Heterogeneous gold(III)-catalyzed tandem cyclization of 2-alkynylbenzamides with ammonium acetate toward 1-aminoisoquinolines

Abstract

Heterogeneous tandem cyclization of 2-alkynylbenzamides with ammonium acetate is achieved in acetonitrile at 85 °C using a magnetic nanoparticles-immobilized bipy-gold(III) complex and AgSbF₆ as catalysts to afford a variety of 1-aminoisoquinoline derivatives in moderate to high yields. This heterogeneous gold catalyst can be easily recovered from the reaction mixture by simply applying an external magnetic field and can be recycled at least seven times without any apparent loss of catalytic activity.

Keywords

1-aminoisoquinolines gold heterogeneous catalysis magnetic nanoparticles tandem reactions

Introduction

1-Aminoisoquinolines are a class of important N-heterocycles and exhibit a wide range of biological activities. For instance, they are inhibitors of thrombin, factor Xa, and rho kinase-1, and they demonstrate activity toward cancers, tumors, malaria, and Parkinson’s disease.^1–4 There is a high demand for efficient syntheses of 1-aminoisoquinoline derivatives for high-throughput drug screening due to their excellent biological profiles. The most common method for the preparation of 1-aminoisoquinolines involves the nucleophilic aromatic substitution reaction of 1-haloisoquinolines with amino compounds.^5–8 One main drawback of this method is that harsh reaction conditions are required such as the use of strong bases, high reaction temperatures, or high pressures for the preparation of either the target products or the starting materials. In recent years, several alternative approaches have been developed for the construction of 1-aminoisoquinolines. These methods include the domino electrophilic cyclization reactions of 2-alkynylbenzamides⁹ or 2-alkynylbenzaldoximes^10–12 and transition-metal-catalyzed annulations of benzamidine derivatives with internal alkynes using rhodium,^13,14 ruthenium,^15,16 or cobalt¹⁷ complexes as catalysts.

Over the past decades, homogeneous gold-catalyzed organic reactions have become highly efficient and powerful tools for the construction of valuable building blocks.^18–22 Recently, gold-catalyzed synthesis of N-heterocycles such as pyrroles,^23,24 indoles,^25–27 oxazoles,^28–30 and quinolines or isoquinolines^31,32 has attracted considerable attention due to its high efficiency and mild reaction conditions. Long et al. reported the synthesis of 1-aminoisoquinolines by gold(III)-mediated domino reactions from 2-alkynylbenzamides and ammonium acetate.³³ However, homogeneous gold catalysts are expensive, not recyclable, and difficult to recover from reaction mixtures, which restrict their applications in large-scale or multistep syntheses. Recycling of homogeneous metal catalysts represents one of the most important features of green synthetic methods. Immobilization of existing homogeneous catalysts on various solid supports appears to be a logical solution to this problem.³⁴ Furthermore, heterogeneous catalysis can minimize the waste generated from reaction work-up, thus developing green and sustainable chemical processes.³⁵ However, to our knowledge, no examples of the heterogeneous gold-catalyzed synthesis of isoquinolines have been reported until now.

To address the problems of catalyst recovery and recycling, magnetic nanoparticles-supported catalysts have proven to be advantageous because their magnetic separation is an attractive alternative to conventional filtration as it avoids loss of the catalyst and improves the reusability.^36–38 Recently, we described the preparation of a magnetic nanoparticle-supported bipy-gold(III) complex (Fe₃O₄@SiO₂-bipy-AuCl₃) and its application to the oxidative α-cyanation of tertiary amines.³⁹ To further expand the application range of this heterogeneous gold catalyst, herein we report a heterogeneous gold(III)-catalyzed tandem cyclization reaction of 2-alkynylbenzamides with ammonium acetate by using Fe₃O₄@SiO₂-bipy-AuCl₃ and AgSbF₆ as the catalysts leading to 1-aminoisoquinolines in moderate to good yields. The heterogeneous gold(III) catalyst could be easily recovered from the reaction mixture by simply applying an external magnet, and its catalytic activity remains almost unchanged even after recycling seven times.

Results and discussion

The magnetic nanoparticles-immobilized bipy-gold(III) complex (Fe₃O₄@SiO₂-bipy-AuCl₃) was synthesized by a simple two-step procedure, as presented in Scheme 1.³⁹ First, the condensation reaction of silica-coated Fe₃O₄ (Fe₃O₄@SiO₂) with 4,4′-bis[3-(triethoxysilyl)propylaminomethyl]-2,2′-bipyridine (BTESBPY) in toluene at 110 °C for 24 h provided the bipyridine-modified magnetic nanoparticles (Fe₃O₄@SiO₂-bipy). The Fe₃O₄@SiO₂-bipy was then reacted with AuCl₃ in methanol at reflux for 24 h to afford the magnetic nanoparticles-immobilized bipy-gold(III) complex (Fe₃O₄@SiO₂-bipy-AuCl₃) as brown nanoparticles; the gold content was found to be 0.62 mmol g⁻¹ based on inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis.

Scheme 1.

Preparation of the Fe₃O₄@SiO₂-bipy-AuCl₃ complex.

The magnetic nanoparticles-immobilized bipy-gold(III) complex (Fe₃O₄@SiO2-bipy-AuCl₃) was then used as the catalyst for the tandem cyclization reactions of 2-alkynylbenzamides with ammonium acetate. In our initial screens, the cyclization of 2-(phenylethynyl)benzamide (1a) with ammonium acetate was chosen as a model reaction to optimize the reaction conditions and the results are summarized in Table 1. When AuCl₃ or AgSbF₆ alone was used as the catalyst, the reaction in MeCN at 85 °C gave the desired product 2a in 53%–62% yields (entries 1 and 2). The reaction did not occur at all in the absence of any catalyst (entry 3). The Fe₃O₄@SiO₂-bipy-AuCl₃ complex exhibited similar activity to AuCl₃ and afforded the desired product 2a in 61% yield (entry 4). However, a combination of Fe₃O₄@SiO₂-bipy-AuCl₃ (6 mol%) and AgSbF₆ (6 mol%) proved to be more efficient than Fe₃O₄@SiO₂-bipy-AuCl₃ or AgSbF₆ alone and afforded a 88% yield of product 2a (entry 5). Reducing the reaction temperature to 60 °C resulted in a significant decrease in the yield (entry 6). We next examined the effect of solvents on the model reaction. Replacement of MeCN with other solvents such as 1,2-dichloroethane (DCE), 1,2-dimethoxyethane (DME), and tetrahydrofuran (THF) furnished 2a in low yields of 13%–36% (entries 7–9). Lowering the amount of NH₄OAc to 2 equiv. gave a lower yield of 2a (entry 10). When the amount of the gold catalyst was decreased to 3 mol%, a moderate yield of 42% was obtained (entry 11). Thus, the optimized reaction conditions for this transformation are the use of Fe₃O₄@SiO₂-bipy-AuCl₃ (6 mol%) and AgSbF₆ (6 mol%) as catalysts in MeCN as the solvent at 85 °C under Ar for 24 h (entry 5).

Table 1.

Optimization of the reaction conditions.^a


Entry	Catalyst (mol%)	Solvent	Temperature (°C)	Yield (%)^b
1	AuCl₃ (6)	MeCN	85	62
2	AgSbF₆ (6)	MeCN	85	53
3	–	MeCN	85	0
4	Fe₃O₄@SiO₂-bipy-AuCl₃ (6)	MeCN	85	61
5	Fe₃O₄@SiO₂-bipy-AuCl₃ (6)/AgSbF₆ (6)	MeCN	85	88
6	Fe₃O₄@SiO₂-bipy-AuCl₃ (6)/AgSbF₆ (6)	MeCN	60	37
7	Fe₃O₄@SiO₂-bipy-AuCl₃ (6)/AgSbF₆ (6)	DCE	85	13
8	Fe₃O₄@SiO₂-bipy-AuCl₃ (6)/AgSbF₆ (6)	DME	85	36
9	Fe₃O₄@SiO₂-bipy-AuCl₃ (6)/AgSbF₆ (6)	THF	85	29
10^c	Fe₃O₄@SiO₂-bipy-AuCl₃ (6)/AgSbF₆ (6)	MeCN	85	81
11	Fe₃O₄@SiO₂-bipy-AuCl₃ (3)/AgSbF₆ (3)	MeCN	85	42

DCE: 1,2-dichloroethane; DME: 1,2-dimethoxyethane; THF: tetrahydrofuran.

All reactions were performed using 1a (0.3 mmol), NH₄OAc (0.9 mmol), and solvent (3 mL) under Ar for 24 h.

Isolated yield.

Two equivalents of NH₄OAc were used.

Having optimized the reaction conditions, we next examined the scope of this heterogeneous gold(III)-catalyzed cyclization reaction using a variety of 2-alkynylbenzamides as the substrates and the results are summarized in Table 2. The cyclization reactions of 2-alkynylbenzamides 1a–e, bearing various aryl groups at the distal position of the alkyne triple bond, with ammonium acetate proceeded smoothly under the optimized conditions to afford the corresponding 1-aminoisoquinolines 2a–e in 70%–89% yields. 2-Alkynylbenzamide 1e bearing an electron-deficient aryl group showed a comparatively lower reactivity than 2-alkynylbenzamides 1a–d bearing electron-neutral or electron-rich aryl groups. When a bulky naphthyl group was introduced at the same position of the alkyne triple bond, a slower reaction was observed and the expected product 2f was obtained in only 50% yield. Notably, 2-alkynylbenzamides 1g, h bearing heteroaryl 3-pyridyl and 3-thienyl groups at the distal position of the alkyne triple bond also proved to be suitable substrates and afforded the desired products 2g, h in good yields. Besides, 2-alkynylbenzamides 1i–k bearing an alkyl group at the distal position of the alkyne triple bond were compatible with the standard conditions and delivered the corresponding 1-aminoisoquinolines 2i–k in 72%–80% yields. Interestingly, a sterically hindered tert-butyl group and an alkenyl moiety were well accommodated at the distal position of the alkyne triple bond and the desired products 2l and 2m were produced in good yields. Subsequently, a range of 4- or 5-substituted 2-alkynylbenzamides having methyl, methoxy, and fluoro groups were then subjected to these reaction conditions and all were found to be compatible. For example, 5-methyl-substituted 2-alkynylbenzamides 1n–p and 4-methyl-substituted 2-alkynylbenzamides 1q–s underwent the intermolecular cyclization effectively to furnish the corresponding 1-aminoisoquinolines 2n–s in good yields. The reaction of 5-methoxy-substituted 2-alkynylbenzamides 1t–v (bearing a strong electron-donating group) gave the desired products 2t–v in 63%–70% yields. It is noteworthy that 5- or 4-fluoro-substituted 2-alkynylbenzamides 1w–y were also good substrates and afforded the expected products 2w–y in 69%–72% yields.

Table 2.

Heterogeneous Au(III)-catalyzed synthesis of 1-aminoisoquinolines.^a,^b

Reaction conditions: 1 (0.3 mmol), NH₄OAc (0.9 mmol), Fe₃O₄@SiO₂-bipy-AuCl₃ (6 mol%), AgSbF₆ (6 mol%), MeCN (3 mL), 85 ºC, Ar, 24 h.

Isolated yield.

To confirm the heterogeneous nature of this reaction, we focused on the reaction of 2-(phenylethynyl)benzamide (1a) with ammonium acetate. After the reaction had been conducted for 10 h, the catalyst was separated magnetically from the reaction mixture at 85 °C and the catalyst-free solution was transferred into another reaction tube and allowed to react further under identical conditions for 14 h. It was found that no increase in the conversion of 2-(phenylethynyl)benzamide (1a) was observed and no gold species could be detected in the solution based on ICP-AES analysis, which rules out the contribution to observed catalysis from a soluble gold species and confirms the heterogeneous nature of this cyclization reaction.

A possible mechanism for this heterogeneous gold(III)-catalyzed synthesis of 1-aminoisoquinolines 2 from 2-alkynylbenzamides 1 and NH₄OAc is illustrated in Scheme 2.³³ First, coordination of the Fe₃O₄@SiO₂-bipy-AuCl₃ complex to alkyne moiety in 2-alkynylbenzamide 1 produces an Fe₃O₄@SiO₂-bound gold(III)–alkyne–π complex intermediate A. The latter undergoes an intramolecular 6-endo-dig cyclization to generate an Fe₃O₄@SiO₂-bound vinylgold cation intermediate B, which is converted to the isobenzopyrylium salt intermediate C after protodeauration. The nucleophilic addition of ammonia to intermediate C provides the isochromene intermediate D. After deprotonation of the ammonium nitrogen atom and protonation of the oxygen atom in intermediate D, isochromenylium intermediate E forms. The C‒O bond in intermediate E dissociates to produce enol intermediate F, which subsequently converts to intermediate G after deprotonation and tautomerizes to ketone intermediate H. Intramolecular nucleophilic addition of the amino group to the ketone carbonyl group delivers intermediate I. Finally, intermediate I undergoes dehydration and subsequent aromatization to afford the desired target product 2.

Scheme 2.

Proposed catalytic cycle.

For the practical application of a supported metal catalyst, its ease of separation from the product and the ability to recycle it are important factors that have to be examined. We next studied the recycling of the Fe₃O₄@SiO₂-bipy-AuCl₃ catalyst in the reaction of 2-(phenylethynyl)benzamide (1a) with ammonium acetate. Upon completion of the reaction, the reaction mixture was cooled to room temperature and diluted with EtOAc. More than 99% of the gold catalyst could be conveniently recovered by simply fixing a magnet to the outside of the reaction tube. The recovered gold catalyst was washed with MeCN, air-dried, and used directly in the next cycle. The recovered gold catalyst was employed for seven consecutive cycles under identical conditions and the results are summarized in Table 3. As shown in Table 3, the isolated yield of the product 2a in eight consecutive cycles was found to be over 83%, which indicated that this heterogeneous gold(III) catalyst can be recycled up to seven times with only a slight decrease in the catalytic activity. It is noteworthy that the cyclization reaction catalyzed by the recovered gold catalyst did not require the addition of AgSbF₆ because the Fe₃O₄@SiO₂-bipy-AuCl₃ complex had been transformed into the [Fe₃O₄@SiO₂-bipy-AuCl₂]SbF₆ complex after the first cycle. The good reusability of the Fe₃O₄@SiO₂-bipy-AuCl₃ catalyst might arise from the chelating action of the bidentate bipyridine ligand on the gold center.

Table 3.

Recycling of the Fe₃O₄@SiO₂-bipy-AuCl₃ complex.^a


Entry	Catalyst	Time (h)	Yield (%)^b	Entry	Catalyst	Time (h)	Yield (%)^b
1	Fresh	24	88	5	Recycle 4	24	85
2	Recycle 1	24	87	6	Recycle 5	26	84
3	Recycle 2	24	86	7	Recycle 6	28	84
4	Recycle 3	24	87	8	Recycle 7	30	83

Reaction conditions: 1a (0.3 mmol), NH₄OAc (0.9 mmol), Fe₃O₄@SiO₂-bipy-AuCl₃ (6 mol%), AgSbF₆ (6 mol%), MeCN (3 mL), 85 °C, Ar, 24 h.

Isolated yield.

In conclusion, we have developed a novel, efficient, and practical method for the construction of 1-aminoisoquinolines through the gold(III)-catalyzed cyclization reaction of 2-alkynylbenzamides with ammonium acetate using a magnetic nanoparticles-supported gold(III)-bipy complex [Fe₃O₄@SiO₂-bipy-AuCl₃] and AgSbF₆ as catalysts. The reactions produced a variety of 1-aminoisoquinoline derivatives in moderate to high yields under mild conditions. Importantly, this supported gold catalyst can be easily recovered by simply fixing an external magnet near to the reaction tube and can be recycled up to eight times without any apparent loss of activity. The Fe₃O₄@SiO₂-bipy-AuCl₃ catalyst not only solves the basic problems of catalyst separation and recovery but also avoids the use of AgSbF₆ in the recycling process. This makes our protocol facile, economical, and environmentally benign.

Experimental

All reagents were used as received without further purification unless otherwise indicated. 2-Alkynylbenzamides 1a–y were prepared according to a literature method.³³ The Fe₃O₄@SiO₂-bipy-AuCl₃ complex was prepared according to our previous procedure;³⁹ the gold content was found to be 0.62 mmol g⁻¹. All reactions were carried out under Ar in oven-dried glassware with magnetic stirring. ¹H NMR spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer with TMS as an internal standard using CDCl₃ as the solvent. ¹³C NMR spectra were recorded on a Bruker Avance 400 (100 MHz) spectrometer using CDCl₃ as the solvent. Microanalyses were measured using a Yanaco MT-3 CHN microelemental analyzer. The gold content was determined with an inductively coupled plasma atom emission Atomscan16 (ICP-AES, TJA Corporation). HRMS spectra were recorded on an AGILENT 6520 Accurate-Mass QTOF LC/MS spectrometer with the electrospray mode (ES).

General procedure for the heterogeneous gold-catalyzed synthesis of 1-aminoiso-quinolines

A 20-mL Schlenk tube was charged with Fe₃O₄@SiO₂-bipy-AuCl₃ (29 mg, 0.018 mmol), AgSbF₆ (6.2 mg, 0.018 mmol), NH₄OAc (69 mg, 0.9 mmol), 2-alkynylbenzamide 1 (0.3 mmol), and aceonitrile (3 mL) under Ar. The reaction mixture was stirred at 85 °C for 24 h. After being cooled to room temperature, the resulting mixture was diluted with ethyl acetate (10 mL) and the supported catalyst was magnetically separated. The reaction solution was washed with brine (10 mL) and the aqueous phase was extracted with ethyl acetate (2 × 10 mL). The combined organic layers were dried over anhydrous MgSO₄, evaporated under reduced pressure, and the residue purified by column chromatography on silica gel (eluting with hexane/ethyl acetate = 5:1) to give the desired product 2. The recovered catalyst was washed with MeOH (2 × 2 mL), air-dried, and used directly for the next run.

3-Phenylisoquinolin-1-amine (2a):³³ Light yellow solid. m.p. 91 °C–93 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.05 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.64–7.58 (m, 1H), 7.50–7.41 (m, 4H), 7.39–7.36 (m, 1H), 5.36 (br s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 148.5, 139.0, 138.1, 130.7, 128.6, 128.4, 127.5, 126.9, 126.2, 122.9, 117.0, 108.9.

3-(p-Tolyl)isoquinolin-1-amine (2b):⁴⁰ White solid. m.p. 105 °C–107 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.62–7.57 (m, 1H), 7.46 (s, 1H), 7.45–17.4 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 5.26 (br s, 2H), 2.40 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 149.6, 138.3, 138.1, 137.1, 130.2, 129.3, 127.5, 126.7, 125.8, 122.6, 116.9, 108.5, 21.3.

3-(4-Methoxyphenyl)isoquinolin-1-amine (2c):³³ White solid. m.p. 137 °C–139 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.48–7.41 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 5.22 (br s, 2H), 3.87 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.9, 155.8, 149.3, 138.4, 132.5, 130.2, 128.0, 127.4, 125.6, 122.6, 116.7, 114.0, 107.9, 55.4.

3-(m-Tolyl)isoquinolin-1-amine (2d): Light yellow solid. m.p. 84 °C–86 °C. IR (KBr, cm⁻¹): ν = 3345, 3207. ¹H NMR (400 MHz, CDCl₃): δ = 7.88 (s, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.80–7.71 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (s, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 5.29 (br s, 2H), 2.44 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 149.8, 139.9, 138.3, 138.2, 130.3, 129.0, 128.5, 127.6, 127.5, 125.9, 124.0, 122.6, 117.0, 109.0, 21.6. HRMS (ESI): m/z [M]⁺ calcd for C₁₆H₁₄N₂⁺: 234.1157; found: 234.1164.

3-(4-Chlorophenyl)isoquinolin-1-amine (2e):⁴⁰ Light yellow solid. m.p. 128 °C–130 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (dd, J = 6.4, 2.0 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.65–7.60 (m, 1H), 7.51–7.48 (m, 1H), 7.47 (s, 1H), 7.43 (dd, J = 6.8, 2.0 Hz, 2H), 5.23 (br s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 148.3, 138.3, 138.2, 134.2, 130.4, 128.7, 128.1, 127.6, 126.2, 122.6, 117.1, 108.8.

3-(Naphthalen-1-yl)isoquinolin-1-amine (2f):³³ Light yellow solid. m.p. 168 °C–170 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.17 (d, J = 8.4 Hz, 1H), 7.92–7.85 (m, 2H), 7.80 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.68–7.62 (m, 2H), 7.57–7.42 (m, 4H), 7.29 (s, 1H), 5.34 (br s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.8, 151.2, 139.1, 138.0, 134.0, 131.6, 130.3, 128.4, 128.2, 127.4, 127.2, 126.3, 126.1, 126.0, 125.7, 125.4, 122.6, 116.7, 113.3.

3-(Pyridin-3-yl)isoquinolin-1-amine (2g):⁴⁰ Light brown solid. m.p. 123 °C–125 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.27 (d, J = 1.6 Hz, 1H), 8.60 (dd, J = 4.8, 1.6 Hz, 1H), 8.38–8.34 (m, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.66–7.62 (m, 1H), 7.53–97.4 (m, 2H), 7.40–7.36 (m, 1H), 5.28 (br s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.2, 149.1, 148.3, 146.8, 138.0, 135.4, 134.2, 130.6, 127.7, 126.5, 123.5, 122.7, 117.2, 109.3.

3-(Thiophen-3-yl)isoquinolin-1-amine (2h):³³ Light yellow solid. m.p. 109 °C–111 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.41–7.36 (m, 2H), 5.24 (br s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 145.7, 142.6, 138.3, 130.3, 127.4, 126.1, 126.0, 125.7, 122.8, 122.7, 117.0, 108.4.

3-Butylisoquinolin-1-amine (2i): Light yellow solid. m.p. 104 °C–106 °C. IR (KBr, cm⁻¹): ν = 3380, 3215. ¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.59–7.53 (m, 1H), 7.43–7.37 (m, 1H), 6.88 (s, 1H), 5.20 (br s, 2H), 2.72 (t, J = 7.8 Hz, 2H), 1.78–1.69 (m, 2H), 1.46–71.3 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.7, 154.1, 138.2, 130.0, 126.7, 125.1, 122.5, 116.2, 109.9, 37.8, 31.9, 22.6, 14.1. HRMS (ESI): m/z [M]⁺ calcd for C₁₃H₁₆N₂⁺: 200.1313; found: 200.1309.

3-(3-Phenylpropyl)isoquinolin-1-amine (2j): Light brown solid. m.p. 89 °C–91 °C. IR (KBr, cm⁻¹): ν = 3367, 3198. ¹H NMR (400 MHz, CDCl₃): δ = 7.75 (d, J = 7.2 Hz, 1H), 7.64–7.53 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.29–7.15 (m, 5H), 6.85 (s, 1H), 5.45 (br s, 2H), 2.79–2.65 (m, 4H), 2.13–2.05 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.8, 153.0, 142.4, 138.1, 130.2, 128.5, 128.3, 126.7, 125.7, 125.3, 122.6, 116.3, 109.9, 37.3, 35.6, 31.2. HRMS (ESI): m/z [M]⁺calcd for C₁₈H₁₈N₂⁺: 262.1470; found: 262.1471.

4-(1-Aminoisoquinolin-3-yl)butanenitrile (2k):³³ Light yellow solid. m.p. 106 °C–108 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.78 (d, J = 8.4 Hz, 1H), 7.67–7.57 (m, 2H), 7.46 (d, J = 7.6 Hz, 1H), 6.90 (s, 1H), 5.30 (br s, 2H), 2.85 (t, J = 7.0 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 2.18–2.10 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.0, 150.8, 138.0, 130.4, 126.8, 125.7, 122.6, 119.7, 116.5, 110.7, 36.1, 25.0, 16.5.

3-(tert-Butyl)isoquinolin-1-amine (2l):³³ Light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.73 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57–27.5 (m, 1H), 7.41–7.36 (m, 1H), 7.01 (s, 1H), 5.15 (br s, 2H), 1.38 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.3, 155.1, 138.2, 129.8, 127.2, 125.3, 122.4, 116.2, 106.3, 36.7, 30.0.

3-(Cyclohex-1-en-1-yl)isoquinolin-1-amine (2m):³³ Light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.74 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.59–7.53 (m, 1H), 7.43–7.37 (m, 1H), 7.04 (s, 1H), 6.96–6.90 (m, 1H), 5.09 (br s, 2H), 2.54–2.49 (m, 2H), 2.34–2.22 (m, 2H), 1.85–1.78 (m, 2H), 1.73–1.64 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.1, 150.5, 138.2, 135.6, 130.0, 127.6, 127.4, 125.4, 122.6, 117.1, 107.0, 26.0, 25.9, 23.0, 22.3.

7-Methyl-3-phenylisoquinolin-1-amine (2n):³³ Light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.99 (d, J = 7.2 Hz, 2H), 7.67–7.61 (m, 2H), 7.49–7.41 (m, 3H), 7.40–7.35 (m, 2H), 5.82 (br s, 2H), 2.51 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.7, 147.1, 138.8, 136.3, 136.2, 133.0, 128.6, 128.3, 127.4, 126.9, 122.2, 117.2, 108.8, 21.8.

3-(4-Methoxyphenyl)-7-methylisoquinolin-1-amine (2o):³³ Light green solid. m.p. 168 °C–170 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 6.98 (d, J = 8.8 Hz, 2H), 5.26 (br s, 2H), 3.85 (s, 3H), 2.50 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.5, 155.3, 148.2, 136.5, 135.4, 132.4, 132.3, 127.9, 127.3, 121.8, 116.8, 114.0, 107.7, 55.3, 21.8.

3-Butyl-7-methylisoquinolin-1-amine (2p): Light yellow solid. m.p. 76 °C–78 °C. IR (KBr, cm⁻¹): ν = 3325, 3184. ¹H NMR (400 MHz, CDCl₃): δ = 7.55–7.49 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 5.18 (br s, 2H), 2.70 (t, J = 7.8 Hz, 2H), 2.47 (s, 3H), 1.75–1.68 (m, 2H), 1.44–1.35 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.2, 153.0, 136.3, 134.8, 132.1, 126.5, 121.7, 116.3, 109.7, 37.6, 31.8, 22.6, 21.7, 14.0. HRMS (ESI): m/z [M]⁺ calcd for C₁₄H₁₈N₂⁺: 214.1470; found: 214.1476.

6-Methyl-3-phenylisoquinolin-1-amine (2q): Reddish brown solid. m.p. 58 °C–60 °C. IR (KBr, cm⁻¹): ν = 3318, 3176. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 7.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 1H), 7.40–7.31 (m, 3H), 7.30–7.23 (m, 2H), 7.12 (d, J = 8.4 Hz, 1H), 5.17 (br s, 2H), 2.37 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.9, 149.8, 140.4, 140.2, 138.6, 128.5, 128.1, 127.9, 126.9, 126.7, 122.5, 115.3, 108.6, 21.7. HRMS (ESI): m/z [M]⁺ calcd for C₁₆H₁₄N₂⁺: 234.1157; found: 234.1148.

3-(4-Fluorophenyl)-6-methylisoquinolin-1-amine (2r): Reddish brown oil. IR (film, cm⁻¹): ν = 3376, 3197. ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (dd, J = 7.6, 5.6 Hz, 2H), 7.70 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 8.8 Hz, 2H), 5.29 (br s, 2H), 2.51 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 163.1 (d, ¹J_C-F = 245.7 Hz), 155.8, 148.4, 140.7, 138.6, 135.9 (d, ⁴J_C-F = 2.8 Hz), 130.8, 128.5 (d, ³J_C-F = 8.0 Hz), 128.1, 126.7, 122.5, 115.3 (d, ²J_C-F = 21.4 Hz), 108.2, 21.7. HRMS (ESI): m/z [M]⁺ calcd for C₁₆H₁₃FN₂⁺: 252.1063; found: 252.1058.

3-(tert-Butyl)-6-methylisoquinolin-1-amine (2s): Light yellow solid. m.p. 93 °C–95 °C. IR (KBr, cm⁻¹): ν = 3381, 3219. ¹H NMR (400 MHz, CDCl₃): δ = 7.65 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.24 (dd, J = 8.4, 1.2 Hz, 1H), 6.93 (s, 1H), 5.11 (br s, 2H), 2.48 (s, 3H), 1.37 (s, 9H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.9, 152.6, 138.4, 137.2, 127.4, 126.4, 122.3, 114.4, 106.0, 36.6, 30.0, 21.8. HRMS (ESI): m/z [M]⁺ calcd for C₁₄H₁₈N₂⁺: 214.1470; found: 214.1468.

7-Methoxy-3-phenylisoquinolin-1-amine (2t):³³ Light brown solid. m.p. 126 °C–128 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.05–8.02 (m, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.49–7.42 (m, 3H), 7.39–7.33 (m, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 5.14 (br s, 2H), 3.92 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.9, 155.0, 147.5, 139.9, 133.4, 129.2, 128.6, 127.9, 126.6, 122.3, 117.8, 109.0, 101.7, 55.5.

3-(4-Chlorophenyl)-7-methoxyisoquinolin-1-amine (2u): Light brown solid. m.p. 137 °C–139 °C. IR (KBr, cm⁻¹): ν = 3375, 3206. ¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 9.2 Hz, 1H), 7.43–7.39 (m, 3H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 5.27 (br s, 2H), 3.94 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.0, 154.0, 145.0, 137.2, 132.8, 132.2, 128.2, 127.6, 126.8, 121.4, 116.9, 107.9, 100.7, 54.5. HRMS (ESI): m/z [M]⁺ calcd for C₁₆H₁₃ClN₂O⁺: 284.0716; found: 284.0710.

3-Butyl-7-methoxyisoquinolin-1-amine (2v): Reddish brown oil. IR (film, cm⁻¹): ν = 3371, 3202. ¹H NMR (400 MHz, CDCl₃): δ = 7.57 (d, J = 9.2 Hz, 1H), 7.27–7.23 (m, 1H), 7.01 (d, J = 2.0 Hz, 1H), 6.86 (s, 1H), 5.02 (br s, 2H), 3.91 (s, 3H), 2.70 (t, J = 7.8 Hz, 2H), 1.75–1.69 (m, 2H), 1.44–1.38 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.2, 154.7, 151.8, 133.3, 128.3, 122.1, 116.8, 110.0, 101.5, 55.5, 37.6, 32.0, 22.6, 14.1. HRMS (ESI): m/z [M]⁺ calcd for C₁₄H₁₈N₂O⁺: 230.1419; found: 230.1417.

7-Fluoro-3-phenylisoquinolin-1-amine (2w):³³ Light yellow solid. m.p. 113 °C–115 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.06–8.01 (m, 2H), 7.77 (dd, J = 8.4, 5.6 Hz, 1H), 7.50–7.44 (m, 3H), 7.43–7.40 (m, 2H), 7.39–7.36 (m, 1H), 5.16 (s, 2H). ¹³C NMR (100 MHz, CDCl₃): δ = 160.4 (d, ¹J_C-F = 245.8 Hz), 155.4 (d, ⁴J_C-F = 4.9 Hz), 149.1 (d, ⁴J_C-F = 2.7 Hz), 139.6, 135.2, 130.0 (d, ³J_C-F = 8.2 Hz), 128.7, 128.3, 126.8, 120.4 (d, ²J_C-F = 24.4 Hz), 117.4 (d, ³J_C-F = 7.4 Hz), 108.6, 106.9 (d, ²J_C-F = 21.4 Hz).

3-Butyl-7-fluoroisoquinolin-1-amine (2x): Brown oil. IR (film, cm⁻¹): ν = 3377, 3195. ¹H NMR (400 MHz, CDCl₃): δ = 7.64 (dd, J = 8.8, 5.6 Hz, 1H), 7.45–7.41 (m, 1H), 7.39–7.35 (m, 1H), 6.88 (s, 1H), 5.12 (br s, 2H), 2.71 (t, J = 7.8 Hz, 2H), 1.76–1.66 (m, 2H), 1.45–1.36 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.9 (d, ¹J_C-F = 244.5 Hz), 155.2, 153.2 (d, ⁴J_C-F = 2.6 Hz), 134.1, 129.1 (d, ³J_C-F = 8.1 Hz), 120.2 (d, ²J_C-F = 24.6 Hz), 116.5 (d, ³J_C-F = 7.4 Hz), 109.6, 106.7 (d, ²J_C-F = 21.4 Hz), 37.5, 31.8, 22.6, 14.1. HRMS (ESI): m/z [M]⁺ calcd for C₁₃H₁₅FN₂⁺: 218.1219; found: 218.1230.

6-Fluoro-3-(4-methoxyphenyl)isoquinolin-1-amine (2y): Reddish brown oil. IR (film, cm⁻¹): ν = 3245, 3116. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (d, J = 8.0 Hz, 2H), 7.79–7.74 (m, 1H), 7.33–7.25 (m, 2H), 7.13 (t, J = 8.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 2H), 5.29 (br, 2H), 3.85 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ = 163.7 (d, ¹J_C-F = 249.6 Hz), 160.3, 155.8, 149.9, 140.3 (d, ³J_C-F = 10.2 Hz), 131.5, 128.9, 128.2, 125.8 (d, ³J_C-F = 9.8 Hz), 115.4 (d, ²J_C-F = 25.0 Hz), 114.1, 110.8 (d, ²J_C-F = 20.7 Hz), 107.4 (d, ⁴J_C-F = 4.4 Hz), 55.4. HRMS (ESI): m/z [M]⁺ calcd for C₁₆H₁₃FN₂O⁺: 268.1012; found: 268.1015.

Supplemental Material

Supporting_Information_for – Supplemental material for Heterogeneous gold(III)-catalyzed tandem cyclization of 2-alkynylbenzamides with ammonium acetate toward 1-aminoisoquinolines

Supplemental material, Supporting_Information_for for Heterogeneous gold(III)-catalyzed tandem cyclization of 2-alkynylbenzamides with ammonium acetate toward 1-aminoisoquinolines by Weisen Yang, Yingying Du, Feiyan Yi and Mingzhong Cai in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We thank the National Natural Science Foundation of China (No. 21462021) and the Natural Science Foundation of Jiangxi Province of China (No. 20161BAB203086) for financial support.

ORCID iD

Mingzhong Cai

Supplemental material

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