2.3.4- trisubstituted pyridine derivative

Nucleophilic addition at the 2-position of pyrylium salts (223) occurs readily under mild conditions and when ammonia or primary amines are used the subsequent ring-opening/ring-closure sequences give pyridines (224) and pyridinium salts (222), respectively (Section 3.2.1.6.4.iii). The process is most useful for the synthesis of 2,4,6-trisubstituted pyridine derivatives. Thiinium salts (226) are conveniently prepared from pyrylium salts (225) by treatment with sodium sulfide (Section 3.2.1.6.5), Thiinium salts (226) react with ammonia and amines similarly to their pyrylium analogues. 

The research team of E.-S. Lee synthesized and evaiuated severai 2,4,6-trisubstituted pyridine derivatives as potential topoisomerase I inhibitors. One of these compounds, 4-furan-2-yl-2-(2-furan-2-yl-vinyl)-6-thiophen-2-yl-pyridine, was prepared by the Krohnke pyridine synthesis and showed strong topoisomerase I inhibitory activity. 

This reaction was first reported by Krohnke et al. in 1961. It is the synthesis of 2,4,6-trisubstituted pyridine derivatives involving the formation of pyridinium ylide from pyridine and a-bromoketone, which undergoes the 1,4-Michael addition to an a, -unsaturaled compound to form 1,5-dicarbonyl compounds and cyclizes with ammonium acetate. Therefore, it is generally known as the Krohnke pyridine synthesis or Krohnke reaction. In this reaction, the intermediate 1,5-dicarbonyl compounds do not need to be isolated from reaction mixture. Because three different substituents can be introduced into pyridine ring, this reaction becomes the ideal model for combinatorial synthesis, and a library pool containing pyridine from 9 to over 200 has been generated by this reaction. 

In 1999, Katritzky reported a novel [3+2+1] synthesis of 2,4,6-trisubstituted pyridine derivatives that used the Michael addition of a-benzotriazolyl ketones to a,P-unsaturated carbonyl compounds. This reaction resembles the Krohnke pyridine synthesis and is an extension of Katritzky s earlier studies with benzotriazolyl derivatives that provided access to pyridones, 2-thiopyridones, 5-alkyl-2,4-diphenylpyridines and 2-aminopyridines. This approach is attractive as both components are readily synthesized or commercially available. The availability of these starting materials allows for an efficient access to structurally diverse 2,4,6-triaryl pyridines when combined with ammonium acetate in acetic acid at reflux. In addition, it is possible to access fused 2,3,4,6-tetrasubstituted pyridines from the requisite fused bicyclic ketone starting material. The preparation of the pyridine ring via benzotriazole methodology has resulted in improved yields for many compounds and the opportunity to synthesize molecules with a substitution pattern that would be difficult to prepare by other methods. 

An efficient Cu(OTf)2-catalyzed 2,4,6-trisubstituted pyridine derivatives synthesis via C-N bond cleavage of aromatic methylamines and C(sp )-H bond activated of ketones was developed by Jiang s group (Scheme 8.80). A wide range of 2,4,6-trisubstituted pyridines could be obtained up to 95% yield at 100 °C under CU/O2 under this catalytic system with neat conditions. This process should be initiated by copper-catalyzed aerobic oxidative cleavage of C-N bond of aromatic methylamines [150]. 

Scheme 8.80 Synthesis of 2,4,6-trisubstituted pyridine derivative from aromatic methylamines and ketones.

The 2,3,4-trisubstituted pyridine derivative 24 was designed as a potential L-Pro-L-Leu-Gly-NH2 (PLG) tripeptidomimetic scaffold based on conformational and electrostatic comparison with the natural peptide. Compound 24 exhibits higher potency with enhanced the response of the dopamine agonist A-propylapomorpholine (NPA) at human E>2 receptors compared to PLG in a cell-based assay. 

SCHEME 48 Synthesis of trisubstituted pyridine derivatives using aryne MCRs [70]. 

Microwave reaction conditions have been reported for the synthesis of 2-pyridones in a modern version of the traditional three-component condensation reaction (Scheme 108) <2004T8633>. A library of 18 3,5,6-trisubstituted pyridines was generated and includes aryl, alkyl, and fused derivatives. 

Imatinib mesylate 94 containing a 3-substituted pyridine ring <2000EP0564409>, and a trisubstituted quinoline derivative, topotecan hydrochloride 95, are antineoplastic agents <2002EP0802915>. 

In the total synthesis of ( )-WS75644B 360, a biaryl endothelin converting enzyme inhibitor, pyrone 357 derived from kojic acid was converted to pyridone 358 by reaction with concentrated ammonium hydroxide in a sealed flask at 90 °C. The resulting pyridine was subsequently converted to 2,4,5-trisubstituted pyridine 359 and ultimately elaborated to complete the total synthesis (Scheme 54) <1997TL1297>. 

Amythiamicin D was the first in the family to be synthesized. The 2,3,6-trisubstituted pyridine core was synthesized from serine-derived l-alkoxy-2-azadienes and thiazoyl enamide dienophiles ultilizing a biosynthesis-inspired hetero-Diels-Alder route under MW irradiation. After successive incorporation of glycine and bis-thiazole fragments, amythismicin D was obtained by macrocyclization <2005JA15644, 2004CC946>. 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

The trisubstituted thiophenes 21 were accessed by treatment of the intermediates 22 with ethyl 2-diazo-3-trimethylsilyloxy-3-butenoate 23 in the presence of Hg(OAc)2. The products 21 subsequently served as precursors for some thieno[3,2-6]pyridine derivatives <03JOC4867>. 

Pyridinium salts corresponding to 2,4,6-trisubstituted pyridines, which must be prepared by reacting a primary amine with 2,4,6-trisubstituted pyrylium perchlorate (see section 8.1.2.2) are attacked by a variety of nucleophiles with transfer of the N-substituent to the attacking reagent and as such are convenient alkylating agents, and, recalling that the precursor to the pyridinium salt is the primary amine, the sequence also represents the overall transformation of a primary amine into a variety of derivatives. 

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