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Article

Isoquinolone Synthesis via Zn(OTf)2-Catalyzed Aerobic Cyclocondensation of 2-(1-Alkynyl)-benzaldehydes with Arylamines

by
Dost Muhammad Khan
and
Ruimao Hua
*
Department of Chemistry, Tsinghua University, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education, Beijing 100084, China
*
Author to whom correspondence should be addressed.
Catalysts 2020, 10(6), 683; https://doi.org/10.3390/catal10060683
Submission received: 8 June 2020 / Revised: 15 June 2020 / Accepted: 16 June 2020 / Published: 17 June 2020
(This article belongs to the Special Issue Catalysts for the Synthesis of Heterocyclic Compounds)
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Abstract

:
A zinc(II) triflate-catalyzed cyclocondensation of ortho-alkynylbenzaldehydes with arylamines in the presence of base under an oxygen atmosphere affording isoquinolones in good to high yields has been developed. The advantages of the present catalyst system include the use of an air-stable and cheap commercially available Lewis acid as the catalyst, high atom utilization and easily available starting materials.

Graphical Abstract

1. Introduction

Alkyne annulation is an important and efficient method for the synthesis of various heterocyclic compounds with high atom utilization [1,2,3,4,5,6,7,8,9,10]. Isoquinolones are one of the interesting and important nitrogen-heterocyclic compounds with versatile biological and physiological activities [11,12], and over the past decades, transition-metal-catalyzed isoquinolone formation through intermolecular annulation with the use of alkyne as one of the reaction partners has been well developed [13,14,15,16,17,18,19,20,21,22,23,24,25,26]. Among the different protocols for achieving this goal, the synthetic strategies starting from 2-(1-alkynyl)benzaldehydes are the most interesting due to their high atom utilization [15,21] (Scheme 1). Although the readily available 2-(1-alkynyl)benzaldehydes have been well-applied in the synthesis of benzo-fused six-membered heterocycles [27,28,29,30,31,32,33] and carbocycles [34,35,36,37,38,39], their applications for isoquinolone synthesis are very rare. As shown in Scheme 1, only two procedures have been reported to approach isoquinolones from the direct intermolecular cyclocondensation of 2-(1-alkynyl)-benzaldehydes with primary amines. One is the aerobic cyclocondensation of 2-(1-alkynyl)benz-aldehydes with benzyl amines and primary aliphatic amines in the presence of an excess amount of CuBr·SMe2 to afford 4-bromoisoquinolin-1(2H)-ones, and no reaction example was given with the use of arylamines under the reaction conditions (Scheme 1, eq. 1) [15]. The other procedure focuses on the Cu(OAc)2-catalyzed construction of isoquinolones by the reaction of H2O with 2-(1-alkynyl)benzaldimines, giving one example from the direct cyclocondensation of 2-(1-phenylethynyl)benzaldehyde with aniline to produce 2,3-diphenylisoquinolin-1(2H)-one in 63% yield (Scheme 1, eq. 2) [21].
Recently, we have been interested in the applications of 2-(1-alkynyl)benzaldehydes in the synthesis of benzo-fused cyclic compounds [28,33,39], air-stable Lewis acids as catalysts in organic transformation [40,41,42,43,44], and the development of synthetic methods for the formation of nitrogen-heterocyclic compounds via alkyne annulations [45,46,47,48,49,50,51,52,53]. Therefore, in continuation of our interests in the application of 2-(1-alkynyl)benzaldehydes, we herein describe a simple and efficient method for the construction of isoquinolone from the cyclocondensation of 2-(1-alkynyl)benzaldehydes with arylamines in the presence of a catalytic amount of Zn(OTf)2 (Scheme 1, eq. 3).

2. Results and Discussion

The optimizing reaction conditions were performed by the reaction of 2-(1-phenylethynyl)benzaldehyde (1a) with 1.2 equivalents of aniline (2a) as the substrates under an oxygen atmosphere (Table 1). Initially, we performed the reaction without the use of any metal salts, in DMSO (dimethyl sulfoxide) at 120 °C for 24 h, no desired product was formed, but the dehydrated product 3aa’ between 1a and 2a could be obtained in 20% yield (entry 1). With K2CO3 as the additive, however, the reaction yielded 2,3-diphenylisoquinolin-1(2H)-one (3aa) in 50% yield and 3aa’ in 33% yield, indicating that the base displays an important role in the intermolecular cyclocondensation of 1a with 2a, due to the nucleophilic addition of 2a to the carbonyl group of 1a promoted by the base (entry 2). In addition, it is well-known that Lewis acid can promote the nucleophilic addition of nitrogen to alkyne via the intermolecular π-coordinating of carbon-carbon triple bonds to Lewis acids, thus repeating the same reaction in the presence of a catalytic amount of Fe(OTf)2, ZhCl2 and Zn(OTf)2, which are not only cheap and easily available, but also air-stable Lewis acids (entries 3–5). Although Fe(OTf)2 and ZhCl2 showed no activity, Zn(OTf)2 could greatly promote the formation of the desired product 3aa, and 3aa could be obtained in 87% yield. Decreasing the catalyst loading from 4.0 to 3.0 mol%, the yield was not changed at all (entry 6), and the use of 2.0 mol% of the catalyst resulted in a considerable decrease in the yield (78%) (entry 7). In addition, when KHCO3 and KOtBu were used as the base to replace K2CO3, or when N,N-dimethyllformamide (DMF) and 1,4-dioxane were employed as solvents instead of DMSO, all were found to be inferior, and the yields of 3aa were significantly decreased (entries 8–11).
Encouraged by the results obtained above, we studied the substrate scope for the formation of isoquinolin-1(2H)-ones using various ortho-alkynylbenzaldehydes and amines bearing different substituents under the conditions of entry 6 in Table 1. As can be seen from Table 2, β-aminonaphthalene (2b), para-substituted anilines (para-Me, 2c; para-iPr, 2d; para-Br, 2f), 2-methyl-3-methoxyaniline (3e), and 2,4-difluoroaniline (2g) underwent cyclocondensation with 1a affording the corresponding isoquinolin-1(2H)-ones (2ab~2ag) in 76%–85% yields, indicating that arylamines with electron-donating and electron-withdrawing group(s) show similar reactivity under the reaction conditions. When 5-methoxy-2-(1-phenylethynyl)benzaldehyde (1b), 5-fluoro-2-(1-phenylethynyl)benzaldehyde (1c), and 5-chloro-2-(1-phenylethynyl)benzaldehyde (1d) were used, reactions with 2a and electron-rich and/or electron-poor arylamines also showed no significant difference in reactivity and gave the expected products in 73%–81% yields. In addition, the present catalyst conditions could be applied to primary alkylamine. For example, the reaction between 1d and n-propylamine (2h) produced 3dh in 62% yield.
Moreover, we also tested the effects of electron-donating and electron-withdrawing groups by using meta-methylphenylethynyl (1e) and para-cyanophenylethynyl (1f) groups to replace the phenylethynyl group on 1a. It was found that 1e showed similar reactivity to 1a in the cases of both the electron-rich and the electron-poor arylamines employed. However, it was apparent that 1f bearing an electron-poor group of para-cyanophenylethynyl is not beneficial to the reaction with 2a to give the corresponding product of 3fa in 50% yield.
It should be noted that the present catalyst system is highly tolerant to various C(sp2)-X bonds, such as the C-O, C-Br, C-F, and CN groups, the products bearing these groups have have important potential applications for further transformation.
A possible mechanism for the formation of isoquinolin-1(2H)-ones is shown in Scheme 2. It involves two well-known and normal steps: the nucleophilic addition of arylamines to aldehyde giving 1,2-aminoalcohol intermediate 4aa, and intramolecular hydroamination followed by an oxidation reaction constructing isoquinolin-1(2H)-one 3aa. Apparently, Zn(OTf)2 plays an important role in promoting the nucleophilic addition of arylamines and the intramolecular hydroamination of carbon-carbon triple bonds. The formation of 3aa’ (Table 1, entries 1 and 2) is reasonable from the dehydration reaction of 4aa.

3. Materials and Methods

3.1. General Methods

All commercial organic/inorganic reagents and solvents were analytically pure and used without further purification; 2-(1-alkynyl)benzaldehydes (1a–f) are known compounds and were prepared by cross-coupling reactions of 2-bromobenzaldehydes with terminal aryl acetylenes [39]. Nuclear magnetic resonance (NMR) spectra were recorded on a JEOL ECA-400 spectrometer (JEOL, Tokyo, Japan) using CDCl3 as solvent at 298 K. The 1H NMR (400 MHz) chemical shifts (δ) were referenced to internal standard TMS (for 1H, δ = 0.00); 13C NMR (100 MHz) chemical shifts were referenced to internal solvent CDCl3 (for 13C, δ = 77.16). High-resolution mass spectra (HRMS) with electron spray ionization (Supplementary Materials) were obtained with a micrOTOF-Q spectrometer (Agilent, CA, USA).

3.2. Typical Procedure for the Synthesis of 2,3-Diphenylisoquinolin-1(2H)-one (3aa)

A mixture of 2-(phenylethynyl)benzaldehyde (1a, 1.0 mmol), aniline (2a, 1.5 mmol), Zn(OTf)2 (0.04 mmol), and K2CO3 (2.0 mmol) in DMSO (5.0 mL) under an oxygen atmosphere was stirred at 120 °C, and the reaction was monitored by GC-MS and TLC. After 24 h, the conversion of 1a was complete, and then the reaction mixture was cooled to room temperature. Water (10 mL) was added to the reaction mixture with vigorous stirring, and the mixture was then extracted with ethyl acetate three times (3 × 10 mL). The combined organic phases were dried overnight by anhydrous MgSO4. The filtered solution was then concentrated by a rotary evaporator under reduced pressure, and the obtained crude residue was purified by column chromatography on silica gel (eluent solvents: petroleum ether/ethyl acetate with the gradient mixture ratio from 100:0 to 80:20) to afford 3aa (258.0 mg, 87%).

4. Conclusions

We have demonstrated that Zn(OTf)2 is a very effective catalyst for the aerobic cyclocondensation of 2-(1-alkynyl)benzaldehydes with arylamines in the presence of base to afford 2,3-diarylisoquinolin-1(2H)-ones in good to high yields. The present catalyst system is preferred over the known procedures starting from 2-(1-alkynyl)benzaldehydes to construct an isoquinolin-1(2H)-one ring with the use of an air-stable and cheap commercially available Lewis acid as the catalyst, high atom utilization and easily available starting materials.

Supplementary Materials

The following are available online at https://www.mdpi.com/2073-4344/10/6/683/s1, characterization data and copies of 1H-NMR and 13C-NMR charts of products.

Author Contributions

Investigation, writing—original draft preparation, D.M.K.; conceptualization, supervision, writing—review and editing, R.H. All authors have read and agreed to the published version of the manuscript.

Funding

This project was supported by the National Natural Science Foundation of China (21673124, 21972072). Dost Muhammad Khan thanks the China Scholarship Council (CSC) for generous support for his study in Tsinghua University as a PhD candidate.

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 10 00683 sch001 550
Scheme 1. Isoquinolone from cyclocondensation of 2-(1-alkynyl)benzaldehydes with amines.
Scheme 1. Isoquinolone from cyclocondensation of 2-(1-alkynyl)benzaldehydes with amines.
Catalysts 10 00683 sch001
Catalysts 10 00683 sch002 550
Scheme 2. A possible mechanism for the formation of isoquinolin-1(2H)-ones.
Scheme 2. A possible mechanism for the formation of isoquinolin-1(2H)-ones.
Catalysts 10 00683 sch002
Table
Table 1. Optimal conditions for the formation of 2,3-diphenylisoquinolin-1(2H)-ones (2a) a.
Table 1. Optimal conditions for the formation of 2,3-diphenylisoquinolin-1(2H)-ones (2a) a.
Catalysts 10 00683 i001
EntryCatalyst (mol%)Base (2 equiv)SolventYield of 3aa (%)b
1c−−DMSOtrace
2d−K2CO3DMSO51
3Fe(OTf)2 (4.0)K2CO3DMSO45
4ZnCl2 (4.0)K2CO3DMSO50
5Zn(OTf)2 (4.0)K2CO3DMSO87
6Zn(OTf)2 (3.0)K2CO3DMSO87
7Zn(OTf)2 (2.0)K2CO3DMSO78
8Zn(OTf)2 (4.0)KHCO3DMSO40
9Zn(OTf)2 (4.0)KOtBuDMSO50
10Zn(OTf)2 (4.0)K2CO3DMF60
11Zn(OTf)2 (4.0)K2CO3Dioxane55
a Reactions were carried out using 1.0 mmol of 1a, 1.2 mmol of 2a, and 2.0 mmol of base in 5.0 mL of solvent under oxygen atmosphere at 120 °C for 24 h. b Isolated yields. c 20% of 3aa’. d 33% of 3aa’.
Table
Table 2. Substrate scopes for the formation of isoquinolin-1(2H)-ones a.
Table 2. Substrate scopes for the formation of isoquinolin-1(2H)-ones a.
Catalysts 10 00683 i002
a The reactions were carried out using 1.0 mmol of 1, 1.2 mmol of 2, and 2.0 mmol of K2CO3 in 5.0 mL of DMSO under an oxygen atmosphere.

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Khan, D.M.; Hua, R. Isoquinolone Synthesis via Zn(OTf)2-Catalyzed Aerobic Cyclocondensation of 2-(1-Alkynyl)-benzaldehydes with Arylamines. Catalysts 2020, 10, 683. https://doi.org/10.3390/catal10060683

AMA Style

Khan DM, Hua R. Isoquinolone Synthesis via Zn(OTf)2-Catalyzed Aerobic Cyclocondensation of 2-(1-Alkynyl)-benzaldehydes with Arylamines. Catalysts. 2020; 10(6):683. https://doi.org/10.3390/catal10060683

Chicago/Turabian Style

Khan, Dost Muhammad, and Ruimao Hua. 2020. "Isoquinolone Synthesis via Zn(OTf)2-Catalyzed Aerobic Cyclocondensation of 2-(1-Alkynyl)-benzaldehydes with Arylamines" Catalysts 10, no. 6: 683. https://doi.org/10.3390/catal10060683

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