HETEROCYCLES

Paper | Regular issue | Vol. 81, No. 4, 2010, pp. 935-942
Received, 19th December, 2009, Accepted, 8th February, 2010, Published online, 9th February, 2010.
DOI: 10.3987/COM-09-11890

■ A Highly Effective One-Pot Synthesis of Quinolines from 2-Alkynylnitrobenzenes

Kentaro Okuma,* Saori Ozaki, Jun-ichi Seto, Noriyoshi Nagahora, and Kosei Shioji

Department of Chemistry, Faculty of Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

A highly effective one-pot synthesis of poly-substituted quinolines from 2-alkynylnitrobenzenes using inexpensive reagents has been developed. Reaction of 2-alkynylnitrobenzenes with Sn/HCl in EtOH resulted in the formation of 2-aminophenyl ketones and subsequently condensed in situ with ketones to form tri-substituted quinolines in 80-97% yields.

INTRODUCTION
Palladium-catalyzed cross-coupling reactions between terminal alkynes and aryl halides, known as the Sonogashira reaction, have been used extensively in natural products chemistry and materials science for the synthesis of substituted and conjugated alkynes.1 If 2-alkynylnitrobenzenes (1) prepared from Sonogashira coupling reaction were reduced and hydrated in one-pot operation, the corresponding vinyl alcohols were easily rearranged to 2-aminophenyl ketones (2), which are useful intermediates for many heterocycles such as quinolines, imidazoles, benzotriazoles, and benzodiazepines.2 Especially, quinolines and their derivatives are very important compounds because of their wide occurrence in natural products and biologically active compounds.3 Amongst various methodologies reported for the preparation of quinolines, Friedländer annulation is one of the simplest and most straightforward protocols.4 One of the drawbacks of this method remains the relative instability of the intermediate 2-aminobenzaldehydes or 2-aminophenyl ketones, which can readily undergo self-condensation. These results prompted us to investigate the one-pot synthesis of quinolines from 2-alkynylnitrobenzenes by reduction, hydration and acidic cyclization by Friedländer reaction. We report herein the one-pot synthesis of 2,3,4-trisubstituted quinolines from 2-alkynylnitrobenzenes.

RESULTS AND DISCUSSION
2-Alkynylnitrobenzenes were synthesized from 2-iodonitrobenzene and terminal alkynes by Sonogashira oupling reaction.1 We first tried the reduction and hydration of 2-phenylethynylnitrobenzene (1a) (Scheme 1). Treatment of 1a with Sn (1 eq) and Na2S (0.3 eq) followed by the addition of conc. HCl (4 eq) resulted in the formation of 1-(2-aminophenyl)-2-phenylethanone (2a) in 50% yield (entry 1, Table 1). When conc. HCl (10 eq) was added to a suspension of 1a and Sn (2 eq) and Na2S (0.3 eq) in refluxing EtOH for 8 h, 2a was obtained in 90% yield, indicating that reduction and hydration were performed in one-pot operation (entry 2). 0.3 eq of Na2S is essential for the present reaction, because, in the absence of Na2S, less than 10% of 2-phenylindole was obtained as a side product, suggesting that a very small amount of palladium chloride catalyzed the intramolecular cyclization (entry 3).5 When Zn or Fe was used as a reducing reagent, 2a was also obtained in 50% and 65% yields, respectively (entries 4 and 5). Thus, Sn found to be a better reducing reagent for the synthesis of 2-aminophenyl ketones. Other substituted 2-alkynylnitrobenzenes 1b-i gave 2-aminophenyl ketones 2b-i in good yields (entries 6-13).

Simple 2-aminophenylethanones, such as 2-aminoacetophenone and 2-aminobenozophenone, were commercially available; however, few reports on the synthesis of more complicated 2-aminophenyl ketones 2 were known. Among them are photo Fries rearrangement, reduction of 2-nitrophenyl ketones, o-acylation of anilines, and addition of 2-cyanoanilines with Grignard reagents.6 The present method provides a general method on the synthesis of 2.
We then investigated tandem synthesis of quinolines from 2-alkynylnitrobenzenes, Sn/HCl, and acetylacetone by a combination of reduction/hydration and Friedländer reaction.4 Acidic Friedlander reaction was generally carried out acetic acid as a solvent. If we want to synthesize quinolines in one-pot operation, other solvent should be required. Thus, we first tried the reaction of 2a with acetylacetone under several reaction conditions to find an optimum condition. Treatment of 2a with acetylacetone and sulfuric acid in acetic acid gave 2-methyl-3-acetyl-4-phenylquinoline (3a) in 96% yield. When the reaction was carried out by using HCl as acid in refluxing ethanol, 3a was obtained in 91% yield (Scheme 2).

Then one-pot reaction was carried out under these conditions (conc HCl in refluxing EtOH).
Treatment of 1a with Sn (2 eq)/HCl (10 eq), Na2S (0.3 eq), and acetylacetone (1.2 eq) in refluxing EtOH for 18 h gave 2-methyl-3-acetyl-4-benzylquinoline (3a) in 89% yield (entry 1, Table 2). As shown in Table 2, quinolines 3b-i were obtained in 80-93% yields (Scheme 3). Thus, one-pot synthesis of quinolines from 2-alkynylnitrobenzenes was accomplished.

Similarly, one-pot synthesis of quinolines from cyclohexanone was accomplished (Scheme 4).

While 2-alkynylnitrobenzenes were easily synthesized by the CuI-PdCl2 catalyzed reaction of 2-iodonitrobenzene with terminal alkynes, we finally tried the one-pot synthesis of 2,3,4-trisubstituted quinolines from 2-iodonitrobenzene. Treatment of 2-iodonitrobenzene with ethynylbenzene in the presence of catalytic amount of PdCl2-CuI in refluxing Et3N, followed by the evaporation and addition of Sn/HCl and acetylacetone in refluxing ethanol resulted in the formation of 3a in 65% yield (Scheme 5).

In summary, we have accomplished the general synthesis of 2-aminophenyl ketones from 2-alkynylnitrobenzenes. One-pot reaction of 2-alkynylnitrobenzenes with ketones afforded the corresponding quinolines in high yields. Thus, general and convenient synthesis of polysubstituted quinolines from 2-nitroalkynylbenzenes was achieved.

EXPERIMENTAL
General
All chemicals were obtained from commercial suppliers and were used without further purification. Analytical TLC was carried out on precoated plates (Merck silica gel 60, F254) and flash column chromatography was performed with silica (Merck, 70-230 mesh). NMR spectra (1H at 400 MHz; 13C at 100 MHz) were recorded in CDCl3, and chemical shifts are expressed in ppm relative to internal TMS for 1H- and 13C-NMR. Melting points were uncorrected.
Materials: 2-Alkynylnitrobenzenes were synthesized by Sonogashira coupling reaction.1 1-Butyl-4-(2-(2-nitrophenyl)ethynyl)benzene 1d: red needles. mp 146-148 oC 1H NMR (CDCl3) δ = 0.92 (t, 3H, J = 7.4 Hz, CH3), 1.33 (dt, 2H, J = 7.4 and 7.4 Hz, CH2), 1.57-1.60 (m, 2H, CH2), 2.61 (dd, 2H, J = 7.6 and 7.8 Hz, CH2), 7.18 (d, 2H, J = 8.0 Hz, Ar), 7.42 (dd, 1H, J = 7.6 and 7.8 Hz, Ar), 7.50 (d, d, 2H, J = 8.0 Hz, Ar), 7.56 (dd, 1H, J = 7.6 and 8.0 Hz, Ar), 7.69 (d, 1H, J = 7.8 Hz, Ar), 8.06 (d, 1H, J = 8.0 Hz, Ar). 13C NMR (CDCl3) δ = 14.15 (CH3), 22.54 (CH2), 33.58 (CH2), 35.92 (CH2), 84.92 (≡C), 97.84 (≡C), 119.75, 124.93, 128.51, 128.83, 132.19, 132.21, 132.99, 134.74, 144.83 (Ar). HRMS: Calcd for C18H17NO2; 279.1259. Found; (M+) 279.1258.
Synthesis of 1-(2-aminophenyl)-2-phenylethanone 2a
To a suspension of 2-phenylethynylnitrobenzene 1a (0.11 g, 0.50 mmol), Sn (0.12 g, 1.0 mmol) and Na2S.9H2O (0.036 g, 0.15 mmol) in EtOH:H2O (9:1, 5 mL) was added conc, HCl (0.42 mL, 5.0 mmol) in one portion. After refluxing for 8 h, the reaction mixture was washed with 5% aq. Na2CO3 (10 mL) and extracted with EtOAc (10 mL x 3). The combined extracts were dried over magnesium sulfate, filtered, and evaporated to give yellow crystals, which was chromatographed over silica gel by elution with hexane:EtOAc (5:1) to give yellow leaflets of 1-(2-aminophenyl)-2-phenylehanone 2a (0.095 g, 0.41 mmol) was obtained in 82%. Compound 2a: mp 99-100 oC (lit.,7 mp 98-99 oC). 1H NMR (CDCl3) δ = 4.26 (s, 2H, CH2), 6.29 (br, 2H, NH2), 6.63-6.66 (m, 2H, Ar), 7.23-7.26 (m, 4H, Ar), 7.31 (dd, 2H, J = 7.4 Hz and 8.0 Hz, Ar), 7.82 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 46.33 (CH2), 116.04, 117.66, 117.74, 126.98, 128.83, 129.72, 131.81, 134.71, 135.62, 151.07 (Ar), 200.20 (CO).
Other 2-aminophenylethanones were obtained in a similar manner.
1-(2-Aminophenyl)-1-hexan-1-one 2b (0.19 g, 0.93 mmol, 93%). Yellow oil,8 1H NMR (CDCl3) δ = 0.90 (dd, 3H, J = 6.0 Hz and 6.4 Hz, CH3), 1.35-1.38 (m, 4H, CH2), 1.70 (dt, 2H, J = 7.2 Hz and 7.4 Hz, CH2), 2.91 (t, 2H, J = 7.5 Hz, CH2), 6.25 (br, 2H, NH2), 6.62-6.66 (m, 2H, Ar), 7.23-7.27 (m, 1H, Ar), 7.73 (d, 1H, J = 8.0 Hz, Ar). 13C NMR (CDCl3) δ = 14.21 (Me), 22.80, 24.92, 31.88, 39.51 (CH2), 115.94, 117.58, 118.26, 131.45, 134.33, 150.58 (Ar), 203.44 (C=O).
1-(2-Aminophenyl)-1-heptan-1-one 2c (0.11 g, 0.49 mmol, 98%). Yellow oil,9 1H NMR (CDCl3) δ = 0.88 (dd, 3H, J = 6.8 Hz and 7.0 Hz, Me), 1.30-1.40 (m, 6H, CH2), 1.68 (dt, 2H, J = 7.6 Hz and 7.6 Hz, CH2), 2.91 (t, 2H, J = 7.5 Hz, CH2), 6.26 (br 2H, NH2), 6.67-6.70 (m, 2H, Ar), 7.24-7.28 (m, 1H, Ar), 7.74 (d, 1H, J = 8.0 Hz, Ar). 13C NMR (CDCl3) δ = 14.27 (Me), 22.77, 25.18, 29.36, 31.93, 39.55 (CH2), 115.92, 117.56, 118.26, 131.44, 134.30, 150.56 (Ar), 203.41 (C=O).
1-(2-Aminophenyl)-2-(4-butylphenyl)ethanone 2d (0.16 g, 0.60 mmol, 86%). Colorless leaflets: mp 72-73 oC. 1H-NMR (CDCl3) δ = 0.90 (dd, 3H, J = 7.4 Hz and 7.4 Hz, Me), 1.32 (dt, 2H, J = 7.4 Hz and 7.6 Hz, CH2), 1.57-1.60 (m, 2H, CH2), 2.56 (dd, 2H, J = 7.6 Hz and 7.8 Hz, CH2), 4.22 (s, 2H, CH2), 6.23 (br, 2H, NH2), 6.63-6.66 (m, 2H, Ar), 7.13 (d, 2H, J = 8.4 Hz, Ar), 7.16 (d, 2H, J = 8.4 Hz, Ar), 7.25-7.27 (m, 1H, Ar), 7.84 (d, 1H, J = 8.2 Hz, Ar). 13C NMR (CDCl3) δ = 14.21 (Me), 22.65, 33.82, 35.53, 45.94, (CH2), 116.01, 117.64, 117.81, 128.90, 129.55, 131.86, 132.70, 130.64, 141.56, 151.09 (Ar), 200.46 (C=O). Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.86; H, 7.78; N, 5.27.
1-(2-Aminophenyl)-4-hydroxy-1-butan-1-one 2e (0.066 g, 0.37 mmol, 74%). Pale brown oil,10 1H NMR (CDCl3) δ = 1.99 (dt, 2H, J = 6.0 Hz and 6.8 Hz, CH2), 3.09 (t, 2H, J = 6.8 Hz, CH2), 3.73 (t, 2H, J = 6. 0 Hz), 6.66-6.68 (m, 2H, Ar), 7.26-7.27 (m, 1H, Ar), 7.76 (d, 1H, J = 8.0 Hz, Ar). 13C NMR (CDCl3) δ = 27.67, 36.16, 62.60 (CH2), 116.06, 117.64, 118.03, 131.45, 134.64, 150.65 (Ar), 203.14 (C=O). HRMS: Calcd for C10H13NO2; 179.0946. Found; (M+) 179.0942.
1-(2-Aminophenyl)-3,3-dimethyl-1-butan-1-one 2f (0.18 g, 0.93 mmol, 93%). Yellow oil, 1H NMR (CDCl3) δ = 1.06 (s, 9H, 3Me), 2.82 (s, 2H, CH2), 6.29 (br, 2H, NH2), 6.58-6.62 (m, 2H, Ar), 7.19-7.23 (m, 1H, Ar), 7.73 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 30.50 (Me), 31.96 (C(Me)3), 50.77 (CH2), 115.75, 117.57, 119.73, 132.24, 134.25, 150.59 (Ar), 203.40 (C=O). HRMS: Calcd for C12H17NO; 191.1310. Found; (M+) 191.1315.
1-(2-Amino-4-chrolophenyl)-2-phenyletanone 2g (0.090 g, 0.37 mmol, 73%). Yellow leaflets: mp 98-99 oC. 1H NMR (CDCl3) δ = 4.22 (s, 2H, CH2), 6.37 (br, 2H, NH2), 6.59 (d, 1H, J = 8.8 Hz, Ar), 6.65 (s, 1H, Ar), 7.23-7.35 (m, 5H, Ar), 7.74 (d, 1H, J = 8.8 Hz, Ar). 13C NMR (CDCl3) δ = 46.43 (CH2), 116.19, 116.49, 116.80, 127.13, 128.91, 129.63, 133.18, 135.29, 140.62, 151.90, (Ar), 199.50 (C=O). HRMS: Calc for C14H1235ClNO; 245.0607. Found; (M+) 245.0612.
1-(2-Amino-4-methoxyphenyl)-2-phenylethanone 2h (0.054 g, 0.22 mmol, 75%). Yellow granules11: mp 92-93 oC. 1H NMR (CDCl3) δ = 3.79 (s, 3H, OMe), 4.19 (s, 2H, CH2), 6.06 (s, 1H, Ar), 6.22 (d, 1H, J = 8.8 Hz, Ar), 6.42 (br, 2H, NH2), 7.24-7.34 (m, 5H, Ar), 7.75 (d, 1H, J = 8.8 Hz, Ar). 13C NMR (CDCl3) δ = 46.21 (CH2), 55.47 (OMe), 99.55, 104.91, 112.33, 126.91, 128.84, 129.68, 134.00, 136.13, 153.74, 164.44 (Ar), 198.53 (C=O). HRMS: Calcd for C15H15NO2; 241.1103. Found; (M+) 241.1100.
1-(2-Amino-5-methylphenyl)-2-phenyletanone 2i (0.094 g, 0.42 mmol, 84%). Colorless amorphous solid12: mp 95-96 oC. 1H NMR (CDCl3) δ = 2.26 (s, 3H, Me), 4.26 (s, 2H, CH2), 6.13 (br, 2H, NH2), 6.58 (d, 1H, J = 8.0 Hz, Ar), 7.09 (d, 1H, J = 8.0 Hz, Ar), 7.26-7.36 (m, 5H, Ar), 7.64 (s, 1H, Ar). 13C NMR (CDCl3) δ = 20.75 (Me), 46.25 (CH2), 117.71, 117.79, 124.97, 126.95, 128.81, 134.00, 129.80, 131.33, 135.74, 135.96, 149.00 (Ar), 200.07 (C=O). HRMS: Calcd for C15H15NO; 225.1154. Found; (M+) 225.1158.
Reaction of 2a with acetylacetone (acidic Friedländer reaction)
To a solution of 2a (0.11 g, 0.50 mmol) in EtOH (8 mL) was added conc HCl (0.20 mL, 2.5 mmol) and acetylacetone (52 mL, 0.50 mmol). After refluxing for 18h, the reaction mixture was concentrated and 5% aq. Na2CO3 (10 mL) was added to this solution. The mixture was extracted with EtOAc (5 mL x 3). The combined extract was dried over sodium sulfate, filtered, and evaporated to give yellow solid, which was chromatographed over silica gel (hexane:EtOAc = 5:1) to give 3-acetyl-4-benzyl-2-methylquinoline (3a) (0.125 g, 0.45 mmol). 3a: colorless amorphous solid. mp 84-86 oC. 1H NMR (CDCl3) δ = 2.42 (s, 3H, Me), 2.68 (s, 3H, Me), 4.37 (s, 2H, CH2), 7.06 (d, 2H, J = 6.3 Hz, Ar), 7.16-7.24 (m, 3H, Ar), 7.44 (dd, 1H, J = 7.7 Hz and 8.4 Hz, Ar), 7.66 (dd, 1H, J = 7.7 Hz and 8.4 Hz, Ar), 7.87 (d, 1H, J = 8.4 Hz, Ar), 8.03 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 23.92, 32.85 (Me), 34.92 (CH2), 124.87, 125.83, 126.87, 126.88, 128.49, 128.99, 129.62, 130.15, 136.77, 138.62, 140.59, 147.85, 153.15 (Ar), 206.77 (CO). HRMS: Calc for C19H17NO; 275.1310. Found; (M+) 275.1303.
One-pot Synthesis of Quinoline 6a from 1a
To a solution of 1a (0.13 g, 0.60 mmol), Sn (0.14 g, 1.2 mmol), Na2S.9H2O (0.44 g, 0.18 mmol), and acetylacetone (0.072 mL, 0.72 mmol) in 10 mL of EtOH:H2O (9:1) was added conc HCl (0.50 mL, 6.0 mmol). After refluxing for 18 h, 5% aq. Na2CO3 solution was added, and extracted with EtOAc (5 mL x 3). The combined extract was dried over magnesium sulfate, filtered, evaporated, and chromatographed over silica gel (hexane:EtOAc = 5:1) to give 3-acetyl-4-benzyl-2-methylquinoline (3a) (0.15 g, 0.53 mmol) in 89% yield.
Other reactions were carried out in a similar manner by using 0.3 mmol of 3.
3-Acetyl-2-methyl-4-pentylquinoline 3b (0.061 g, 0.24 mmol, 80%). Yellow oil. 1H NMR (CDCl3) δ = 0.90 (dd, 3H, J = 7.2 Hz and 7.6 Hz, Me), 1.34-1.46 (m, 4H, CH2), 1.64-1.70 (m, 2H, CH2), 2.60 (s, 3H, Me), 2.63 (s, 3H, Me), 2.87 (t, 2H, J = 8. 4 Hz, CH2), 7.52 (dd, 1H, J = 7.6 Hz and 8.4 Hz, Ar), 7.67 (dd, 1H, J = 7.6 Hz and 8.4 Hz, Ar), 7.96 (d, 1H, J = 8.4 Hz, Ar), 8.01 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 14.16 (Me), 22.58 (CH2), 23.78 (Me), 30.04, 31.23, 32.53 (CH2), 32.94 (Me), 124.01, 125.39, 126.52, 129.68, 129.86, 135.51, 143.73, 147.67, 152.86 (Ar), 206.72 (CO). HRMS: Calcd for C17H21NO; 255.1623. Found; (M+) 255.1623.
3-Acetyl-4-hexyl-2-methylquinoline 3c (0.069 g, 0.26 mmol, 86%). Yellow oil. 1H NMR (CDCl3) δ = 0.90 (dd, 3H, J = 6.6 Hz and 7.0 Hz, Me), 1.30-1.34 (m, 4H, CH2), 1.44-1.48 (m, 2H, CH2), 1.62-1.69 (m, 2H, CH2), 2.59 (s, 3H, Me), 2.63 (s, 3H, Me), 2.86 (t, 2H, J = 8.2 Hz, CH2), 7.52 (dd, 1H, J = 7.6 Hz and 8.4 Hz, Ar), 7.67 (dd, 1H, J = 7.6 Hz and 8.4 Hz, Ar), 7.96 (d, 1H, J = 8.4 Hz, Ar), 8.02 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 14.26 (Me), 22.79 (CH2), 23.71 (Me), 30.10, 30.14, 31.53, 31.68 (CH2), 32.96 (Me), 124.03, 125.41, 126.59, 129.57, 129.94, 135.52, 143.94, 147.49, 152.84 (Ar), 206.64 (CO). HRMS: Calcd for C18H23NO; 269.1773. Found; (M+) 269.1737.
3-Acetyl-(4-butylbenzyl)-2-methylquinoline 3d (0.086 g, 0.26 mmol, 87%). Yellow oil. 1H NMR (CDCl3) δ = 0.87 (dd, 3H, J = 7.2 Hz and 7.4 Hz, Me), 1.26-1.34 (m, 2H, CH2), 1.51-1.55 (m, 2H, CH2), 2.40 (s, 3H, Me), 2.51 (t, 2H, J = 7. 6 Hz, CH2), 2.68 (s, 3H, Me), 4.32 (s, 2H, CH2), 6.96 (d, 2H, J = 7.8 Hz, Ar), 7.03 (d, 2H, J = 7.8 Hz, Ar), 7.42 (dd, 1H, J = 7.6 Hz and 8.4 Hz, Ar), 7.65 (dd, 1H, J = 7.6 Hz and 8.4 Hz, Ar), 7.88 (d, 1H, J = 8.4 Hz, Ar), 8.02 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 14.16 (Me), 22.55 (CH2), 23.89 (Me), 32.82, 33.78 (CH2), 34.55 (Me), 35.38 (CH2), 124.96, 125.90, 126.82, 128.36, 129.01, 129.57, 129.99, 135.75, 136.71, 140.95, 141.48, 147.84, 153.10 (Ar), 206.78 (CO). HRMS: Calcd for C23H25NO; 331.1936. Found; (M+) 331.1937.
3-Acetyl-4-(3-hydroxylpropyl)-2-methylquinoline 3e (0.069 g, 0.29 mmol, 95%). Pale brown oil. 1H NMR (CDCl3) δ = 1.65 (br, 1H, OH), 1.93-1.99 (m, 2H, CH2), 2.62 (s, 3H, Me), 2.65 (s, 3H, Me), 3.05 (dd, 2H, J = 7.4 Hz and 7.6 Hz, CH2), 3.67 (dd, 2H, J = 5.6 Hz and 5.6 Hz, CH2), 7.54 (dd, 1H, J = 7.2 and 7.6 Hz, Ar), 7.70 (dd, 1H, J = 7.2 Hz and 7.6 Hz, Ar), 7.98 (d, 1H, J = 8.4 Hz, Ar), 8.02-8.05 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 23.84 (Me), 26.29, 33.06 (CH2), 33.90 (Me), 61.78 (CH2), 124.16, 125.28, 126.73, 129.67, 130.08, 135.82, 143.05, 147.68, 152.78 (Ar), 207.62 (CO). HRMS: Calcd for C15H17NO2; 243.1259. Found; (M+) 243.1248.
3-Acetyl-2-methyl-4-neopentylquinoline 3f (0.074 g, 0.29 mmol, 97% yield). Yellow oil. 1H NMR (CDCl3) δ = 0.93 (s, 9H, Me) 0.98 (s, 2H, CH2), 2.54 (s, 3H, Me), 2.64 (s, 3H, Me), 7.51 (dd, 1H, J = 7.6 Hz and 8.0 Hz, Ar), 7.69 (dd, 1H, J = 7.2 Hz and 7.6 Hz, Ar), 8.01 (d, 1H, J = 8.4 Hz, Ar), 8.09 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 24.30 (Me), 31.21 (3Me), 33.37 (CH2), 34.17 (Me), 41.35 (C(Me)3), 125.74, 125.88, 126.88, 129.41, 129.84, 136.95, 141.99, 147.63, 153.08 (Ar), 206.71 (CO). HRMS: Calcd for C17H21NO; 255.1623. Found; (M+) 255.1621.
3-Acetyl-4-benzyl-7-chloro-2-methylquinoline 3g (0.056 g, 0.18 mmol, 60%). Yellow granules: mp. 88-89 oC. 1H NMR (CDCl3) δ = 2.42 (s, 3H, Me), 2.67 (s, 3H, Me), 4.33 (s, 2H, CH2), 7.04 (d, 2H, J = 7.4 Hz, Ar), 7.20-7.26 (m, 3H, Ar), 7.37 (d, 1H, J = 8.8 Hz, Ar), 7.78 (d, 1H, J = 8.8 Hz, Ar), 8.03 (s, 1H, Ar). 13C NMR (CDCl3) δ = 23.92, 32.78 (Me), 34.96 (CH2), 124.29, 126.28, 127.02, 127.80, 128.40, 128.60, 129.08, 135.95, 136.88, 138.28, 140.73, 148.34, 154.56, (Ar), 206.29 (C=O). HRMS: Calcd for C19H1635ClNO; 309.0920. Found; (M+) 309.0925.
3-Acetyl-4-benzyl-7-methoxy-2-methylquinoline 3h (0.070 g 0.23 mmol, 76%). Yellow amorphous solid: mp 132-133 oC. 1H NMR (CDCl3) δ = 2.39 (s, 3H, Me), 2.65 (s, 3H, Me), 3.94 (s, 3H, OMe), 4.33 (s, 2H, CH2), 7.05 (d, 2H, J = 7.2 Hz, Ar), 7.08 (d, 1H, J = 9.2 Hz, Ar), 7.18-7.25 (m, 3H, Ar), 7.37 (s, 1H, Ar), 7.75 (d, 1H, J = 9.2 Hz, Ar). 13C NMR (CDCl3) δ = 22.60, 31.67 (Me), 33.62 (CH2), 55.49 (OMe), 106.34, 118.59, 119.59, 124.76, 125.55, 127.20, 127.69, 133.61, 137.47, 139.50, 148.49, 152.23, 159.87 (Ar), 205.65 (C=O). HRMS: Calcd for C20H19NO2; 305.1416. Found; (M+) 305.1408.
3-Acetyl-4-benzyl-2,6-dimethylquinoline 3i (0.058 g 0.20 mmol) in 67% yield. Yellow granules: mp 123-124 oC. 1H NMR (CDCl3) δ = 2.37 (s, 3H, Me), 2.44 (s, 3H, Me), 2.65 (s, 3H, Me), 4.34 (s, 2H, CH2), 7.06 (d, 2H, J = 7.2 Hz, Ar), 7.18-7.26 (m, 3H, Ar), 7.49 (d, 1H, J = 8.4 Hz, Ar), 7.64 (s, 1H, Ar), 7.92 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 22.13, 23.75, 32.78 (Me), 34.70 (CH2), 123.68, 123.70, 125.83, 126.80, 128.49, 128.95, 129.29, 132.28, 136.73, 138.72, 139..90, 146.42, 152.00 (Ar), 206.97 (C=O). HRMS: Calcd for C20H19NO; 289.1467. Found; (M+) 289.1467.
9-Hexyl-5,6,7,8-tetrahydroacridine 3j (0.055 g, 0.20 mmol, 68%). Yellow oil. 1H NMR (CDCl3) δ = 0.90 (dd, 3H, J = 6.8 Hz and 6.8 Hz, Me), 1.32-1.48 (m, 4H, CH2), 1.48 (dt, 2H, J = 6.8 Hz and 7.0 Hz, CH2), 1.56 (dt, 2H, J = 6.8 Hz and 8.0 Hz, CH2), 1.93-1.98 (m, 4H, CH2), 2.92 (dd, 2H, J = 7.6 Hz and 8.0 Hz, CH2), 3.11 (dd, 2H, J = 6.0 Hz and 6.2 Hz, CH2), 7.43 (dd, 1H, J = 7.6 Hz and 8.0 Hz, Ar), 7.57 (dd, 1H, J = 7.6 Hz and 8.4 Hz, Ar), 7.93 (d, 1H, J = 8.0 Hz, Ar), 7.96 (d, 1H, J = 8.4 Hz, Ar). 13C NMR (CDCl3) δ = 14.33 (Me), 22.90, 23.04, 23.46, 26.57, 27.90, 29.84, 30.24, 31.91, 34.74 (CH2), 123.54, 125.47, 126.41, 128.22, 128.25, 129.33, 145.94, 146.55, 159.04 (Ar). HRMS: Calcd for C19H25N; 267.1987. Found; (M+) 267.1989.
9-Neopentyl-5,6,7,8-tetrahydroacridine 3k (0.043 g, 0.17 mmol, 57%). Yellow oil. 1H NMR (CDCl3) δ = 0.98 (s, 9H, Me), 1.86-1.97 (m, 4H, CH2), 2.94 (dd, 2H, J = 6.0 Hz and 6.2 Hz, CH2), 3.09-3.16 (m, 4H, CH2), 7.39 (dd, 1H, J = 7.2 Hz and 8.0 Hz, Ar), 7.55 (dd, 1H, J = 7.2 Hz and 8.0 Hz, Ar), 7.95 (d, 1H, J = 8.0 Hz, Ar), 8.02 (d, 1H, J = 8.0 Hz, Ar). 13C NMR (CDCl3) δ = 22.67, 23.16, 28.09 (CH2), 31.22 (Me), 34.42, 34.82 (CH2), 38.71 (C(Me)3), 124.70, 125.49, 127.98, 128.02, 129.09, 130.92, 143.22, 146.51, 159.27 (Ar). HRMS: Calcd for C18H23N; 253.1830. Found; (M+) 253.1826.
One-pot synthesis of quinoline 3a from 2-iodonitrobenzene.
To a suspension of 2-iodonitrobenzene (0.124 g, 0.5 mmol), PdCl2(PPh3)2 (0.004 g, 0.005 mmol), and CuI (0.005 g, 0.025 mmol) in diethylamine (8 mL) was added phenylacetylene (0.066 mL, 0.6 mmol) in one portion. After refluxing for 6 h, the suspension was evaporated and added Sn (0.118 gm 1.0 mmol), Na2S·9H2O (0.060 g, 0.25 mmol), acetylacetone (0.062 mL, 0.6 mmol), EtOH (6 mL), H2O (1 mL), and HCl (0.42 mL, 5 mmol). After refluxing for 16 h, 5% aq. Na2CO3 was added and extracted with EtOAc (5mL x 3). The combined extract was dried over magnesium sulfate, filtered, and evaporated to give brown solid, which was chromatographed over silica gel by elution with hexane: EtOAc (5:1) to afford quinoline 3a (0.088 g, 0.33 mmol, 65%). Other reactions were carried out in a similar manner.

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