Microwave-induced Synthesis of N -Substituted 1-Alkyl and 1-Aryl 3-Aminoisoquinolines

: Background : Aminoisoquinolines are an important class of heterocyclic compounds. These compounds present a wide range of pharmacological properties including antimalaric, anticonvulsant and anti-inflammatory. Although several preparation routes may be found in the literature for the preparation of these compounds, many of these methods present difficulties, including laborious isolation methods, drastic conditions and extended reaction times. Methods : The synthesis of N -substituted 1-alkyl and 1-aryl- 3-aminoisoquinolines is developed through the reaction of 2-acylphenylacetonitriles with amines under microwave irradiation conditions. The reactions were performed in ethanol as a solvent without the use of catalyst. In parallel, these reactions were performed under identical conditions of temperature using P 2 O 5 /SiO 2 as a catalyst in different amounts. Results : A series of N -substituted 1-alkyl and 1-aryl- 3-aminoisoquinolines were synthesized using microwave irradiation with as high selectivity, short reaction times and without the use of catalyst. The use of P 2 O 5 /SiO 2 as catalyst under microwave irradiation conditions was not effective for these reactions. Conclusion : The results show an efficient method for the synthesis of N -substituted 1-alkyl and 1-aryl-3-aminoisoquinolines by the reaction of 2-acylphenylacetonitriles with amines using microwave irradiation. Some important advantages for this method include a strong decrease in reaction time, a good selectivity, and the absence of catalyst, with simplicity in operation and a benefit to the environment.


INTRODUCTION
Aminoisoquinolines are an important class of heterocyclic compounds that occur in natural and synthetic products. These compounds exhibit remarkable antimalaric [1,2], anticonvulsant and anti-inflammatory activities [3,4].
In addition, aminoisoquinolines were evaluated as Rhoassociated protein kinase (ROCK) inhibitors, involved in a variety of important physiological functions including the regulation of smooth muscle contraction, migration and cell proliferation, cytoskeletal rearrangement, and inflammatory responses [5,6]. Several synthesis pathways are described in the literature to obtain these compounds [7]. Within the scope of investigation of this broad family of substances, the synthesis of 3aminoisoquinolines has been studied in the literature through different methods. Furthermore, only a few of these methods allow obtaining 1-substituted 3-aminoisoquinolines [8].
In spite of their potential utility, some of these methods include long reaction times, large amounts of catalysts and expensive reagents.
In our research group, we have previously studied the synthesis of N-substituted 1-alkyl and 1-aryl 3aminoisoquinolines. This involves the cyclocondensation of 2-acylphenylacetonitriles 1 with amines 2 using trifluoroacetic acid as catalyst to obtain a series of 3-aminoisoquinolines 3 in good yields [10] (Scheme 1). Although the reaction has good yields, this process presents problems related with the use of polluting acids and extensive reaction time required to complete the reactions (2-5 days).
More recently, we studied the reaction using P 2 O 5 /SiO 2 and HClO 4 /SiO 2 as heterogeneous catalysts as eco-friendly alternatives. The results indicate that both catalysts are efficient for the reaction with similar yields [11]. However, P 2 O 5 /SiO 2 demonstrated to have a much better performance: a minor amount of catalyst was needed; it showed greater selectivity as well as a lower formation of byproducts than HClO 4 /SiO 2 . Additionally, HClO 4 is known to be potentially explosive; hence safety problems represent a serious limit for the use of this reagent for large scale preparations.
Nevertheless, although the yields of the final products were good with the use of both types of catalysts a similar problem was observed in relation to extensive reaction time required to afford the final products. In addition, reactions performed using P 2 O 5 /SiO 2 required high proportions of catalyst (10% w/w), with environment consequences. In this sense, an eco-safe and efficient alternative method for the preparation of 3-aminoisoquinolines is highly desirable.
The drive to environmentally sustainable or also called "green chemistry" has provided one of the greatest challenges for chemistry in this era. [12]. In this context, the use of microwave (MW) irradiation in reactions is well docu-mented in the literature for their reduced reaction times, increased product yields and enhanced product purities by reducing undesired side reactions compared to conventional heating methods [13]. For this reason, microwave irradiation has been widely applied in organic synthesis in the last decades and achieved great success for many reactions, including Friedel Crafts acylation [14], Biginelli reaction in aqueous medium [15], carbon-carbon cross-coupling reactions [16], transesterification reactions [17], Diels-Alder cycloaddition [18], N-alkylation of amines [19], Hantzsch condensation [20] among many others.
As a part of our search for new methods of synthesis of biologically active heterocyclic compounds, we focused on the possibility of optimizing this procedure to obtain the products in shorter reaction times with a lower amount of catalyst. According to this goal, we report an optimization of the synthesis of 3-aminoisoquinolines 3 via cyclocondensation of 2-acylphenylacetonitriles 1 with amines 2 using microwave irradiation.

RESULTS AND DISCUSSION
The substrates 1 were prepared following a procedure previously reported by our group via reaction of 2cyanomethylbenzoylchloride with Grignard reagents in the presence of cuprous iodide at -5 o C [21]. P 2 O 5 /SiO 2 was prepared according to the literature procedures [22].
Initially, to optimize the reaction conditions, we studied the reaction between 2-benzoylphenylacetonitrile (1a) (1 mmol) and aniline 2a (2.5 mmol) to obtain 1-phenyl-Nphenylisoquinolin-3-amine (3a). The reactions were performed using P 2 O 5 /SiO 2 in ethanol as solvent using various reaction conditions (catalyst amount, temperature and reaction time). Regarding the temperature, tests determined as optimum 180 o C (850 W) for carrying out these process. In parallel these reactions were performed under identical conditions of temperature without the use of catalyst ( Table 1).
We believe the most significant advance was the speed with which the reaction proceeded under microwave conditions.  The optimal reaction yield of 40% (Table 1, entry 3) obtained after 40 minutes, was significantly lower than that obtained via conventional method (120 hours), although the latter performance yield was slightly higher, i.e, 48% [11]. No increase in performance yield was observed at longer reaction times under microwave conditions (entries 4 and 5).
Another important fact was that the microwave reaction occurred in significantly better yields in the absence of catalyst. In this regard, we observed a lower yields of product 3a using the catalyst P 2 O 5 /SiO 2 in varying proportions from 1 to 10 % (w/w), showing the formation of byproducts, among them 1-phenyl-(2H)isoquinolin-3-one, generated by intramolecular cyclization in acid medium of substrate 2a [23] (Scheme 2). After completion of the reaction, the resulting yellow solid was washed three times with hexane/ethyl acetate (7:3) to remove unreacted reagent accompanied by a small percentage of impurities. The aminoisoquinoline 3a was obtained in good purity in a moderate yield (40%).
The reagent 1a was recovered in 36 % yield, after purification of the combined organic extracts by flash column chromatography.
With the optimized microwave conditions, we expanded the scope of the reaction to various 2-acylphenylacetonitriles 1 and amines 2 in ethanol as solvent. The reaction is applicable to both aromatic and aliphatic amines.
The yields of the reactions are summarized in Table 2. All products are known compounds and were identified by comparison of their physical and spectroscopic data with those of reported ones [10,11]. Assignments of carbon resonance were performed using both 1D and 2D NMR (COSY) and heteronuclear 1 H/ 13 C (HSQC and HMBC) experiments. Table 2, the reactions proceeded with various amines in moderate to good yields. Examination of the results revealed that the steric effects play an important role in the yield of the reactions, resulting in minor yields when either substrates or amines with bulky substituents were employed.

As observed in
Unreacted reagents, 2-acylphenylacetonitriles 1 were recovered in all reactions. This may be considered an important advantage of this method.
Comparisons of synthetic method using the conventional thermal with the microwave assisted reaction revealed a drastic reduction in the reaction time ( Table 3).

EXPERIMENTAL
Thin-layer chromatography (TLC) was performed on silica gel 60 F 254 sheets (Merck). Column chromatography was carried out using silica gel (Merck 60, 70-230 mesh). All reagents were of commercial quality or were purified before use. Melting points were determined with a Büchi apparatus. NMR spectra were recorded on a Varian Mercury Plus spectrometer at 200 MHz using TMS as the internal standard. Initially, 2-acylphenylacetonitriles 1 was obtained via reaction of 2-cyanomethylbenzoylchloride with Grignard reagents in the presence of cuprous iodide at -5 ºC [21]. P 2 O 5 /SiO 2 was prepared according to the literature procedures [22].
Microwave reactions were carried out using a commercially available Anton-Paar-monowave-300 reactor at 180 o C (monowave, maximum power 850 W, temperature control via IR-sensor) employing a 10 mL Pyrex vial in a closed vessel mode. Reactions were carried out with simultaneous cooling with stirring at a fixed rate of 600 rpm.