Synthesis of Polysubstituted Quinolines from α-2 ... - ACS Publications

Jan 18, 2018 - Sanju Das, Debabrata Maiti, and Suman De Sarkar*. Department of Chemical Sciences, Indian Institute of Science Education and Research ...
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Cite This: J. Org. Chem. 2018, 83, 2309−2316

Synthesis of Polysubstituted Quinolines from α‑2-Aminoaryl Alcohols Via Nickel-Catalyzed Dehydrogenative Coupling Sanju Das, Debabrata Maiti, and Suman De Sarkar* Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, West Bengal, India S Supporting Information *

ABSTRACT: This study reports a nickel-catalyzed sustainable synthesis of polysubstituted quinolines from α-2-aminoaryl alcohols by a sequential dehydrogenation and condensation process that offers the advantages of a low catalyst loading and wide substrate scope. In contrast to earlier reported methods, this strategy allows the use of both primary as well as secondary α-2-aminoaryl alcohols in combination with either ketones or secondary alcohols for desired product formation. Using this methodology, 30 substituted quinoline derivatives were synthesized with up to 93% isolated yields.

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INTRODUCTION Quinolines1 are broadly found in natural products2 and largely used in pharmaceutical industries, particularly as anticancer, antiviral, antimalarial, and antituberculosis agents (Figure 1).3

partner to form the desired product in a sustainable manner. While a significant development in the field of C−C and C−N bond-forming reactions has been reported using precious 4d and 5d transition metals,8 a recent trend has drifted toward the usage of earth-abundant, nonprecious, base metals like Mn,9 Fe,10 Co,11 and Ni.12 The catalytic synthesis of quinolines by the indirect Friedländer reaction via an oxidative cyclization of 2-aminobenzyl alcohol in combination with either ketones or alcohols was described by the groups of Milstein,13 Shim,14 Yus,15 Verpoort,16 Kaneda,17 and others18 employing Ru catalysis. Other precious metals like Ir19 and Pd20 have also been used for similar transformations. In comparison, the earth-abundant, eco-friendly, and inexpensive first-row transition metals are much less explored in the synthesis of quinoline derivatives.9e,21 In addition, most of the reported methods are limited to the use 2-aminobenzyl alcohols as substrates with a higher catalyst loading (5−8 mol %) and superstoichiometric amount of base.22 Therefore, an economical and universal synthetic strategy toward 4-substituted quinoline derivatives employing variety of different alcohols including secondary α-2-aminoaryl alcohols is highly desirable. In the present work, we have addressed the aforementioned issues by developing a generalized and efficient nickel-catalyzed dehydrogenative method for the synthesis of polysubstituted quinolines (Scheme 1). The used nickel catalyst 3 was first synthesized by Jäger and Goedken23 and was readily prepared in a single step by the improved method reported by Niewahner.24

Figure 1. Examples of bioactive quinoline derivatives.

In addition, wide applications of quinolines and their derivatives are found in the preparation of functional materials with improved physical properties.4 Consequently, there is an increasing demand for developing new methods toward the synthesis of highly functionalized quinolines, preferably in an atom-economical and sustainable manner.5 The traditional methods for constructing quinolines include the Combes synthesis from anilines and 1,3-diketones, the Skraup synthesis from anilines and glycerin, and the Friedländer synthesis from orthoacylanilines and α-methylene aldehydes/ketones.6 However, harsh reaction conditions and undesired self-condensation of the starting materials limit the scope and practicality of the quinoline synthesis.5b In recent years, the relatively stable α-2-aminoaryl alcohols have been successfully employed for dehydrogenative synthesis of quinolines. Methods using acceptorless dehydrogenation (AD) of alcohols,7 especially, have become a prevailing tool for the sustainable synthesis of various heterocyclic compounds. The key features of the AD process are the generation of more reactive carbonyl compounds from alcohols by the release of dihydrogen as a stoichiometric byproduct. The in situ generated carbonyl further reacts with a suitable coupling © 2018 American Chemical Society

Received: December 19, 2017 Published: January 18, 2018 2309

DOI: 10.1021/acs.joc.7b03198 J. Org. Chem. 2018, 83, 2309−2316

Article

The Journal of Organic Chemistry Scheme 1. Nickel-Catalyzed Synthesis of Polysubstituted Quinolines by Acceptorless Dehydrogenation

Table 2. Substrate Scope Using 2-Aminobenzyl Alcohol and Various Carbonyl Compoundsa,b

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RESULTS AND DISCUSSION We commenced our study by treating 2-aminobenzyl alcohol 1 (1.2 equiv) and acetophenone 2a (1.0 equiv) in various solvents (1.5 mL) at 135 °C for 16 h in the presence of nickel catalyst 3 (5 mol %) and tBuONa (1.0 equiv) under an argon atmosphere (Table 1). Reactions were performed in a closed Table 1. Optimization of the Reaction Conditionsa,b

entry

3 (mol %)

T (°C)

solvent

base

yield (%)b

1 2 3 4 5 6 7c 8 9 10 11d 12d

5 5 5 5 5 0 5 2 2 2 2 2

135 135 135 135 120 120 120 120 120 120 120 100

toluene DMF DCE 1,4-dioxane toluene toluene toluene toluene toluene toluene toluene toluene

tBuONa tBuONa tBuONa tBuONa tBuONa tBuONa tBuONa tBuONa tBuOK K2CO3 tBuONa tBuONa

90 trace trace 81 90 0 trace 92 85 trace 92 45

a

Reaction conditions: 1a (0.6 mmol), 2b−r (0.5 mmol), 3 (2 mol %), tBuONa (0.5 mmol) in toluene (2 mL), under Ar. bIsolated yields are shown.

antibiotic agent 4al.26 The reaction was not limited to the acetophenone derivatives. Both acyclic diaryl ketone and αtetralone delivered the desired quinolines in good yields (4am and 4an). Alicyclic as well as open-chain aliphatic ketones underwent efficient dehydrogenative coupling to form the targeted heterocyclic motif. In the case of the unsymmetrically substituted dialkylketone, exclusive formation of the kinetic product (4ap) was observed.27 Disubstituted quinoline (4aq) was prepared by applying β-keto ester as the carbonyl partner. Finally, an aldehyde was also used to synthesize the 3substituted quinoline derivative (4ar) in a moderate yield. The catalytic behavior of the nickel complex was further explored by coupling differently substituted 2-aminobenzyl alcohols with acetophenone (Table 3). Both electron-rich and electron-poor 2-aminobenzyl alcohols underwent smooth oxidation followed by cyclization to the corresponding quinolines (4ba−4fa). Disubstituted derivatives also delivered the desired product in good yields (4ga and 4ha). We were pleased find that the acceptorless dehydrogenation process is not limited to the primary benzyl alcohols. Both alkyl- and arylsubstituted secondary 2-aminoaryl alcohols are also competent substrates, and good to excellent yields were obtained in all cases (4ia−4ma). However, elevated temperatures and extended reaction times were required for dehydrative cyclization of the less reactive ketones formed by the initial nickel-catalyzed dehydrogenation. In order to further demonstrate the potential of nickel catalyst 3, a double dehydrogenative coupling was also studied by using 2-aminoaryl alcohols in combination with various secondary alcohols 5 (Table 4). Under the similar reaction conditions used for ketones, both of the alcohols smoothly dehydrogenated to the corresponding carbonyls, and the follow-up condensation reaction yielded the

a Reaction conditions: 1a (0.3 mmol), 2a (0.25 mmol), 3 (2−5 mol %), solvent (1.5 mL), 16 h, under Ar. bIsolated yields. cNiCl2 as a catalyst. dSolvent (1.0 mL).

vial, and no specialized setup for the removal of H2 from the reaction mixture was necessary for the progress of the reaction.12b,25 Toluene was found as the optimal solvent leading to an excellent yield of the desired quinoline derivative (entry 1). The reaction was completely shut down in the absence of the nickel catalyst (entry 6). Another nickel catalyst (NiCl2) was also inefficient (entry 7). Lowering the temperature to 120 °C did not affect the yield (entry 5), but a further lowering resulted in a significant drop (entry 12). We were pleased to find that only 2 mol % catalyst 3 is sufficient for an effective reaction, proving the high efficiency of the nickel catalyst (entry 8). Notably, tBuOK was also found to be active, while the weak carbonate base was inefficient (entry 9 and 10), which indicates that an effective deprotonation of the alcohol is necessary for the dehydrogenation process. Finally, the reaction at a higher substrate concentration (0.25 M), using a lower amount of toluene, also showed equal efficiency (entry 11). After the optimal reaction conditions were established, this methodology was applied to other carbonyl derivatives (Table 2). Differently substituted acetophenones smoothly yielded 2aryl quinolines (4ab−4ah) irrespective of the electronic nature of the aryl group. Naphthyl and heteroaryl methyl ketones were also found to be the competent substrates (4ai−4ak). The method was successfully utilized in the synthesis of the 2310

DOI: 10.1021/acs.joc.7b03198 J. Org. Chem. 2018, 83, 2309−2316

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The Journal of Organic Chemistry

nickel catalysis (Scheme 2). The reaction was quenched after partial conversion, and the crude mixture was carefully analyzed

Table 3. Substrate Scope Using Substituted 2-Aminoaryl Alcohols and Acetophenonea,b

Scheme 2. Mechanistic Studies

by 1H NMR study. A major extent of deuterium was found to be retained in the quinoline product as well as in the unreacted 2-aminobenzyl alcohol (1a-d2). Another interesting observation revealed the formation of a deuterated secondary alcohol (5c-d1). This indicates that initially the used carbonyl partner (2c) acts as a hydrogen acceptor, which upon progress of the reaction regenerates the ketone by reversible dehydrogenation. The α,β-unsaturated ketone 628 was prepared and treated under the standard reaction conditions to check the mode of cyclization after the initial aldol condensation.27 Only a 15% yield of the corresponding quinoline was obtained after 16 h; this is most likely due to the constricted cyclization arising from the trans-geometry of the double bond. Interestingly, the inclusion of water was found to accelerate the annulation process supposedly by eliminating the geometric constrain via a reversible oxa-Michael addition to the double bond (Scheme 3).

a

Reaction conditions: 1b−m (0.6 mmol), 2a (0.5 mmol), 3 (2 mol %), tBuONa (0.5 mmol) in toluene (2 mL), under Ar. bIsolated yields are shown. cReaction performed at 135 °C for 24 h.

Table 4. Double Dehydrogenative Coupling Using 2Aminoaryl Alcohols and Secondary Alcoholsa,b

Scheme 3. Proposed Mechanism

a Reaction conditions: 1 (0.6 mmol), 5 (0.5 mmol), 3 (2 mol %), tBuONa (0.5 mmol) in toluene (2 mL), under Ar. bIsolated yields are shown. cReaction performed at 135 °C for 24 h.

A probable catalytic cycle is depicted in Scheme 3 based on the literature reports and aforementioned mechanistic studies. Dehydrogenation of the 2-aminobenzyl alcohol 1 generates reactive amino aldehyde 9 and nickel hydride 8 via an alkoxy nickel species 7. The generated nickel hydride 8 either reacts with another molecule of 1 to regenerate 7 with the liberation of dihydrogen or hydrogenates the ketone to form secondary alcohols 5. The nickel-catalyzed reversible interconversion between 2 and 5 is associated with the follow-up aldol reaction with the amino aldehyde 9. As the aldol reaction proceeds, the equilibrium shifts toward the ketone following the Le Chatelier’s principle with the generation of dihydrogen. Finally,

quinoline derivatives 4. Various functional groups including halogens, alkoxy, and heteroaryls were well-tolerated in the reaction medium. Likewise, the ketone substrates, for the secondary alcohols as well, in all of the reactions were performed in a closed vial under an argon atmosphere, and the removal of evolved H2 from the reaction vessel was not required for effective coupling. Thus, this methodology truly represents an operationally simple, sustainable, and highyielding single-step access to the quinoline derivatives. Control experiments were performed to investigate the mechanistic aspects of the reaction. An isotope labeled 1a-d2 was treated with acetophenone derivative 2c under the standard 2311

DOI: 10.1021/acs.joc.7b03198 J. Org. Chem. 2018, 83, 2309−2316

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The Journal of Organic Chemistry

was then added, and the mixture was stirred at 120 °C for 16−24 h. At ambient temperature, EtOAc (8 mL) was added, and the reaction mixture was washed with brine (5 mL), dried over sodium sulfate, concentrated under a vacuum, and purified by silica gel column chromatography using 0.5−15% ethyl acetate in hexanes to deliver the quinoline 4. 2-Phenylquinoline (4aa).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4aa (94 mg, 92%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-(phenyl)ethanol 5a (61 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4aa (71 mg, 69%) as a white solid (mp 81−82 °C): 1H NMR (400 MHz, CDCl3) δ 8.23−8.17 (m, 4H), 7.87 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.74 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.58−7.45 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 157.5, 148.4, 139.8, 136.8, 129.9, 129.7, 129.4, 128.9, 127.7, 127.6, 127.3, 126.4, 119.1. 2-(4-Methoxyphenyl)quinoline (4ab).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 4-methoxyacetophenone 2b (75 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ab (86 mg, 73%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-(4methoxyphenyl)ethanol 5b (76 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ab (85 mg, 72%) as a white solid (mp 123−124 °C): 1H NMR (400 MHz, CDCl3) δ 8.24−8.06 (m, 4H), 7.83 (d, J = 8.6 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.71 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 161.0, 157.1, 148.5, 136.7, 132.4, 129.7, 129.0, 127.6, 127.1, 126.0, 118.7, 114.4, 55.5. 2-p-Tolylquinoline (4ac).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 4-methylacetophenone 2c (67 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ac (101 mg, 92%) as a white solid (mp 82−83 °C): 1 H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 4.5 Hz, 1H), 8.17 (d, J = 4.5 Hz, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.72 (m, 1H), 7.51 (t, J = 6.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.3, 148.3, 139.4, 136.9, 136.6, 129.6, 129.5, 127.4, 127.4, 127.1, 126.0, 118.8, 21.3. 2-(4-Chlorophenyl)quinoline (4ad).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 4-chloroacetophenone 2d (77 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ad (111 mg, 93%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-(4chlorophenyl)ethanol 5d (76 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ad (98 mg, 82%) as a white solid (mp 111−112 °C): 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.7 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.76−7.71 (m, 1H), 7.56−7.51 (m, 1H), 7.49 (d, J = 8.4 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 156.1, 148.4, 138.2, 137.0, 135.7, 129.9, 129.8, 129.1, 128.9, 127.6, 127.3, 126.6, 118.6. 2-(4-Bromophenyl)quinoline (4ae).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 4-bromoacetophenone 2e (100 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ae (128 mg, 91%) as a white solid (mp 118−119 °C): 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.7 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.73 (m,1H), 7.65 (d, J = 8.5 Hz, 2H), 7.54 (dd, J =

dehydrative cyclization of the aldol product 10 resulted in the formation of quinoline 4.

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CONCLUSION In summary, an atom-efficient and versatile nickel-catalyzed practical synthesis of polysubstituted quinolines from α-2aminoaryl alcohols in combination with either ketones or secondary alcohols is reported. The sequential dehydrogenation and condensation process results in the selective formation of C−C and C−N bonds with the liberation of dihydrogen and water. A major highlight of this strategy is the use of secondary α-2-aminoaryl alcohols, leading to the synthesis of various 4substituted quinolines. This methodology represents an operationally simple and sustainable synthetic method and offers future opportunities for method developments based on earth-abundant metals.

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EXPERIMENTAL SECTION

General Information. Catalytic reactions were performed under an argon atmosphere using predried glassware and standard sealed tubes. Toluene was dried with calcium hydride and freshly distilled under argon. Nickel catalyst 3 was prepared by following the reported procedure.24 The following starting materials were synthesized according to previously described methods: α-2-aminoaryl alcohols 1b−1c,29 1d−h,30 and 1i−m;30b,31 ketones 2l32 and 2m;9g secondary alcohol 5,30b isotope labeled 1a-d2,30b,33 and aldol product 6.28 Other substrates were obtained from commercial sources and were used without further purification. Yields refer to isolated compounds, estimated to be >95% pure as determined by 1H NMR. Thin-layer chromatography (TLC) was performed on Merck precoated silica gel 60 F254 aluminum sheets with detection under UV light at 254 nm. Chromatographic separations were carried out on Chempure silica gel (100−200 mesh). Melting points (mp) were taken on a Labtronics LT-110 capillary melting point apparatus. Nuclear magnetic resonance (NMR) spectroscopy was performed using JEOL 400 MHz and Bruker 500 MHz spectrometers. If not otherwise specified, chemical shifts (δ) are provided in ppm. Optimization Studies for the Direct Synthesis of Quinolines (Table 1). The 2-aminobenzyl alcohol 1a (37 mg, 0.3 mmol, 1.2 equiv), acetophenone 2a (30 mg, 0.25 mmol, 1 equiv), nickel catalyst 3 (2−5 mg, 0.01 mmol, 2−5 mol %), and base (0.25 mmol, 1 equiv) were placed in a predried 15 mL sealed tube. The tube was degassed and purged with argon three times. Solvent (1.0−1.5 mL) was then added, and the mixture was stirred at a variable temperature (110−135 °C) for 16 h. At ambient temperature, EtOAc (8 mL) was added, and the reaction mixture was washed with brine (5 mL), dried over sodium sulfate, concentrated under a vacuum, and purified by silica gel column chromatography using 1% ethyl acetate in hexane to deliver 4aa. General Procedure for the Synthesis of Quinolines by Dehydrogenative Coupling of α-2-Aminoaryl Alcohols and Carbonyl Compounds (GP 1). The α-2-aminoaryl alcohol 1 (0.60 mmol, 1.2 equiv), carbonyl compound 2 (0.50 mmol, 1 equiv), nickel catalyst 3 (4 mg, 0.01 mmol, 2 mol %), and tBuONa (48 mg, 0.50 mmol, 1 equiv) were placed in a predried 15 mL sealed tube. The tube was degassed and purged with argon three times. Toluene (2.0 mL) was then added, and the mixture was stirred at 120 or 135 °C for 16− 24 h. At ambient temperature, EtOAc (8 mL) was added, and the reaction mixture was washed with brine (5 mL), dried over sodium sulfate, concentrated under a vacuum, and purified by silica gel column chromatography using 0.5−15% ethyl acetate in hexanes to deliver the quinoline 4. General Procedure for the Synthesis of Quinolines by Dehydrogenative Coupling of α-2-Aminoaryl Alcohols and Secondary Alcohols (GP 2). The α-2-aminoaryl alcohol 1 (0.60 mmol, 1.2 equiv), secondary alcohol 5 (0.50 mmol, 1 equiv), nickel catalyst 3 (4 mg, 0.01 mmol, 2 mol %), and tBuONa (48 mg, 0.50 mmol, 1 equiv) were placed in a predried 15 mL sealed tube. The tube was degassed and purged with argon three times. Toluene (2.0 mL) 2312

DOI: 10.1021/acs.joc.7b03198 J. Org. Chem. 2018, 83, 2309−2316

Article

The Journal of Organic Chemistry 11.1, 4.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 156.1, 148.4, 138.6, 137.0, 132.1, 129.9, 129.8, 129.2, 127.6, 127.4, 126.6, 124.0, 118.6. 2-(2-Bromophenyl)quinoline (4af).34 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 2-bromoacetophenone 2f (100 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4af (111 mg, 79%) as a yellow solid (mp 74−75 °C): 1H NMR (500 MHz, CDCl3) δ 8.22 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.77−7.73 (m, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.64 (dd, J = 7.6, 1.6 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.45 (m, 1H), 7.30 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 158.9, 148.1, 141.8, 135.8, 133.4, 131.7, 130.1, 129.8, 127.8, 127.7, 127.3, 126.9, 122.8, 122.0. 2-(3-Chlorophenyl)quinoline (4ag).35 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 3-chloroacetophenone 2g (77 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ag (97 mg, 81%) as a pale-yellow solid (mp 66−68 °C): 1H NMR (400 MHz, CDCl3) δ 8.23−8.16 (m, 3H), 8.04−8.00 (m, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.74 (t, J = 7.4 Hz, 1H), 7.57−7.51 (m, 1H), 7.44 (dd, J = 4.8, 1.4 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 155.8, 148.4, 141.6, 137.1, 135.1, 130.1, 130.0, 129.9, 129.4, 127.8, 127.6, 127.5, 126.7, 125.7, 118.8. 2-(3-Methoxyphenyl)quinoline (4ah).36 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 3-methoxyacetophenone 2h (75 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ah (99 mg, 84%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-(3methoxyphenyl)ethanol 5h (76 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ah (99 mg, 84%) as a brown liquid: 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.83−7.78 (m, 2H), 7.73 (m, 2H), 7.55−7.49 (m, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.4, 2.0 Hz, 1H), 3.94 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.3, 157.2, 148.3, 141.3, 136.8, 129.9, 129.9, 129.7, 127.5, 127.4, 126.4, 120.1, 119.2, 115.5, 112.9, 55.5. 2-(Naphthalen-2-yl)quinoline (4ai).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-naphthalen-2-yl-ethanone 2i (85 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ai (106 mg, 83%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-naphthalen-2yl-ethanol 5i (86 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ai (106 mg, 83%) as a white solid (mp 161−162 °C): 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.39 (dd, J = 8.7, 1.8 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.04−7.97 (m, 3H), 7.91 (dd, J = 5.9, 3.4 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.76 (m, 1H), 7.58−7.51 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 157.3, 148.5, 137.1, 136.9, 134.0, 133.7, 130.0, 129.8, 129.0, 128.7, 127.8, 127.6, 127.4, 127.3, 126.8, 126.5, 125.2, 119.3. 2-(Thiophen-2-yl)quinoline (4aj).37 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-thiophen-2-yl-ethanone 2j (63 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4aj (91 mg, 86%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-thiophen-2-ylethanol 5J (64 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4aj (93 mg, 88%) as a white solid (mp 130−131 °C): 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J = 8.6 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.74 (dd, J = 3.6, 0.7 Hz, 1H), 7.71−7.66 (m, 1H), 7.51−7.45 (m, 2H), 7.16 (dd, J = 4.9, 3.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 152.5, 148.3, 145.6, 136.7, 129.9, 129.4, 128.7, 128.2, 127.6, 127.3, 126.2, 126.0, 117.8.

2-(Pyridin-3-yl)quinoline (4ak).21a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-pyridine-3-yl-ethanone 2k (60.5 mg, 0.5 mmol). After 16 h, purification by column chromatography using 15% ethyl acetate in hexanes yielded 4ak (79 mg, 77%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-pyridine-3-ylethanol 5k (62 mg, 0.5 mmol). After 16 h, purification by column chromatography using 15% ethyl acetate in hexanes yielded 4ak (78 mg, 76%) as a brown solid (mp 66−67 °C): 1H NMR (400 MHz, CDCl3) δ 9.36 (d, J = 2.1 Hz, 1H), 8.70 (dd, J = 4.8, 1.6 Hz, 1H), 8.52 (dt, J = 7.7, 1.7 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.76 (ddd, J = 8.3, 6.9, 1.4 Hz, 1H), 7.60−7.53 (m, 1H), 7.46 (dd, J = 7.8, 4.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 154.8, 150.3, 149.0, 148.5, 137.3, 135.3, 135.1, 130.1, 129.9, 127.7, 127.5, 126.9, 123.8, 118.7. 3-(Imidazol-1-yl-2-phenyl)quinoline (4al).26 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and 2-imidazol-1-yl-phenyl-ethanone 2l (93 mg, 0.5 mmol). After 16 h, purification by column chromatography using 8% ethyl acetate in hexanes yielded 4al (60 mg, 44%) as a viscous liquid: 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.5 Hz, 1H), 8.16 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.81 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.41−7.33 (m, 5H), 7.12 (s, 1H), 6.93 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 155.0, 147.7, 137.7, 137.4, 133.2, 130.9, 129.9, 129.8, 129.4, 128.8, 128.5, 127.9, 127.5, 127.0, 120.9. 3-Benzyl-2-(4-methoxy-phenyl)quinoline (4am).38 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-methanol 1a (74 mg, 0.6 mmol), and 1-(4-methoxy-phenyl)3-phenyl-propane-1-one 2m (120 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4am (135 mg, 83%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.69−7.61 (m, 1H), 7.50−7.46 (m, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.29−7.15 (m, 3H), 7.04−7.00 (m, 2H), 6.96 (d, J = 8.9 Hz, 2H), 4.15 (s, 2H), 3.85 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.5, 159.8, 146.8, 140.2, 137.2, 133.3, 132.7, 130.4, 129.3, 129.2, 129.1, 128.6, 127.5, 127.2, 126.4, 126.4, 113.9, 55.5, 39.3. 5,6-Dihydrobenzo[c]acridine (4an).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol), and α-tetralone 2n (73 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4an (100 mg, 87%) as a white solid (mp 64−65 °C): 1 H NMR (500 MHz, CDCl3) δ 8.59 (d, J = 7.7 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.65 (dd, J = 8.2, 7.1 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.4 Hz, 1H), 3.13 (t, J = 6.8 Hz, 2H), 3.03−3.00 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 153.5, 147.8, 139.5, 134.9, 133.8, 130.7, 129.8, 129.6, 128.7, 128.0, 128.0, 127.5, 127.0, 126.2, 126.2, 29.0, 28.6. 1,2,3,4-Terahydro-acridine (4ao).39 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (62 mg, 0.5 mmol), and cyclohexanone 2o (74 mg, 0.75 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ao (62 mg, 68%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.61−7.53 (m, 1H), 7.44−7.36 (m, 1H), 3.10 (t, J = 6.5 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H), 2.00−1.92 (m, 2H), 1.85 (qd, J = 6.2, 2.9 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 159.3, 146.7, 135.0, 131.0, 128.5, 128.3, 127.3, 126.9, 125.5, 33.6, 29.3, 23.3, 22.9. 2-Isobutyl-quinoline (4ap).39 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (62 mg, 0.5 mmol), and 4-methylpentan-2-one 2p (75 mg, 0.75 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ap (57 mg, 62%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 3.1 Hz, 1H), 8.04 (d, J = 3.0 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.67 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.51− 7.44 (m, 1H), 7.26 (d, J = 8.4 Hz, 1H), 2.85 (d, J = 7.3 Hz, 2H), 2.28− 2.14 (m, 1H), 0.98 (d, J = 6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) 2313

DOI: 10.1021/acs.joc.7b03198 J. Org. Chem. 2018, 83, 2309−2316

Article

The Journal of Organic Chemistry δ 162.4, 148.0, 136.0, 129.4, 129.0, 127.6, 126.8, 125.8, 122.2, 48.5, 29.6, 22.7. 2-Methyl-quinoline-3-carboxylic Acid Ethyl Ester (4aq).40 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-methanol 1a (62 mg, 0.5 mmol), and ethylacetoacetate 2q (98 mg, 0.75 mmol). After 16 h, purification by column chromatography using 3% ethyl acetate in hexanes yielded 4aq (63 mg, 59%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.04 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.82−7.75 (m, 1H), 7.54 (dd, J = 11.2, 4.1 Hz, 1H), 4.44 (q, J = 7.2 Hz, 2H), 2.99 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 166.7, 158.6, 148.8, 140.0, 131.8, 128.7, 128.6, 126.6, 125.9, 124.2, 61.5, 25.8, 14.47. 3-Phenylquinoline (4ar).35 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)methanol 1a (74 mg, 0.6 mmol), and phenylacetaldehyde 2r (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ar (44 mg, 43%) as a pale-yellow solid (mp 49−51 °C): 1H NMR (400 MHz, CDCl3) δ 9.19 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.92−7.87 (m, 1H), 7.76− 7.68 (m, 3H), 7.62−7.51 (m, 3H), 7.47−7.41 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 150.1, 138.1, 134.0, 133.4, 129.5, 129.4, 129.3, 128.3, 128.2, 128.2, 128.1, 127.6, 127.2. 6-Bromo-2-phenylquinoline (4ba).34 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-5-bromophenyl)methanol 1b (121 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ba (131 mg, 92%) as a colorless solid (mp 114−115 °C): 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 7.9 Hz, 2H), 8.10 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H), 7.97 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.49 (d, J = 6.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 157.8, 147.0, 139.3, 135.8, 133.2, 131.6, 129.7, 129.6, 129.0, 128.4, 127.7, 120.2, 119.9. 6-Iodo-2-phenylquinoline (4ca).41 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-5-iodophenyl)methanol 1c (149 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ca (146 mg, 88%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-5-iodophenyl)methanol 1c (149 mg, 0.6 mmol), and 1phenylethanol 5a (61 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ca (108 mg, 65%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 1.7 Hz, 1H), 8.15 (d, J = 6.9 Hz, 2H), 8.09 (d, J = 8.7 Hz, 1H), 7.95 (dd, J = 8.9, 2.0 Hz, 1H), 7.89 (dd, J = 8.9, 3.8 Hz, 2H), 7.56− 7.45 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 158.0, 147.4, 139.4, 138.5, 136.4, 135.6, 131.6, 129.8, 129.0, 129.0, 127.7, 119.7, 91.7. 8-Methyl-2-phenylquinoline (4da).19a GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-3-methylphenyl)methanol 1d (82 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4da (93 mg, 85%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-3-methylphenyl)methanol 1d (82 mg, 0.6 mmol), and 1phenylethanol 5a (61 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4da (89 mg, 81%) as a pale-yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.30 (dd, J = 7.1, 1.4 Hz, 2H), 8.18 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.61−7.57 (m, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.49 (ddd, J = 8.5, 4.4, 1.4 Hz, 1H), 7.45−7.40 (m, 1H), 2.94 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 155.6, 147.3, 140.0, 137.8, 137.0, 129.8, 129.3, 128.9, 127.6, 127.2, 126.1, 125.5, 118.3, 18.0. 8-Chloro-2-phenylquinoline (4ea).42 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-3- chlorophenyl)methanol 1e (94 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ea (98 mg, 82%) as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 8.32−8.26 (m, 2H), 8.23 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.85 (dd, J = 7.6, 1.4 Hz, 1H), 7.76− 7.73 (m, 1H), 7.54 (dd, J = 8.3, 6.5 Hz, 2H), 7.51−7.46 (m, 1H),

7.45−7.40 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 157.6, 144.5, 139.2, 137.3, 134.2, 129.9, 129.0, 128.6, 127.8, 126.7, 126.2, 119.5. 7-Fluoro-2-phenylquinoline (4fa).43 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-4-fluorophenyl)methanol 1f (85 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4fa (94 mg, 84%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 7.3 Hz, 2H), 7.85 (d, J = 8.7 Hz, 1H), 7.80 (dd, J = 9.5, 2.7 Hz, 2H), 7.57−7.45 (m, 3H), 7.32 (td, J = 8.6, 2.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 163.4 (d, J = 249.6 Hz), 158.5, 149.4 (d, J = 13.0 Hz), 139.4, 136.8, 129.7, 129.6 (d, J = 10.0 Hz), 129.0, 127.7, 124.3, 118.5 (d, J = 2.0 Hz), 116.9 (d, J = 25.5 Hz), 113.4 (d, J = 20.2 Hz): 19F NMR (376 MHz, CDCl3) δ −109.5 (dd, J = 8.4, 8.4 Hz). 6,8-Dibromo-2-phenylquinoline (4ga).44 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-3,5-dibromophenyl)methanol 1g (169 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ga (158 mg, 87%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-3,5-dibromophenyl)methanol (169 mg, 0.6 mmol), and 1phenylethanol 5a (61 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ga (136 mg, 75%) as a white solid (mp 95−97 °C): 1H NMR (400 MHz, CDCl3) δ 8.31−8.26 (m, 2H), 8.15 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.57−7.47 (m, 3H); 13C NMR (126 MHz, CDCl3) δ 157.8, 143.9, 138.5, 136.3, 136.0, 130.2, 129.4, 129.0, 128.9, 127.7, 126.6, 120.0, 119.4. 6,7-Dimethoxy-2-phenylquinoline (4ha).35 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-4,5dimethoxyphenyl)methanol 1h (110 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 15% ethyl acetate in hexanes yielded 4ha (106 mg, 76%) as a pale-yellow solid (mp 132−134 °C): 1H NMR (400 MHz, CDCl3) δ 8.13−8.08 (m, 2H), 8.06 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.54−7.48 (m, 3H), 7.47−7.39 (m, 1H), 7.07 (s, 1H), 4.06 (s, 3H), 4.03 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 155.6, 152.7, 149.8, 145.4, 140.2, 135.1, 129.0, 128.9, 127.4, 122.9, 117.5, 108.5, 105.0, 56.3, 56.2. 4-Methyl-2-phenylquinoline (4ia).34 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2-amino-phenyl)ethanol 1i (82 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ia (73 mg, 67%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-ethanol 1a (82 mg, 0.6 mmol), and 1-phenylethanol 5a (61 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ia (63 mg, 58%) as a yellow viscous liquid: 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.5 Hz, 1H), 8.17−8.14 (m, 2H), 8.01 (d, J = 8.3 Hz, 1H), 7.75−7.69 (m, 2H), 7.58−7.50 (m, 3H), 7.46 (dd, J = 8.4, 6.1 Hz, 1H), 2.78 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 157.2, 148.3, 145.0, 140.0, 130.4, 129.5, 129.3, 128.9, 127.7, 127.4, 126.2, 123.8, 119.9, 19.1. 4-Ethyl-2-phenylquinoline (4ja).45 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2-aminophenyl)propanol 1j (91 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 24 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ja (52 mg, 45%) as a viscous liquid: 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.3 Hz, 1H), 8.17−8.14 (m, 2H), 8.05 (d, J = 8.3 Hz, 1H), 7.75−7.68 (m, 2H), 7.54 (m, 3H), 7.48−7.43 (m, 1H), 3.18 (q, J = 7.6 Hz, 2H), 1.46 (t, J = 7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 157.4, 150.6, 148.5, 140.2, 130.6, 129.3, 129.3, 128.9, 127.7, 126.5, 126.1, 123.4, 118.0, 25.5, 14.4. 4-Butyl-2-phenylquinoline (4ka).46 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2-aminophenyl)pentanol 1k (107 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 24 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ka (87 mg, 67%) as a viscous liquid: 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 5.5, 3.5 Hz, 2314

DOI: 10.1021/acs.joc.7b03198 J. Org. Chem. 2018, 83, 2309−2316

Article

The Journal of Organic Chemistry 2H), 8.05 (d, J = 8.3 Hz, 1H), 7.74−7.68 (m, 2H), 7.57−7.50 (m, 3H), 7.46 (dd, J = 8.4, 6.3 Hz, 1H), 3.17−3.10 (m, 2H), 1.81 (ddd, J = 12.8, 8.7, 6.7 Hz, 2H), 1.56−1.44 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.2, 149.4, 148.6, 140.1, 130.6, 129.3, 128.9, 127.7, 126.7, 126.1, 123.6, 118.9, 32.5, 32.4, 23.0, 14.1. 2,4-Diphenylquinoline (4la).37 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2-aminophenyl)phenylmethanol 1l (119 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 24 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4la (100 mg, 71%). GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2aminophenyl)phenylmethanol 1l (119 mg, 0.6 mmol), and 1phenylethanol 5a (61 mg, 0.5 mmol). After 24 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4la (65 mg, 46%) as a solid (mp 111−112 °C): 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.4 Hz, 1H), 8.21 (d, J = 7.3 Hz, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.78−7.72 (m, 1H), 7.60−7.52 (m, 7H), 7.51−7.45 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 157.0, 149.3, 148.9, 139.8, 138.5, 130.3, 129.7, 129.6, 129.5, 129.0, 128.7, 128.5, 127.7, 126.5, 125.9, 125.8, 119.5. 4-(4-Methoxyphenyl)-2-phenylquinoline (4ma).47 GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-(4-methoxyphenyl)methanol 1m (137 mg, 0.6 mmol), and acetophenone 2a (60 mg, 0.5 mmol). After 24 h, purification by column chromatography using 5% ethyl acetate in hexanes yielded 4ma (87 mg, 56%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.1 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 7.76−7.68 (m, 1H), 7.58−7.43 (m, 6H), 7.09 (d, J = 8.5 Hz, 2H), 3.92 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.1, 157.1, 149.1, 149.0, 140.0, 131.0, 130.9, 130.3, 129.6, 129.4, 129.0, 127.7, 126.4, 126.2, 125.8, 119.5, 114.3, 55.6. Reaction with Isotope Labeled 1a-d2 (Scheme 2a). Solid 1ad2 (0.1 mmol, 1.0 equiv) and tBuONa (10 mg, 0.1 mmol, 1 equiv) were placed in a predried 15 mL sealed tube. The tube was degassed and purged with argon three times. To a standard solution containing 1-(p-tolyl)ethenone 2c (13 mg, 0.10 mmol, 1 equiv) was then added nickel catalyst 3 (0.8 mg, 2 μmol, 2 mol %) in degassed toluene (1.0 mL), and the mixture was stirred at 120 °C for 4 h. At ambient temperature, EtOAc (5 mL) was added, and the reaction mixture was washed with brine (5 mL), dried over sodium sulfate, concentrated under a vacuum, and the crude mixture was analyzed by 1H NMR using tetrachloroethane as an internal standard. Reaction with Aldol Product 6 (Scheme 3b): Anhydrous Condition. (E)-3-(2-Aminophenyl)-1-phenylprop-2-en-1-one (6) (112 mg, 0.50 mmol), nickel catalyst 3 (4 mg, 0.01 mmol, 2 mol %), and tBuONa (48 mg, 0.50 mmol, 1 equiv) were placed in a predried 15 mL sealed tube. The tube was degassed and purged with argon three times. Toluene (2.0 mL) was then added, and the mixture was stirred at 120 °C for 16 h. At ambient temperature, EtOAc (8 mL) was added, and the reaction mixture was washed with brine (5 mL), dried over sodium sulfate, and concentrated under a vacuum. Purification by silica gel column chromatography using 1% ethyl acetate in hexanes yielded 4aa (15 mg, 15%). In the Presence of Water. (E)-3-(2-Aminophenyl)-1-phenylprop-2en-1-one (6) (112 mg, 0.50 mmol), nickel catalyst 3 (4 mg, 0.01 mmol, 2 mol %), and tBuONa (48 mg, 0.50 mmol, 1 equiv) were placed in a predried 15 mL sealed tube. The tube was degassed and purged with argon three times. Toluene (2.0 mL) and H2O (10.8 μL, 0.6 mmol, 1.2 equiv) were then added, and the mixture was stirred at 120 °C for 16 h. At ambient temperature, EtOAc (8 mL) was added, and the reaction mixture was washed with brine (5 mL), dried over sodium sulfate, and concentrated under a vacuum. Purification by silica gel column chromatography using 1% ethyl acetate in hexanes yielded 4aa (56 mg, 55%).

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Copies of 1H and 13C NMR spectra for all compounds (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Suman De Sarkar: 0000-0002-6342-4711 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Generous support by the CSIR [Fellowship to D.M. and S.D.], SERB, DST, India [ECR/2016/000225 to S.D.S.] and IISER Kolkata for infrastructure is gratefully acknowledged.

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DOI: 10.1021/acs.joc.7b03198 J. Org. Chem. 2018, 83, 2309−2316

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