Eco-Friendly Methodology to Prepare N-Heterocycles Related to Dihydropyridines: Microwave-Assisted Synthesis of Alkyl 4-Arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate and 4-Arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-dione

Here we describe the efficient synthesis of alkyl 4-arylsubstituted-6-chloro-5-formyl-2-methyl-1,4-dihydropyridine-3-carboxylates and 4-arylsubstituted-4,7-dihydro-furo[3,4-b]pyridine-2,5(1H,3H)-diones via microwave-accelerated reaction of alkyl 4-arylsubstituted-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylates with the appropriate reagents. This eco-friendly approach to these valuable dihydropyridine derivatives does not involve the harsh or highly contaminating conditions common in classical heating and offers a reduction or even elimination of solvent use and recovery, simplification of the work-up procedures, facility of scale up, and low energy consumption, in addition to moderate to higher yields.


Introduction
Nitrogen heterocycles are frequently found in privileged (pharmacophore) structures [1,2], but their incorporation is often hindered (multistep sequences, lack of generality, preparation from acyclic precursors, etc.); thus, only a limited number of strategies have been successfully applied in the synthesis of heterocyclic scaffolds [3][4][5]. The development of new, rapid, and clean synthetic routes toward focused libraries of such compounds is of relevance to medicinal and synthetic chemists alike [6]. Undoubtedly, the most efficient strategies involve multicomponent reactions (MCRs), which are powerful tools for the rapid introduction of molecular diversity [7,8]. Consequently, interest in the design and development of MCRs for the generation of heterocycles is growing [9].
In recent years, increasing interest has been focused on the synthesis of 1,4-dihydropyridine derivatives (1, owing to their significant biological activity [10][11][12]. In particular, dihydropyridine drugs, such as nifedipine, nicardipine, amlodipine, and others, are effective cardiovascular agents for the treatment of hypertension [13]. However, in spite of the potential utility of these drugs, their synthesis usually involves expensive reagents, organic solvents, long reaction times, and affords unsatisfactory yields. Thus, the development of an efficient and versatile method for the execution of of the Hantzsch reaction is an active ongoing field of research, and there is scope for further improvements in the form of milder reaction conditions, shorter reaction times, and improved yields [14][15][16]. The application of microwave irradiation (MW) as a non-conventional energy source for the activation of reactions, in general and under solvent-free conditions in particular, has now gained popularity compared to standard homogeneous and heterogeneous reactions because it provides enhanced reaction rates and (usually) improved product yields. In addition, in the context of green chemistry, MW irradiation has several eco-friendly advantages, which have been extended to modern drug discovery processes. Generally, the rapid heating induced by MW avoids the harsh classical conditions and decomposition of reagents, thus facilitating the formation of products under milder reaction conditions with a consequent increase in yield [17][18][19].
For the MWAS, the irradiation was provided by a CEM Discover LabMate Focused Single Mode MW Synthesis System, which allows for continuous stirring and irradiation with temperature control [22]. All the reactions were followed by TLC and the experiments were replicated in order to ensure reproducibility.
The MWAS of compounds IIa-j was performed in a one-step procedure by reaction in an open vessel with previously prepared POCl 3 /DMF. The MW-accelerated Vilsmeier-Haack reaction is typically carried out in a MW reactor at 180 Watts and a controlled temperature of 50 °C for 5 min. Subsequent hydrolysis produces almost analytically pure compounds IIa-j, which requires minimal if any purification (Scheme 1).  Table 1 shows the results obtained for the MWAS of compounds IIa-j and the comparison with the classic method previously reported by our group (Method B) [24,25]. Table 1. Results of MWAS (Method A) of alkyl 4-arylsubstituted-6-chloro-5-formyl-2methyl-1,4-dihydropyridine-3-carboxylate (IIa-j) and comparison with the conventional method (Method B) [24,25]. effect accelerating the reaction with respect to conventional heating, we carried out all the experiments using classical heating (thermostated oil bath) in the same conditions as under MWAS (time, profiles of rise in temperature, vessels, etc.). When the starting materials were heated at 50 °C for 5 min to 2 h without solvent, only a complex mixture of by-products was detected (TLC and 1 H-NMR).
The improvement achieved with MWAS (Method A) could be associated with the reaction mechanism and the evolution of polarity during the MW-assisted reaction. This reaction was shown to proceed through a mechanism involving several steps, beginning with the formation of the electrophilic VH reagent from DMF and POCl 3 . Reaction of the electrophilic reagent with the enolic form of the intermediate compound I proceeded through a pyridone intermediate, followed by reaction with POCl 3 to give the chloro derivative intermediate, which, via subsequent hydrolysis, provided the desired 6-chloro-5-formyl-1,4-DHP II (Scheme 2).

Scheme 2.
The proposed mechanism of the chloroformylation reaction.
On the basis of the previous result and the postulated mechanism, we propose that the specific MW effect is attributable to the following: Improvements in the formation of the chloroiminium species (VH reagent), and the enhancement of the subsequent reaction of the electrophilic reagent with the enolic form of the intermediate compound I. In both cases, the polarity increased from the ground state to the transition state (Scheme 3), thereby resulting in an enhancement of reactivity as a result of a decrease in the corresponding activation energy [30]. Scheme 3. Postulated transition states (ET) for the formation of VH reagent and for the reaction between the electrophilic reagent and the enolic form in the chloroformylation reaction.
The final products IIa-j were characterized by melting point, NMR and mass spectral data. Most compounds synthetized in this study were known and their spectral characterization showed satisfactory agreement with previous literature data [12,[23][24][25]. The 1 H-NMR spectra of the DHP derivatives IIa-j showed two singlets at δ ~ 10.6 ppm and δ ~ 9.6 ppm, corresponding to the NH and CHO protons, respectively. The singlet corresponding to the H4 proton appeared in the range of δ 4.9-5.3 ppm and the methyl group on C-2 as a singlet at δ ~ 2.3 ppm. The alkoxycarbonyl group on C3 appeared as a singlet (δ ~ 3.5 ppm) in the case of R = CH 3 (compounds 5a-f) and as a quadruplettriplet when R = CH 2 CH 3 (compounds 5g-j) at δ ~ 3.9 ppm and δ ~ 1.1 ppm, respectively. The 1 H-NMR spectra also showed signals corresponding to the phenyl protons, depending upon the substitution present on the aromatic ring. The 13 C-NMR spectra of these compounds displayed signals in the carbonyl, aromatic and aliphatic regions. For the nitrogen heterocyclic ring, the spectra showed four quaternary carbon signals (C-2, C-3, C-5, and C-6), and one secondary carbon signal (C-4). The formyl group (CHO) carbon in these systems appeared at 187-186 ppm. The alkoxycarbonyl group appeared at 166.2-166.9 ppm.
MWAS of chloroformyl derivatives IIa-j offers considerable improvements over our previously reported conventional Vilsmeier-Haack chloroformylation [12,[23][24][25]. The reaction time was notably reduced (conventional synthesis: 18 h, and MWAS: 5 min), and the final product was obtained with excellent purity and hence could be used in further synthetic steps without any need for wasteful purification.

Microwave Assisted Synthesis (MWAS) of 4-Arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-diones IIIa-i
Some substituents on the 1,4-DHP ring have a dramatic effect on its biological activities [31]. Specifically, cyclohexanone and -lactone rings fused to the 1,4-DHP moiety result in a striking effect on the entry of calcium ions into the intracellular space (calcium antagonist effect) [32]. Our classical method for the synthesis of 4-arylsubstituted-4,7-dihydrofuro[3,4-b]pyridine-2,5(1H,3H)-diones III in moderate to good yields, comprised a one-pot reaction of the alkyl 2-methyl 6-oxo-1,4,5,6tetrahydropyridine-3-carboxylates I with N-bromosuccinimide (NBS) as the brominating reagent by refluxing in chloroform in 12-14 h [33][34][35]. The microwave-accelerated lactonization to obtain the furo [3,4-b]pyridines IIIa-i were performed in a one-step procedure by reaction of previously synthesized I with NBS without solvent. This reaction was carried out at 240 Watts and under a controlled temperature of 80 °C for 10 min (Scheme 4). When the irradiation was stopped, the mixture was treated with the adequate solvents and filtered to give the pure products IIIa-i in excellent yields.  Table 2 shows the results obtained for the MWAS of compounds IIIa-i, compared with the classical method previously reported by our group (Method B) [33][34][35]. To check the possibility of intervention of specific non-pure thermal effects of MWs, the reaction was performed by heating in thermostated oil bath under the same experimental conditions used for MW irradiation (time, profiles of rise in temperature, vessels). In no case was a reaction detected by TLC at 10 min of reaction, and after 2 h of reaction the TLC showed a complex mixture of byproducts.  In all cases, the MWAS yields for these compounds (Method A) were higher than those achieved previously with conventional synthesis conditions [33][34][35]. Moreover, the time of reaction was dramatically reduced from 12 h (720 min) in the conventional synthesis (Method B) to 10 min for the MWAS method. The presence of two distinct alkoxy groups in the three positions of the starting dihydropyridine derivative I did not significantly alter the yields obtained.
Lactonization could be accounted for by the Wohl-Ziegler bromination (allylic bromination) [36] at the methyl group to the 2nd position of the heterocycle I, yielding the non-isolable monobrominated intermediate via a free radical process, followed by intramolecular cyclization to give the corresponding -lactone (Scheme 5) in similar way to the pyridinium bromide perbromide procedure reported for 1,4-DHPs [37]. Given the higher reactivity of the radical species, we propose that the second stage is the determining step in the mechanism postulated for this reaction. The intramolecular cyclization could take place through a polar mechanism. The non-isolable monobrominated intermediate leads to a charged species as a result of an intramolecular nucleophilic attack through SN2 mechanism. Subsequently, the bromide originated in this process could act as a nucleophile on the methyl carbon, with the loss of a bromomethane molecule, to obtain the final product of reaction III (Scheme 5). In both postulated steps for this second stage, the polarity is increased from the ground states to the transition states (ET-1 and ET-2) (Scheme 5), thus resulting in an enhancement of reactivity under MW irradiation by lowering the activation energy [30]. The final products IIIa-i were characterized by melting point, NMR and mass spectral data. Most compounds synthesized in this study were known and their spectral characterization showed satisfactory agreement with the previous literature data [33][34][35]. The 1 H-NMR spectra of DHP derivatives IIIa-i showed one singlet corresponding to the NH at δ ~ 10.7-11.3 ppm. The signals corresponding to the lactone ring methylene protons appeared as an AB system at δ 4.97 and δ 5.37 ppm, due to the germinal coupling between them, and confirmed the formation of lactone-fused DHP. The 13 C-NMR spectra of these compounds displayed signals in the carbonyl, aromatic, and aliphatic regions. For the nitrogen heterocyclic ring, the spectra showed three quaternary carbon signals (C-2, C-4a, and C-7a), one secondary carbon signal (C-4), and one primary carbon signal (C-3). The signals of the quaternary carbons C-7a appeared at higher δ values than those expected for typical olefinic carbon atoms. In contrast, the quaternary carbon C-4a was observed at unusually lower δ values. This displacement of the signals is due to the strong push-pull effect of the groups linked to the olefinic double bonds [33][34][35].
The MWAS without solvent of furopyridone derivatives IIIa-i (Method A) thus offers considerable advantages over our previous reported conventional lactonization synthesis [33][34][35]. The reaction time was notably reduced [conventional synthesis (Method B): 12 h, and MWAS (Method A): 10 min), and the final product was obtained in excellent purity and yield and hence could be used in further procedures without the need for any wasteful purification steps.

General
Reagents and solvents were purchased from Fluka or Aldrich. The progress of the reaction and the purity of compounds were monitored on TLC analytical silica gel plates (Merck 60F250) using n-hexane-chloroform-ethyl acetate (3:2:1) and benzene-methanol (7:2) as eluents for the compounds IIa-j and IIIa-I, respectively. The MW irradiation was provided by a CEM Discover LabMate Focused Single Mode MW Synthesis Reactor, which produced continuous stirring and irradiation with control of pressure and temperature. Melting points were determined in capillary tubes in an Electrothermal C14500 apparatus and are uncorrected. The NMR spectra were recorded on a Mercury 400 spectrometer [400 MHz ( 1 H) and 75.4 MHz ( 13 C)]. Chemical shifts are given as δ values against tetramethylsilane as the internal standard and J values are given in Hz. Mass spectra were obtained in a LC/MSD-TOF(2006) Instrument (Agilent Technologies).

General Procedure for the MWAS of Methyl 4-Arylsubstituted-6-chloro-5-formyl-2-methyl-1,4dihydropyridine-3-carboxylates IIa-j
4-Aryl-substituted alkyl 1,4,5,6-tetrahydro-2-methyl-6-oxopyridine-3-carboxylates (I, 7 mmol) were added to the Vilsmeier-Haack reagent prepared from a mixture of POCl 3 (1.1 mL, 12.2 mmol) and DMF (1.4 mL, 18.2 mmol) at 5 °C. This mixture was then irradiated in the CEM Discover reactor at 180 Watts for 5 min at the controlled temperature of 50 °C. After the completion of the reaction, an aqueous sodium acetate solution was added (12 g in 21 mL of water). After 0.5 h, the mixture was partitioned between water and chloroform, and the aqueous phase was extracted with ethyl acetate. The organic phases were mixed and dried with anhydrous magnesium sulfate. The organic solvent was removed in vacuo and the solid was precipitated from diethyl ether, filtered and washed with small portions of cooled ethanol. The chracterization data of the compounds is given below.