Synthesis of Polysubstituted Quinolines from Î±-2-Aminoaryl Alcohols

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Synthesis of Polysubstituted Quinolines from #-2-Aminoaryl Alcohols Via Nickel-catalyzed Dehydrogenative Coupling Sanju Das, Debabrata Maiti, and Suman De Sarkar J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03198 • Publication Date (Web): 18 Jan 2018 Downloaded from http://pubs.acs.org on January 18, 2018

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The Journal of Organic Chemistry

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 KEYWORDS: homogeneous catalysis. acceptorless dehydrogenation; nickel catalyst, quinoline, earth-abundant metal

ABSTRACT: This study reports a nickel catalyzed sustainable synthesis of polysubstituted quinolines from α-2aminoaryl alcohols by a sequential dehydrogenation and condensation process that offers the advantages of 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, thirty substituted quinoline derivatives were synthesized with up to 93% isolated yield.

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 In addition, wide application 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 towards the synthesis of highly functionalized quinolines, preferably in an atom-economical and sustainable manner.5

acceptorless dehydrogenation (AD) of alcohols7 have become a prevailing tool for the sustainable synthesis of various heterocyclic compounds. The key features of AD process are the generation of more reactive carbonyl compounds from alcohols by the release of dihydrogen as stoichiometric byproduct. The in situ generated carbonyl further reacts with a suitable coupling partner to form the desired product in a sustainable manner. While 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 recent trend has drifted toward the usage of earth-abundant, non-precious base metals like Mn,9 Fe,10 Co,11 and Ni.12 Scheme 1. Nickel Catalyzed Synthesis of Polysubstituted Quinolines by Acceptorless Dehydrogenation

Figure 1. Examples of bioactive quinoline derivatives

The traditional methods for constructing quinolines include the Combes synthesis from anilines and 1,3diketones, the Skraup synthesis from anilines and glycerin, and the Friedlä nder synthesis from orthoacylanilines and α-methylene aldehydes/ketones.6 However, harsh reaction conditions and undesired self-condensation of the starting materials limits the scope and practicality of the quinoline synthesis.5b In the recent years, the relatively stable α-2-aminoaryl alcohols have been successfully employed for dehydrogenative synthesis of quinolines. Especially, methods using

The catalytic synthesis of quinolines by indirect Friedlä nder reaction via an oxidative cyclization of 2aminobenzyl alcohol in combination with either ketones or alcohols was described by the groups of Milstein,13 Shim,14 Yus,15 Verpoort,16 Kaneda17 and others18 employing Rucatalysis. Other precious metals like Ir19 and Pd20 has also been used for similar transformations. In comparison, the earth-abundant, eco-friendly and inexpensive first-row

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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 higher catalyst loading (5-8 mol %) and superstoichiometric amount of base.22 Therefore, an economical and universal synthetic strategy towards 4substituted 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 improved method reported by Niewahner.24

RESULTS AND DISCUSSION We commenced our study by treating 2-aminobenzyl alcohol 1 (1.2 equiv) and acetophenone 2 (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 argon atmosphere (Table 1). Reactions were performed in a closed 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 excellent yield of the desired quinoline derivative (entry 1). Reaction was completely shut down in absence of the nickel catalyst (entry 6). Another nickel catalyst (NiCl2) was also inefficient (entry 7). Lowering of temperature to 120 °C did not affect the yield (entry 5) but further lowering resulted a significant drop (entry 12). We were pleased to find that only 2 mol % catalyst 3 is sufficient for effective reaction proving 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, reaction at higher substrate concentration (0.25 M) using lower amount of toluene also showed equal efficiency (entry 11).

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9

2

120

toluene

tBuOK

85

10

2

120

toluene

K2CO3

trace

11d

2

120

toluene

tBuONa

92

12d

2

100

toluene

tBuONa

45

aReaction

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 catalyst. dSolvent (1.0 mL).

After establishing the optimal reaction condition, this methodology was applied to other carbonyl derivatives (Table 2). Differently substituted acetophenones smoothly yielded 2-aryl 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 antibiotic agent 4al.26 The reaction was not limited to the acetophenone derivatives. Both acyclic diaryl ketone and α-tetralone 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 case of 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 3substituted quinoline derivative (4ar) in moderate yield. Table 2. Substrate Scope Using 2-Aminobenzyl Alcohol and Various Carbonyl Compoundsa,b

Table 1. Optimization of the Reaction Conditionsa, b

Entry

3

T

[mol %]

[°C]

1

5

135

toluene

tBuONa

90

2

5

135

DMF

tBuONa

trace

3

5

135

DCE

tBuONa

trace

4

5

135

1,4-dioxane

tBuONa

81

5

5

120

toluene

tBuONa

90

6

0

120

toluene

tBuONa

0

7c

5

120

toluene

tBuONa

trace

8

2

120

toluene

tBuONa

92

Solvent

Base

Yield [%]b

aReaction 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.

The catalytic behavior of the nickel complex was further explored by coupling differently substituted 2aminobenzyl alcohols with acetophenone (Table 3). Both electron rich and electron poor 2-aminobenzyl alcohols


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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 to found that the acceptorless dehydrogenation process is not limited to the primary benzyl alcohols. Both alkyl and aryl substituted secondary 2-aminoaryl alcohols are also competent substrates and good to excellent yields were obtained in all cases (4ia-4ma). However, elevated temperature and extended reaction time were required for dehydrative cyclization of the less reactive ketones formed by the initial nickel catalyzed dehydrogenation. Table 3. Substrate Scope Using Substituted 2Aminoaryl Alcohols and Acetophenonea,b

aReaction 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.

aReaction 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.

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

Under similar reaction conditions as used for ketones, both the alcohols smoothly dehydrogenated to the corresponding carbonyls and follow-up condensation reaction yielded the 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, all the reactions were performed in a close vial under argon atmosphere and removal of evolved H2 from the reaction vessel was not required for effective coupling. Thus, this methodology truly represents an operationally simple, sustainable and high-yielding single step access to the quinoline derivatives. Control experiments was performed to investigate the mechanistic aspects of the reaction. An isotope labelled 1ad2 was treated with acetophenone derivative 2c under the standard nickel catalysis (Scheme 2). Reaction was quenched after partial conversion and the crude mixture was carefully analyzed by 1H NMR study. Major extent of deuterium was found to be retained in the quinoline product as well as in the unreacted 2-aminobenzyl alcohol (1ad2). Another interesting observation revealed the formation of 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 condition to check the mode of cyclization after the initial aldol condensation.27 Only 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, 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). Scheme 2. Mechanistic Studies



A probable catalytic cycle is depicted in Scheme 3 based on the literature reports and afore mentioned 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 nickelhydride 8 either reacts with another molecule of 1 to regenerate 7 with the liberation of dihydrogen or hydrogenate 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 towards the ketone following the Le Chatelier's principle with the generation of dihydrogen. Finally, dehydrative cyclization of the aldol product 10 resulted in the formation of quinoline 4. Scheme 3. Proposed Mechanism

CONCLUSION In summary, an atom efficient and versatile nickel catalyzed practical synthesis of polysubstituted quinolines from α-2-aminoaryl alcohols in combination with either ketones or secondary alcohols is reported. The sequential dehydrogenation and condensation process result 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 4-substituted quinolines. This methodology represents an operationally simple, sustainable synthetic method and offers future opportunities for method developments based on earthabundant metals.

EXPERIMENTAL SECTION General Information. Catalytic reactions were performed under argon atmosphere using pre-dried glassware and standard sealed tube. Toluene was dried with calcium hy-

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dride and freshly distilled under argon. Nickel catalyst 3 was prepared following reported procedure.24 The following starting materials were synthesized according to previously described methods: α-2-aminoaryl alcohols 1b1c,29 1d-h,30 1i-m;30b,31 ketones 2l,32 2m;9g secondary alcohol 5,30b isotope labelled 1a-d230b,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 by1HNMR. Thin layer chromatography (TLC) was performed on Merck precoated silica gel 60 F254 aluminum sheets, detection under UV light at 254nm. Chromatographic separations were carried out on Chempure Silica gel (100–200 mesh). Melting point (M. p.): Labtronics LT110 capillary melting point apparatus was used. 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 pre-dried 15 mL sealed tube. The tube was degassed and purged with argon for three times. Solvent (1.0-1.5 mL) was then added and the mixture was stirred at 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 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 pre-dried 15 mL sealed tube. The tube was degassed and purged with argon for three times. Toluene (2.0 mL) was then added and the mixture was stirred at 120 °C 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 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 pre-dried 15 mL sealed tube. The tube was degassed and purged with argon for three times. Toluene (2.0 mL) 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, con-


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centrated under 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 The 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%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-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 (M. p.: 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, CDCl ) δ 157.5, 148.4, 139.8, 136.8, 3 129.9, 129.7, 129.4, 128.9, 127.7, 127.6, 127.3, 126.4, 119.1. 2-(4-Methoxyphenyl)quinoline (4ab):19a The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 4methoxyacetophenone 2b (75 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ab (86 mg, 73%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 1-(4-methoxyphenyl)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 (M. p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)methanol 1a (74 mg, 0.6 mmol) and 4methylacetophenone 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 (M. p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 4chloroacetophenone 2d (77 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethyl acetate in hexanes yielded 4ad (111 mg, 93%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 1-(4-chlorophenyl)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 (M. p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 4bromoacetophenone 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 (M. p.: 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 = 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-methanol 1a (74 mg, 0.6 mmol) and 2bromoacetophenone 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 (M.p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-methanol 1a (74 mg, 0.6 mmol) and 3chloroacetophenone 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 (M.p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 3methoxyacetophenone 2h (75 mg, 0.5 mmol). After 16 h, purification by column chromatography using 2% ethyl acetate in hexanes yielded 4ah (99 mg, 84%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 1-(3-methoxyphenyl)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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 1naphthalen-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%). The GP 2 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-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 (M. p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-methanol 1a (74 mg, 0.6 mmol) and 1-thiophen-2yl-ethanone 2j (63 mg, 0.5 mmol). After 16 h, purification by column chromatography using 1% ethylacetate in hexanes yielded 4aj (91 mg, 86%). The GP 2 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-ethanol 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 (M. p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-methanol 1a (74 mg, 0.6 mmol ), and 1-pyridine3-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%). The GP 2 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-ethanol 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 (M.p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and 2imidazol-1-yl-phenyl-ethanone 2l (93 mg, 0.5 mmol). After

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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 The 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-(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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-phenyl)-methanol 1a (74 mg, 0.6 mmol) and αtetralone 2n (73 mg, 0.5 mmol). After 16 h, purification by column chromatography 2% ethyl acetate in hexanes yielded 4an (100 mg, 87%) as a white solid (M. p.: 64-65 °C). 1H 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)-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 The 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 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) 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.


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2-Methyl-quinoline-3-carboxylic acid ethyl ester (4aq):40 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-phenyl)-methanol 1a (62 mg, 0.5 mmol) and ethylacetoacetate 2q (98 mg, 0.75 mmol). After 16 h, purification by column chromatography 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-aminophenyl)methanol 1a (74 mg, 0.6 mmol) and phenylacetaldehyde 2r (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 1% ethyl acetate in hexanes yielded 4ar (44 mg, 43%) as a pale-yellow solid (M. p.: 4951 °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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino5-bromophenyl)methanol 1b (121 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 2% ethyl acetate in hexanes yielded 4ba (131 mg, 92%) as a colorless solid (M. p.: 114115 °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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino5-iodophenyl)methanol 1c (149 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 2% ethyl acetate in hexanes yielded 4ca (146 mg, 88%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-5-iodophenyl)methanol 1c (149 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 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino3-methylphenyl)methanol 1d (82 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 2% ethyl acetate in hexanes yielded 4da (93 mg, 85%).

The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-3-methylphenyl)methanol 1d (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 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino3- chlorophenyl)methanol 1e (94 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino4-fluorophenyl)methanol 1f (85 mg, 0.6 mmol ) and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-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 2% ethyl acetate in hexanes yielded 4ga (158 mg, 87%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-3,5-dibromophenyl)methanol (169 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 4ga (136 mg, 75%) as a white solid (M. p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2amino-4,5-dimethoxyphenyl)methanol 1h (110 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 15% ethyl acetate in hexanes yielded 4ha (106 mg, 76%) as a pale-yellow



solid (M.p.: 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2amino-phenyl)ethanol 1i (82 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 16 h, purification by column chromatography 2% ethyl acetate in hexanes yielded 4ia (73 mg, 67%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), (2-amino-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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2aminophenyl)propanol 1j (91 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 24 h, purification by column chromatography 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2aminophenyl)pentanol 1k (107 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 24 h, purification by column chromatography 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, 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). 13C 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 The GP 1 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2aminophenyl)phenylmethanol 1l (119 mg, 0.6 mmol) and acetophenone 2a (60 mg, 0.5 mmol). After 24 h, purification by column chromatography 1% ethyl acetate in hexanes yielded 4la (100 mg, 71%). The GP 2 was followed using nickel catalyst 3 (4 mg, 2.0 mol %), 1-(2-aminophenyl)phenylmethanol 1l (119 mg, 0.6 mmol) and 1-phenylethanol 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 (M.p.: 111-112 °C). 1H NMR (400 MHz, CDCl3) δ 8.27

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(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 The 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 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 labelled 1a-d2 (Scheme 2a): Solid 1a-d2 (0.1 mmol, 1.0 equiv) and tBuONa (10 mg, 0.1 mmol, 1 equiv) were placed in a pre-dried 15 mL sealed tube. The tube was degassed and purged with argon for three times. A standard solution containing 1-(ptolyl)ethenone 2c (13 mg, 0.10 mmol, 1 equiv), nickel catalyst 3 (0.8 mg, 2µmol, 2 mol %) in degassed toluene (1.0 mL) was then added 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 vacuum and the crude mixture was analyzed by 1H NMR using tetrachloroethane as an internal standard. Reaction with aldol product 6 (Scheme 3b): 1) Anhydrous condition: (E)-3-(2-aminophenyl)-1phenylprop-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 pre-dried 15 mL sealed tube. The tube was degassed and purged with argon for 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, concentrated under vacuum and purified by silica gel column chromatography using 1% ethyl acetate in hexanes yielded 4aa (15 mg, 15%). 2) In presence of water: (E)-3-(2-aminophenyl)-1phenylprop-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 pre-dried 15 mL sealed tube. The tube was degassed and purged with argon for three times. Toluene (2.0 mL) and H2O (10.8 µl, 0.6 mmol, 1.2 equiv) 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, concentrated under vacuum and purified by silica gel column chromatography using 1% ethyl acetate in hexanes yielded 4aa (56 mg, 55%).

ASSOCIATED CONTENT


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Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Copies of 1H and 13C NMR spectra for all compounds (PDF).

AUTHOR INFORMATION Corresponding Author * Email: [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT Generous support by the CSIR [Fellowship to DM and SD], SERB, DST, India [ECR/2016/000225 to SDS] and IISER Kolkata for infrastructure is gratefully acknowledged.

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