, 1529, 1441, 1335, 1289; HRMS Calculated 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, DMSO-d6) 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); 13C 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): 3060, 2925, 2866, 2850, 2754, 1670, 1598, 1577, 1533, 1450, 1370, 1325, 1267; HRMS Calculated for [M+H]+: C17H13N2O3: 293.0921; found: 293.0931. 2-(2-Formylphenylamino)-8-methylquinoline 1-oxide (3l): Yellow amorphous solid, Yield 79% (21.9 mg); 1H NMR (400 MHz, DMSO-d6) 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): 3046, 2927, 2832, 2754, 1677, 1600, 1582, 1523, 1398, 1315; HRMS Calculated 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);

13

C 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): 3067, 2925, 2839, 2752, 1676, 1603, 1580, 1534, 1460, 1405, 1329, 1289; HRMS Calculated 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,

16


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~

110.9, 18.6; FT-IR:  = (KBr, cm‐1): 3062, 2839, 2762, 1665, 1598, 1573, 1526, 1444, 1362, 1279; HRMS Calculated 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, DMSO-d6) 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): 3054, 2927, 2856, 2749, 1675, 1603, 1578, 1532, 1452, 1400, 1321, 1277, 1209; HRMS Calculated 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): 3046, 2929, 2839, 2743, 1678, 1604, 1589, 1537, 1436, 1407, 1329, 1285, 1221; HRMS Calculated 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): 3051, 2920, 2845, 2754, 1670, 1591, 1570, 1541, 1475, 1426, 1307; HRMS Calculated 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); 1H 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, 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): 3042, 2927, 2837, 2744, 1669, 1597, 1575, 1525, 1457, 1400, 1326; HRMS Calculated for [M+H]+: C19H17N2O2: 305.1285; found: 305.1297

17



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Page 18 of 26

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): 3048, 2952, 2846, 2757, 1678, 1607, 1578, 1529, 1436, 1398, 1334; HRMS Calculated 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): 3057, 2923, 2844, 2737, 1679, 1589, 1575, 1525, 1497,

1449, 1307, 1298; HRMS Calculated 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): 3052, 2954, 2862, 2734, 1676, 1601, 1586, 1525, 1490, 1431, 1321, 1264;

HRMS Calculated 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, DMSO-d6) 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): 3059, 2978, 2837, 2751, 1679, 1591, 1566, 1521, 1476, 1423, 1332, 1296; HRMS Calculated 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, DMSO-d6) 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); 13

C 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,

18


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117.4, 117.2, 109.1; FT-IR:

~ = (KBr, cm‐1): 3064, 2834, 2755, 1671, 1596, 1574, 1516, 1448, 1383, 1300, 1263; HRMS

Calculated 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, DMSO-d6) 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, DMSO-d6) 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): 3056, 2841, 2722, 1688, 1589, 1576, 1529, 1467, 1397, 1327, 1283; HRMS Calculated 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, 123.9, 121.9, 119.9, 119.7, 118.3; FT-IR:  = (KBr, cm‐1): 3045, 2849, 2758, 1677, 1583, 1561, 1531, 1457, 1400, 1332; HRMS Calculated 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): 3049, 2844, 2745, 1679, 1579, 1568, 1543, 1467, 1408, 1325; HRMS Calculated 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. FT-IR:  = (KBr, cm‐1): 3060, 2927, 1659, 1603, 1576, 1521, 1442, 1353, 1301, 1254; HRMS Calculated 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

19



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Page 20 of 26

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): 3054, 2961, 2858, 2741, 1643, 1586, 1539, 1459, 1407, 1338, 1276; HRMS

Calculated 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, DMSO-d6) 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); 13C 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): 3042, 2832, 2754, 1673, 1590, 1541, 1457, 1373, 1319; HRMS Calculated for [M+H]+: C16H1279BrN2O2: 343.0077; found:343.0094 2-(5-Chloro-2-formylphenylamino)quinoline 1-oxide (4d): Yellow amorphous solid, Yield 79% (23.5mg); 1H NMR (400 MHz, DMSO-d6) 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): 3089, 2842, 2722, 1666, 1578, 1523, 1489, 1431, 1377, 1298; HRMS Calculated 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, DMSOd6) 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): 3063, 2927, 2856, 2739, 1679 , 1604 ,1535 ,1486 ,1409 ,1369, 1292; HRMS Calculated 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 = 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): 3059, 2936, 2857, 2724, 1677, 1606, 1528, 1501, 1411, 1373, 1286; HRMS

Calculated for [M+H]+: C17H14N2O3 : 295.1077; found: 295.1080.

20


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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): 3067, 2926, 2845, 2709, 1675, 1600, 1531, 1478, 1405, 1368, 1290; HRMS Calculated 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; 19F NMR (376 MHz, DMSO-d6) δ -113.19; FT-IR:  = (KBr, cm‐1): 3060, 2929, 2853, 2732, 1686, 1596, 1542, 1483, 1398, 1377, 1296; HRMS Calculated 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): 3047, 2929, 2836, 2751, 1665, 1601, 1572, 1525, 1449, 1398, 1325; HRMS Calculated 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): 3046, 2920, 2850, 1686, 1603, 1545, 1471, 1320, 1275; HRMS Calculated 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:

21



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Page 22 of 26

~ = (KBr, cm‐1): 3055, 2922, 1618 ,1595 ,1533 ,1482 ,1455 ,1400 ,1318, 1292; HRMS Calculated for [M+H]+: C16+H13N2: 233.1073; found:233.1054 Benzimidazo[1,2-a]quinolines (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): 3030, 2957, 2917, 1894, 1611, 1541, 1451, 1393, 1328, 1278; HRMS Calculated for [M+H]+: C15H11N2: 219.0917; found:219.0904 (E)-2-(2-(3-Ethoxy-3-oxoprop-1-enyl)phenylamino)quinoline 1-oxide (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): 3055, 2922, 1722, 1618 ,1595 ,1533 ,1482 ,1455 ,1400 ,1318, 1293; HRMS Calculated 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): 3232, 3077, 2929, 1632, 1619, 1596, 1578, 1529, 1423, 1364; HRMS Calculated 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); 13C 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): 3066 2928, 1694, 1597, 1551, 1508, 1449, 1328, 1287; HRMS Calculated 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

22


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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(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): 3053, 3004, 2929, 2862, 1702, 1616, 1593, 1571, 1507, 1425, 1384, 1260; HRMS Calculated for [M+H]+ : C19H13N2O3 : 317.0921; found: 317.0928

ASSOCIATED CONTENT Supporting Information 1

H, 13C NMR spectra of new compounds and X-ray data for compound 3p. This material is available free of charge via the

Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author *E-mail: [email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT

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.

REFERENCES

(1) a) Liu, W.; Khedkar, V.; Baskar, B.; Schürmann, M.; Kumar, K. Angew. Chem. Int. Ed. 2011, 50, 6900. b) Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Angew. Chem. Int. Ed. 2009, 48, 104. c) Wang, M.; Zhang, X.; Zhuang, Y.-X.; Xu, Y.-H.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 1341. (2) (a) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem. 2008, 12, 1116. (b) Hughes, G.; Bryce, M. R. J. Mater. Chem. 2005, 15, 94. (c) Kimyonok, A.; Wang, X. Y.; Weck, M. Polym. Rev. 2006, 46, 47. (d) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166. (3) Representative reviews on transition metal catalyzed direct functionalizations of N-oxides: (a) Nakao, Y. Synthesis 2011, 3209. (b) Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem. 2010, 2, 20. (c) Iwai, T.; Sawamura, M. ACS Catal. 2015, 5, 5031. (d) Stephens, D. E.; Larionov, O. V. Tetrahedron 2015, 71, 8683. (e) Yan, G.; Borah, A. J.; Yang, M. Adv. Synth. Catal. 2014, 356, 2375.

23



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 26

(4) Recent transition metal catalyzed direct functionalizations of N-oxides: (a) Stephens, D. E.; Lakey-Beitia, J.; Chavez, G.; Ilie, C.; Armana, H. D.; Larionov, O. V.; Chem. Commun. 2015, 51, 9507. (b) Gwon, D.; Hwang, H.; Kim, H. K.; Marder, S. R.; Chang, S. Chem. Eur. J. 2015, 21, 17200. (c) Yu, S.; Wan, B.; Li, X. Org. Lett. 2015, 17, 58. (d) Stephens, D. E.; Lakey-Beitia, J.; Atesin, A. C.; Atesin, T. A.; Chavez, G.; Arman, H. D.; Larionov, O. V. ACS Catal. 2015, 5, 167. (e) Kalsi, D.; Laskar, R. A.; Barsu, N.; Premkumar, J. R.; Sundararaju, B. Org. Lett. 2016, 18, 4198. (f) Chen, X. P.; Cui, X. L.; Wu, Y. J. Org. Lett. 2016, 18, 3722. (5) Selected transition metal catalyzed arylations: (a) Campeau, L. C.; Stuart, D. R.; Leclerc, J. P.; Bertrand-Laperle, M.; Villemure, E.; Sun, H. Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291. (b) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. (c) Ackermann, L.; Fenner, S. Chem. Commun. 2011, 47, 430. (d) Liu, B.; Wang, Z.; Wu, N.; Li, M.; You, J.; Lan, J. Chem. Eur. J. 2012, 18, 1599. (6) Transition metal catalyzed heteroarylations (a) Odani, R.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2015, 80, 2384. (b) Gosselin, F.; Savage, S. J.; Blaquiere, N.; Staben, S. T. Org. Lett. 2012, 14, 862. (c) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822. (d) Fu, X. P.; Xuan, Q. -Q.; Liu, L.; Wang, D.; Chen, Y. J.; Li, C. J. Tetrahedron 2013, 69, 4436. (e) Wang, Z.; Song, F.; Zhao, Y.; Huang, Y.; Yang, L.; Zhao, D.; Lan, J.; You, J. Chem. Eur. J. 2012, 18, 16616. (f) Willis, N. J.; Smith, J. M. RSC Adv. 2014, 4, 11059. (g) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem. Int. Ed. 2011, 50, 5365. (h) Gong, X.; Song, G. Y.; Zhang, H.; Li, X. W. Org. Lett. 2011, 13, 1766. (i) Liu, W.; Yu, X.; Li, Y.; Kuang, C. Chem. Commun. 2014, 50, 9291. (7) Transition metal catalyzed alkylations: (a) Larionov, O. V.; Stephens, D.; Mfuh, A.; Chavez, G. Org. Lett. 2014, 16, 864. (b) Wu, Z. Y.; Pi, C.; Cui, X. L.; Bai, J.; Wu, Y. J. Adv. Synth. Catal. 2013, 355, 1971. (c) Xiao, B.; Liu, Z. J.; Liu, Z. L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 616. (d) Ryu, J.; Cho, S. H.; Chang, S. Angew. Chem. Int. Ed. 2012, 51, 3677. (e) Jhaa, A. K.; Jain, N. Chem. Commun. 2016, 52, 1831. (8) Transition metal catalyzed alkenylation: Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc. 2009, 131, 13888. (9) Transition metal catalyzed C-O bond formation: Chen, X.; Zhu, C.; Cui, X.; Wu, Y. Chem. Commun. 2013, 49, 6900. (10) Transition metal catalyzed C-S bond formations: (a) Wu, Z.; Song, H.; Cui, X.; Pi, C.; Du, W.; Wu, Y. Org. Lett. 2013, 15, 1270. (b) Du, B.; Qian, P.; Wang, Y.; Mei, H.; Han, J.; Pan, Y. Org. Lett. 2016, 18, 4144. (11) Recent transition metal free amidation (a) Li, P.; Zhao, J.; Xiaa, C.; Li, F. Org. Chem. Front., 2015, 2, 1313. (b) Aithagani, S. K.; Kumar, M.; Yadav, M.; Vishwakarma, R. A.; Singh, P. P. J. Org. Chem. 2016, 81, 5886. (c) Bering, L.; Antonchick, A. P. Org. Lett. 2015, 17, 3134. (d) Chen, X.; Cui, X.; Yang, F.; Wu, Y. Org. Lett. 2015, 17, 1445. (e) Xia, H.; Liu, Y.; Zhao, P.; Gou, S.; Wang, J. Org. Lett. 2016, 18, 1796. (f) Tang, R. J.; Kang, L.; Yang, L. Adv. Synth. Catal. 2015, 357, 2055.

24


Page 25 of 26

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(12) (a) Li, G.; Jia, C.; Sun, K. Org. Lett. 2013, 15, 5198. (b) Li, G.; Jia, C.; Sun, K.; Lv, Y.; Zhao, F.; Zhoua, K.; Wu. H. Org. Biomol. Chem. 2015, 13, 3207. (c) Zhu, C.; Yi, M.; Wei, D.; Chen, X.; Wu, Y.; Cui, X. Org. Lett., 2014, 16, 1840. (d) Yu, H.; Dannenberg, C. A.; Li, Z.; Bolm, C. Chem. Asian J. 2016, 11, 54. (e) Li, Y.; Gao, M.; Wang, L.; Cui, X. Org. Biomol. Chem. 2016, 14, 8428. (13) (a) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2016, 55, 12688. (b) Jin, H.; Huang, L.; Xie, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2016, 55, 794. (14) (a) Yu, S.; Tang, G.; Li, Y.; Zhou, X.; Lan, Y.; Li, X. Angew. Chem. Int. Ed. 2016, 55, 8696. (b) Li, L.; Wang, H.; Yu, S.; Yang, X.; Li, X. Org. Lett. 2016, 18, 3662. (c) Tang, C.; Zou, M.; Liu, J.; Wen, X.; Sun, X.; Zhang, Y.; Jiao, N. Chem. Eur. J. 2016, 22, 11165. (d) Zou, M.; Liu, J.; Tang, C.; Jiao, N. Org. Lett. 2016, 18, 3030. (e) Yu, S.; Li, Y.; Zhou, X.; Wang, H.; Kong, L.; Li, X. Org. Lett. 2016, 18, 2812. (f) Shi, L.; Wang, B. Org. Lett. 2016, 18, 2820. (g) Li, H.; Jie, J.; Wu, S.; Yang, X.; Xu, H. Org. Chem. Front. 2017, 4, 250. (h) Mishra, N. K.; Jeon, M.; Oh, Y.; Jo, H.; Park, J.; Han, S.; Sharma, S.; Han, S. H.; Jung, Y. H.; Kim, I. S. Org. Chem. Front. 2017, 4, 241. (i) Tiwari, D. K.; Phanindrudu, M.; Wakade, S. B.; Nanuboluc, J. B.; Tiwari, D. K. Chem. Commun. 2017, 53, 5302. (j) Debbarma, S.; Maji, M. S. Eur. J. Org. Chem. 2017, 10.1002/ejoc.201700457. (15) Baum, J. S.; Condon, M. E.; Shook, D. A. J. Org. Chem. 1987, 52, 2983. (16) For recent representative reviews: (a) Yamaguchi, J.; Muto, K.; Itami, K. Top. Curr. Chem. 2016, 374, 55. (b) Zhu, X.; Chiba, S. Chem. Soc. Rev., 2016, 45, 4504. (c) Moselage, M.; Li, J.; Ackermann, L. ACS Catal. 2016, 6, 498. (d) Liu, W.; Ackermann, L. ACS Catal. 2016, 6, 3743. (e) Liu, J.; Chen, G.; Tan, Z. Adv. Synth. Catal. 2016, 358, 1174. (f) Hirano, K.; Miura, M. Chem. Lett. 2015, 44, 868. (g) Castro, L. C. M.; Chatani, N. Chem. Lett. 2015, 44, 410; (h) Guo, X. -X.; Gu, D. –W.; Wu, Z.; Zhang, W. Chem. Rev. 2015, 115, 1622. (17) (a) Das, D.; Biswas, A.; Karmakar, U.; Chand, S.; Samanta, R. J. Org. Chem. 2016, 81, 842. (b) Das, D.; Poddar, P.; Maity, S.; Samanta, R. J. Org. Chem. 2017, 82, 3612. (c) Karmakar, U.; Das, D.; Samanta, R. Eur. J. Org. Chem. 2017, 2017, 2780. (18) Biswas, A.; Karmakar, U.; Pal, A.; Samanta, R. Chem. Eur. J. 2016, 22, 13826. (19) Selected reviews (a) Anthony, J. E. Angew. Chem. Int. Ed. 2008, 47, 452. (b) Allard, S.; Forster, M.; Souharce, B. Thiem, H.; Scherf, U. Angew. Chem. Int. Ed. 2008, 47, 4070. (c) Wang, C.; Dong, H.; Hu, W.; Liu, Y.; Zhu, D. Chem. Rev. 2011, 111, 2208. (d) Watanabe, M.; Chen, K. Y.; Chang, Y. J.; Chow, T. J. Acc. Chem. Res. 2013, 46, 1606. (e) Sun, Z.; Zeng, Z.; Wu, J. Acc. Chem. Res. 2014, 47, 2582. (20) (a) Mishra, K.; Pandey, A. K.; Singha, J. B.; Singh, R. M. Org. Biomol. Chem. 2016, 14, 6328. (b) Wertz, S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928.

25



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 26

(21) (a) Zhao, J.; Li, P.; Xia, C.; Li, F. RSC Adv. 2015, 5, 32835. (b) Li, G.; Jia, C.; Sun, K.; Lv, Y.; Zhao, F.; Zhoua, K.; Wu, H. Org. Biomol. Chem. 2015, 13, 3207. (c) Xia, H.; Liu, Y.; Zhao, P.; Gou, S.; Wang, J. Org. Lett. 2016, 18, 1796. (d) Larionov, O. V.; Stephens, D.; Mfuh, A.; Chavez, G. Org. Lett. 2014, 16, 864. (22) Chauhan, J.; Fletcher, S. Tetrahedron Lett. 2012, 53, 4951. (23) Zhu, C.-W.; Yi, M. -L.; Wei, D. -H.; Chen, X.; Wu, Y. -J.; Cui, X. -L. Org. Lett. 2014, 16, 1840. (24) Liu, M; Shu, M.; Yao, C.; Yin, G.; Wang, D.; Huang, J. Org. Lett. 2016, 18, 824. (25) He, Y.; Huang, J.; Liang, D.; Liu, L.; Zhu, Q. Chem. Commun. 2013, 49, 7352. (26) (a) Ohira, S. Synth. Commun. 1986, 19, 561. (b) Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett. 1996, 521.

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