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

: 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.


Results and Discussion
The optimizing reaction conditions were performed by the reaction of 2-(1phenylethynyl)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 KO t Bu 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][9][10][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, βaminonaphthalene (2b), para-substituted anilines (para-Me, 2c; parai Pr, 2d; para-Br, 2f), 2-methyl-3methoxyaniline (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-(1phenylethynyl)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(sp 2 )-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. Table 2. Substrate scopes for the formation of isoquinolin-1(2H)-ones a .
. 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.

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%).

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.

Conflicts of Interest:
The authors declare no conflict of interest.