Regioselective Arylation of Quinoline N-Oxides (C8), Indolines (C7) and N-tert-Butylbenzamide with Arylboronic Acids

Abstract

Herein, we disclose Ru(II)-catalyzed regioselective distal C(sp²)–H arylation of quinoline N-oxide with arylboronic acids to 8-arylquinolines. In the developed method, the Ru(II)-catalyst shows dual activity, that is, distal C–H activation of quinoline N-oxides followed by in situ deoxygenation of arylated quinoline N-oxide in the same pot. The current catalytic method features use of Ru metal as the catalyst and arylboronic acids as the arylating source under mild reaction conditions. Use of the Rh(III)-catalyst in place of Ru(II) under the same conditions afforded 8-arylquinoline N-oxides with excellent regioselectivity. Furthermore, the developed Ru(II) catalytic system is also extended for the C(sp²)–H arylation of indolines, N-tert-butylbenzamide, and 6-(5H)-phenanthridinone. Formation of the quinoline N-oxide coordinated ruthenium adduct is found to be the key reaction intermediate, which has been characterized by single crystal X-ray diffraction and NMR spectroscopy.

Introduction

N-heterocyclic aromatic scaffolds are often encountered in a wide range of compounds including natural products, pharmaceuticals, agrochemicals, and ligands.¹ Quinoline, a prominent structural scaffold, is found in a wide range of natural products and capable of showing diverse type of therapeutic activity.² Among them the 8-arylated quinoline moiety has its own importance as it is often found in bioactive compounds (Scheme 1).³ Therefore, functionalization of the quinoline scaffold to corresponding 8-arylquinolines is highly desirable, in order to produce bioactive compounds synthetically.

Scheme 1. Selected Example of Bioactive 8-Arylquinoline Scaffolds.

Transition metal-catalyzed regioselective C–H functionalization has emerged as an ideal strategy for the synthesis of therapeutically active quinoline scaffolds.⁴ In this direction, N-oxide has been explored as an excellent directing group for the selective functionalization of quinolines.^4d,5 Although, C8 functionalization of quinoline N-oxides is not explored much,⁶ various methods have been developed for C2 functionalization.^5a,5b,7 Among them, few reports are available on C8 arylation of quinolines (Scheme 2).^6a,6c,6d,6h In 2011, first Rh(II)(NHC)-catalyzed direct C8 arylation of quinolines through C–H functionalization with aryl bromide as a coupling partner has been reported by the Chang group.^6a Later, Pd(II)-catalyzed C8 arylation of quinoline N-oxide has been reported with aryl halide as a coupling partner by the Larionov group.^6c In this direction, the Chang group also reported Ir(III)-catalyzed C8 arylation^6d of quinoline N-oxide with aryldiazonium salt as an arylating source. In addition to these reports, the Liu group reported C8 arylation of quinoline N-oxide by using potassium aryltrifluoroborate as a coupling partner with a limited substrate scope and low yields. In spite of all these examples, cheaper metal, i.e., ruthenium has never been explored for C8 functionalization of quinoline N-oxides. Arylboronic acid is also most predominantly available and a cost-effective choice for arylation. Herein, we disclosed Ru(II)-catalyzed distal sp²(C8–H) arylation with arylboronic acids under mild reaction conditions (Scheme 2). During the compilation of this work, similar transformation was also reported by the Chang group,⁸ but the current methodology is not limited only for quinoline N-oxide, it is also applicable for the arylation of indolines, 6-(5H)-phenanthridinone and N-tert-butylbenzamide substrates. Additionally, use of the Rh(III) catalyst in place of Ru(II), afforded an arylated product with N-oxide which provides opportunity for further derivatization (Scheme 2).

Scheme 2. Regioselective C8 Functionalization of Quinoline N-Oxide.

Result and Discussion

Initially, quinoline N-oxide (1a) and arylboronic acid (2a) were reacted in the presence of [RuCl₂(p-cymene)]₂ (5 mol %), AgSbF₆ (20 mol %), Cu(OTf)₂ (20 mol %), Ag₂CO₃ (2.5 equiv), and dimethoxyethane (DME) as solvent at 100 °C under open air to afford 20% yield of the desired product (3a) along with quinoline (4a) as a side product (Table 1, entry 4). Therefore, we screened different silver additives and oxidants, in order to reduce undesired quinoline and we found that the combination of AgOTf, Cu(OTf)₂, and Ag₂O were appreciable to afford the arylated product and quinoline in a 70:30 ratio (Table 1, entry 9). Further optimization study shows that triflic anhydride (25 mol %) is also significant to carry out the reaction, which replaced costlier metal triflate salt, that is, AgOTf and Cu(OTf)₂ without affecting the reaction yield (Table 1, entry 1). Additionally, triphenylboroxine (1 equiv) was found to be of approximately equal potency (entry 2). Solvent screening indicated tetrahydrofuran (THF) as a solvent of choice (entry 1, 4–5). Oxidant screening have shown Ag₂O as the best one, while Ag₂CO₃, Cu₂O, and Mn₂O have shown inferior result than Ag₂O (Table 1, entry 6–8). Alone Cu(OTf)₂ as an additive with oxidant Ag₂O gave 45% product yield (Table 1, entry 10). AgOTf instead of Tf₂O was not able to give the product (Table 1, entry 11). Moreover, heat energy analysis indicated that the forward reaction is compatible broadly throughout 30–100 °C, but traces of the side product was also observed at 100 °C (Table 1, entry 12). Notably, we got rid of the undesired side reaction by performing the reaction at 40 °C instead of 100 °C. We have also tried other arylating agents such as trimethoxyphenylsilane (1 equiv AgF added additionally in order to make silane more reactive), triphenylborane, and tetraphenyltin, which afforded low to moderate yield of the desired product (Table 1, entry 3). We finalized the standard condition as 3 equiv phenylboronic acid, 5 mol % [RuCl₂(p-cymene)]₂, 25 mol % triflic anhydride, 2.5 equiv Ag₂O, and THF as the solvent at 40 °C to afford 70% arylated product along with quinoline as a byproduct.

Table 1. Optimization Study for Ru-Catalyzed C(8)–H Arylation^a.

		yield (%)b
entry	variation from standard condition	3a	4a
1	none	70 (60)e	30
2	triphenylboroxine instead of 2a	70	30
3	phenyltrimethoxysilane, triphenylborane, and tetraphenyltin instead of 2a	upto 40
4c	DME as solvent along with AgSbF6 & Cu(OTf)2 salt and Ag2CO3 as oxidant	20
5	1,4-dioxane instead of THF	40	40
6	Ag2CO3 instead of Ag2O	40
7	Cu2O instead of Ag2O	25
8	Mn2O instead of Ag2O	10
9	AgOTf and Cu(OTf)2 instead of Tf2O	70	30
10	Cu(OTf)2 instead of Tf2O	45	55
11	AgOTf instead of Tf2O	ND
12	at 100 °C	45	35
13d	[RhCp*Cl2]2 instead of RuCl2(p-cymene)	92 (90)e

^aReaction condition: 1a (0.1 mmol), 2a (0.3 mmol), dry THF (0.5 mL), 40 °C, 16 h.

^bNMR Yield by using 1,1,2,2-tetrachloroethane as an internal standard.

^cAt 100 °C.

^dProduct with N-oxide.

^eIsolated yield, ND: not detected, Tf₂O: trifluoromethanesulfonate anhydride, DME: dimethoxyethane, THF: tetrahydrofuran.

With the best optimized condition, substrate scopes with various arylboronic acids as well as quinoline N-oxide have been studied (Table 2). The reaction of C-2-substituted quinoline N-oxide 1b and 1c with 2a afforded the corresponding C8 arylated products (3b–3c) in a good yield. On the other hand, electron deficient quinoline N-oxide (1d and 1i) as well as polyaromatic quinoline N-oxide (1j) provided up to 28% desired product yield (3d, 3i–3j). Variation of methyl at 4-position and 6-position gave a product yield of 32 and 28%, respectively (3e & 3f), while 6-bromo quinoline N-oxide afforded 24% of the product yield (3h). Electron-rich quinoline N-oxide (1g) rings were able to give the product in 35% yield (3g). Next, differentially substituted arylboronic acids were tested with 1a under optimal reaction conditions. Electron-rich arylating sources like 4-amylphenylboronic acid, 3,5-dimethylphenylboronic acid, 4-methylphenylboronic acid, and 4-methoxyphenylboronic acid were able to afford the corresponding arylated product in moderate to good yield (3k, 3l, 3m, 3o), while the electron-deficient arylating source like 4-nitrophenylboronic acid gave no product. This indicates that nucleophilicity of the arylating source is significant; more nucleophilic arylating sources are good and vice-versa. Additionally, 4-chloro and 4-bromophenylboronic acids gave 52 and 35% yield, respectively (3p and 3q), while 4-phenyl and 4-formylphenylboronic acid afforded 25 and 22% of product yield (3n and 3r).

Table 2. Substrate Scope of Ru-Catalyzed C–H Arylation^a.

^aReaction condition: 1 (0.4 mmol), 2 (1.2 mmol), [RuCl₂(p-cymene)]₂ (5 mol %), Ag₂O (2.5 equiv), Tf₂O (25 mol %), dry THF (2.0 mL) 40 °C, 16 h.

In order to investigate the standardized condition scope with other metal catalysts, we replaced Ru(II) metal with its isoelectronic species Rh(III) (Table 1, entry 13), which gave 90% isolated yield of 8-phenylquinoline N-oxide instead of the deoxygenated product (3a). With these re-optimized reaction conditions substrate scope was studied (Table 3). Halogenated quinoline N-oxide gave a good yield of the desired product (5b), and additionally electron-rich quinoline rings were twice better as compare to the electron-deficient ones (5c and 5d). Moreover, 4-nitrophenylboronic acid was not compatible, possibly due to weaker nucleophilic arylating agent (5i). Besides this, 2-fluorophenylboronic acid was not able to give the product (5j), and it may be due to the steric factor as well as the fluoro group which is also the electron withdrawing group inductively, deteriorating its reactivity. Further, variation of meta and para-substituted phenylboronic acid gave up to 66% of the corresponding arylated product with N-oxide (5e–5h).

Table 3. Scope of Rh(III)-Catalyzed C–H Arylation^a.

^aReaction condition: 1 (0.4 mmol), 2 (1.2 mmol), [Cp*RhCl₂]₂ (5 mol %), Ag₂O (2.5 equiv), Tf₂O (25 mol %), dry THF (2.0 mL), 40 °C, 16 h.

Indoline scaffolds are also one of the most important bioactive structural moieties which are widely present in vinblastine, strychnine, and (−)-physostigmine.⁹ There were also few reports for derivatization of the indoline scaffold in order to get more valuable bioactive products.¹⁰

Therefore, we have tried to explore our arylation methodology for this important heterocyclic scaffolds with pyrimidine as the directing part, which can be removed easily by heating it at 110 °C in dimethyl sulfoxide solvent.¹¹ Interestingly, we got 90% corresponding C-7 arylated indoline product (7a) under slightly varied reaction conditions, that is, at 100 °C with an oxygen atmosphere. Subsequently, electronically different substituents at para and meta-position of phenylboronic acids were found to be well tolerated under revised reaction conditions and afforded a good yield of arylated products (7b–7f). We have also tried heteroarylation, as well as methylation by utilizing their corresponding boronic acid on indolines but it was found to be incompatible (7g–7h). Consequently, we have also explored arylation of benzo[h]quinoline and 6-(5H)-phenanthridinone with 2a, which afforded 55 and 20% yield, respectively, at 100 °C with no oxygen atmosphere (Table 4, entry 8 and 9). In the same direction, the weak coordinating directing group-containing scaffold, that is, N-tert-butylbenzamide was reacted with 2a, which gave 65% arylation on the ortho position of the amide group (10). These results show broad applicability of our developed methodology.

Table 4. Scope of Ru(II)-Catalyzed Arylation of Indolines and Other Substrates^a.

^aReaction condition: 6 (0.4 mmol), 2 (1.2 mmol), [RuCl₂(p-cymene)]₂ (5 mol %), Ag₂O (2.5 equiv), Tf₂O (25 mol %), dry THF (2.0 mL), 100 °C, 20 h, O₂ atmosphere for indoline substrates only.

In order to anticipate the mechanistic pathway, we have carried out control experiments. A parallel experiment showed that K_H/K_D = 1.40 (Scheme 3.), which implies that the C–H bond cleavage might not be the rate limiting step.

Scheme 3. Parallel Experiment for KIE.

We have also tried to synthesize the ruthenacycle intermediate by the previously reported method¹² but we got quinoline oxygen coordinated ruthenium adduct Ru1, which have been characterized by NMR and single crystal X-ray diffraction technique (Scheme 4a). Further, Ru1 is utilized in place of an active ruthenium catalyst, which afforded the desired product in 50% yield (Scheme 4b).

Scheme 4. Synthesis of the Ruthenium Adduct and Its Utility as an Catalyst.

No product was observed by reacting quinoline with 2a, which confirmed the necessity of N-oxide as a directing part in the quinoline moiety (Scheme 5a). In order to confirm the role of Ru as an deoxygenating agent, we have performed a preliminary experiment, one with the Ru(II) metal and second with the Rh(III) metal in the absence of 2a, which afforded 35% yield of 4a in the first case, while 1a was intact in the second case (Scheme 5b,c). In the same consequence, we have added 1 mol % of the Ru catalyst under Rh-catalyzed reaction conditions, which gave 48% arylated product 3a (Scheme 5d). These experiments strongly recommend the role of the Ru(II) metal as a deoxygenating agent along with catalytic activity in the same pot.

Scheme 5. Preliminary Experiment Showing Ru as a Deoxygenating Agent.

Further studies have shown that there is stronger bond dissociation energy in case of the Ru–O bond as compared to that of the Rh–O bond;¹³ therefore, it can act as a driving force for the deoxygenation process in case of Ru-catalyzed reaction conditions.

On the basis of these preliminary experiments, we proposed the probable catalytic cycle (Scheme 6). The reaction may proceed through the intermediacy of Ru1 species, which may be formed through lewis acid (ruthenium metal) and lewis base (N-oxide) interaction, followed by C(8)–H activation leading to complex B, which can undergo transmetallation with arylboronic acid to afford complex C, which may oxidized to their higher valent metal complex D, in order to facilitate easy reductive elimination to afford product with N-oxide 5a, which can be easily deoxygenated by the ruthenium catalyst in the same pot to afford the traceless product 3a. Further, complex E can be oxidized to their active Ru species to continue the catalytic cycle.

Scheme 6. Proposed Mechanistic Pathway.

Conclusions

In conclusion, we have developed a new methodology for C8 arylation of quinoline N-oxide, with by utilizing Ru(II)-catalyst to afford deoxygenated arylated product in one pot. Moreover, we have also explored the Rh(III) catalyst, which afforded an arylated product with N-oxide. Additionally, we have also extended this methodology for other class of important heterocyclic scaffolds, indolines. Beside this, 6-(5H)-phenanthridinone and N-tert-butylbenzamide were also utilized for arylation. The role of the Ru metal as a deoxygenating agent was well explored which might be applied in future for other important application.

Experimental Section

General Information

All the reactions were carried out in screw cap reaction vials under an air atmosphere. All the solvents were bought from Aldrich in sure-seal bottle and used as such. Chemicals were bought from Sigma-Aldrich, Alfa Aesar, and TCI. For column chromatography, silica gel (230–400 mesh) and silica gel C18 from Merck was used. A gradient elution using n-hexane/ethyl acetate and MeOH/H₂O was performed based on Merck aluminum TLC sheets (silica gel 60F₂₅₄) and silica gel C18 on TLC plates.

Analytical Information

The melting points were recorded on a Brønsted Electrothermal 9100. All isolated compounds are characterized by ¹H NMR, ¹³C NMR, IR, and liquid chromatography (LC)/mass spectrometry (MS). In addition, all the compounds are further characterized by high-resolution mass spectrometry (HRMS). Mass spectra were recorded on Water Q-ToF-Micro Micromass, high-resolution 6560 Ion Mobility Q-TOF LC/MS (Agilent, Santa Clara,USA). IR was analyzed by Shimadzu IR Prestige-21 with a ZnSe Single reflection ATR accessory. Copies of ¹H, ¹³C NMR, and ¹⁹F NMR are provided in Supporting Information. Nuclear magnetic resonance spectra were recorded either on a Bruker-Avance 600 or 300 and 565 (¹⁹F NMR) MHz instrument. All ¹H NMR experiments were reported in units, ppm and were measured relative to the signals for residual chloroform (7.24) and methanol (3.31 and 4.78) in the deuterated solvents. All ¹³C NMR spectra were reported in ppm relative to deuterated chloroform (77.23) and methanol (49.15) and all were obtained with ¹H decoupling.

General Procedure for the Preparation of Quinoline N-Oxides^5a,14

All the solid reactants, m-CPBA (4 mmol) and quinoline (2 mmol) were added in a Schlenk tube and put under vacuum for 2 h, then CH₂Cl₂ (4 mL) was added at 0 °C. The reaction was allowed to stirred at room temperature for 12 h. On completion, the reaction mixture was extracted with ethyl acetate and the organic extract was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (230–400 mesh size) with n-hexane/EtOAc to yield desired N-oxides.

General Procedure Preparation of Ru1(8)

Under an argon atmosphere, to an oven-dried reaction vial equipped with a magnetic stirring bar was added a solution of [(p-cymene)RuCl₂]₂ (60 mg, 0.1 mmol) in CH₂Cl₂ (1 mL), quinoline N-oxide (21.75 mg, 0.15 mmol), silver trifluoroacetate (44.17 mg, 0.2 mmol), and Li₂CO₃ (14.80 mg, 0.2 mmol). The reaction mixture was stirred at 25 °C for 12 h. An additional portion of silver trifluoroacetate (44.17 mg, 0.2 mmol) was added and the reaction mixture was further stirred at 25 °C for 12 h. The mixture was filtered through a pad of Celite and concentrated under reduced pressure. n-Hexane (1 mL) was added to the oily residue and the mixture was stirred for 16 h to form a yellow-green precipitant. After filtration, the filtrate was removed and the residue was dissolved in CH₂Cl₂ (2 mL), doped with n-hexane (3 mL), and the mixture was shaken to precipitate out the dark green chunk, which was removed by filtration through a pad of Celite. Slow evaporation of the filtrate at 25 °C provided the crude product as an orange crystal, which was further purified by recrystallization in CH₂Cl₂/n-hexane. Orange crystal (36.4 mg, 60%). ¹H NMR (600 MHz, CDCl₃): δ 8.54–8.58 (m, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.90–7.93 (m, 2H), 7.69–7.72 (m, 1H), 7.24–7.26 (m, 1H), 2.98–3.04 (m, 1H), 2.29 (s, 3H), 1.33 (d, J = 7.2 Hz, 6H). ¹³C NMR (150 MHz, CDCl₃): δ 162.5, 143.4, 140.9, 135.4, 132.4, 129.8, 129.1, 128.4, 120.0, 119.1 114.92 (q, J_CF = 289.5 Hz), 99.7, 95.6, 79.8, 31.2, 22.5, 18.3. ¹⁹F NMR (565 MHz, CDCl₃): δ −75.28.

General Procedure for C8 Arylation of Quinoline N-Oxides with Arylboronic Acids

To an oven-dried screw cap reaction vial charged with a Spinvane magnetic stirbar, the starting material (0.4 mmol), arylboronic acid (1.2 mmol), [Ru(p-cymene)Cl₂]₂ (5 mol %), and silver oxide (2.5 equiv) were weighed, whereas liquid trifluoromethanesulfonate anhydride (25 mol %) were added by a micropipette and dry THF was added by a laboratory syringe, respectively. The reaction vial was closed with a screw cap and allowed to stir at 40 °C for 16 h. After completion, the reaction mixture was allowed to cool, filtered through a silica plug, and washed with CH₂Cl₂, followed by workup with aqueous NaHCO₃ solution and CH₂Cl₂. The collected CH₂Cl₂ fraction of the crude reaction mixture was evaporated under reduced pressure. The residue was purified by flash chromatography using silica gel (230–400 mesh size) and n-hexane/EtOAc as an eluent. Note, [RhCp*Cl₂]₂ was used instead of the Ru catalyst in order to get the arylated product with N-oxide.

Characterization Data

8-Phenylquinoline (Table 2, Entry 3a)^6a

It was obtained as a light yellow liquid. Yield = 49.3 mg (60%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.96–8.97 (m, 1H), 8.21 (dd, J = 7.8, 1.8 Hz, 1H), 7.84 (dd, J = 8.4, 1.2 Hz, 1H), 7.74 (dd, J = 7.2, 1.2 Hz, 1H), 7.70–7.72 (m, 2H), 7.60–7.63 (m, 1H), 7.51 (t, J = 7.8 Hz, 2H), 7.41–7.44 (m, 2H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 150.4, 146.2, 141.1, 139.7, 136.4, 130.7, 130.5, 128.9, 128.1, 127.7, 127.5, 126.4, 121.1. HRMS (ESI-TOF) m/z: calcd for C₁₅H₁₂N [M + H]⁺, 206.0964; found, 206.0969.

7-Chloro-2-methyl-8-phenylquinoline (Table 2, Entry 3b)

It was obtained as a light pale solid. Yield = 66.0 mg (65%), mp 125–127 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.19 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.44–7.46 (m, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.30–7.31 (m, 2H), 2.54 (s, 3H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 161.1, 147.9, 139.4, 138.0, 137.3, 135.2, 131.7, 129.2, 128.4, 128.2, 128.0, 126.6, 122.9, 24.88. IR (ZnSe) ν_max (cm^–1): 1654, 1170, 1033, 763, 630. HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₃ClN [M + H]⁺, 254.0731; found, 254.0732.

2,8-Diphenylquinoline (Table 2, Entry 3c)¹⁵

It was obtained as a light yellow viscous liquid. Yield = 67.5 mg (60%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.27 (d, J = 8.4 Hz, 1H), 8.18 (dd, J = 8.4, 1.2 Hz, 2H), 7.97 (d, J = 9.0 Hz, 1H), 7.88–7.89 (m, 2H), 7.80–7.84 (m, 2H), 7.60 (t, J = 7.8 Hz, 1H), 7.53–7.56 (m, 2H), 7.45–7.50 (m, 3H), 7.41–7.44 (m, 1H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 156.3, 145.9, 141.1, 139.9, 139.8, 137.4, 131.5, 130.8, 129.6, 129.2, 129.1, 128.0, 127.9, 127.7, 127.5, 126.5, 118.4. HRMS (ESI-TOF) m/z: calcd for C₂₁H₁₆N [M + H]⁺, 282.1277; found, 282.1271.

Methyl 8-Phenylquinoline-3-carboxylate (Table 2, Entry 3d)

It was obtained as a red-brown solid, yield = 26.3 mg (25%), mp 118–120 °C. Isolated from flash chromatography (8% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 9.47 (d, J = 2.4 Hz, 1H), 8.89 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 7.4, 1.2 Hz, 1H), 7.85 (dd, J = 7.2, 1.8 Hz, 1H), 7.68–7.70 (m, 3H), 7.51 (t, J = 7.8 Hz, 2H), 7.42–7.45 (m, 1H), 4.02 (s, 3H).·¹³C{¹H} NMR (75 MHz, CDCl₃): δ 166.1, 149.9, 147.7, 141.2, 139.1, 139.1, 132.7, 130.7, 128.9, 128.2, 127.8, 127.5, 127.3, 123.0, 52.6. IR (ZnSe) ν_max (cm^–1): 1722, 1614, 1433, 1263, 1219, 1099, 997, 777, 696. HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₄NO₂ [M + H]⁺, 264.1019; found, 264.1019.

4-Methyl-8-phenylquinoline (Table 2, Entry 3e)^6a

It was obtained as a brownish semisolid. Yield = 28.1 mg (32%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.82 (d, J = 4.5 Hz, 1H), 8.03 (dd, J = 8.1, 1.5 Hz, 1H), 7.56–7.73 (m, 4H), 7.46–7.51 (m, 2H), 7.37–7.43 (m, 1H), 7.25–7.26 (m, 1H), 2.76 (s, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃) δ: 150.0, 145.8, 144.5, 141.6, 140.1, 130.8, 130.3, 128.9, 128.1, 127.4, 126.1, 123.6, 122.0, 19.3. HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₄N [M + H]⁺, 220.1121; found, 220.1122.

6-Methyl-8-phenylquinoline (Table 2, Entry 3f)^6a

It was obtained as a whitish yellow semisolid. Yield = 24.6 mg (28%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.88–8.89 (m, 1H), 8.10–8.13 (m, 1H), 7.69–7.72 (m, 2H), 7.58–7.59 (m, 2H), 7.49–7.52 (m, 2H), 7.35–7.44 (m, 2H), 2.58 (s, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 149.6, 144.9, 140.7, 139.8, 136.1, 135.7, 132.8, 130.7, 129.0, 128.1, 127.5, 126.5, 121.1, 21.7. HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₄N [M + H]⁺, 220.1121; found, 220.1142.

6-Methoxy-8-phenylquinoline (Table 2, Entry 3g)^6a

It was obtained as a light yellow viscous semisolid. Yield = 32.9 mg (35%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.80 (dd, J = 4.2, 1.8 Hz, 1H), 8.10 (dd, J = 8.4, 1.5 Hz, 1H), 7.77–7.70 (m, 2H), 7.35–7.53 (m, 5H), 7.10 (m, 1H), 3.97 (s, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 157.37, 149.1, 147.9, 142.6, 142.5, 139.2, 139.2, 130.7, 128.2, 127.7, 122.9, 121.4, 105.2, 55.7. HRMS (ESI-TOF) (m/z): calcd for C₁₆H₁₄NO [M + H]⁺, 236.1070; found, 236.1077.

6-Bromo-8-phenylquinoline (Table 2, Entry 3h)

It was obtained as a white solid. Yield = 27.3 mg (24%). mp 71–72 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.95 (dd, J = 4.2, 1.8 Hz, 1H), 8.12 (dd, J = 8.4, 1.8 Hz, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.67–7.68 (m, 2H), 7.49–7.52 (m, 2H), 7.42–7.45 (m, 2H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 150.5, 144.8, 142.9, 138.1, 135.3, 133.4, 130.6, 130.0, 129.3, 128.1, 128.0, 121.8, 120.1. IR (ZnSe) ν_max (cm^–1): 3062, 3028, 1722, 1583, 1570, 1481, 854, 781, 754, 684. HRMS (ESI-TOF) m/z: calcd for C₁₅H₁₁BrN [M + H]⁺, 284.0069; found, 284.0061.

6-Nitro-8-phenylquinoline (Table 1, Entry 3i)

It was obtained as a yellow solid. Yield = 28.0 mg (28%). mp 150–152 °C. Isolated from flash chromatography (8% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 9.12 (dd, J = 4.2, 1.8 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 8.4, 1.8 Hz, 1H), 7.71–7.73 (m, 2H), 7.59 (dd, J = 8.4, 4.2 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.48–7.50 (m, 1H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 153.4, 148.0, 145.1, 143.1, 138.2, 137.5, 130.5, 128.4, 128.2, 127.7, 123.6, 123.2, 122.6. IR (ZnSe) ν_max (cm^–1): 2337, 1481, 1442, 1193, 1028, 783, 754, 686. HRMS (ESI-TOF) m/z: calcd for C₁₅H₁₁N₂O₂ [M + H]⁺, 251.0815; found, 251.0811.

5-Phenylbenzo[f]quinoline (Table 2, Entry 3j)^6a

It was obtained as a yellowish brown solid. Yield = 28.6 (28%). mp 100–102 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 9.04 (dd, J = 8.4, 1.2 Hz, 1H), 9.00 (dd, J = 8.4, 1.8 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.96–7.98 (m, 1H), 7.76 (dd, J = 8.4, 1.2 Hz, 2H), 7.67–7.73 (m, 2H), 7.59 (dd, J = 8.4, 4.2 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H), 7.43–7.46 (m, 1H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 149.56, 146.86, 139.85, 139.47, 131.59, 131.33, 130.96, 130.70, 129.65, 128.95, 128.14, 127.66, 127.59, 127.12, 125.94, 122.57, 121.28. HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₄N [M + H]⁺, 256.1121; found, 256.1124.

8-(3,5-Dimethylphenyl)quinoline (Table 2, Entry 3k)

It was obtained as a greenish viscous semisolid. Yield = 42.0 (45%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.98 (dd, J = 4.2, 1.8 Hz, 1H), 8.20 (dd, J = 8.4, 1.8 Hz, 1H), 7.81 (dd, J = 8.4, 1.2 Hz, 1H), 7.70 (dd, J = 7.2, 1.8 Hz, 1H), 7.57–7.60 (m, 1H), 7.43 (dd, J = 8.4, 4.2 Hz, 1H), 7.27 (br s, 2H), 7.05 (s, 1H), 2.43 (s, 6H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 150.4, 146.3, 141.5, 139.6, 137.5, 136.4, 130.4, 129.3, 128.8, 128.5, 127.4, 126.4, 121.0, 21.6. IR (ZnSe) ν_max (cm^–1): 3059, 1722, 1604, 1481, 1265, 1193, 1028, 854, 783. HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₆N [M + H]⁺, 234.1277; found, 234.1279.

8-(p-Tolyl)quinoline (Table 2, Entry 3l)^6a

It was obtained as a yellowish viscous liquid. Yield = 45.6 mg (52%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.19–8.21 (m, 1H), 7.81–7.82 (m, 1H), 7.73 (dd, J = 7.2, 1.2 Hz, 1H), 7.59–7.61 (m, 3H), 7.41 (dd, J = 8.4, 4.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 150.6, 146.5, 141.3, 137.4, 137.0, 136.6, 130.8, 130.4, 129.12, 129.09, 127.6, 126.6, 121.3, 21.6. HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₄N [M + H]⁺, 220.1121; found, 220.1119.

8-(4-Pentylphenyl)quinoline (Table 2, Entry 3m)

It was obtained as a yellowish viscous liquid. Yield = 66.1 mg (60%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.96 (dd, J = 4.2, 1.8 Hz, 1H) 8.20 (dd, J = 4.2, 1.8 Hz, 1H), 7.81 (dd, J = 7.8, 1.2 Hz, 1H), 7.74 (dd, J = 7.2, 1.2 Hz, 1H), 7.63 (d, J = 7.8 Hz, 2H), 7.58–7.61 (m, 1H), 7.41 (dd, J = 7.8, 4.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H), 1.68–1.73 (m, 2H), 1.39–1.41 (m, 4H), 0.92–0.94 (m, 3H).·¹³C{¹H} NMR (150 MHz, CDCl₃): δ 150.2, 146.1, 142.1, 140.9, 136.8, 136.3, 130.5, 130.3, 128.8, 128.1, 127.3, 126.3, 120.9, 35.8, 31.7, 31.1, 22.6, 14.1. IR (ZnSe) ν_max (cm^–1): 2926, 1571, 823, 792, 756. HRMS (ESI-TOF) m/z: calcd for C₂₀H₂₂N [M + H]⁺, 276.1747; found, 276.1746.

8-[(1,1′Biphenyl-4-yl)quinoline (Table 2, Entry 3n)

It was obtained as a white solid. Yield = 28.1 mg (25%). mp 155–157 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.99 (dd, J = 4.2, 1.8 Hz, 1H), 8.23 (dd, J = 8.4, 1.8 Hz, 1H), 7.61–7.87 (m, 9H), 7.34–7.50 (m, 4H). ¹³C NMR (75 MHz, CDCl₃): δ 150.5, 150.0, 141.3, 140.6, 140.4, 138.7, 136.5, 131.2, 130.5, 129.0, 128.9, 127.8, 127.7, 127.4, 127.0, 126.5, 121.2. IR (ZnSe) ν_max (cm^–1): 1487, 1377, 825, 794, 761, 694. HRMS (ESI-TOF) m/z: calcd for C₂₁H₁₆N [M + H]⁺, 282.1277; found 282.1277.

8-(4-Methoxyphenyl)quinoline (Table 1, Entry 3o)^6a

It was obtained as a white solid. Yield = 28.2 mg (30%). mp 109–110 °C. Isolated from flash chromatography (8% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.97 (dd, J = 4.2, 1.8 Hz, 1H), 8.20–8.23 (m, 1H), 7.80 (dd, J = 8.1, 1.5 Hz, 1H), 7.57–7.69 (m, 4H), 7.40–7.44 (m, 1H), 7.04–7.07 (m, 2H), 3.89 (s, 3H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 159.3, 150.2, 146.1, 140.6, 136.6, 132.0, 131.9, 130.2, 129.0, 127.2, 126.5, 121.1, 113.8, 55.5. HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₄NO [M + H]⁺, 236.1070; found, 236.1055.

8-(4-Chlorophenyl)quinoline (Table 1, Entry 3p)

It was obtained as a light brown solid. Yield = 49.9 mg (52%). mp 81–82 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.22 (dd, J = 8.4, 1.8 Hz, 1H), 7.85–7.86 (m, 1H), 7.72 (dd, J = 7.2, 1.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.60–7.63 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.44 (m, 1H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 150.3, 145.8, 139.6, 137.9, 136.3, 133.4, 131.8, 130.1, 128.7, 128.2, 127.8, 126.2, 121.1. IR (ZnSe) ν_max (cm^–1): 1658, 1593, 1489, 1087, 817, 729. HRMS (ESI-TOF) m/z: calcd for C₁₅H₁₁ClN [M + H]⁺, 240.0575; found, 240.0574.

8-(4-Bromophenyl)quinoline (Table 2, Entry 3q)^6c

It was obtained as a bright white solid. Yield = 39.8 mg (35%). mp 70–72 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.94–8.99 (m, 1H), 8.20–825 (m, 1H), 7.83–7.89 (m, 1H), 7.70–7.74 (m, 1H), 7.57–7.67 (m, 5H), 7.41–7.47 (m, 1H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 150.5, 146.0, 139.8, 138.6, 136.5, 132.4, 131.3, 130.2, 128.9, 128.1, 126.4, 121.9, 121.3. HRMS (ESI-TOF) m/z: calcd for C₁₅H₁₁BrN [M + H]⁺, 284.0069; found, 284.0061.

8-(4-Formylphenyl)quinoline (Table 1, Entry 3r)

It was obtained as a red-brown solid. Yield = 20.5 mg (22%). mp 108–110 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 10.10 (s, 1H), 8.96 (dd, J = 4.2, 1.8 Hz, 1H), 8.24 (dd, J = 8.4, 1.8 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.88–7.90 (m, 3H), 7.77 (dd, J = 7.2, 1.2 Hz, 1H), 7.64 (t, J = 7.8 1H), 7.46 (q, J = 4.2 Hz, 1H). ¹³C NMR (150 MHz, CDCl₃): δ 192.4, 150.7, 146.2, 145.9, 139.7, 136.6, 135.4, 131.5, 130.6, 129.6, 128.9, 128.7, 126.4, 121.5. IR (ZnSe) ν_max (cm^–1): 3051, 2922, 1660, 1593, 1489, 1463, 1381, 1087, 962, 817, 763, 729. HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₂NO [M + H]⁺, 234.0913; found, 234.0911.

8-Phenylquinoline N-Oxide (Table 3, Entry 5a)^6c

It was obtained as a yellow semisolid. Yield = 79.7 mg (90%). Isolated from flash chromatography (95% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.37 (d, J = 5.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4, 1H), 7.61 (t, J = 7.2, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.36–7.39 (m, 2H), 7.32–7.34 (m, 3H), 7.27–7.30 (m, 1H). ¹³C{¹H} (150 MHz, CDCl₃): δ 142.8, 139.2, 137.2, 136.5, 134.4, 132.1, 128.5, 128.2, 127.8, 127.0, 126.4, 126.3, 121.3. HRMS (ESI-TOF) m/z: calcd for C₁₅H₁₂NO [M + H]⁺, 222.0913; found, 222.0916.

6-Fluoro-8-phenylquinoline N-oxide (Table 3, Entry 5b)

It was obtained as a yellowish viscous semisolid. Yield = 71.7 mg (75%). Isolated from flash chromatography (90% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.31 (d, J = 6.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 7.8, 3.0 Hz, 1H), 7.35–7.40 (m, 3H), 7.30–7.32 (m, 4H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 161.0, 159.4, 141.7, 139.9, 136.6, 133.3, 127.9, 127.2, 126.8, 125.6, 124.0, 122.4, 111.6. IR (ZnSe) ν_max (cm^–1): 3055, 1511, 1325, 1276, 1159, 904, 763, 696, 638. HRMS (ESI-TOF) calcd for C₁₅H₁₁FNO [M + H]⁺, 240.0819; found, 240.0815.

6-Methoxy-8-phenylquinoline N-oxide (Table 3, Entry 5c)

It was obtained as a yellow solid. Isolated Yield = 60.3 mg (60%). mp 52–54 °C. Isolated from flash chromatography (90% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.29 (dd, J = 6.0, 1.2 Hz, 1H), 7.72 (dd, J = 8.4, 1.2 Hz, 1H), 7.37–7.40 (m, 2H), 7.32–7.36 (m, 3H), 7.27–7.28 (m, 1H), 7.20 (d, J = 3.0 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 3.97 (s, 3H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 158.0, 142.3, 138.3, 135.7, 135.0, 133.7, 128.1, 127.0, 126.5, 126.3, 121.7, 106.4, 102.4, 55.9. IR (ZnSe) ν_max (cm^–1): 3325, 1606, 1575, 1365, 1328, 1207, 1174, 1028, 763. HRMS (ESI-TOF) calcd for C₁₆H₁₄NO₂ [M + H]⁺, 252.1019; found, 252.1020.

6-Nitro-8-phenylquinoline N-oxide (Table 3, Entry 5d)

It was obtained as a yellowish brown semisolid. Yield = 33.0 mg (31%). Isolated from flash chromatography (90% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.79 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 6.0 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4, 6.0 Hz, 1H), 7.38–7.44 (m, 3H), 7.33 (dd, J = 7.8, 1.8 Hz, 2H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 145.79, 141.32, 140.84, 139.62, 139.47, 131.80, 127.94, 127.43, 127.33, 126.79, 124.32, 123.50, 102.40. IR (ZnSe) ν_max (cm^–1): 3379, 1608, 1514, 1286, 1238, 1174, 1028, 823, 758. HRMS (ESI-TOF) calcd for C₁₅H₁₁N₂O₃ [M + H]⁺, 267.0764; found, 267.0769.

8-(4-Methoxyphenyl)quinoline N-oxide (Table 3, Entry 5e)

It was obtained as a yellow solid. Yield = 66.3 mg (66%), mp 150–152 °C. Isolated from flash chromatography (95% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.36 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 8.4, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.53 (dd, J = 7.2, 1.8 Hz, 1H), 7.25–7.29 (m, 3H), 6.92 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H). ¹³C NMR (150 MHz, CDCl₃): δ 158.3, 139.5, 137.2, 136.3, 135.2, 134.6, 132.3, 129.4, 128.3, 127.8, 126.2, 121.2, 112.5, 55.4. IR (ZnSe) ν_max (cm^–1): 2939, 2854, 1514, 1244, 1103, 1031, 823, 792, 758, 638. HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₄NO₂ [M + H]⁺, 252.1019; found, 252.1015.

8-(3,5-Dimethylphenyl)quinoline N-oxide (Table 3, Entry 5f)

It was obtained as a light Yellow solid. Yield = 49.9 mg (50%), mp 64–65 °C. Isolated from flash chromatography (95% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.36 (d, J = 6.0 Hz, 1H), 7.85–7.86 (m, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59 (m, 1H), 7.50 (dd, J = 7.2, 1.2 Hz, 1H), 7.26–7.29 (m, 1H), 6.97 (s, 1H), 6.94 (s, 2H), 2.36 (s, 6H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 150.1, 142.8, 139.4, 137.1, 136.8, 136.3, 134.4, 132.1, 128.4, 128.1, 127.7, 126.1, 121.2, 21.6. IR (ZnSe) ν_max (cm^–1): 2920, 2852, 1656, 1598, 1413, 1219, 1031, 819, 756. HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₆NO [M + H]⁺, 250.1226; found, 250.1222.

8-(4-Bromophenyl)quinoline N-oxide (Table 3, Entry 5g)^6d

It was obtained as a brownish yellow solid. Yield = 60.99 mg (51%), mp 148–150 °C. Isolated from flash chromatography (90% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.36 (d, J = 6.0 Hz, 1H), 7.90 (dd, J = 8.1, 1.5 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.60–7.64 (m, 1H), 7.48–7.50 (m, 3H), 7.28–7.32 (m, 1H), 7.20 (d, J = 8.4 Hz, 2H). ¹³C{¹H}NMR (75 MHz, CDCl₃): δ 141.8, 139.2, 137.1, 135.3, 134.2, 132.2, 130.1, 129.9, 128.9, 127.8, 126.1, 121.5, 120.5. HRMS (ESI-TOF) m/z: calcd for C₁₅H₁₁BrNO [M + H]⁺, 300.0019; found, 300.0020.

8-(4-Trimethysilylphenyl)quinoline N-oxide (Table 1, Entry 5h)

It was obtained as a red-brown solid. Yield = 30.5 mg (26%), mp 60–62 °C. Isolated from flash chromatography (90% EtOAc/n-hexane). ¹H NMR (600 MHz, CD₃OD): δ 8.46 (d, J = 6 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.07 (m, J = 8.2, 1H), 7.73 (t J = 7.8, 1H), 7.59 (m, 1H), 7.54–7.51 (m, 1H), 7.49 (d, J = 7.8 Hz, 2H)., 7.26 (d, J = 7.8 Hz, 2H), 0.27 (s, 9H). ¹³C{¹H} NMR (150 MHz, CD₃OD): δ 144.5, 139.4, 138.7, 137.1, 136.7, 133.6, 132.9, 131.4, 130.1, 129.4, 128.9, 122.7, −1.0. IR (ZnSe) ν_max (cm^–1): 2954, 2924, 1658, 1382, 1246, 835, 815, 758, 655. HRMS (ESI-TOF) m/z: calcd for C₁₈H₂₀NOSi [M + H]⁺, 294.1309; found, 294.1304.

General Procedure for Arylation of Indolines and Other Substrates with Arylboronic Acids

To an oven-dried screw cap reaction vial charged with a Spinvane magnetic stirbar, the starting material (0.4 mmol), arylboronic acid (1.2 mmol), [Ru(p-cymene)Cl₂]₂ (5 mol %), and silver oxide (2.5 equiv) were weighed, whereas liquid trifluoromethanesulfonate anhydride (25 mol %) were added by a micropipette and dry THF was added by a laboratory syringe, respectively. The reaction vial was closed with a screw cap and allowed to stir at 100 °C for 20 h. After completion, the reaction mixture was allowed to cool, filtered through a silica plug, and washed with CH₂Cl₂, followed by workup with aqueous NaHCO₃ solution and CH₂Cl₂. The collected CH₂Cl₂ fraction of the crude reaction mixture was evaporated under reduced pressure. The residue was purified by flash chromatography using silica gel (230–400 mesh size) and n-hexane/EtOAc as an eluent. C₁₈-reversed phase silica gel was required in case of the benzamide substrate by using MeOH and water as an eluent. An oxygen atmosphere is required only in the case of indoline substrates.

Characterization Data

7-Phenyl-1-(pyrimidin-2-yl)indoline (Table 4, Entry 7a)^10f

It was obtained as a yellow solid. Yield = 98.4 mg (90%), mp 90–91 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, J = 4.8 Hz, 2H), 7.33–7.36 (m, 2H), 7.24–7.30 (m, 2H), 7.10–7.19 (m, 4H), 6.38 (t, J = 4.8 Hz, 1H), 4.46 (m, 2H), 3.19 (m, 2H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 159.3, 156.6, 142.4, 141.2, 135.1, 130.5, 129.1, 128.0, 126.8, 126.1, 123.9, 123.7, 111.9, 52.3, 29.7. HRMS (ESI-TOF) m/z: calcd for C₁₈H₁₆N₃ [M + H]⁺, 274.1339; found, 274.1319.

7-(4-Chlorophenyl)-1-(pyrimidin-2-yl)indoline (Table 4, Entry 7b)^10f

It was obtained as a oale solid. Yield = 61.5 (50%), mp 130–132 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 8.04 (d, J = 4.8 Hz, 2H), 7.28–7.32 (m, 3H), 7.24 (dd, J = 7.8, 1.2 Hz, 1H), 7.13–7.17 (m, 3H), 6.48 (t, J = 4.8 Hz, 1H), 4.49 (m, 2H), 3.20 (t, J = 7.8 Hz, 2H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 157.5, 156.7, 141.0, 140.9, 135.3, 132.0, 129.5, 128.9, 128.2, 128.2, 124.2, 124.1, 112.2, 52.5, 29.7. HRMS (ESI-TOF) m/z: calcd for C₁₈H₁₅ClN₃ [M + H]⁺, 308.0949; found, 308.0950.

7-(4-Amylphenyl)-1-(pyrimidin-2-yl)indoline (Table 4, Entry 7c)

It was obtained as a light Yellow semisolid, yield 55.0 = (40%). Isolated from flash chromatography (7% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 7.95 (d, J = 4.8 Hz, 2H), 7.26–7.28 (m, 1H), 7.21–7.24 (m, 3H), 7.08–7.10 (m, 1H), 6.95 (d, J = 7.8 2H), 6.34 (t, J = 4.8 Hz, 1H), 4.44 (t, J = 7.8 Hz, 2H), 3.18 (t, J = 7.8 Hz, 2H), 2.50 (t, J = 7.8 Hz, 2H), 1.50–1.55 (m, 2H), 1.30–1.35 (m, 2H), 1.24–1.27 (m, 2H), 0.87–0.89 (m, 3H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 156.9, 156.6, 141.2, 140.9, 139.6, 135.0, 130.5, 129.0, 128.1, 126.7, 123.8, 123.5, 111.8, 52.3, 35.6, 31.5, 31.4, 29.7, 22.7, 14.2. IR (ZnSe) ν_max (cm^–1): 2924, 1573, 1548, 1452, 1429, 1379, 796. HRMS (ESI-TOF) m/z: calcd for C₂₃H₂₆N₃ [M + H]⁺, 344.2121; found 344.2129.

7-(4-Cyanophenyl)-1-(pyrimidin-2-yl)indoline (Table 4, Entry 7d)

It was obtained as a yellow crystal. Yield = 41.8 mg (35%), mp 169–170 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, J = 4.8 Hz, 2H), 7.46 (s, 4H), 7.30 (m, 1H), 7.22–7.25 (m, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.45 (t, J = 4.8 Hz, 1H), 4.47 (t, J = 8.1 Hz, 2H), 3.19 (m, 2H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 157.6, 156.8, 147.5, 141.3, 140.0, 135.5, 132.0, 128.72, 128.68, 127.5, 124.9, 124.1, 112.5, 109.6, 52.2, 29.5. IR (ZnSe) ν_max (cm^–1): 2918, 2220, 1552, 1452, 1402, 786, 771, 738. HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₅N₄ [M + H]⁺, 299.1291; found, 299.1289.

7-(3,5-Dimethyl)phenyl)-1-(pyrimidin-2-yl)indoline (Table 4, Entry 7e)^10f

It was obtained as a pale yellow solid. Yield = 60.3 mg (50%), mp 90–92 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 7.97 (dd, J = 4.8, 1.2 Hz, 2H), 7.421–7.29 (m, 2H), 7.05–7.12 (m, 1H), 6.96 (s, 2H), 6.74 (s, 1H), 6.37–6.41 (m, 1H), 4.45 (m, 2H), 3.18 (t, J = 7.8 Hz, 2H), 2.17 (s, 6H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 159.4, 156.5, 142.1, 141.2, 137.4, 134.9, 130.2, 129.0, 127.7, 124.7, 123.7, 123.6, 111.8, 52.3, 29.7, 21.2. HRMS (ESI-TOF) m/z: calcd for C₂₀H₂₀N₃ [M + H]⁺, 302.1652; found, 302.1649.

7-(3,5-Bis(trifluoromethyl)phenyl)-1-(pyrimidin-2-yl)indoline (Table 4, Entry 7f)

It was obtained as a light yellow solid. Yield = 101.5 mg (62%), mp 78–79 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 7.94 (d, J = 4.8 Hz, 2H), 7.78 (s, 2H), 7.61 (s, 1H), 7.33 (dd, J = 7.2, 6.0 Hz, 1H), 7.26–7.28 (m, 1H), 7.14–7.17 (m, 1H), 6.43 (t, J = 4.8 Hz, 1H), 4.48–4.51 (m, 2H), 3.22 (t, J = 7.8 Hz, 2H). ¹³C NMR (150 MHz, CDCl₃): δ 158.9, 156.7, 144.8, 141.4, 135.7, 131.36 (q, J_CF = 33.0 Hz), 128.6, 127.3, 127.1, 125.2, 124.15, 123.43 (q, J_CF = 291.0 Hz), 119.54 (q, J_CF = 4.5 Hz), 112.46, 52.29, 29.43. ¹⁹F NMR (565 MHz, CDCl₃): δ −62.87. IR (ZnSe) ν_max (cm^–1): 1575, 1548, 1465, 1440, 1381, 1276, 1165, 1114, 1091, 798, 682. HRMS (ESI-TOF) m/z: calcd for C₂₀H₁₄F₆N₃ [M + H]⁺, 410.1086; found, 410.1086.

10-Phenylbenzo[h]quinoline (Table 4, Entry 8)¹⁷

It was obtained as a light yellow liquid. Yield = 56.2 mg (55%). Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (600 MHz, CDCl₃): δ 8.45 (dd, J = 4.2, 1.8 Hz, 1H), 8.09 (dd, J = 8.4, 1.8 Hz, 1H), 7.94 (dd, J = 7.8, 1.2 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.69–7.71 (m, 2H), 7.58 (dd, J = 7.2, 1.8 Hz, 1H), 7.42–7.44 (m, 2H), 7.37–7.40 (m, 3H), 7.33 (dd, J = 7.8, 4.2 Hz, 1H). ¹³C{¹H} NMR (150 MHz, CDCl₃): δ 146.99, 146.95, 146.6, 141.8, 135.3, 135.1, 131.6, 129.2, 128.9, 128.4, 128.1, 127.5, 127.4, 127.2, 126.0, 125.8, 121.2. HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₄N [M + H]⁺, 256.1121; found, 256.1132.

7-Phenylphenanthridin-6(5H)-one (Table 4, Entry 9)

It was obtained as a light yellow solid. Yield = 21.7 mg (20%). mp 265–266 °C. Isolated from flash chromatography (5% EtOAc/n-hexane). ¹H NMR (300 MHz, CDCl₃): δ 11.24 (br s, 1H, NH), 8.36 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 7.75–7.80 (m, 1H), 7.43–7.46 (m, 4H), 7.36–7.41 (m, 3H), 7.27–7.30 (m, 1H), 6.87 (d, J = 7.8 Hz, 1H). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ 162.6, 145.4, 144.0, 136.5, 136.5, 131.7, 131.4, 129.6, 128.6, 127.5, 126.4, 123.2, 122.6, 121.9, 118.6, 116.6. IR (ZnSe) ν_max (cm^–1): 3313, 1658, 1438, 1280, 1020. HRMS (ESI-TOF) m/z: calcd for C₁₉H₁₄NO [M + H]⁺, 272.1070; found, 272.1070.

N-(tert-Butyl)-[1,1′-biphenyl]-2-carboxamide (Table 4, Entry 10)¹⁸

It was obtained as a whitish brown solid. Yield = 65.9 mg (65%), mp 97–100 °C. Isolated from manual column chromatography by using reverse phase C-18 silica (75% MeOH/H₂O). ¹H NMR (600 MHz, CDCl₃): δ 7.72 (d, J = 7.8 Hz, 1H), 7.39–7.46 (m, 7H), 7.33 (d, J = 7.8 Hz, 1H), 5.00 (br s, 1H, NH), 1.10 (s, 9H). ¹³C NMR (150 MHz, CDCl₃): δ 168.5, 140.6, 139.5, 136.9, 130.1, 129.9, 129.1, 129.0, 128.7, 127.8, 127.8, 51.5, 28.3. HRMS (ESI-TOF) m/z: calcd for C₁₇H₂₀NO [M + H]⁺, 254.1539; found, 254.1544.

Parallel Reaction for KIE Study

In two different screw capped vials with a Spinvane triangular-shaped stirbar separately placed quinoline N-oxide (1a) (0.1 mmol) and C8-d₁-quinoline N-oxide (1a-d₁), (0.1 mmol) were reacted with arylboronic acid 2a (3 equiv), [Ru(p-cymene)Cl₂]₂ (5 mol %), Tf₂O (25 mol %), and Ag₂O (2.5 equiv) in dry THF. Both the reaction mixtures were stirred at 40 °C for 5 h. Both the reactions mixtures were filtered through a silica plug and extracted with aqueous NaHCO₃ and CH₂Cl₂. The organic phase was dried over Na₂SO₄ and removed under reduced pressure. Further, it has been isolated by flash chromatography and the analysis was performed on the basis of the isolated yield (Scheme 3).

Ru1 as an Intermediate (Scheme 4)

To a screw capped vial with a Spinvane triangular-shaped stirbar quinoline N-oxide (0.1 mmol), arylboronic acid (3 equiv), Ru1 (5 mol %), Tf₂O (25 mol %), Ag₂O (2.5 equiv), and dry THF were added. The reaction was stirred at 40 °C for 16 h. After completion, the reaction was filtered through a silica plug and extracted with aqueous NaHCO₃ and CH₂Cl₂. The organic phase was dried over Na₂SO₄ and removed under reduced pressure for ¹H NMR analysis by using 1,1,2,2-tetrachloroethane as an internal standard, which have shown 50% yield.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.9b03884.

• Optimization details and a copy of ¹H and ¹³C NMR spectra for all synthesized compounds including X-ray data for Ru1 (PDF)

The authors declare no competing financial interest.