4-Ferrocenylpyridine- and 4-Ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles: Multi-Component Synthesis, Structures and Electrochemistry

The reactions of 2-cyano-3-ferrocenylacrylonitrile (1) with malononitrile (2) in a MeOH/H2O or 2-PrOH/H2O medium in the presence of Na2CO3 afforded 6-alkoxy-2-amino-4-ferrocenylpyridine-3,5-dicarbonitriles 3a,b (multi-component condensation) and 6-alkoxy-2-amino-4-ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5-dicarbonitriles 4a,b (multi-component cyclodimerization). Analogous reactions of 1 with 2 in an MeOH/H2O medium in the presence of NaOH, piperidine, or morpholine gave compounds 3a, 4a and 2-amino-4-ferrocenyl-6-hydroxy-, 6-piperidino- and 6-morpholinopyridine-3,5-dicarbonitriles 3c–e, respectively. The structures of the compounds 3b, 4a and 4b were established by the spectroscopic data and X-ray diffraction analysis. The electrochemical behaviour of compounds 3b, 3d and 4b was investigated by means of cyclic voltammetry.


Introduction
Pyridine derivatives have been studied for over a century as an important class of heterocyclic compounds and they still continue to attract considerable attention due to the wide range of medicinal properties they possess, such as vasodilators, anticoagulants, hypolipidemic, tuberculostatic, antihistamine, antihypertensive, cardiovascular and gastrointestinal activities [1,2]. Pyridine systems are also found in important vitamins (PP, B 6 ), alkaloids and herbicides [1].

Scheme 1.
Reaction of 2-cyano-3-ferrocenylacrylonitrile (1) with malononitrile (2) in the presence of Na 2 CO 3 .  CO 3 Other products + The compounds 3a,b and 4a,b were isolated by column chromatography on alumina and their structures were characterized by IR and NMR spectroscopy, mass spectrometry, and elemental analysis (see Experimental section). According to the 1 H-and 13 C-NMR data, the cyclodimerization of 1 occurs with high diastereoselectivity, and compounds 4a and 4b were isolated as a single diastereomeric form. One cannot rule out the formation of minor diastereomeric products; however they could not be isolated and characterized.
The molecular structures of compounds 3b, 4a and 4b were determined by X-ray diffraction analysis of their single crystals. The general views of molecules 3b, 4a, and 4b are shown in Figures 1-3, respectively, while the principal geometric parameters are listed in Table 1.   X-Ray diffraction analysis confirmed the aromatic ferrocenylpyridine structure for compound 3b, and diferrocenyl(dihydro)pyridine structures for compounds 4a and 4b. Central fragment of the molecule 3b is a flat six-membered ring with one nitrogen atom. The N(1)-C (14) bond length in the compound 3b is somewhat shorter [d = 1.318(2) Å] compared to the standard length (cf. d = 1.338 Å [24]). The bond lengths of the C-Fe and C-C bonds in the ferrocenyl substituents as well as the geometric parameters of the ferrocene sandwiches are close to standard values [25]. Table 1. Selected bond lengths and bond angles for compounds 3b, 4a and 4b.

Selected bond lengths (Å)
Selected bond angles (°) 3b N(1)-C (13) were not detected (Schemes 2 and 3). As in the case of reaction of 1 with 2 in the presence Na 2 CO 3 , the polymerization products of the starting compounds were also present in minor quantities.

Scheme 2.
Reaction of 2-cyano-3-ferrocenylacrylonitrile (1) with malononitrile (2) in the presence of NaOH. Both reaction mixtures were separated by column chromatography on alumina, and the structures of the isolated products were characterized by IR, 1 H and 13 C-NMR spectroscopy, mass spectrometry, and elemental analysis. These physicochemical characterizations of compounds 3c-e corroborate completely their structures.
The formation of 2-amino-4-ferrocenylpyridine-3,5-dicarbonitriles 3a-e in the presence of bases and nucleophiles proceeds, in our opinion, via multi-component condensation reaction [26] (Scheme 4). Possibly the intermediate 5 is generated in one step and then transformed into pyridines 3a-e.

Scheme 4. Possible mechanism for the formation of compounds 3a-e.
A tentative mechanism for the formation of the diferrocenyl(dihydro)pyridine-3,5-dicarbonitriles 4a,b is represented in Scheme 5.

Scheme 5. Possible mechanism for the formation of compounds 4a,b.
To verify the mechanism described in Scheme 5 above, the cyclodimerization of 2-cyano-3ferrocenylacrylonitrile (1) was carried out under identical conditions in 2-propanol in the presence of water and Na 2 CO 3 . The product of the cyclodimerization, 2-amino-4-ferrocenyl-3-ferrocenylmethyl-6isopropoxy-3,4-dihydropyridine-3,5-dicarbonitrile (4b), was obtained with ~27% yield. Thus, cyclodimerization of compound 1 represents a novel type of the three-component anomalous reaction of [4+2]-cycloadition, absolutely different from the Diels-Alder reaction. Figure 4 shows a typical voltammogram of compound 3b recorded from open circuit potential to positive direction using a platinum electrode. It was observed one oxidation signal I a with anodic peak potential value E pa (I a ) = 0.247 V/Fc-Fc + and, one reduction signal I c , with cathodic peak potential value E pc (I c ) = 0.184 V/Fc-Fc + . The ΔEp = 0.063 was independent of scan rate (from 0.1 to 1 V·s −1 ). The cathodic peak current and the anodic peak current were proportional to v 1/2 , indicating that I is a diffusion-controlled process [27]. The evidence presented above suggests that process I can be attributed to the reversible electron transfer for the ferrocene moiety Fc-Fc + . The formal potential electrode value was E 0' = 0.215 V/Fc-Fc + , estimated as E 0' = 1/2(E pa + E pc ). The electrochemical behaviour of compound 3d is very similar to that observed for 3b. There are slight changes in peak potential values: E pa (I a ) = 0.241 V/Fc-Fc + , E pc (I c ) = 0.174 V/Fc-Fc + , ΔEp = 0.067 V and E 0' = 0.207 V/Fc-Fc + . Figure 5 shows a cyclic voltammogram of compound 4b. When the scan was started from open circuit potential to positive direction two oxidation signals (I a ) and (II a ) were observed. The anodic peak potentials values for these signals are E pa (I a ) = 0.198 V/Fc-Fc + and E pa (II a ) = 1.149 V/Fc-Fc + . When the cycle was complete only one reduction signal I c (related to the oxidation process I a ) was observed. The estimated cathodic peak potential value was E pc (I c ) = 0.099 V/Fc-Fc + . Despite the use of different scan rates (0.1 V·s −1 -1.0 V·s −1 ) in the voltammetric experiments, the product of the electrochemical reduction in the process IIa was not detected. This result points out the absence of electronic communication between the two proximal ferrocenyl centres, which is contrary to the observations reported recently [28], where the communication between ferrocenyl fragments was detected in 3,5-diferrocenylpyridine. The electrochemical process I is attributed to the ferrocene moiety at the para position to the nitrogen atom of the heterocycle, Fc para − /Fc para + . The estimated formal potential electrode value was E 0' = 0.1485 V/Fc-Fc + .

Electrochemistry
The second oxidation process (IIa) is related to the ferrocene moiety at the meta position to the nitrogen atom of the heterocycle (Fc meta /Fc meta + ) with high positive electronic density due to its proximity to the CN group. The absence of the reduction signal in the process II could be attributed to a low stabilization of the electro-generated dication (Fc + para -Fc meta + ) by the solvent [29,30]. This fact was confirmed when the experiment was performed in a coordinative solvent such as DMSO, where electrochemical response becomes more irreversible.

Crystal Structures of 3b, 4a and 4b
Single crystals of 3b and 4b were obtained by crystallization from chloroform, while crystals of 4a were obtained by crystallization from methanol. The unit cell parameters and the X-ray diffraction intensities were recorded on a Gemini (detector Atlas CCD, Cryojet N 2 , Loveland, CO, USA) diffractometer. The structures of compounds 3b, 4a and 4b were solved by the direct method (SHELXS-97 [35]) and refined using full-matrix least-squares on F 2 .
Crystal data for C 20

Conclusions
The reaction of 2-cyano-3-ferrocenylacrylonitrile (1) with malononitrile (2) in a MeOH/H 2 O or 2-PrOH/H 2 O medium in the presence of Na 2 CO 3 , NaOH, piperidine or morpholine affords products of multi-component condensation: 6-alkoxy-2-amino-, 2-amino-6-hydroxy-, 2,6-diamino-4ferrocenylpiridine-3,5-dicarbonitriles 3a-e, respectively, as well as products of multi-component cyclodimerization: 6-alkoxy-2-amino-4-ferrocenyl-3-ferrocenylmethyl-3,4-dihydropyridine-3,5dicarbonitriles 4a,b. This method can be widely used in the synthesis of various pyridine derivatives with ferrocenyl substituents. The reactions described in this study should be of interest to synthetic, theoretical and practical organic chemists seeking ways to prepare functionalized ferrocenylpyridines. The electrochemical behavior of compounds 3b, 3d and 4b was investigated by means of cyclic voltammetry. For 3b and 3d two electrochemical processes (Ia,Ic), attributed to the oxidation and reduction of the ferrocene moieties were found. On the other hand, for compound 4b a double electron transfer for both ferrocene groups (Ia,IIa) and the electrochemical monogeneration of the dication species (Ic) were detected.