Enaminones in a multicomponent synthesis of 4-aryldihydropyridines for potential applications in photoinduced intramolecular electron-transfer systems

An efficient three component reaction with enaminones, primary amines and aldehydes resulted in easy access to 1,4-dihydropyridines with different substituents at the 1-, 3-, 4- and 5-positions. Microwaves improved the reaction yield, reducing also considerably the reaction time and the amount of solvent used. Chiral primary amines gave chiral 1-substituted-1,4-dihydropyridines. The 4-(1-naphthyl) and 4-(phenanthren-9-yl)dihydropyridine derivatives exhibited an interesting photoluminescence behavior, which suggests their potential application as suitable photoinduced intramolecular electron-transfer systems.


Introduction
There is a lot of interest in supramolecular assemblies based on transition-metal ions, which have proved to be useful for a variety of light-induced applications, from molecular machines to systems that mimic chlorophyll photosynthesis [1][2][3][4][5][6]. Recently, 4-aryl-2,6-dihydropyridine-3,5-dicarboxylates have been investigated as useful organic dyads for the vectorial transport of energy or charge transfer [7,8] (Scheme 1). A few photochemical applications of dyads of this structure have been demonstrated including their use in photosensitive polymers [9,10], in biosensors or in the mapping of enzyme kinetics by means of the fluorescence similarity to NADH [11][12][13].
Moreover, there has been recent interest in the synthesis of dihydropyridine derivatives, due to their wide range of biological activity [14,15], by a one-pot three-component reaction  with aliphatic/aromatic amines, ethyl propiolate and benzaldehyde [14], or by a cascade reaction of 1-phenylpropynone or ethyl propiolate with primary amines and aldehyde [15].
Enaminones are versatile starting materials for the synthesis of many classes of organic compounds and heterocyclic systems [16,17], and are prepared by various methods, for example, 1 is readily obtained in excellent yield by the condensation of different methylketones with dimethylformamide dimethylacetal (DMFDMA) [16,17]. In this work we investigated the potential utility of 1 in a three-component synthesis of dihydropyridines (DHP) (Scheme 2). This is expected to produce DHP with no substitution at the 2-position and different substituents at the 1-, 3-, 4-and 5-positions. This system contains the characteristic cyclic enaminone chromophore, which is expected to exhibit strong UV absorption with a maximum around 350 nm and extending to the border of the visible region. In the presence of an appropriate electron-acceptor substituent in position 4, the absorbed UV irradiation can cause intramolecular electron transfer, thus converting light into charge separation over a distance of ca. 6 Å. This expectation is based on the recent studies of DHPs containing the enaminocarboxylate chromophore with suitable substituents in the 4-position [7,8]. The DHP products reported in the present synthesis allow an easy method for a wide range of DHP derivatives having this expected characteristic of a photoinduced intramolecular electron-transfer system.

Results and Discussion
In the present work we have investigated the synthesis of DHPs 2 from 1, aromatic aldehydes, and ammonia or primary amines, in a three-component one-pot reaction. First, we investigated different conditions to achieve this goal (Scheme 2, Table 1). Thus, the reaction (2.1:1:1 molar ratios) of 1, different primary amines or ammonium acetate, and aromatic aldehydes in acetic acid under reflux (condition A) for 2-4 h gave the corres- Conducting this reaction in a microwave at 150 °C increased the yields to 84-95%, decreased the reaction time to 2 min and also reduced the amount of the solvent used by ca. 90% (condition B, Scheme 2). Alternatively, compounds 2 were obtained also in good yield by reacting one equiv of the appropriate Schiff's base 3 with two equiv of the enaminones 1 in acetic acid (condition C, Scheme 2). Table 1 summarizes the dihydropyridines prepared and the yields obtained under different reaction conditions shown in Scheme 2.
This study was extended to include the synthesis of the chiral (R)-1-(1-phenylethyl)dihydropyridines 4a,b obtained in 78% yield by heating in acetic acid and in 93-94% yield by microwave irradiation with R-1-phenylethylamine in this threecomponent reaction. The bis(dihydropyridines) 5a,b were obtained in 75-92% yield with ethylenediamine and 1,3diaminopropane as the primary amines, respectively. The 4-(1naphthyl)dihydropyridines 6a-f and 4-(phenanthren-9-yl)dihydropyridine derivatives 7a,b were obtained from 1-naphthaldehyde and phenanthrene-9-carboxaldehyde in moderate yields after heating in acetic acid for 24 h (Scheme 3). The intermediate N-substituted enaminones 8 were isolated as the main product when the reaction was conducted for shorter time [15]. The longer reaction time and the low yields are attributed to the steric hindrance of the bulky naphthyl and phenanthryl groups. The flanking dione groups in positions 3 and 5 keep the aryl groups in position 4 perpendicular to the dienaminoketone moiety of the dihydropyridine ring, and this is shown in the X-ray crystal structure of 4b, 6d,f and 7a (Figure 1) [18].  6a-f, 7a,b, 2j and 4a. Compounds 6 and 7 are similar to the recently reported dihydropyridine dicarboxylate derivatives and are expected to act as photoinduced intramolecular electron-transfer systems [7,8]. Table 2 shows the UV-vis absorption-emission maxima of compounds 6a-f and 7a,b. The investigated compounds exhibit absorption spectra (Figure 2) with λ max = 277-308 nm and 389-406 nm. The shorter absorption wavelength is attributable to the aryl groups and the longer absorption is due to the DHP moiety [8]. Upon excitation at each of these two λ max these compounds gave fluorescence spectra (Figure 3 and Figure 4) with λ max = 454-492 nm ( Table 2). This photoluminescence behavior of 6 and 7 resembles that of dihydropyridinedicarboxylate derivatives [7,8], which suggests their potential application as suitable photoinduced intramolecular electron-transfer systems. For comparison the absorption and emission spectra of 2j and 4a have also been measured, and the results indicate weak emissions relative to 7b. This compound, with the p-methoxyphenyl groups in the 1, 3 and 5 positions, showed the most intense absorption ( Figure 2) and emission spectra ( Figure 4) upon excitation in the 400 nm ranges. Relative fluorescence quantum yields ( This synthesis of dihydropyridines was extended to enamino aldehyde 9, enamino ester 11 and enaminonitrile 13. Thus, 1,4dihydropyridine-3,5-dicarboxaldehyde 10a,b, 1,4-dihydropyridine-3,5-dicarboxylate 12 and 1,4-dihydropyridine-3,5-dicar-

Conclusion
The present work offers an alternative and efficient method for the synthesis of dihydropyridines with potentially wide applicability, compared to the recently reported [14] synthesis of 3,5dibenzoyl-1,4-disubstituted-dihydropyridine derivatives. The present method has the following advantages: 1. The starting enaminones 1 can be readily synthesized from any methylketone, whereas the reported method is limited to arylpropynones. 2. This is a one-pot three-component reaction; on the other hand, the reported method involves two steps starting with the reaction of phenylpropynone with a primary amine, followed by reaction with different aldehydes. 3. The synthesis of suitable substituted derivatives, such as 6 and 7, possessing interesting fluorescence and structural characteristics for remarkable photoluminescence behavior, which suggests their potential application as suitable photoinduced intramolecular electron-transfer systems. 4. This method can be extended to the synthesis of enaminoaldehydes 10, enaminoesters 12 and enaminonitriles 14.

Experimental
General: All melting points are uncorrected. The microwave oven used was a single-mode cavity explorer microwave (CEM Corporation, NC, USA) and irradiation was conducted in heavy-walled pyrex tubes (capacity 10 mL). IR spectra were recorded in KBr disks on a Perkin Elmer System 2000 FTIR spectrophotometer. 1 H and 13 C NMR spectra were recorded on Bruker DPX 400, 400 MHz, Avance II 600, 600 MHz superconducting NMR spectrometers. Mass spectra were measured on GCMSDFS-Thermo and with LCMS by using Agilent 1100 series LC/MSD with an API-ES/APCI ionization mode. Microanalyses were performed on LECO CH NS-932 Elemental Analyzer. The UV-vis absorption spectra were scanned by using a Varian Cary 5 instrument in the wavelength range 250-450 nm with dry, clean quartz cuvettes of 1.0 cm path length. From the spectra obtained, absorbance values at λ max were used to calculate the extinction coefficient. The emission spectra were measured at the same concentration after excitation at the specified λ shown in Figure 2, by using a Horiba-Jobin Vyon Fluromax-4 instrument. Relative fluorescence quantum yields were measured at 25 °C taking quinine bisulfate (in 0.1 M H 2 SO 4 , 22 °C) as standard (Φ f = 0.58 at λ ex = 350 nm, Φ f = 0.55 at λ ex = 365 nm) [19]. X-rays structures were determined by single-crystal X-ray crystallography RIGAKU RAPID II. Enaminones 1 were prepared according to the previously reported procedure [16,17] and compound 8 was identical with an authentic sample that was prepared as reported [15].

Supporting Information
Supporting Information File 1 Experimental procedures and characterization of compounds, including copies of 1 H and 13 C NMR spectra.