Recently Adopted Synthetic Approaches to Pyridine and Analogs: A Review

*Corresponding Author:

R. Kumar
Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida, Uttar Pradesh 201310, India
E-mail: mpharm.rajnish@gmail.com

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms

Abstract

On basis of various research reports, pyridine was found to possess a wide spectrum of pharmacological activities along with many other industrial applications. Because of its diverse applications, pyridine moiety is the centre of attraction for researchers and a large number of patents have been granted focusing on it. Several synthetic protocols such as cyclo-condensation, cyclization, cycloaddition, electrolysis, etc., were used by researchers to synthesize pyridine and analogs. Each synthetic protocol has its merits and demerits and required several types of reagents, catalysts and reaction conditions. So, there is always a need for careful analysis of reported synthetic protocols whenever researchers like to initiate research consisting of the synthesis of pyridine and its analogs.

Keywords

Pyridine, pharmacological activities, patents, synthetic protocols

Nitrogen comprising heterocyclic moieties has high pharmacologically active molecules[1]. Pyridine (C₅H₅N) is a six-membered heterocyclic compound that exists as a colourless liquid at room temperature, is water-soluble and has an acrid smell[2]. It was discovered by Scottish chemist Thomas Anderson in 1849. Arthur Hantzch afterward synthesized pyridine compounds in 1881 through a multi-component reaction, consisting of β-ketoester, an aldehyde and ammonia[3]. Like benzene, all pyridine ring atoms are sp2 hybridized involving π electron resonance. The N atom is highly electronegative and its lone pair in an aromatic environment makes pyridine distinctive in chemistry[3]. The presence of an electronegative nitrogen atom in the ring prevents equal distribution of electron density over the ring because of its negative inductive effect causing weaker resonance stabilization[2]. Pyridine is also used as a chemical solvent and reagent[4]. Pyridine is found in many natural products like vitamins such as niacin, pyridoxal phosphate, alkaloids like nicotine and many drugs[5]. Based on numerous research reports pyridine was found to be effective as an anti-cancer[6], anticonvulsant[7], anti-microbial[8], anti-tubercular[9], anti-viral[10], anti-depressant[11], anti-inflammatory[12], antidiabetic[ 13], anti-Alzheimer[14], analgesic agent[15]. Pyridine also has many other industrial applications, such as optics[16] and agrochemicals[17]. The targets for pyridine and its derivatives are diverse such as enzymes, proteins and deoxyribonucleic acid[18,19]. This pyridine ring is a biologically active core (pharmacophore) in a large number of pharmaceutically available drugs (Table 1)[20-27]. Due to the wide range of pharmacological and industrial applications of pyridine, it has always been the focus of researchers. Several patents have been granted on the synthetic and pharmacological works related to pyridine and its derivatives. The recently granted patents in 2022 are highlighted in Table 2[28-39].

Table 1: Marketed Drugs Bearing Pyridine Ring

Table 2: List of Patents Bearing Pyridine Ring

Synthetic Approaches

The synthesis of pyridine involves several methods like Chichibabin synthesis, Bonnemann cyclization, Krohnke pyridine synthesis, Gattermann-Skita synthesis and several other methods. In Chichibabin pyridine synthesis firstly, acrolein is formed via Knoevenagel condensation from acetaldehyde and formaldehyde, then acrolein condenses with acetaldehyde and ammonia to give aminopyridine[40]. In Bonnemann cyclization, the trimerization of one part of a nitrile molecule and two parts of acetylene gives pyridine[41]. In Krohnke pyridine synthesis, the reaction of pyridine with bromomethyl ketones gives related pyridinium salt[42]. In Gattermann-Skita synthesis, malonate ester was made to react with dichloro methylamine[43].

Green synthesis:

Dohare et al.[44] introduced ultrasound-induced synthesis of 3,5-dimethyl-4-phenyl-1,4,7,8- tetrahydrodipyrazolopyridine (5). The reaction takes place between hydrazine hydrate (1), β-dicarbonyl compound (2), substituted aldehydes (3) and ammonium acetate (4) using ethanol as a catalyst. The whole reaction takes 30- 40 min to complete (fig. 1a). Biswas et al., synthesized 2-benzoyl-4,6-diphenylpyridine (8) from cyclic sulfamidate imines (6) and β,γ- unsaturated α-keto carbonyl (7) in the presence of 1,4-diazabicyclo[2.2.2]octane. The reaction concoction was exposed to microwave irradiation in an open atmosphere at 70° for 30-40 min giving the desired product benzoyl-4,6-diphenylpyridine (fig. 1b)[45]. Raja et al., showed the synthesis of 2-(1-benzyl-5-methyl-1H-1,2,3-triazol-4- yl)-4,6-diphenylpyridine (12) by microwaveassisted reaction. The product was synthesized by a reaction of 1-benzyl-5-methyl-1,2,3-triazol- 4-yl-3-arylprop-2-en-1-ones (9), ammonium acetate (10) and ketone (11) in water. The product was obtained with a yield of 90 % (fig. 1c)[46].

Metal-catalyzed reaction:

Copper (Cu)-catalyzed synthesis: Xi et al., stated Cu-catalyzed aerobic reaction for the synthesis of 2-arylpyridines (18). On heating acetophenone (13), with 1,3-diamino propane (14) in the presence of Copper(II) triflate (Cu(OTf)₂) in ethanol for 80° in an oxygen environment for 72 h giving 2-arylpyridine with 22 % yield (fig. 1d); The second method consists of a reaction of 13 with 14 in the presence of Cu(OTf)₂ in ethanol and benzoic acid giving 2-arylpyridine with 51 % yield (fig. 1d). The third method consists of acetophenone with 1,3-diamino propane in the presence of Cu(OTf)₂ in ethanol and p-Toluene Sulphonic Acid (PTSA) giving 2-arylpyridine with 60 % yield (fig. 1e)[47].

Rhodium (Rh) (III)-catalyzed synthesis: Chen et al., synthesized a one-step method for the preparation of 3-fluoropyridine (18) from α-fluoro- α,β-unsaturated oximes (16) with terminal alkyne (17) by Rh(III)-catalyzed C-H functionalization (fig. 1)[48].

Fig. 1: Schematic representation of synthesis of compounds, (a): 3,5-dimethyl-4-phenyl-1,4,7,8-tetrahydrodipyrazolopyridine; (b): 2-benzoyl-4,6-diphenylpyridine; (c): 2-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-4,6-diphenylpyridine; (d): 2-arylpyridines and (e): 3-fluoropyridine

Cyclization:

In presence of PTSA: Ghodse et al., showed the synthesis of 2-phenyl pyridine (21) by acetophenone (19) and 1,3-diaminopropane (20) in presence of palladium acetate and PTSA in tetrahydrofuran as solvent at reflux temperature for 10 h in presence of oxygen. The product was obtained with a good yield (fig. 2a)[49].

In the presence of triethylamine: Albratti et al., synthesized oxadiazole-based pyridine derivative 6-amino-4-methyl-1-phenyl-5(5- t h i o x o - 4 , 5 - d i h y d r o - 1 , 3 , 4 - o x a d i a z o l - 2 - y l ) pyridine-2(1H)-one (24). When 2-(5-thioxo-4,5- dihydro-1,3,4-oxadiazole-2-yl) acetonitrile (22) reacts with acetylacetone or acetoacetanilide to form 4-cyano-3-methyl-N-phenyl-4(5- thioxo-4,5-dihydro-1,3,4-oxadiazole-2-yl) but-3-enamid (23). 1,5-diphenylpent-4-yn- 1-one oxime goes through cyclization to afford 2,6-diphenylpyridin-3-ol (fig. 2b)[50].

By electrophilic cyclization: Karadeniz et al., showed a facile electrophilic cyclization for the synthesis of 5-iodo-2,4-diphenylpyridin-3- yl (phenyl)methanone (26) from N-propargylic β-enaminones (25) in the presence of CH3CN, NaHCO₃ and iodine at 82°. The product was obtained with an 80 % yield (fig. 2c)[51].

2-Iodoxybenzoic acid-mediated selected oxidative cyclization: Gao et al., reported the synthesis of methyl-2-phenylnictoniate (28) by reaction of enaminoesters (27) bearing hydroxypropyl derivatives, which were made to react with 1.6 equivalent of 2-iodoxybenzoic acid in tetrahydrofuran as solvent gave desired product with 82 % yield (fig. 2d)[52].

By Potassium carbonate (K₂CO₃)-mediated cyclization: Wang et al., designed K₂CO₃-mediated cyclization and rearrangement of γ,δ-alkynyl oximes for the synthesis of 2,6-diphenylpyridin- 3-ol (30). Compound (E)-1,5-diphenylpent-4-yn- 1-one oxime (29) in presence of K₂CO₃ as base and glycerol as solvent at 120° for 12 h giving 2,6-diphenylpyridin-3-ol in 74 % yield (fig. 2e)[53].

Fig. 2: Schematic representation of synthesis of compounds, (a): 2-phenyl pyridine; (b): 6-amino-4-methyl-1-phenyl-5 (5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine-2(1H)-one; (c): 5-iodo-2,4- diphenylpyridin-3-yl(phenyl) methanone; (d): Methyl-2-phenylnictoniate and (e): 2,6-diphenylpyridin-3-ol

By metal-free cyclization: Huang et al., reported synthesis for 2,4-diphenyl pyridine (33) by reaction of o-acetyl ketoxime (31) and α,β- unsaturated aldehydes (32) in presence of iodine, triethylamine and toluene as solvent (fig. 3a)[54].

By Cu-catalyzed cyclization: Zhang et al., synthesized 2,4,6-triphenyl-pyridine (35) in presence of acetophenone (34) and NH₄AOc, using Cu(OTf)₂ as a catalyst in the solventfree environment releasing CH₄. The product was obtained with a yield of 71 % (fig. 3b)[55].

By concomitant cyclization: Arabhshahi et al., showed the synthesis of 3-amino-N-phenyl-6,7- dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine- 2-carboxamide (41) in a three-step process. Initially, sodium (E) and (Z)-(2-oxocyclopentylidene) methanolate (37) was produced from the reaction of cyclopentanone (36) with freshly-prepared sodium methoxide and methyl formate. Secondly, (Z)-(2-oxocyclopentylidene) methanolate was made to react with cyanothioacetamide and piperidinium acetate followed by acidification with acetic acid giving 2-thioxo-2,5,6,7-tetrahydro- 1H-cyclopenta[b] pyridine-3-carbonitrile (38). Further, 2-bromo-N-phenylacetamide (40) was synthesized from the reaction between aniline (39) and bromoacetyl bromide in presence of triethylamine. Lastly, 2-bromo-N-phenylacetamide was mixed with 2-thioxo-2,5,6,7-tetrahydro-1Hcyclopenta[ b] pyridine-3-carbonitrile in presence of anhydrous sodium carbonate in absolute ethanol giving desired product in 55 % yield (fig. 3c)[56].

By regioselective cyclization: Luo et al., reported the synthesis of N-benzyl-4,6-diphenylpyridin- 2-amine (44) by regioselective Michael reaction, cyclization and loss of one molecule of NO₂. In this, when α, β-unsaturated ketones (42) and reductive aminases (43) in presence of 1,4-dioxane as solvent was made to react with 1,4-dioxane. Further piperidine was added to the mixture and the solution was stirred at heating conditions (fig. 3d)[57].

Fig. 3: Schematic representation of synthesis of compounds, (a): 2,4-diphenyl pyridine; (b): 2,4,6-triphenyl-pyridine; (c): 3-amino- N-phenyl-6,7-dihydro-5H-cyclopenta[b]thieno[3,2-e]pyridine-2-carboxamide; (d): N-benzyl-4,6-diphenylpyridin-2-amine and (e): 7-azaindoles

Condensation reaction:

Motati et al., demonstrated that 7-azaindoles (48) were synthesized through a multicomponent condensation reaction. The reaction occurs between 2-amino-4-cyano pyrrole (47) with compounds having active methylene group (45) and different aldehydes (46) followed by oxidation using AcOH and AcONH₄ as catalysts (fig. 3e)[58]. Peicherla et al., established the synthesis of imidazo[1,2-a]pyridine (51) by using cyclocondensation. The reaction forms an intermediate of α-halo carbonyl compound (50) by the reaction of alkenes (49) in the presence of 2-iodoxy-benzoic acid/iodine/dimethyl sulfoxide. Further, the α-iodo ketones (50) were mixed with 2-aminopyridine in presence of K₂CO₃ and dimethylformamide to give imidazo[1,2-a]pyridine. The product was obtained with a yield of 55 %-71 % (fig. 4a)[59].

Addition reaction:

By ammonium acetate+β-dicarbonyl compound cycloaddition: Bartko et al., designed the synthesis of 3-ethyl-4-methyl-2-tosyl-5,6,7,8- tetrahydroquinoline (63) in presence of 1-(cyclohexyl-1-en-yl)-5-phenylpent-1-yn-3-ol (62) in presence of toluenesulfonyl cyanide and toluene as solvent (fig. 4b)[60]. Wu et al., reported the synthesis of bipyridines (66) by reaction of N-vinyl amide (64) and alkyne (65) in the presence of [(p-cymene RuCl₂]_m, Na₂CO₃, KOAc and toluene at 100° under argon atmosphere at 56 h gave highly substituted bipyridines (fig. 4c)[61].

By Michael addition: Shen et al., reported the synthesis of 4-phenyl-2-(thiophen-2yl)-6-(p-tolyl) pyridine (69) from ynones (67) and 1-arylethamine (68) through intramolecular Michael addition reaction in presence of dimethyl sulfoxide and potassium tert-butoxide at 100° under an air atmosphere. The product was obtained with a 68 % yield (fig. 4d)[62]. Song et al., reported the synthesis of 2,3,4-trisubstituted pyridines (72a-c) by reaction of α-fluoro-β-ketoester (70) reacted with α, β-unsaturated aldehydes (71) as Michael acceptors in presence of Cs₂CO₃ and MeCN at 60° (fig. 4e)[63].

Fig. 4: Schematic representation of synthesis of compounds, (a): Imidazo[1,2-a]pyridine; (b): 3-ethyl-4-methyl-2-tosyl-5,6,7,8- tetrahydroquinoline; (c): Bipyridine; (d): 4-phenyl-2-(thiophen-2yl)-6-(p-tolyl)pyridine and (e): 2,3,4-trisubstituted pyridines

Electrolysis:

Upadhyay et al., synthesized 7-amino-1,2,3,4- tetrahydro-1methyl-2,4-dioxo5-phenyl-pyrido [2,3-d] pyrimidine-6-carbonitrile (76) by an electrochemical induced transformation of aryl aldehydes (73), malononitrile (74) and 6-aminouracil (75) in presence of NaBr in ethanol giving 7-amino-1,2,3,4-tetrahydro- 1methyl-2,4-dioxo5-phenyl-pyrido [2,3- d] pyrimidine-6-carbonitrile (fig. 5a)[64].

Wittig reaction:

Wei et al., gave an efficient strategy for the synthesis of 2,5-dimethyl-4-pyridine (79). Wittig reaction of benzaldehyde (77) and phosphorus ylide (78) was conducted at a temperature of 90° for 5 h in the presence of PhMe.

The mixture was then cooled until it reached room temperature. When it reached room temperature propargyl azide was added along with triphenylphosphine. The product was obtained with a 79 % yield (fig. 5b)[65].

Annulation type reaction:

By Hantzch-type annulation: Huang et al., displayed the synthesis of 2,3,4,6-tetrasubstituted pyridines (82a-b) by a three-component reaction of oximes (80) with trifluoromethyl-diketones (81) and aldehydes in presence of NH₄I and triethylamine giving 2,3,4,6-tetrasubstituted pyridines in moderate yields (fig. 5c)[66].

By Ammonium iodide (NH₄I)-triggered (ammonium acetate+β-dicarbonyl compound) annulation: Duan et al., designed and synthesized ethyl-2,6-diphenylisonicotinate (85). The reaction between ketoxime-enoates (83) and N-acetyl enamide (84) in presence of NH₄I and sodium bisulfate, the product was obtained when 1,4-dioxane was added and the mixture was stirred for 8 h at 120° with 83 % yield (fig. 5d)[67].

Miscellaneous:

By using glacial acetic acid: Maria et al., synthesized pyrazolo[3,4-b] pyridine (88) by reacting 3-substituted-(5-amino-1Hpyrazol- 1-yl) benzenesulfonamide (86) with trifluoromethyl-β-diketone (87) (fig. 5e)[3].

Fig. 5: Schematic representation of synthesis of compounds, (a): 7-amino-1,2,3,4-tetrahydro-1methyl-2,4-dioxo5-phenyl-pyrido [2,3-d]pyrimidine-6-carbonitrile; (b): 2,5-dimethyl-4-pyridine; (c): 2,3,4,6-tetrasubstituted pyridines; (d): Ethyl-2,6- diphenylisonicotinate and (e): pyrazolo[3,4-b] pyridine

By using Phosphoryl chloride (POCl₃): Salem et al., synthesized 2-chloro-4-(furan- 2 - y l ) - 6 - ( n a p h t h a l e m - 1 - y l ) - n i c o t i n o n i t r i l e (92) by the four-component reaction. Firstly, the one-pot reaction between 1-acetylnaphthalene (89), furfural (90), ethyl cyanoacetate and ammonium acetate in absolute ethanol giving 4-(furan-2-yl)-6-(naphthalen-1- yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (91). Secondly, the chlorination of enaminoesters in a mixture of phosphorus oxychloride and phosphorus pentachloride was heated giving off 2-chloro-4-(furan-2-yl)-6- (naphthalem-1-yl)-nicotinonitrile (fig. 6a)[68].

By using malononitrile: Siddiqui et al., designed and synthesized 2-amino-6-(3,5- d i p h e n y l - 4 , 5 - d i h y d r o p y r a z o l - 1 - y l ) - 4 - ( 4 - hydroxyphenyl) nicotinonitrile (97). The reaction takes place among substituted acetophenone (93) and benzaldehyde (94) giving 1-(hydroxy phenyl)-3-phenylpropenones (95). 1-(hydroxy phenyl)-3-phenylpropenones on reaction with hydrazine hydrate gave 1-(3-hydroxy p h e n y l - 5 - p h e n y l - 4 , 5 - d i h y d r o p y r a z o l - 1 - yl) ethanones (96), was further treated with malononitrile and ammonium acetate and refluxed for 10 h giving 2-amino-6-(3,5-diphenyl-4,5- dihydropyrazol-1-yl)-4-(4-hydroxyphenyl) nicotinonitrile in good yield (fig. 6b)[69].

By using piperidine: Kamal et al., synthesized some new heterocyclic pyridine derivative 3-cyano- 4,6-dimethylpyridine-2(1H)-one (100) from the reaction of malononitrile (98) with acetylacetone (99) to give 3-cyano-4,6-dimethylpyridine-2(1H)- one (fig. 6c)[70].

By using aqueous ammonia: Lachowicz et al., presented a synthesis of 5-benzyloxy-2- (hydroxymethyl)pyridine-4(1H)-one (103) obtained by using kojic acid (101). Firstly, it comprises the protection of the 5-hydroxyl group of kojic acid with a benzyl group, by a reaction of benzyl chloride leading to the formation of 5-benzyloxy- 2-(hydroxymethyl)-4H-pyran-4-one (102). It was further converted into 5-benzyloxy- 2 - ( h y d r o x y m e t h y l ) p y r i d i n e - 4 ( 1 H ) - one by reaction with aqueous ammonia under reflux conditions (fig. 6d)[71].

By using methyl pyruvate: Sun et al., synthesized 2-quinolinecarboxylic acid (105) by treating 2-nitrobenzaldehyde (104) with ferrous sulphate and ammonia in the presence of N, N-dimethylformamide giving 2-aminobenzaldehyde (104). Further, 2-aminobenzaldehyde was treated with methyl pyruvate in alkaline conditions giving 2-quinolinecarboxylic acid (fig. 6e)[72]. In conclusion, this article mainly highlights newly stated synthetic procedures for pyridine-containing compounds accompanied by pharmacological activity and structure-activity relationship. In this, different approaches for the synthesis of pyridine derivatives like green synthesis, metal-catalyzed reaction, condensation, cyclization, addition, annulation-type reaction, etc., are reported. Out of these, green synthesis was reported as most easy and time-saving method, as they need easily available solvents (water, ethanol) and operate at an optimum temperature (70°-100°) requiring lesser time (30-40 min) as compared to conventional methods.

Fig. 6: Schematic representation of synthesis of compounds, (a): 2-Chloro-4-(furan-2-yl)-6-(naphthalem-1-yl)-nicotinonitrile; (b): 2-amino-6-(3,5-diphenyl-4,5-dihydropyrazol-1-yl)-4-(4-hydroxyphenyl)nicotinonitrile; (c): 3-cyano-4,6-dimethylpyridine-2(1H)-one; (d): 5-benzyloxy-2-(hydroxymethyl)pyridine-4(1H)-one and (e): 2-quinolinecarboxylic acid

Metal-catalyzed reactions were found not so favourable for small scale preparations as they required expensive solvents (i-PrOH, 2,2,6,6-tetramethylpiperidine 1-oxyl radical, tert-butyl alcohol), yields were also found to be moderate but reagents required were easily available (cyclohexanone, acetophenone, propiophenone). Further, cyclization reactions showed good yield of derivatives (55 %-85 %) and mostly easily available reagents were used (ketones). In addition reaction, optimum temperature was used (50°- 110°) and mostly least expensive solvent was used (toluene). Lastly, an annulation-type reaction was carried out at 120° for approximately 8-12 h showing moderate to good yields using easily available solvent (toluene, 1.4-dioxane). In the structure-activity relationship section, a link was recognized between various pyridine-containing derivatives and functional groups.

Pyridine is a pharmacologically active moiety exhibiting anti-cancer, anti-viral, anti-depressant, anti-convulsant, anti-diabetic, anti-inflammatory, anti-tubercular, and anti-microbial. We hope that this article provides much-needed recent information to researchers who are engaged with pyridine in any way.

Conflict of interests:

The authors declare no conflict of interest.

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