Synthesis of Highly Substituted Pyridines

Ben-Naim, Hydrophobic Interaction, Plenum Press, New York, 1980 (b) C. Tanford, The Hydrophobic Effect, 2nd ed., John Wiley Sons, Inc, New York, 1980. 

Radiocontrast Agents Handbook of Experimental Pharmacology, Springer, Berlin, 1993. 

Yokoyama, H. Hikawa, M. Mitsuhashi, A. Uyama and Y. Murakami, Tetrahedron Lett., 1999, 40, 7803. 

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The acyclic version of Larock s heteroannulation was successfully applied to the synthesis of highly substituted pyridines [166]. The annulation of rert-butylimine 210 with phenyl propargyl alcohol produced pyridine 211 regioselectively in excellent yield. The regiochemistry obtained was governed by steric effects. Furthermore, the choice of imines was crucial to the success of the heteroannulations. terr-Butylimine was the substrate of choice, since all other imines including methyl, isopropyl, allyl and benzyl imines failed completely to produce the desired heterocyclic products. 

Fig. 12.26 Proposed mechanism for the synthesis of highly substituted pyridines in [bmim][OH]...

Remu BC, Jana R, Sowmitih S (2007) An improved procedure for the three-component synthesis of highly substituted pyridines using ionic liquid. J Oig Lett 72 3152-3154... 

Recently, Ranu and coworkers [45] used basic ionic liquid, l-butyl-3-methyUm-idazolium hydroxide [bmimJOH, in place of conventional bases to provide a selective, high-yielding one-pot synthesis of highly substituted pyridines through a three-component condensation of aldehydes, malononitrile, and Ihiophenols at room temperature (Scheme 17.3). The other advantages of this procedure are a lack of hazardous organic solvents in the reaction and the reusability of ionic liquids. 

Scheme 17.3 A one-pot synthesis of highly substituted pyridines under [bmimJOH ionic liquid...

Pyrrolidine has been the common organocatalyst used by Boger and coworkers for the synthesis of highly substituted pyridines based on the inverse-electron-demand Diels-Alder reaction of in situ formed enamines and 1,2,4-triazines. Barbas and coworkers have described the amine-catalysed direct self-Diels-Alder reaction of a,p-unsaturated ketones. The inverse-electron-demand hetero-Diels-Alder reaction of nitrosoalkenes and in situ formed enamines as dienophiles was also shown to be possible. ... 

Wang ZQ, Ge ZM, Cheng TM, Li RT (2009) Synthesis of highly substituted pyridines via a one-pot, three-component caseade reaction of malononitrile with aldehydes and S-alkyliso-thiouronium salts in water. Synlett 2009 2020-2022... 

Safaei-Ghomi J, Ghasemzadeh MA, Mehrabi M (2013) Calcium oxide nanoparticles catalyzed one-step multicomponent synthesis of highly substituted pyridines in aqueous ethanol... 

A novel protocol for the synthesis of highly substituted pyridines in a single synthesis step by the microwave-assisted Michael addition-cyclodehydration of ethyl p-aminocrotonate, an alky none, has been developed by Bagley et al. (2002). This new one-pot Bohlmann-Rahtz procedure was conducted at 170°C in a self tunable microwave synthesizer giving high yield with total control of regiochemistry. 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

In an interesting study with potential for the synthesis of 3-substituted pyridines, Katritzky has shown that LDA metalation of the benzothiazol-2-yl thioether 479 gives the highly coordinated lithio species 480, as demonstrated by quench with several electrophiles to give products 481 (Scheme 144) [87H(26)427]. 

The benefits obtained with microwave-assisted dry chemistry was recently advocated for combinatorial chemistry and applied to the high output, automated, one-step, parallel synthesis of various substituted pyridines using this procedure [131]. 

A facile one-pot synthesis of trifluoromethyl-substituted pyridine derivatives has been reported (93JHC71). The procedure depends on the high reactivity of trifluroacetoacetyl chloride, which is generated in situ from trifluoroacetyl chloride and ketene. Thus, the enaminone 391 gives the intermediate enamide 392, which is refluxed in triethylamine to give the... 

This sequential substitution methodology, therefore, offers great scope for the synthesis of a wide range of highly substituted pyridine derivatives that are of continuing interest to the life science and materials industries. 

The Diels-Alder reaction of oxazoles with alkenes, alkynes, and heterodieno-philes has become a valuable tool for the construction of highly substituted pyridines, furans, and other heterocycles and has now been exploited for the synthesis of diverse compounds from pharmaceuticals to complex natural products. These reactions have been extensively reviewed. The purpose of this chapter is to provide an introduction to the use of oxazoles in Diels-Alder cycloadditions and an update on these reactions since 1985. 

Overall, while this excursion has been brief, the above examples should provide a preliminaiy indication of the power of azadiene-based inverse-electron-demand Diels—Alder reactions in the context of total synthesis, particularly for the synthesis of highly substituted heterocyclic systems such as pyridines, diazines, and pyrimidines. Arguably, few if any other methods enable such facile, diverse, and consistent constructions of these challenging aromatic systems. With this background in place, we are now prepared to analyze the total synthesis of isochrysohermidin (1) by Boger and Baldino. 

An InCls-catalyzed sequential multicomponent reaction for pyridines synthesis was developed in 2014 [84]. Then on using 2-furfurylamine, /3-dicarbonyl compounds, and a,/3-unsaturated aldehydes as the substrates with ethanol as the solvent, good to excellent yields of highly substituted pyridines were prepared under the assistance of microwave irradiation (Scheme 3.39). 2-Furylmethyl side chain was lost as the byproduct. Quinolones, isoquinolines, phenanthridines, and more complex fused pyridine systems could be prepared by this method as well. 

Ellman, Bergman, and coworker reported a rhodium-catalyzed procedure for the synthesis of pyridines from alkynes and a,/ -unsaturated N-benzyl aldimines and ketimines in 2008 [107]. The reaction proceeded via C-H alkenylation/electrocyclization/aromatization sequence through dihydropyridine intermediates. The C-H activated complex was isolated and determination by X-ray analysis. Good yields of highly substituted pyridines were produced in one-pot manner (Scheme 3.50). 

More recently, this chemistry has been extended to the synthesis of isoquinolines by employing the i-butylimines of o-halobenzaldehydes (Scheme 4).5 By employing vinylic halides, one obtains highly substituted pyridines. 

Inverse type hetero-Diels-Alder reactions between p-acyloxy-a-phenylthio substituted a, p-unsaturated cabonyl compounds as 1-oxa-1,3-dienes, enol ethers, a-alkoxy acrylates, and styrenes, respectively, as hetero-dienophiles result in an efficient one step synthesis of highly functionalized 3,4-dihydro-2H-pyrans (hex-4-enopyranosides). These compounds are diastereospecifically transformed into deoxy and amino-deoxy sugars such as the antibiotic ramulosin, in pyridines having a variety of electron donating substituents, in the important 3-deoxy-2-gly-culosonates, in precursors for macrolide synthesis, and in C.-aryl-glucopyranosides. 

A novel solid-phase synthesis of pyrrolo[3,4- ]pyridines using a sequence of Knoevenagel and Hantzsch condensation reactions has been reported <199981951 >. The reactions lead to a variety of highly substituted pyrrolo[3,4- ]pyridines, 70. 

Historically, the first example of such a cyclization was the high-yield synthesis of 2-substituted benzimidazoles 104, on treatment of A -aryl-A -hydroxyamidines 101 with benzenesulfonyl chloride in the presence of a base (usually Et3N or pyridine) under anhydrous conditions (58JCS2086). The reaction most likely proceeds through... 

The application of polyphosphoric acid as a reagent for the synthesis of 2-substituted imidazo[4,5-cjpyridines (349) has been frequently used <89JHC289,90JHC1825). For example, the condensation of p-aminobenzoic acid with an equimolar amount of 3,4-diaminopyridine (348) in polyphosphoric acid (85% phosphorus pentoxide) gave a good yield of the highly colored imidazo[4,5-c]pyridine (349) (Equation (27)). 

Krohnke pyridine synthesis Condensation of an unsaturated ketone with an a-halo ketone to give highly substituted pyridines. 254... 

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