A mild and metal-free synthesis of 2- and 1-alkyl/aryl/dialkyl-aminoquinolines and isoquinolines

Abstract

A simple synthetic strategy has been developed for the synthesis of 2- and 1-alkyl/aryl/dialkylaminoquinolines and isoquinolines from the easily available quinoline and isoquinoline-N-oxides, different amines, triflic anhydride as activating agent and acetonitrile as solvent in a one-pot reaction under metal-free conditions at 0 °C to room temperature.

---

Introduction

The basic motifs of 2-aminoquinolines and 1-aminoisoquinolines are present in a number of alkaloids¹ that have a broad range of biological activities, including antimicrobial activity,² anti-Alzheimer disease,³ anti-HIV,⁴ antihelmintic,⁵ antidepressant,⁶ and antihypertensive⁷ activities. This type of skeleton-containing molecule is an interesting target as potent leads for the medicinal chemist. Some representative examples are given below in Fig. 1. Compound 1 selectively modulates native TRPC4/C5 ion channels and is a potent antagonist. This compound has a broad scope in physiological and pathophysiological studies,^1b whereas compound 2, as an antagonist of MCH-1R, is used for the treatment of obesity.^2c

Fig. 1 Representative examples of biologically important 2-aminoquinolines.

There are several reports in the literature for the synthesis of 2-aminoquinoline and 1-aminoisoquinoline derivatives.⁸ The Chichibabin reaction is one of them, in which amino or alkylamino groups can be incorporated directly into the quinoline and isoquinoline nucleus by the reaction of quinoline and isoquinoline with alkali amide or alkylamide. The Chichibabin reaction does, however, have some drawbacks, such as low yields, functional group intolerance and poor regioselectivity due to strong basic conditions, high temperatures and longer reaction times (Scheme 1a).⁹ Earlier, it was noted that 2-(dialkylamino)quinolines/(1-dialkylamino)isoquinolines cannot be prepared by other variants of the Chichibabin reaction. This shows that we cannot introduce dialkylamino groups into the quinoline/isoquinoline nucleus by the use of alkali dialkylamides.¹⁰ A literature survey shows that derivatization of the 2-unsubstituted quinoline moiety to the corresponding 2-dialkylaminoquinoline was obtained via indirect synthetic methods. The other important approach is amination of 2-haloquinolines with alkyl/dialkylamines.¹¹ However, to use this approach, first, a halogen atom should be incorporated at the 2-position of quinoline and its derivatives, which is achieved by chlorination of quinoline-N-oxides with 2- and 4-regioselectivity and poor yields (Scheme 1b).¹¹ Londregan reported the amination method for the synthesis of 2-aminopyridines, and when 2-cyclohexylamino-quinoline was made utilising this method, poor yield was observed. They used the phosphonium salt PyBroP as the activating agent in this reaction, which is expensive.¹² Pedersen also described the synthesis of 2-(dialkylamino)quinolines by the reaction of acetanilides and N,N-dialkylformamides in the presence of phosphorus pentoxide and a dialkylamine at 250 °C.^13a This method has drawbacks of high temperature, prolonged reaction time, and poor yield (Scheme 1c). Further, Yin and Xiang reported a two-step synthetic route for the synthesis of 2-aminoquinolines in which an expensive solvent, PhCF₃, was used, and excess (5–9 equiv.) of t-BuNH₂ was needed to react with quinoline-N-oxide in the first step to form N-(t-butyl)-substituted 2-aminoquinolines (Scheme 1d).^13b Zhuo developed a methodology for the preparation of 2-dialkylaminoquinolines from quinoline-N-oxides, diisopropyl H-phosphonate, tertiary amines and carbon tetrachloride under metal-free reaction conditions at room temperature (Scheme 1e)¹⁴ and the limitation of this reaction is the use of symmetrical tertiary amine. In 2017, Karchava reported a simple, one-pot preparation of N-(2-pyridyl)-N-ethyl-piperazines¹⁵ from pyridine-N-oxide and 1,4-diazabicyclo[2.2.2]octane (DABCO), which generates N-(2-pyridyl)-DABCO salt and further ring opening yields the product by nucleophilic attack. Hence, the development of a simple and handy method for the synthesis of 2-(alkyl/aryl/dialkyl-amino)quinolines and 1-(alkyl/aryl/dialkylamino)quinolines from easily available starting materials without the use of metal is still needed.

Scheme 1 Comparison of earlier work with the present work.

Results and discussion

Here, we report a synthetic method by which a series of 2- and 1-alkyl/aryl/dialkylaminoquinolines and isoquinolines are easily prepared by reaction of quinoline and isoquinoline-N-oxides with different alkyl/aryl/dialkylamines at 0 °C to room temperature in the presence of triflic anhydride as activator and acetonitrile as solvent in a one-pot reaction (Scheme 1f).

We began our study to optimize reaction conditions for the synthesis of 2-morpholinoquinoline, 5a, between reaction of quinoline-N-oxide, 3a, and morpholine, 4a, in the presence of triflic anhydride as activator under different reaction conditions, as shown in Scheme 2 and Table 1 (entries 1–9). It was found that 2-morpholinoquinoline 5a was obtained in good yield (82%) when the N-oxide of quinoline 3a (1.0 equiv.) was reacted with morpholine 4a (1.2 equiv.) and triflic anhydride (Tf₂O) (1.5 equiv.) in acetonitrile as solvent at 0 °C to room temperature for 8 h (Table 1, entry 9). There is also the possibility of formation of the isomeric 4-morpholinoquinoline 5a′. Compound 5a′ was never observed.

Scheme 2 Synthesis of 2-morpholinoquinoline 5a.

Table 1 Optimization table for the synthesis of 2-morpholinoquinoline 5a

Entry	Reaction condition	% yield of product 5a
a 5a was observed in TLC and could not be isolated.
1	CH2Cl2, Tf2O, 0 °C to rt, 12 h	No reaction
2	Et2O, Tf2O, 0 °C to rt, 12 h	No reaction
3	Toluene, Tf2O, 0 °C to rt, 12 h	^aTrace product
4	CH3CN, Tf2O (2 equiv.), 0 °C to rt, 8 h	80%
5	DMSO, Tf2O, 0 °C to rt, 12 h	^aTrace product
6	THF, Tf2O, 0 °C to rt, 12 h	^aTrace product
7	THF, t-BuOK, 0 °C to rt, 12 h	^aTrace product
8	THF, NaH, 0 °C to rt, 12 h	^aTrace product
9	CH3CN, Tf2O (1.5 equiv.), 0 °C to rt, 8 h	82%

---

The above optimised reaction conditions were employed for the synthesis of other 2-alkyl/aryl/dialkylamino-substituted quinolines (5b–l) as shown in Scheme 3 and Table 2.

Scheme 3 Synthesis of 2-alkyl/aryl/dialkylaminoquinolines 5b–l.

Table 2 Synthesis of 2-alkyl/aryl/dialkylaminoquinolines 5b–k

Entry	Amine	Product 5b–k	% yield of 5b–k
1			79
2			82
3			84
4			68
5			76
6			74
7	PhNH2		79
8	BrC6H4NH2		77
9	MeOC6H4NH2		78
10	FC6H4NH2		67
11	NO2C6H4NH2		62

---

Further, the optimized methodology was extended for the synthesis of 2-alkyl/aryl/dialkyl-aminosubstituted-6-methoxy-quinolines 7a–f from the reaction of 5-methoxyquinoline-N-oxide (6) with different amines (Scheme 4 and Table 3). Next, the optimized reaction conditions were utilised for the synthesis of 1-alkyl/aryl/dialkylamino-substituted isoquinolines 9a–f, when isoquinoline-N-oxide 8 was reacted with different alkyl/aryl/dialkyl amines at 0 °C to room temperature for 6–8 h in the presence of triflic anhydride and acetonitrile, as shown in Scheme 5 and Table 4.

Scheme 4 Synthesis of 2-alkyl/aryl/dialkylamino-6-methoxyquinolines 7a–f.

Table 3 Synthesis of 2-alkyl/aryl/dialkylamino-6-methoxyquinolines 7a–f

Entry	Amine	Product 7a–f	% yield of 7a–f
1			83
2			66
3			64
4	PhNH2		62
5	MeOC6H4NH2		65
6	NO2C6H4NH2		60

---

Scheme 5 Synthesis of 1-alkyl/aryl/dialkylaminoisoquinolines 9a–f.

Table 4 Synthesis of 1-alkyl/aryl/dialkylaminoisoquinolines 9a–f

Entry	Amine	Product 9a–f	% yield of 9a–f
1			83
2			77
3			74
4	PhNH2		64
5	MeOC6H4NH2		62
6	NO2C6H4NH2		60

---

In the mechanistic step, triflic anhydride reacts with quinoline-N-oxide to produce the activated quinoline-N-oxide intermediate 10. Further, the activated quinoline-N-oxide intermediate 10 reacted with amine via nucleophilic addition to produce intermediate 11. The hydrogen of the ammonium intermediate 11 is abstracted by the trifluoromethane sulfonate anion, followed by aromatization to give the 2-amino-substituted quinoline (Scheme 6). Trifluoromethane sulfonic anhydride enhanced the CH-acidity and electrophilicity of the C-2 position by reacting with the N-oxide.

Scheme 6 Proposed mechanism for amination of quinoline- and isoquinoline-N-oxides.

Conclusions

In conclusion, we have developed a straightforward and metal-free methodology for the regioselective amination of quinoline-N-oxides and isoquinoline-N-oxides with different aliphatic and aromatic amines utilising triflic anhydride as activator in a one-pot reaction. A wide range of 2-alkyl/aryl/dialkylamino-substituted quinolines and 1-alkyl/aryl/dialkylamino-substituted isoquinolines were synthesised in up to 84% yield. This amination exposed a good functional group tolerance and proceeds well when electron-donating and -withdrawing substituted amines were used.

Experimental

General

Unless otherwise noted, all the reactions were performed in oven-dried glassware. The solvents used were dried and distilled. The reactions were performed under a nitrogen atmosphere. Acetonitrile was distilled from CaH₂ and stored over 4 Å molecular sieves. The N-oxides and amines used were commercially available. All other commercial reagents were used without further purification, unless otherwise indicated. ¹H NMR and ¹³C NMR spectra were recorded on 400 MHz and 101 MHz Bruker spectrometers, respectively, using either CDCl₃ or DMSO-d₆ as solvent, with tetramethylsilane (TMS) as internal standard.

General experimental procedure

To a solution of quinoline-/isoquinoline-N-oxide (1.0 mmol, 1.0 equiv.) and amine (1.2 mmol, 1.2 equiv.) in CH₃CN (8 mL) was added Tf₂O (0.25 mL, 1.5 mmol, 1.5 equiv.) drop by drop at 0 °C. The reaction mixture was stirred for 6–8 h at room temperature and the reaction was monitored by thin layer chromatography. After completion of the reaction, the solvent was evaporated under vacuum, and the residue was quenched with saturated NaHCO₃ solution (20 mL), and extracted with CH₂Cl₂ (3 × 50 mL). The combined organic layer was washed with brine (15 mL) and dried over anhydrous Na₂SO₄. The combined organic layer was concentrated and purified by column chromatography on silica gel (60–120 mesh) using a mixture of petroleum ether and ethylacetate as eluent to give pure product.

4-(Quinolin-2-yl)morpholine, 5a^14a

Yield 82% (175 mg); bone off-white solid; mp 88–89 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 1.1 Hz, 1H), 7.56–7.46 (m, 1H), 7.20–7.16 (m, 1H), 6.90 (d, J = 9.1 Hz, 1H), 3.79 (t, J = 4.8 Hz, 4H), 3.65 (t, J = 5.0 Hz, 4H); ¹³C NMR (101 MHz, CDCl₃) δ: 157.6, 147.6, 137.6, 129.7, 127.3, 126.8, 123.3, 122.7, 109.3, 66.9, 45.6; HRMS (ESI) m/z calcd for C₁₃H₁₅N₂O: 215.1184, found: 215.1182.

2-(Piperidin-1-yl)quinoline, 5b^16b

Yield 79% (167.0 mg); mp 46–47 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.41 (d, J = 9.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 8.10–8.02 (m, 1H), 7.82–7.73 (m, 1H), 7.55 (d, J = 9.2 Hz, 1H), 4.31–4.26 (m, 4H), 2.25 (brs, 6H); ¹³C NMR (101 MHz, CDCl₃) δ: 157.7, 148.0, 137.5, 129.3, 127.2, 126.5, 122.8, 121.8, 109.8, 46.3, 25.8, 24.8; HRMS (ESI) m/z calcd for C₁₄H₁₇N₂: 213.1392, found: 213.1382.

N-Butylquinolin-2-amine, 5c^16b

Yield 82% (164 mg); viscous liquid; ¹H NMR (400 MHz, CDCl₃) δ: 7.83 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.57–7.51 (m, 1H), 7.24–7.18 (m, 1H), 6.65 (d, J = 8.9 Hz, 1H), 4.76 (brs, 1H), 3.50 (q, J = 7.2 Hz, 2H), 1.77–1.55 (m, 2H), 1.53–1.44 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 157.2, 148.2, 137.3, 129.5, 127.5, 126.0, 123.4, 121.9, 111.2, 41.6, 31.9, 20.3, 13.9.

N-Benzylquinolin-2-amine, 5d^14c

Yield 84% (196 mg); colourless crystalline solid; mp 97–98 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.84 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.0, 1.1 Hz, 1H), 7.59–7.55 (m, 1H), 7.47–7.42 (m, 2H), 7.40–7.34 (m, 2H), 7.34–7.28 (m, 1H), 7.28–7.23 (m, 1H), 6.66 (d, J = 8.9 Hz, 1H), 5.06 (s, 1H), 4.76 (d, J = 5.6 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ: 156.8, 148.1, 139.5, 137.5, 129.7, 128.7, 127.9, 127.5, 127.4, 126.3, 123.6, 122.2, 111.5, 45.9; HRMS (ESI) m/z calcd for C₁₆H₁₅N₂: 235.1235, found: 235.1240.

N-(tert-Butyl)quinolin-2-amine, 5e¹⁸

Yield: 68% (136 mg); light yellow oil; ¹H NMR (400 MHz, CDCl₃) δ: 1.53 (s, 9H), 5.49 (brs, 1H), 6.65 (d, J = 9.0 Hz, 1H), 7.16–7.21 (m, 1H), 7.48–7.7.53 (m, 1H), 7.55 (dd, J = 8.0 Hz, 1.0 Hz, 1H), 7.77 (d, J = 9.0 Hz, 1H).

N-Benzyl-N-methylquinolin-2-amine, 5f^16c

Yield 76% (188 mg); colourless crystalline solid; mp 94–95 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.88 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.63 (dd, J = 8.0 Hz, 1.3 Hz, 1H), 7.59–7.55 (m, 1H), 7.38–7.20 (m, 6H), 6.91 (d, J = 9.1 Hz, 1H), 4.98 (s, 2H), 3.26 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 157.3, 148.3, 138.7, 137.5, 129.6, 128.7, 127.4, 127.3, 127.2, 126.6, 122.8, 121.9, 109.1, 53.3, 36.3; HRMS (ESI) m/z calcd for C₁₇H₁₇N₂: 249.1392, found: 249.1397.

N,N-Dibenzylquinolin-2-amine, 5g^14c

Yield 74% (240 mg); bone off-white solid; mp 101–102 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (d, J = 9.1 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.65–7.54 (m, 2H), 7.38–7.20 (m, 11H), 6.85 (d, J = 9.1 Hz, 1H), 4.97 (s, 4H); ¹³C NMR (101 MHz, CDCl₃) δ: 157.1, 148.2, 138.6, 137.7, 129.6, 128.7, 127.5, 127.3, 127.2, 126.8, 122.9, 122.0, 109.2, 50.8; HRMS (ESI) m/z calcd for C₂₃H₂₁N₂: 325.1705, found: 325.1708.

N-Phenylquinolin-2-amine, 5h^14c

Yield 79% (174 mg); brown solid; mp 93–94 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.94 (d, J = 8.9 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.0 Hz, 1.3 Hz, 1H), 7.64–7.59 (m, 1H), 7.57 (dd, J = 8.6 Hz, 1.1 Hz, 2H), 7.43–7.35 (m, 2H), 7.33–7.29 (m, 1H), 7.14–7.08 (m, 1H), 7.01 (d, J = 8.9 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 154.5, 147.0, 140.0, 138.2, 130.1, 129.3, 127.6, 126.2, 124.9, 124.0, 123.3, 120.9, 111.7; HRMS (ESI) m/z calcd for C₁₅H₁₃N₂: 221.1079, found: 221.1071.

N-(4-Bromophenyl)quinolin-2-amine 5i^14c

Yield 77% (230 mg); colourless crystalline solid; mp 146–147 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J = 8.9 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.65–7.58 (m, 3H), 7.49 (d, J = 8.9 Hz, 2H), 7.35 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 6.73 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 153.7, 147.4, 139.5, 137.9, 132.1, 129.8, 127.5, 126.9, 124.2, 123.5, 121.4, 115.0, 112.1.

N-(4-Methoxyphenyl)quinolin-2-amine 5j^14c

Yield 78% (195 mg); colourless crystalline solid; mp 125–126 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.89 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 8.9 Hz, 2H), 7.32–7.26 (m, 1H), 6.96–6.93 (m, 2H), 6.89 (d, J = 8.9 Hz, 1H), 6.79 (s, 1H), 3.85 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 156.3, 155.7, 147.8, 137.7, 133.2, 129.8, 127.5, 126.2, 123.9, 122.5, 114.6, 111.3, 55.4; HRMS (ESI) m/z calcd for C₁₆H₁₅N₂O: 251.1184, found: 251.1173.

N-(4-Fluorophenyl)quinolin-2-amine 5k^14c

Yield 67% (159 mg); colourless crystalline solid; mp 101–103 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 4.4 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.53–7.48 (m, 1H), 7.46–7.42 (m, 2H), 7.25–7.21 (m, 1H), 6.99 (t, J = 8.7 Hz, 2H), 6.75 (d, J = 8.8 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.3 (d, J = 252.5 Hz), 154.4, 146.4, 138.5, 135.7 (d, J = 2.7 Hz), 130.3, 127.6, 126.6 (d, J = 8.1 Hz), 125.7, 123.9, 123.5, 123.1 (d, J = 7.9 Hz), 116.0 (d, J = 22.5 Hz), 115.6 (d, J = 12.9 Hz), 111.5; HRMS (ESI) m/z calcd for C₁₅H₁₂FN₂: 239.0985, found: 239.0990.

N-(4-Nitrophenyl)quinolin-2-amine 5l¹⁷

Yield 62% (164 mg); yellow solid; mp 202–203 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.80 (s, 1H), 8.28 (d, J = 8.8 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.83–7.76 (m, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.38–7.28 (m, 4H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 150.9, 149.3, 145.3, 140.9, 130.3, 129.6, 126.1, 123.0, 121.8, 118.1, 107.5; HRMS (ESI) m/z calcd for C₁₅H₁₂N₃O₂: 266.0930, found: 266.0936.

4-(6-Methoxyquinolin-2-yl)morpholine, 7a^16b

Yield 83% (203 mg); colourless crystalline solid; mp 129–130 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.87 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.30–7.22 (m, 1H), 6.99–6.95 (m, 2H), 3.90 (s, 3H), 3.88 (t, J = 6.0 Hz, 4H), 3.66 (t, J = 6.0 Hz, 4H); ¹³C NMR (101 MHz, CDCl₃) δ: 156.7, 155.3, 143.3, 136.6, 128.3, 123.8, 121.3, 109.7, 106.0, 66.9, 55.5, 45.9; HRMS (ESI) m/z calcd for C₁₄H₁₇N₂O₂: 245.1290, found: 245.1294.

N-Butyl-6-methoxyquinolin-2-amine, 7b

Yield 66% (152 mg); brown solid; mp 81–82 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.66 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 9.1 Hz, 1H), 7.12 (dd, J = 9.1 Hz, 2.9 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.56 (s, 1H), 3.78 (s, 3H), 3.35 (q, J = 8.0 Hz, 2H), 1.64–1.50 (m, 2H), 1.42–1.33 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 156.1, 154.7, 143.5, 136.4, 127.4, 123.6, 120.9, 111.2, 106.6, 55.5, 41.7, 32.0, 20.2, 13.9; HRMS (ESI) m/z calcd for C₁₄H₁₉N₂O: 231.1497, found: 231.1493.

N-Benzyl-6-methoxy-N-methylquinolin-2-amine, 7c

Yield 64% (178 mg); colourless crystalline solid; mp 93–95 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.81 (d, J = 9.1 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 7.40–7.21 (m, 6H), 6.98 (d, J = 2.8 Hz, 1H), 6.89 (d, J = 9.1 Hz, 1H), 4.93 (s, 2H), 3.90 (s, 3H), 3.23 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 156.3, 154.7, 143.7, 138.8, 136.5, 128.6, 127.9, 127.2, 127.0, 122.9, 121.1, 109.3, 106.2, 55.5, 53.4, 36.2; HRMS (ESI) m/z calcd for C₁₈H₁₉N₂O: 279.1497, found: 279.1494.

6-Methoxy-N-phenylquinolin-2-amine, 7d¹⁸

Yield 62% (155 mg); white powder; mp 145–146 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.86 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.60–7.52 (m, 2H), 7.42–7.33 (m, 2H), 7.30 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 7.13–7.06 (m, 1H), 7.01 (t, J = 5.8 Hz, 2H), 6.86 (s, 1H), 3.91 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 155.6, 153.0, 143.2, 140.6, 136.7, 129.2, 128.2, 124.7, 122.7, 121.4, 120.0, 112.0, 106.3, 55.5; HRMS (ESI) m/z calcd for C₁₆H₁₅N₂O: 251.1184, found: 251.1182.

6-Methoxy-N-(4-methoxyphenyl)quinolin-2-amine, 7e¹⁹

Yield 65% (182 mg); colourless crystalline solid; mp 146–147 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.82 (d, J = 8.9 Hz, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.42 (d, J = 8.9 Hz, 2H), 7.27 (dd, J = 9.1 Hz, 2.9 Hz, 1H), 7.00 (d, J = 2.8 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 3.84 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 156.1, 155.3, 154.1, 143.3, 136.7, 133.5, 127.9, 124.4, 123.5, 121.3, 114.6, 111.2, 106.4, 55.6, 55.6; HRMS (ESI) m/z calcd for C₁₇H₁₇N₂O₂: 281.1290, found: 281.1291.

6-Methoxy-N-(4-nitrophenyl)quinolin-2-amine, 7f

Yield 60% (183 mg); colourless crystalline solid; mp 218–219 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.50 (s, 1H), 8.58 (d, J = 5.0 Hz, 1H), 8.22 (d, J = 9.1 Hz, 2H), 7.92 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 2.6 Hz, 1H), 7.50–7.32 (m, 4H), 3.93 (s, 3H); ¹³C NMR (101 MHz, DMSO-d₆) δ: 157.5, 149.6, 148.6, 145.6, 143.9, 140.7, 131.5, 126.2, 122.8, 122.2, 117.8, 108.8, 101.6, 56.2; HRMS (ESI) m/z calcd for C₁₆H₁₄N₃O₃: 296.1035, found: 296.1038.

4-(Isoquinolin-1-yl)morpholine, 9a^16c

Yield 83% (177 mg); colourless crystalline solid; mp 67–68 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.02 (d, J = 5.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.47 (t, J = 7.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 5.7 Hz, 1H), 3.84 (t, J = 4.6 Hz, 4H), 3.28 (t, J = 4.4 Hz, 4H); ¹³C NMR (101 MHz, CDCl₃) δ: 161.1, 140.7, 138.1, 129.7, 127.2, 126.2, 125.3, 121.6, 116.2, 67.1, 51.9; HRMS (ESI) m/z calcd for C₁₃H₁₅N₂O: 215.1184, found: 215.1182.

N-Butylisoquinolin-1-amine, 9b^20a

Yield 77% (154 mg); viscous liquid; ¹H NMR (400 MHz, CDCl₃) δ: 8.03 (d, J = 5.9 Hz, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.55 (dd, J = 7.0 Hz, 0.9 Hz, 1H), 7.48–7.34 (m, 1H), 6.90 (d, J = 5.8 Hz, 1H), 5.34 (s, 1H), 3.60 (t, J = 7.2 Hz, 2H), 1.78–1.63 (m, 2H), 1.49–1.42 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 155.3, 141.4, 137.0, 129.6, 127.1, 125.8, 121.4, 118.2, 110.6, 41.7, 31.7, 20.4, 14.0; HRMS (ESI) m/z calcd for C₁₃H₁₇N₂: 201.1392, found: 201.1391.

N-Benzyl-N-methylisoquinolin-1-amine, 9c^20b

Yield 74% (184 mg); viscous liquid; ¹H NMR (400 MHz, CDCl₃) δ: 8.03 (t, J = 6.8 Hz, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.49–7.43 (m, 1H), 7.36 (d, J = 7.5 Hz, 2H), 7.33–7.24 (m, 3H), 7.19 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 5.7 Hz, 1H), 4.52 (s, 2H), 2.90 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 161.8, 140.6, 138.8, 138.4, 129.6, 128.6, 127.7, 127.1, 127.1, 125.9, 125.6, 121.6, 115.1, 59.3, 40.1; HRMS (ESI) m/z calcd for C₁₇H₁₇N₂: 249.1392, found: 249.1387.

N-Phenylisoquinolin-1-amine, 9d¹⁸

Yield 64% (141 mg); bone off-white solid, mp 111–112 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (d, J = 5.7 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.76–7.73 (m, 3H), 7.65 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.9 Hz, 2H), 7.16 (d, J = 5.7 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 152.5, 140.9, 140.6, 137.5, 130.0, 129.0, 127.4, 126.5, 122.8, 121.7, 120.6, 119.0, 113.5; HRMS (ESI) m/z calcd for C₁₅H₁₃N₂: 221.1079, found: 221.1074.

N-(4-Methoxyphenyl)isoquinolin-1-amine, 9e¹⁹

Yield 62% (155 mg); crystalline white solid; mp 129–130 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.08 (d, J = 5.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.65 (t, J = 7.3 Hz, 1H), 7.60–7.45 (m, 3H), 7.10 (d, J = 5.8 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 155.8, 153.0, 141.1, 137.5, 133.4, 129.8, 127.4, 126.3, 123.2, 121.5, 118.6, 114.3, 112.8, 55.6; HRMS (ESI) m/z calcd for C₁₆H₁₅N₂O: 251.1184, found: 251.1180.

N-(4-Nitrophenyl)isoquinolin-1-amine, 9f

Yield 60% (159 mg); yellow solid; mp 219–120 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.26 (d J = 9.2 Hz, 2H), 8.22 (d J = 5.6 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 9.2 Hz, 2H), 7.86 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.2 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.53 (s, 1H), 7.34 (d, J = 5.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 150.6, 146.7, 141.7, 140.5, 137.6, 130.4, 127.8, 127.3, 125.4, 121.1, 119.2, 118.0, 115.7; HRMS (ESI) m/z calcd for C₁₅H₁₂N₃O₂: 266.0930, found: 239.0936.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

AKY and SVP acknowledge financial support from the UGC-FRP Start up grant (no. F.4-5/2017-2018) (Cycle-IV) (BSR) under UGC Faculty Recharge Programme UGC Govt. Of India.

Notes and references

1. (a) T. Tomioka, T. Takahashi and T. Maejima, Org. Biomol. Chem., 2012, 10, 5113–5118; (b) M. Miller, J. Shi, Y. Zhu, M. Kustov, J.-B. Tian, A. Stevens, M. Wu, J. Xu, S. Long, P. Yang, A. V. Zholos, J. M. Salovich, C. D. Weaver, C. R. Hopkins, C. W. Lindsley, O. McManus, M. Li and M. X. Zhu, J. Biol. Chem., 2011, 286, 33436–33446.
2. (a) P. P. Jumade, S. J. Wadher, A. J. Chourasia, U. V. Kharabe, D. Mude and P. G. Yeole, Int. J. Chem. Sci., 2009, 7, 1518–1530; (b) S. Al-Khalil, A. Alkofahi, D. El-Eisawi and A. Al-Shibib, J. Nat. Prod., 1998, 61, 262–263; (c) R. Arienzo, D. E. Clark, S. Cramp, S. Daly, H. J. Dyke, P. Lockey, D. Norman, A. G. Roach, K. Stuttle, M. Tomlinson, M. Wong and S. P. Wren, Bioorg. Med. Chem. Lett., 2004, 14, 4099–4102.
3. (a) G. R. Proctor and A. L. Harvey, Curr. Med. Chem., 2000, 7, 295–302; (b) Y. Cheng, T. C. Judd, M. D. Bartberger, J. Brown, K. Chen, R. T. Fremeau Jr, D. Hickman, S. A. Hitchcock, B. Jordan, V. Li, P. Lopez, S. W. Louie, Y. Luo, K. Michelsen, T. Nixey, T. S. Powers, C. Rattan, E. A. Sickmier, D. J. St. Jean Jr, R. C. Wahl, P. H. Wen and S. Wood, J. Med. Chem., 2011, 54, 5836–5857.
4. L. Strekowski, J. L. Mokrosz, V. A. Honkan, A. Czarny, M. T. Cegla, R. L. Wydra, S. E. Patterson and R. F. Schinazi, J. Med. Chem., 1991, 34, 1739–1746 and references cited therein.
5. J. R. Pfister, J. Nat. Prod., 1988, 51, 969–970.
6. A. A. Alhaider, M. A. Abdelkader and E. J. Lien, J. Med. Chem., 1985, 28, 1394–1398.
7. S. F. Campbell, J. D. Hardstone and M. J. Palmer, J. Med. Chem., 1988, 31, 1031–1035.
8. (a) M. A. Solekhova and Yu. V. Kurbatov, Russ. J. Org. Chem., 2002, 38, 1192–1194; (b) G. Li, C. Jia and K. Sun, Org. Lett., 2013, 15, 5198–5201; (c) C. Zhu, M. Yi, D. Wei, X. Chen, Y. Wu and X. Cui, Org. Lett., 2014, 16, 1840–1843; (d) Z. Wang, M.-Y. Han, P. Li and L. Wang, Eur. J. Org. Chem., 2018, 5954–5960; (e) L.-Y. Xie, S. Peng, L.-L. Jiang, X. Peng, W. Xia, X. Yu, X.-X. Wang, Z. Caoc and W.-M. He, Org. Biomol. Chem., 2019, 17, 309–314; (f) L.-Y. Xie, S. Peng, L.-L. Jiang, X. Peng, W. Xia, X. Yu, X.-X. Wang, Z. Cao and W.-M. He, Org. Chem. Front., 2019, 6, 167–171.
9. (a) N. G. Luthy, F. W. Bergstrom and H. S. Mosher, J. Am. Chem. Soc., 1949, 71, 1109–1110; (b) J. Yin, B. Xiang, M. A. Huffman, C. E. Raab and I. W. Davies, J. Org. Chem., 2007, 72, 4554–4557; (c) A. E. Chichibabin and O. A. Seide, Russ. J. Phys. Chem., 1914, 46, 1216–1236.
10. Z. R. Wang, Comprehensive Organic Name Reactions and Reagents, John Wiley & Sons, Inc., Hoboken, N. J., 2009.
11. (a) C. K. McGill and A. Rappa, Adv. Heterocycl. Chem., 1988, 44, 1–79; (b) J. G. Rodriguez, C. de los Rios and A. Lafuente, Tetrahedron, 2005, 61, 9042–9051; (c) D. Cuperly, P. Gros and Y. Fort, J. Org. Chem., 2002, 67, 238–241; (d) J. Mathieu, P. Gros and Y. Fort, Chem. Commun., 2000, 951–952; (e) T. Imahori, M. Uchiyama, T. Sakamoto and Y. Kondo, Chem. Commun., 2001, 2450–2451.
12. (a) A. T. Londregan, S. Jennings and L. Wei, Org. Lett., 2010, 12, 5254–5257; (b) A. T. Londregan, S. Jennings and L. Wei, Org. Lett., 2011, 13, 1840–1843.
13. (a) B. W. Hansen and E. B. Pedersen, Liebigs Ann. Chem., 1981, 1485–1491; (b) J. Yin, B. Xiang, M. A. Huffman, C. E. Raab and I. W. Davies, J. Org. Chem., 2007, 72, 4554–4557.
14. (a) X. Chen, X. Li, Z. Qu, D. Ke, L. Qu, L. Duan, W. Mai, J. Yuan, J. Chen and Y. Zhao, Adv. Synth. Catal., 2014, 356, 1979–1985; (b) W.-Z. Bi, K. Sun, C. Qu, X.-L. Chen, L.-B. Qu, S.-H. Zhu, X. Li, H.-T. Wu, L.-K. Duan and Y.-F. Zhao, Pure Appl. Chem., 2019, 91, 33–41; (c) W.-Z. Bi, K. Sun, C. Qu, X.-L. Chen, L.-B. Qu, S.-H. Zhu, X. Li, H.-T. Wu, L.-K. Duan and Y.-F. Zhao, Org. Chem. Front., 2017, 4, 1595–1600.
15. D. I. Bugaenko, M. A. Yurovskaya and A. V. Karchava, J. Org. Chem., 2017, 82, 2136–2149.
16. (a) Z. Yan, Z. Shiwei, X. Guangxing, L. Min, T. Chunlei and F. Weizheng, Org. Biomol. Chem., 2019, 17, 309–314; (b) H. Zhao, X. Chen, H. Jiang and M. Zhang, Org. Chem. Front., 2018, 5, 539–543; (c) Z. Hua, L. Fang, S. Wu and L. Wang, Eur. J. Org. Chem., 2016, 4953–4956.
17. H.-K. Peng, C.-K. Lin, S.-Y. Yang, C.-K. Tseng, C.-C. Tzeng, J.-C. Lee and S.-C. Yang, Bioorg. Med. Chem. Lett., 2012, 1107–1110.
18. W.-Z. Bi, K. Sun, C. Qu, X.-L. Chen, L.-B. Qu, S.-H. Zhu, X. Li, H.-T. Wu, L.-K. Duana and Y.-F. Zhao, Org. Chem. Front., 2017, 4, 1595–1600.
19. A. K. Dhiman, D. Chandra, R. Kumar and U. Sharma, J. Org. Chem., 2019, 84, 6962–6969.
20. (a) X. Xie, T. Y. Zhang and Z. Zhang, J. Org. Chem., 2006, 71, 6522–6529; (b) A. Ilie, G. -D. Roiban and M. T. Reetz, ChemistrySelect, 2017, 2, 1392–1397.

---

Footnote

† Electronic supplementary information (ESI) available: For further information of spectra, see the Supporting Information. See DOI: 10.1039/c9ra10397j

---