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Acetamidine Synthesis Essay

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  • 2.1.1. Pyridines, Dihydropyridines, Piperidines

    Pyridines form a class of compounds exhibiting potential activities against a wide range of biological targets [18,19,20]. Its derivatives have been designed and synthesized as therapeutic agents [21,22,23,24], as herbicides, fungicides, pesticides and as fluorescent dyes [25,26]. They have been commonly used as scaffolds for natural product synthesis (e.g., NAD nucleotides, pyridoxol (vitamin B6), and pyridine alkaloids) [27,28,29].

    A wide range of practical syntheses of pyridine derivatives using MW-irradiation have been reported in the last decade [30,31,32,33,34]. In a recent work, Hu et al. [30] synthesized a series of novel polyfunctionalized pyrido[2,3-b]indoles. This unusual tricyclic scaffold is found in some natural compounds such as grossularine-1 (1) and -2 (2), mescengricin (3) and a GABA modulator 4 having antianxiolitic properties (Figure 2). The reported synthesis by Hu et al. involved three- or four-component domino reactions, under MW-irradiation, and in the presence of 3-aroylmethylidene-2-oxindoles 5, anilines 6, and acetylenedicarboxylates 7, with or without alcohols 8. Interestingly, the authors observed that a selective transesterification only occurs in the case of the four-component reaction (Scheme 1).

    On the other hand, El-Borai et al. [31] described a new synthesis of pyrazolo[3,4-b]pyridine derivatives through a one-pot multi-component reaction. In this synthesis, 5-amino-1-phenyl-3-(pyridin-3-yl)-1H-pyrazole (11) was allowed to react with either 4-anisaldehyde (12) and p-substituted α-keto-nitriles 13 or with pyruvic acid (16) and some aromatic aldehydes 15 in acetic acid (Scheme 2). The reaction was carried out by conventional heating and under MW irradiation. The authors reported that the use of MW lead to shortened reaction times and higher yields compared to those obtained by conventional heating.

    These newly synthesized compounds were screened for their antibacterial activity against Gram-positive bacteria (Bacillus) and Gram-negative bacteria (Escherichia coli, Enterobacter cloaca and E. serratia), and also for their antifungal activity against Fusarium oxysporum and Penicillium expansum. Most of the compounds showed higher antibacterial potencies against the Gram-negative bacteria rather than the Gram-positive bacteria and fungi.

    6-Amino-3,5-dicarbonitrile-2-thio-pyridines 21 are usually synthesized under base catalysis. The first example of such a reaction catalyzed by a Lewis acid was recently reported by Sridhar et al. [32]. This synthesis was carried out by means of an efficient one-pot multi-component reaction, which combines aliphatic, aryl, or heteroaryl aldehydes 18 with malononitrile (19) and thiophenol (20) in the presence of ZnCl2 either under MW-irradiation or conventional heating conditions. In both cases, the compounds were obtained in moderate to good yield; nevertheless, MW-irradiation allowed shortened reaction times (Scheme 3).

    Another new method allowing the preparation of highly functionalized pyridine derivatives was established by Linder et al. [33]. In this synthesis, 6H-1,2-oxazines 22 and various alkynes 23 reacted in the presence of a Lewis acid catalyst and under MW-irradiation leading to polyfunctionnalized pyridines 24 (Scheme 4).

    This procedure leads to higher yields compared to conventional syntheses. The authors hypothesized that the addition of the Lewis acid (TiCl4 or BF3·OEt2) on the oxazine induced the formation of an 1,2-azapyrylium ion which remains stable even at high temperature. Moreover, the authors postulated that MW-irradiation is mandatory for completing its formation. Next, this azapyrylium ion reacts with substituted alkyne in a [4 + 2] cycloaddition to give a bridged intermediate. The last step of the reaction is a retro Diels-Alder reaction, leading to the expected pyridines.

    A novel one-step synthesis of thieno[2,3-b]pyridine derivatives 27 catalyzed by ytterbium(III) triflate under solvent-free conditions was reported by Wieke et al. [34]. Thus, in the presence of a catalytic amount of Yb(OTf)3 and under MW irradiation with silica gel, several series of 2-amino-3-thiophene-carbonitriles 25 reacted easily with different ketones 26 to afford, in only 5 minutes, the corresponding amino-thieno[2,3-b]pyridines 27 in good to excellent yields. Importantly, the catalyst could be easily recovered and reused several times (Scheme 5).

    1,4-Dihydropyridine derivatives have a wide range of biological and pharmaceutical activities and are also involved in hydride transfer from the reduced nicotinamide adenine dinucleotide (NADH and NADPH) coenzymes, and analogues thereof, which mediate hydrogen transfer reactions in biological systems [35,36,37].

    Among the 1,4-dihydropyridine derivatives, nifedipine (28), amlodipine (29) and nimodipine (30) [38,39] (Scheme 6) are potent calcium channel antagonists, used clinically for the treatment of cardiovascular diseases such as hypertension and angina pectoris [40]. In addition, others 1,4-dihydropyridines have been discovered as potent calcium channel agonists (such as BAY K 8644 (31)) [41,42].

    Surprisingly, very few examples of 1,4-dihydropyridines syntheses under MW-irradiation have been described. Kuraitheerthakumaran et al. [43] reported a simple and efficient three-component protocol starting from β-ketoester 32, aldehydes 33 and ammonium acetate (34). The reactions were performed under solvent-free conditions using lanthanum oxide as a catalyst. This new method provided the expected products 35 in excellent yields (90%–98%) after short reaction times (40–80 s) in comparison to the classical Hantzsch methods (Scheme 7) [44,45,46].

    Ladani et al. [47] synthesized new 1,4-dihydropyridine derivatives by a MW-assisted Hantzsch condensation via three-components reactions involving tetrazolo[1,5-a]quinoline-4-carbaldehydes 36, ethyl/methyl acetoacetate 37 and ammonium acetate (Scheme 8). The resulting series of 1,4-dihydropyridines 38 were screened for their antimicrobial activity. Some of these newly synthesized compounds showed better fungicidal activity, specifically against R. oryzae, than the standard drugs ampicillin and griseofulvin. Conversely, they displayed poor bactericidal activity.

    Compounds containing a piperidine moiety represent a large class of natural products and their syntheses have become an interesting topic due to their relevance as bioactive components in pharmaceutical science in recent years (Figure 3) [48,49,50].

    An interesting example of piperidine synthesis has been described by Ravindran et al. [51]. This approach proceeded through the condensation of diphenacyl anilines 43 with different arylidene acetophenones 44 in the presence of a catalytic amount of sodium ethoxide. This one-pot tandem sequence involved a Michael addition-aldol reaction ring closure and afforded highly substituted piperidines 45 in good yields (Scheme 9).

    2.1.2. Quinolines

    Quinolines and their derivatives are important heterocyclic compounds because of their wide-ranging biological activities [52,53,54] and interesting photochemical properties [55]. For example, chloroquine (46) has been used for its antimalarial activity for more than 60 years; [56,57,58] bedaquiline (47), an inhibitor of the mycobacterial ATP synthase, has been approved to treat multi-drug resistant tuberculosis, [59] and cabozantinib (48), a multitargeted receptor tyrosine kinase inhibitor, showed effective anticancer activity and has been marketed for the treatment of medullary thyroid cancer (Figure 4) [60].

    Therefore, in the last decade, several new synthetic routes to quinoline derivatives under MW-irradiation have been reported [61,62,63,64,65,66]. Kulkarni et al. [61] described a solid acid-catalyzed synthesis of substituted quinolines via a MW-assisted three-component domino reaction between anilines, aldehydes and terminal aryl alkynes. The reaction was catalyzed by montmorillonite K-10, a strong and environmentally safe solid acid and performed under solvent-free conditions. The synthetic pathway involved the formation of an imine by condensation of para-substituted anilines 49 and aldehydes 50, followed by nucleophilic attack of phenylacetylene 51 on the formed imine, intramolecular cyclization and aromatization. The K-10 catalyst was recovered during five successive reaction cycles, remained very stable, showed no sign of deactivation and provided excellent yields. The combination of solid acid catalysis, multicomponent domino reaction approach and microwave irradiation provided the quinolones 52 in excellent selectivities and short reaction times (Scheme 10).

    Another green-chemistry related approach was recently reported by Kumar et al. [62] for the synthesis of novel quinolin-4-ylmethoxy-chromen-2/-4-ones 56, 58 under MW conditions. The protocol involves a one-pot reaction of aromatic amines 53 and aldehydes 54, and a propargylated-flavone (55) or -coumarin (57) using YbCl3 (2 mol%) as catalyst. The reactions were carried out at 100 °C, and led to the expected products with excellent yields after a short reaction time (4 min). The authors hypothesized a three step mechanism: domino-imine formation between the aldehyde and the amine, activation of the imine by the catalyst and subsequent addition to the acetylenyl derivative leading to a cyclization, and finally oxidation of the intermediate. According to this model, Yb3+ as catalyst enhances the electrophilicity of the imine, and therefore plays a key role either in imine formation and cyclization steps. Importantly, the reaction occurs in water, which does not deactivate nor decompose the catalyst (Scheme 11).

    These highly functionalized quinolone derivatives have been examined for their in vitro antibacterial activity against Gram-positive (S. aureus and B. subtilis) and Gram-negative (E. coli and S. flexneri) bacteria, and also for their antifungal potential against Candida albicans. Their activities were compared to those of marketed drugs, i.e., ampicillin and cefadroxil (antiobiotic) and fluconazole (antifungal). Several compounds exhibited better or equally potent antibacterial potencies, expressed as in vitro minimum inhibitory concentration values (MIC), as the reference drugs against the four bacteria of the panel (MIC values in the 0.4–6 mg/mL range). The structure activity relationship study highlights the relevance of the heterocyclic moiety of the quinoline scaffold. Promising results have been also obtained in anti-fungal assay, since one compound exhibited a MIC value of 0.4 mg/mL, which is ten times better than fluconazole.

    Very recently, Li et al. [63] have developed a new synthesis of tetracyclic indolo[2,3-b]quinolone derivatives 61 via domino heterocyclization of 3-aroylidene-2-oxindoles 59 with enaminones 60 in a sealed vessel under microwave irradiation. The reaction cascades consisted of an initial Michael addition, tautomerism, intramolecular cyclization, and dehydration leading to aromatization (Scheme 12). This methodology showed attractive properties, such as short reaction times, high yields and operational simplicity.

    Barluenga et al. [64] have developed the synthesis of tetrahydroquinoline derivatives 65, 66