2,4,6-trisubstituted pyridines

Thiostrepton family members are biosynthesized by extensive modification of simple peptides. Thus, from amino acid iacorporation studies, the somewhat smaller (mol wt 1200) nosiheptide, which contains five thiazole rings, a trisubstituted iadole, and a trisubstituted pyridine, is speculated to arise from a simple dodecapeptide. This work shows that the thiazole moieties arise from the condensation of serine with cysteiae (159,160). Only a few reports on the biosynthesis of the thiostrepton family are available (159,160). Thiostrepton is presently used ia the United States only as a poly antimicrobial vetetinary ointment (Panalog, Squibb), but thiazole antibiotics have, ia the past, been used as feed additives ia various parts of the world. General (158) and mechanism of action (152) reviews on thiostrepton are available. 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

Bohlmann and Rahtz, in 1957, reported the preparation of 2,3,6-trisubstituted pyridines. Their method employed the Michael addition of acetylenic ketones 35 with enamines 36. The 5-aminoketones 37 are typically isolated and subsequently heated at temperatures greater than 120°C to facilitate the cyclodehydration to afford 38. Again one can see the parallels in this mechanism with that for the Hantzsch protocol. However, in this case the pyridine is formed directly removing the need for the oxidation step in the Hantzsch procedure. 

In a related reaction, heating ketones in the presence of TlClsOTf leads to 1,3,5-trisubstituted arenes. " Nitriles react with 2 mol of acetylene, in the presence of a cobalt catalyst, to give 2-substituted pyridines. " Triketones fix nitrogen gas in the presence of TiCU and lithium metal to form bicyclic pyrrole derivatives. " ... 

An efficient procedure for the synthesis of 2,4,6-trisubstituted and 2,3.4,6-tetrasubstituted pyridines 5 and 6 involves the one-pot reaction of in situ generated a,p-unsaturated imines with carbanions <95TL(36)9297>. 

The Bohlmann-Rahtz synthesis of trisubstituted pyridines from /3-aminocrotonates and an ethynyl ketone has found application in the preparation of a variety of heterocycles based on the substituted pyridine motif. Bagley and coworkers have developed a microwave-assisted modification of this one-pot heteroannulation method that is best conducted in dimethyl sulfoxide at 170 °C for 20 min, providing the desired pyridines in 24—94% yield (Scheme 6.227) [406, 407]. Typically, 2 equivalents of the /3-aminocrotonates were employed. 

Michael addition of (benzotriazol-l-yl)acetonitrile 557 to a,[)-unsatu rated ketones followed by heterocyclization provides new means for preparation of 2,4,5-trisubstituted pyridines. The reaction is catalyzed by bases. In the presence of secondary amines, a nucleophilic attack of amine on the CN group in adduct 556 initiates the cyclization to tetrahydropyridine 558 that subsequently eliminates water and benzotriazole to give pyridine 559. Analogously, in the presence of NaOH, pyridone 560 forms, via intermediate 561 (Scheme 88) <1997JOC6210>. 

Another example of a MCR-based strategy for the synthesis of pyridines was reported by Kantevari et al. in 2007. Thus, the three-component condensation of enaminones, 1,3-dicarbonyls, and ammonium acetate in the presence of a catalytic amount of a tangstocobaltate salt as heterogeneous catalyst, either in refluxing solvent or under solvent-free conditions, allowed the regioselective formation of 2,3,6-trisubstituted pyridines and 2,7,7-trisubstituted tetrahydroquinolin-5-ones (Scheme 55) [155]. This methodology combines shorter reaction times and... 

When the 4-position is substituted, Grignard addition occurs at the 2-position, to eventually give a 2,4,6-trisubstituted pyridine via the 6-lithiated species (Scheme 145) (88TL1751). Alternatively, if the 4-substituent is a chloro (88TL1751) or methoxy group (89TL5053), the initial product can be hydrolyzed to an enone rather than being aromatized to a pyridine. 

Cycloaddition of 2-amino-3-cyano-4,5,6-trisubstituted pyridine 360 with formamidine acetate in the presence of diglyme produced the 4-pyridopyrimidinylamine 361 as its hydrochloride salt (Equation 30) <2000USP6030969>. 

Allylic carboxylation. Diethyl oxomalonate (1) undergoes a thermal ene reaction with mono-, di-, and trisubstituted alkenes at 145 180°. The reaction is also subject to catalysis with Lewis acids, which can lead to a different ene product. The products are a-hydroxymalonic esters. The corresponding malonic acids are converted to carboxylic acids by bisdecarboxylation with NaI04 and a trace of pyridine- or with ceric ammonium nitrate (CAN). Diethyl oxomalonate then functions as an cnophilic equivalent of C02. 

Deoxygenation of epoxides. Hpoxidcs, particularly a,/)-disubstituted ones, are deoxygenated by reaction with P2I4 or PI3 in CS2 at room temperature in 70 90% yield. The reaction occurs with retention (>97%) of configuration. In the case of terminal, trisubstituted, and tetrasubstituted epoxides, the yields with P2I4 or PI3 are low ( 50%) unless pyridine or triethylamine is added. 

As broadly demonstrated in aromatic DoM chemistry (90CRV879), iterative metalation of pyridyl O-carbamates are synthetically useful processes. Thus, sequential metalation reactions of 3- and 4-pyridyl O-carbamates with electrophiles that provide incipient DMGs afford 3,4,5-trisubstituted pyridines 327, 328, and 329, respectively (Scheme 99) (85JOC5436). 

However, 2,4,6-trisubstituted pyrylium salts with certain active methyl and methylene compounds undergo ring fission and subsequent cyclization to benzenoid products. 2,4,6-Triphenylpyrylium ion (261 Z = O) in this way forms 2,4,6-triphenylnitrobenzene (299) with nitromethane and the substituted benzoic acid (300) with malonic acid, the latter reaction involving a decarboxylation. In reactions of this type, 1,3-oxazinium salts react with active hydrogen compounds to give pyridines (Scheme 25). 

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. 

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