Photochemistry of 1,4-Dihydropyridine Derivatives: Diradical Formation, Delocalization and Trapping as a Route to Novel Tricyclic and Tetracyclic Nitrogen Heterocyclic Ring Systems

Irradiation of an acetonitrile solution of 4-aryl-3,5-dibenzoyl-1,4-dihydropyridine derivatives 1a–c and maleimides 2a–c using medium pressure Hg-arc lamp (λ > 290) nm afforded three different cycloadducts 4, 5, 6 in addition to the oxidation products 3. These results indicate that compounds 1a–c undergoes intermolecular cycloaddition reaction through three biradical intermediates and behave photochemically different than those reported previously for the analogous 3,5-diacetyl and 3,5-dicarboxylic acid derivatives. The present work also offers simple access to novel tricyclic and tetracyclic nitrogen heterocyclic ring systems of potential biological and synthetic applications. The structure of the photoproducts was established spectroscopically and by single crystal X-ray crystallography.


Introduction
1,4-Dihydropyridines have historically played a very important role in the synthesis and mechanistic organic chemistry. Derivatives of 1,4-dihydropyridine (DHP) are drugs belonging to a class of pharmaceutical agents known as calcium channel blockers. They are inhibitors of calcium ion penetration inside cells and weaken the contractility of the cardiac muscle. These compounds have been shown to be very effective vasodilators and are useful in the treatment of hypertension, ischemic heart disease, and other cardiovascular disorders [1][2][3][4][5][6]. Among the most important representative of this group of drugs are nifedipine (NPDHP) and felodipine (CPDHP).

Results and Discussion
Several photoirradiation experiments were carried out with 1a and 2a in order to optimize the reaction conditions, involving changes of solvent (CH2Cl2, toluene, CHCl3, and CH3CN), irradiation time, type of lamp (low or medium pressure Hg-arc lamps), the molar ratio of the two reactants (see Supplementary Materials). The optimum reaction conditions was achieved by using acetonitrile as a solvent, 3 h irradiation time, a 400 W medium pressure mercury arc-lamp (λ > 290 nm), a 1:3 molar ratio of 1,4-dihydropyridine 1a with maleimide 2a under a nitrogen atmosphere. These conditions were then applied to all photoreactions and the results are summarized in Table 1. Thus, irradiation of 1,4-dihydropyridines 1a-c with maleimides 2a-c using 400 W medium pressure mercury arc-lamp produced novel fused heterocyclic ring systems 4a-h, 5a-e and 6a, together with the photooxidation products, the 3,5-dibenzoyl-4-aryl-pyridine derivatives 3a-c (Scheme 2, Table 1). In this work, we describe the photochemical behavior of 4-aryl-3,5-dibenzoyl-1,4-dihydropyridine derivatives 1a-c and attempts to trap the possible intermediate diradicals with maleimides 2a-c.

Results and Discussion
Several photoirradiation experiments were carried out with 1a and 2a in order to optimize the reaction conditions, involving changes of solvent (CH 2 Cl 2 , toluene, CHCl 3, and CH 3 CN), irradiation time, type of lamp (low or medium pressure Hg-arc lamps), the molar ratio of the two reactants (see Supplementary Materials). The optimum reaction conditions was achieved by using acetonitrile as a solvent, 3 h irradiation time, a 400 W medium pressure mercury arc-lamp (λ > 290 nm), a 1:3 molar ratio of 1,4-dihydropyridine 1a with maleimide 2a under a nitrogen atmosphere. These conditions were then applied to all photoreactions and the results are summarized in Table 1. Thus, irradiation of 1,4-dihydropyridines 1a-c with maleimides 2a-c using 400 W medium pressure mercury arc-lamp produced novel fused heterocyclic ring systems 4a-h, 5a-e and 6a, together with the photooxidation products, the 3,5-dibenzoyl-4-aryl-pyridine derivatives 3a-c (Scheme 2, Table 1). The structure of all products has been established based on the 1 H-NMR, 13 C-NMR, HRMS and the X-ray crystal structures of photoproducts 4d, 5a, 5b and 6a (Figure 1). The 1 H-NMR spectra of compounds 5a-e showed interesting small coupling constants (J 0-2) for the vicinal ring protons (C-4, C-5 or C-1, C-29 shown in the X-ray of 5a) consistent with a dihedral angle around 80° as found by the X-ray structure of two of these compounds 5a,b.
(4d) (5a) The structure of all products has been established based on the 1 H-NMR, 13 C-NMR, HRMS and the X-ray crystal structures of photoproducts 4d, 5a, 5b and 6a ( Figure 1). The 1 H-NMR spectra of compounds 5a-e showed interesting small coupling constants (J 0-2) for the vicinal ring protons (C-4, C-5 or C-1, C-29 shown in the X-ray of 5a) consistent with a dihedral angle around 80˝as found by the X-ray structure of two of these compounds 5a,b. The structure of all products has been established based on the 1 H-NMR, 13 C-NMR, HRMS and the X-ray crystal structures of photoproducts 4d, 5a, 5b and 6a ( Figure 1). The 1 H-NMR spectra of compounds 5a-e showed interesting small coupling constants (J 0-2) for the vicinal ring protons (C-4, C-5 or C-1, C-29 shown in the X-ray of 5a) consistent with a dihedral angle around 80° as found by the X-ray structure of two of these compounds 5a,b.
(4d) (5a)  The formation of the different photo-adducts 4a-h, 5a-e, and 6a can be satisfactorily interpreted by the formation of the diradical intermediates A-D. Diradical A, which is formed from the initial excitation of the (n, π*), undergoes a hydrogen shift from the β-carbon to form diradical B, which then undergoes cycloaddition with 2 followed by dehydrogenation to give 4. Diradical A can also resonate to diradicals C, D and E. Trapping of the diradical C with 2a yields 6a, diradical C which is in resonance with D may also go through loss of H2 to give the pyridine derivatives 3a-c. Finally, trapping of diradical E with the appropriate maleimide gives the corresponding interesting tetracyclic system 5 (Scheme 3).  The formation of the different photo-adducts 4a-h, 5a-e, and 6a can be satisfactorily interpreted by the formation of the diradical intermediates A-D. Diradical A, which is formed from the initial excitation of the (n, π*), undergoes a hydrogen shift from the β-carbon to form diradical B, which then undergoes cycloaddition with 2 followed by dehydrogenation to give 4. Diradical A can also resonate to diradicals C, D and E. Trapping of the diradical C with 2a yields 6a, diradical C which is in resonance with D may also go through loss of H 2 to give the pyridine derivatives 3a-c. Finally, trapping of diradical E with the appropriate maleimide gives the corresponding interesting tetracyclic system 5 (Scheme 3). The formation of the different photo-adducts 4a-h, 5a-e, and 6a can be satisfactorily interpreted by the formation of the diradical intermediates A-D. Diradical A, which is formed from the initial excitation of the (n, π*), undergoes a hydrogen shift from the β-carbon to form diradical B, which then undergoes cycloaddition with 2 followed by dehydrogenation to give 4. Diradical A can also resonate to diradicals C, D and E. Trapping of the diradical C with 2a yields 6a, diradical C which is in resonance with D may also go through loss of H2 to give the pyridine derivatives 3a-c. Finally, trapping of diradical E with the appropriate maleimide gives the corresponding interesting tetracyclic system 5 (Scheme 3).  Furthermore irradiation of 1a alone in acetonitrile solution leads to the corresponding oxidized pyridine derivative 3a. Under the same conditions irradiation of diethyl 4-phenyl-1,4 -dihydropyridine-3,5-dicarboxylate (7) produced the cage compound 8 as shown in Scheme 4 and Figure 2. These facts showed different photochemical behavior for compounds 1a-c than those reported for the other dihydropyridine derivatives. The possibility of the formation of compound 6a by [4 + 2] thermal cycloaddition reaction has also been excluded, when attempts to react 1a with 2a at temperature of 180˝C for 1 h, gave only the unreacted starting material.

General Information
Melting points were recorded on a Gallenkamp apparatus (London, United Kingdom) The UV-Vis absorption spectra were scanned by using a Cary 5 instrument (Agilent, Santa Clara, CA, USA) with dry, clean quartz cuvettes of 1.0 cm path length. IR spectra were recorded in KBr disks on JASCO FTIR 6300 spectrophotometer (JASCO, Easton, MD, USA). 1 H-NMR (400 MHz or 600 MHz) and 13 C-NMR (100 MHz or 150 MHz) spectra were recorded on a DPX 400 MHz NMR spectrometer (Bruker, Karlsruhe, Germany). Mass spectra were measured on (GC-MS DFS) (high resolution, high performance, tri-sector GC/MS/MS (Thermo, Bremen, Germany) and by LC-MS using LC-MS DFS (Thermo). with an API-ES/APCI ionization mode. X-Ray single crystals data were performed using a Rapid II (Rigaku, Tokyo, Japan) and X8 Prospector diffractometer (Bruker) An annular reactor model APQ40 (Applied Photo-Physics Ltd., RG 49PA, England, UK) fitted with a 400 W (λ > 290 nm) medium pressure mercury arc-lamp was used for the irradiation. The starting 1,4-dihydropyridine derivatives 1a-c were synthesized as described recently [18]. procedure for the photoreaction of 1,4-dihydropyridines 1a-c with maleimides 2a-c A solution of each of 1a-c (1 mmol) and the appropriate 2a-c (3 mmol) in acetonitrile (100 mL) in a Pyrex tube was purged with nitrogen for 20 min, and then irradiated under N2 atmosphere for 3

General Information
Melting points were recorded on a Gallenkamp apparatus (London, United Kingdom) The UV-Vis absorption spectra were scanned by using a Cary 5 instrument (Agilent, Santa Clara, CA, USA) with dry, clean quartz cuvettes of 1.0 cm path length. IR spectra were recorded in KBr disks on JASCO FTIR 6300 spectrophotometer (JASCO, Easton, MD, USA). 1 H-NMR (400 MHz or 600 MHz) and 13 C-NMR (100 MHz or 150 MHz) spectra were recorded on a DPX 400 MHz NMR spectrometer (Bruker, Karlsruhe, Germany). Mass spectra were measured on (GC-MS DFS) (high resolution, high performance, tri-sector GC/MS/MS (Thermo, Bremen, Germany) and by LC-MS using LC-MS DFS (Thermo). with an API-ES/APCI ionization mode. X-Ray single crystals data were performed using a Rapid II (Rigaku, Tokyo, Japan) and X8 Prospector diffractometer (Bruker) An annular reactor model APQ40 (Applied Photo-Physics Ltd., RG 49PA, England, UK) fitted with a 400 W (λ > 290 nm) medium pressure mercury arc-lamp was used for the irradiation. The starting 1,4-dihydropyridine derivatives 1a-c were synthesized as described recently [18]. procedure for the photoreaction of 1,4-dihydropyridines 1a-c with maleimides 2a-c   A solution of each of 1a-c (1 mmol) and the appropriate 2a-c (3 mmol) in acetonitrile (100 mL)

General Information
Melting points were recorded on a Gallenkamp apparatus (London, United Kingdom) The UV-Vis absorption spectra were scanned by using a Cary 5 instrument (Agilent, Santa Clara, CA, USA) with dry, clean quartz cuvettes of 1.0 cm path length. IR spectra were recorded in KBr disks on JASCO FTIR 6300 spectrophotometer (JASCO, Easton, MD, USA). 1 H-NMR (400 MHz or 600 MHz) and 13 C-NMR (100 MHz or 150 MHz) spectra were recorded on a DPX 400 MHz NMR spectrometer (Bruker, Karlsruhe, Germany). Mass spectra were measured on (GC-MS DFS) (high resolution, high performance, tri-sector GC/MS/MS (Thermo, Bremen, Germany) and by LC-MS using LC-MS DFS (Thermo). with an API-ES/APCI ionization mode. X-Ray single crystals data were performed using a Rapid II (Rigaku, Tokyo, Japan) and X8 Prospector diffractometer (Bruker) An annular reactor model APQ40 (Applied Photo-Physics Ltd., RG 49PA, England, UK) fitted with a 400 W (λ > 290 nm) medium pressure mercury arc-lamp was used for the irradiation. The starting 1,4-dihydropyridine derivatives 1a-c were synthesized as described recently [18].

General procedure for the photoreaction of 1,4-dihydropyridines 1a-c with maleimides 2a-c
A solution of each of 1a-c (1 mmol) and the appropriate 2a-c (3 mmol) in acetonitrile (100 mL) in a Pyrex tube was purged with nitrogen for 20 min, and then irradiated under N 2 atmosphere for 3 h at room temperature using a 400 W (λ > 290 nm) medium pressure mercury arc-lamp. The reaction progress was monitored by TLC. The solvent was removed under reduced pressure and the resulting residue was subject to column chromatography on silica gel (70-230 mesh) using ethyl acetate/petroleum ether (b.p. 60-80˝C) as eluent to give the corresponding photoproducts.