Study of the Three-Component Reactions of 2-Alkynylbenzaldehydes, Aniline, and Dialkyl Phosphites—The Significance of the Catalyst System

New, practical approaches for the synthesis of α-amino (2-alkynylphenyl)-methylphosphonates and 1,2-dihydroisoquinolin-1-ylphosphonates were developed. By the propylphosphonic anhydride (T3P®)-mediated Kabachnik–Fields reaction of 2-alkynylbenzaldehydes, aniline, and dialkyl phosphites, α-amino (2-alkynylphenyl)-methylphosphonates were obtained selectively in high yields. The method developed is a simple operation and did not require a chromatographic separation since the products could be isolated from the reaction mixture by a simple extraction. At the same time, 2,3-disubstituted-1,2-dihydroisoquinolin-1-ylphosphonates could be prepared effectively from the same kinds of starting materials (2-alkynylbenzaldehydes, aniline, and dialkyl phosphites) at 60 °C in a short reaction time by changing the catalyst for CuCl. Therefore, it was proved that the catalyst system applied played a crucial role with respect to the reaction outcome.


Introduction
Organophosphorus compounds continue to receive widespread interest due to their unique significance in organic, bio-, and medicinal chemistry, as well as in the agriculture and plastic industries [1][2][3]. One of the major classes of organophosphorus compounds is the family of organophosphates. Among them, α-aminophosphonates, as the bioisosteres and structural analogues of natural α-amino acids, have attracted a considerable focus. They were found to be effective as enzyme inhibitors, antibiotics, antiviral, antifungal, or antitumor agents, as well as pesticides [3][4][5][6][7][8]. In addition, the introduction of α-aminophosphonates into an epoxy system can improve flame retardant properties [9,10]. In recent years, the chemistry of heterocyclic derivatives of αaminophosphonates have also received intensively growing attention [11][12][13][14]. Isoquinolines, including 1,2-dihydroisoquinolines as privileged fragments, can be considered as a common structural scaffold in several natural products that exhibit significant biological and pharmaceutical activity [15][16][17].
Multicomponent syntheses, such as the Kabachnik-Fields reaction, in which an amine, an oxo-compound, and a >P(O)H derivative react with each other, are one of the most straightforward and efficient tools for the preparation of α-aminophosphonates and their heterocyclic derivatives [18][19][20]. Applying multicomponent reactions, the target products are usually formed in a "one-pot" manner from simple starting materials with high atom economy. The ability to use various reagents makes these reactions ideal for creating new molecular libraries, and in most cases, the principles of green chemistry also prevail to save time and energy [21,22].
Recently, an enantioselective synthesis of 1,2-dihydroisoquinolin-1-ylphosphonates (2) was also reported [26]. In this case, the multicomponent reaction was catalyzed by a chiral silver spirocyclic phosphate in the presence of 5 Å molecular sieves in methyl tert-butyl ether at −10 • C for 3 days.
Propylphosphonic anhydride (T 3 P ® ) is a green, mild, and low toxic coupling and dehydrating agent, which delivers remarkable advantages, including broad functional group tolerance and easy work-up procedures due to the formation of water-soluble by-products, thus allowing high purity and yield for the products [30]. Several applications have been reported using this reagent, e.g., in multicomponent reactions or in the preparation of various heterocyclic compounds [31].
In this paper, we describe simple and selective preparation methods for the synthesis of new α-amino (2-alkynylphenyl)-methylphosphonates (1), as well as novel 1,2dihydroisoquinolin-1-ylphosphonates (2) by the three-component reaction of 2-alkynylben -zaldehydes, aromatic amines, and dialkyl phosphites using different catalytic systems (T 3 P ® or CuCl) (Scheme 1). There is no example in the literature of the use of T 3 P ® in the three-component reaction mentioned.

General Information
The reactions were carried out at room temperature or under conventional heating in an oil bath under N2 atmosphere.
High resolution mass spectrometry measurements were performed on a Sciex Tri-pleTOF 5600+ high resolution tandem mass spectrometer equipped with a DuoSpray ion source. Electrospray ionization was applied in positive ion detection mode. Samples were dissolved in acetonitrile and flow injected into acetonitrile/water 50:50 flow. The flow rate was 0.2 mL/min. The resolution of the mass spectrometer was 35,000.

General Information
The reactions were carried out at room temperature or under conventional heating in an oil bath under N 2 atmosphere.
The 31 P, 1 H, 13 C, NMR spectra were taken in CDCl 3 solution on a Bruker AV-300 or DRX-500 spectrometer (Bruker AXS GmBH, Karlsruhe, Germany) operating at 121.5, 75.5, and 300 or 202.4, 125.7, and 500 MHz, respectively. Chemical shifts are downfield relative to 85% H 3 PO 4 and TMS. Non-equivalence effect was observed in 1 H and 13 C{ 1 H} NMR spectra. Corresponding pairs of resonances were marked with (I) and (II).
High resolution mass spectrometry measurements were performed on a Sciex TripleTOF 5600+ high resolution tandem mass spectrometer equipped with a DuoSpray ion source. Electrospray ionization was applied in positive ion detection mode. Samples were dissolved in acetonitrile and flow injected into acetonitrile/water 50:50 flow. The flow rate was 0.2 mL/min. The resolution of the mass spectrometer was 35,000.

Results and Discussion
First, the model reaction of 2-(p-tolylethynyl)benzaldehyde (A), aniline (B), and dibutyl phosphite (C) was studied (Table 1). Performing the three-component condensation without any catalyst in acetonitrile at 60 • C for 4 h, the conversion was only 52%, and the dibutyl ((phenylamino)(2-(p-tolylethynyl)phenyl)methyl)phosphonate (3) was the main product; however, 2% of dibutyl (2-phenyl-3-(p-tolyl)-1,2-dihydroisoquinolin-1-yl)phosphonate (4) was also formed ( Table 1, Entry 1). Repeating the reaction in the presence of half equivalent of propylphosphonic anhydride (T 3 P ® ) as the condensing agent, at room temperature for 1 h, it was found that a conversion of 70% could be already reached, and product 3 was formed selectively (Table 1, Entry 2). Increasing the amount of T 3 P ® for one equivalent, resulted in a similar conversion (71%) after 30 min (Table 1, Entry 3). Using one equivalent of T 3 P ® and applying a reaction time of 1 h, the reaction was complete, and phosphonate 3 was formed in a ratio of 100% (Table 1, Entry 4).  In the next round, the T3P ® -promoted Kabachnik-Fields reaction was carried out starting from various 2-alkynylbenzaldehydes, aniline, and dialkyl phosphites under the  Our aim was also to accomplish the synthesis of dibutyl (2-phenyl-3-(p-tolyl)-1,2dihydroisoquinolin-1-yl)phosphonate (4); therefore, the three-component reaction was investigated in the presence of various copper catalysts (Table 1, Entries 5-9). Carrying out the condensation using 5 mol% of CuSO 4 ·5H 2 O at 60 • C for 1 h under solvent-free conditions, the cyclic phosphonate (4) was the main product (68%); however, 5% of phosphonate 3 and 27% of unreacted dibutyl phosphite (C) was also detected in the reaction mixture (Table 1, Entry 5). Repeating this reaction in acetonitrile, the condensation was much more efficient since 86% of cyclic phosphonate (4) was formed (Table 1, Entry 6). Applying CuI, CuBr, or CuCl as catalysts, the results obtained were somewhat similar, but CuCl was proved to be the most effective (Table 1, Entries 7-9). To improve the conversion, an experiment was performed in the presence of 10 mol% of CuCl at 60 • C for 1 h, and another at a higher temperature of 80 • C for 1 h, as well as a third at 60 • C for 1.5 h ( Table 1, Entries 10-12). It was found that the conversion of each reaction did not change significantly. Next, the condensation was carried out using a small excess of aniline in the presence of 5 mol% of CuCl at 60 • C for 1 h, and the reaction was almost complete ( In the next round, the T 3 P ® -promoted Kabachnik-Fields reaction was carried out starting from various 2-alkynylbenzaldehydes, aniline, and dialkyl phosphites under the optimized conditions (1 equiv of T 3 P ® , 25 • C, 1 h) ( Figure 2). The dibutyl ((phenylamino)(2-(p-tolylethynyl)phenyl)methyl)phosphonate (3) was isolated from the experiment marked by Table 1, Entry 4 in a yield of 96% after the extraction. Performing the condensation of (2-(p-tolylethynyl)benzaldehyde with aniline and dibenzyl phosphite, compound 5 was synthesized in a yield of 93%. The three-component reaction of aniline and dibutyl phosphite was also carried out with 4-fluoro-2-(p-tolylethynyl)-, 2-((4-methoxyphenyl)ethynyl)-, and 2-((4-chlorophenyl)ethynyl)benzaldehyde, as well as with 2-(phenylethynyl)benzaldehyde, and the corresponding α-aminophosphonates (6-9) were obtained in yields of 87-98%. The reactions of 2-alkynylbenzaldehydes containing an electron donating group, such as methyl or methoxy group, on the phenyl ring, resulted in slightly lower yields (87% or 89%, respectively). In contrast, α-amino (2-alkynylphenyl)-methylphosphonates bearing a 4-chloro substituent on the phenyl ring (9) or the unsubstituted derivatives (10) were isolated in excellent yields. Finally, the condensation of 2-(phenylethynyl)benzaldehyde and aniline was carried out with diethyl phosphite, and the result obtained was similar to that of the reaction performed with dibutyl phosphite.
In contrast with previous reports, where magnesium perchlorate [23] or Lewis acids [24] were used as catalysts, the T 3 P ® -mediated method developed is a new approach for the synthesis of α-amino (2-alkynylphenyl)-methylphosphonates, which applies green, low toxic additive, and milder reaction conditions (25 • C, 1 h). Altogether seven new derivatives were prepared in high yields and characterized by 31 P, 1 H, and 13 C NMR spectroscopy, as well as by HRMS. (Copies of 31 P, 1 H, and 13 C NMR spectra for all compounds synthesized are presented in the Supplementary Materials.) The formation of α-amino (2-alkynylphenyl)-methylphosphonates by the T 3 P ®promoted Kabachnik-Fields reaction can be explained by the proposed mechanism shown in Scheme 2. First, by the reaction of 2-alkynylbenzaldehyde and aniline, imine III is formed via adduct I. This condensation may be promoted by T 3 P ® to afford imine III along with tripropyl triphosphonic acid (QOH) as the by-product. The dehydration may take place via adduct II. In the next step, imine III reacts with the dialkyl phosphite in a nucleophilic addition, and after a protonation by T 3 P . H 2 O, the phosphonium salt V formed is stabilized by an Arbuzov fission to furnish α-amino (2-alkynylphenyl)-methylphosphonates (1) and the T 3 P . H 2 O by-product. Materials 2021, 14, x FOR PEER REVIEW 9 of 13 a Isolated yield. In contrast with previous reports, where magnesium perchlorate [23] or Lewis acids [24] were used as catalysts, the T3P ® -mediated method developed is a new approach for the synthesis of α-amino (2-alkynylphenyl)-methylphosphonates, which applies green, low toxic additive, and milder reaction conditions (25 °C, 1 h). Altogether seven new derivatives were prepared in high yields and characterized by 31 P, 1 H, and 13 C NMR spectroscopy, as well as by HRMS. (Copies of 31 P, 1 H, and 13 C NMR spectra for all compounds synthesized are presented in the Supplementary Materials.) The formation of α-amino (2-alkynylphenyl)-methylphosphonates by the T3P ® -promoted Kabachnik-Fields reaction can be explained by the proposed mechanism shown in Scheme 2. First, by the reaction of 2-alkynylbenzaldehyde and aniline, imine III is formed via adduct I. This condensation may be promoted by T3P ® to afford imine III along with tripropyl triphosphonic acid (QOH) as the by-product. The dehydration may take place via adduct II. In the next step, imine III reacts with the dialkyl phosphite in a nucleophilic addition, and after a protonation by T3P . H2O, the phosphonium salt V formed is stabilized by an Arbuzov fission to furnish α-amino (2-alkynylphenyl)-methylphosphonates (1) and the T3P . H2O by-product. In the next series of experiments, the CuCl-catalyzed special Kabachnik-Fields reaction of 2-alkynylbenzaldehydes, aniline, and dialkyl phosphites was extended using the optimized conditions (5 mol% CuCl, MeCN, 60 °C, 1 h) (Figure 3). The dibutyl (2-phenyl-3-(p-tolyl)-1,2-dihydroisoquinolin-1-yl)phosphonate (4) was isolated from the experiment marked by Table 1, Entry 14 in a yield of 79% after column chromatography. The condensation of (2-(p-tolylethynyl)benzaldehyde and aniline was also carried out with dimethyl or diethyl phosphite as the P-reagent, and the (2-phenyl-3-(p-tolyl)-1,2-dihydroisoquinolin-1-yl)phosphonates (11 and 12) were obtained in yields of 86% and 83%, respectively. Scheme 2. Proposed mechanism for the T 3 P ® -mediated synthesis of α-amino (2-alkynylphenyl)-methylphosphonates.

Conclusions
In summary, we developed a novel approach for the synthesis of new α-amino (2alkynylphenyl)-methylphosphonates by the T 3 P ® -mediated three-component reaction of 2-alkynylbenzaldehydes, aniline, and dialkyl phosphites. The method developed has the advantages of the simple operation and mild reaction conditions; furthermore, it does not require a chromatographic separation since the products could be recovered from the reaction mixture by an extraction. Moreover, novel 2,3-disubstituted-1,2-dihydroisoquinolin-1ylphosphonates were synthesized by the CuCl-catalyzed condensation of the same kinds of starting materials (2-alkynylbenzaldehydes, aniline, and dialkyl phosphites) at 60 • C for a short reaction time (1 h). This approach is faster and cheaper compared with the examples in the literature, where the reactions were complete after 4-6 h using more expensive catalysts. Applying the methods developed, altogether seven α-amino (2-alkynylphenyl)methylphosphonates and seven 2,3-disubstituted-1,2-dihydroisoquinolin-1-ylphosphonate derivatives were synthesized in good to high yields, and fully characterized, all of them are new compounds.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10.3390/ ma14206015/s1, Copies of 31 P, 1 H, and 13 C NMR spectra for all compounds synthesized are presented.