Highly substituted pyridine synthesi

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. 

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. 

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

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...

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. 

Since 1985, the major application of intramolecular oxazole-alkene Diels-Alder reactions has been in the held of natural product synthesis, in which readily available oxazole-olehns can provide access to highly substituted pyridines. All of the intramolecular reactions described here have four-atom linkers between the oxazole and olehn, found by Turchi to be optimal for these cycloadditions. 

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... 

Park and coworkers developed a rhodium-catalyzed synthesis of pyri-dines from 2i/-azirines and carbenoids [72]. In the presence of catalytic amount of [Rh2(esp)2], highly substituted pyridines were produced in good to excellent yields (Scheme 3.34). This procedure was applied by Liang and CO workers in the synthesis of CFs-containing pyridines recently [73]. 

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. 

A rhodium-catalyzed one-pot synthesis of substituted pyridine derivatives from a,(3-unsaturated ketoximes and alkynes was developed in 2008 by Cheng and coworkers [99], Good yields of the desired pyri-dines can be obtained (Scheme 3.48). The reaction was proposed to proceed via rhodium-catalyzed chelation-assisted activation of the (3—C—H bond of a,(3-unsaturated ketoximes and subsequent reaction with alkynes followed by reductive elimination, intramolecular electro-cyclization, and aromatization to give highly substituted pyridine derivatives finally [100]. Later on, in their further studies, substituted isoquinolines and tetrahydroquinoline derivatives can be prepared by this catalyst system as well [101]. Their reaction mechanism was supported by isolation of the ort/jo-alkenylation products. Here, only asymmetric internal alkynes can be applied. 

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). 

Liebeskind and Liu developed a copper-catalyzed synthesis of pyri-dines from a,(3-unsaturated ketoxime O-pentafluorobenzoates and alkenylboronic acids in 2008 [118], This cascade reaction consisted of a novel A/ -iminative, Cu-catalyzed cross-coupling of alkenylboronic acids at the NsO bond of a,(3-unsaturated ketoxime O-pentafluorobenzoates, electrocyclization of the resulting 3-azatriene, and air oxidation at the last stage. Highly substituted pyridines were formed in moderate to excellent isolated yields (Scheme 3.59). 

Highly substituted pyridines-based molecules represent an important class of heterocycles that are common in natural products and other functional materials. Due to the importance of the core structure, several methods for the synthesis of this motif have been recently developed. ... 

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. 

A synthetically powerful method, an approach based on cycloaddition chemistry, allows one to assemble the pyridine ring in one step. Not only is this method efficient, atom economy, but also its convergency allows for the preparation for highly substituted systems in which one can, in principle, control all five positions on the pyridine ring. A versatile example of this methodology is the Boger reaction. It has been applied to the synthesis of a very diverse set of targets. 

The synthesis of phomazarin 54 utilized the highly oxygenated alkene 52 paired with triazine 51 to produce 53. Further manipulations transformed this fully substituted pyridine into 54. 

Formation of the central six-membered ring is the key to the synthesis of the highly substituted irnidazo[4,5-r]-[2,7]naphthyridines, 67 and 68 (Equations 15 and 16) the bicyclic precursors 65 and 66 are themselves the products of Hantzsch pyridine syntheses <1999PHA814>. 

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>. 

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