Pyridines Diels-Alder approach

With this foundation, Boger communicated the use of 1,2,4-triazines as a dependable, azadiene equivalent for Diels-Alder approaches to substituted pyridines. Electron rich olefin 19, prepared from the corresponding ketone, was allowed to... 

There are other Diels-Alder approaches to pyridines but they do not proceed in one step. For example, Weinreb reported the intramolecular Diels-Alder of oximino malonates tethered to a diene. Thermolysis of 102 produced 103 that upon treatment with base afforded pyridine 104. 

Stanforth and co-workers made additional improvements on the hetero-Diels-Alder approach. They accomplished a one-pot synthesis of pyridines from a p-diketoesters and amidrazones <04T8893>. Deniaud et al. has investigated diazadienium iodide 15 as an aza-diene moiety in the synthesis of pyridines <04TL9557>. They have demonstrated that diazadienium iodide 15 reacts with ketenes, acetylenes and acrylic dienophiles to yield a variety of substituted pyridines as shown in Scheme 5. 

Scheme 14 An aza-Diels-Alder approach to pyrazolo[3,4-b]pyridines.

Martin, J. C. Synthesis of Pyridines from Dicyanopyrimidines. A Diels-Alder Approach to the C-Ring of Streptonigrin. J. Heterocycl. Chem. 17, 1111 (1980). 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

As already described for the all-carbon-Diels-Alder reaction, a hetero-Diels-Alder reaction can also be followed by a retro-hetero-Diels-Alder reaction. This type of process, which has long been known, is especially useful for the synthesis of heterocyclic compounds. Sanchez and coworkers described the synthesis of 2-aminopyridines [48] and 2-glycosylaminopyridines 4-144 [49] by a hetero-Diels-Alder reaction of pyrimidines as 4-143 with dimethyl acetylenedicarboxylate followed by extrusion of methyl isocyanate to give the desired compounds (Scheme 4.30). This approach represents a new method for the synthesis of 2-aminopyridine nucleoside analogues. In addition to the pyridines 4-144, small amounts of pyrimidine derivatives are formed by a Michael-type addition. 

Methods for the synthesis of substituted pyridines remains an intense topic of research. One of the most popular approaches to substituted pyridines remains cycloaddition reactions. While this strategy is not new and many examples are in the current literature <00TL10251>, the state-of-the-art has been expanded. Weinreb and co-workers have reported the regioselective synthesis of pyridines (3) via intramolecular oximino malonate hetero Diels-Alder reactions (1 - 2) <00OL4007>. Similarly, the intramolecular [4 + 2] cycloaddition of... 

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

Steroidal, alicyclic or aromatic annulated pyridines were prepared via a microwave-assisted, base-catalyzed Henry reaction of /1-formyl enamides and nitromethane on an alumina support [97]. Highly substituted tri- and tetrasubstituted pyridines were synthesized in a Bohlmann-Rahtz reaction from ethyl /3-amino crotonate and various alkynones. The reaction involved a Michael addition-cyclodehydration sequence and was effected in a single synthetic step under microwave heating conditions [98]. An alternative approach towards polysubstituted pyridines was based on a reaction sequence involving an inverse electron-demand Diels-Alder reaction between various enamines 45 and 1,2,4-triazines 44 (Sect. 3.6), followed by loss of nitrogen and subsequent elimination-aromatization. Enamines 45 were formed in situ from various ketones and piperidine under one-pot microwave dielectric heating conditions [99]. Furthermore, a remarkable acceleration of the reaction speed (from hours and days to minutes) was observed in a microwave-assisted cycloaddition. Unsymmetrically substituted enamines 45 afforded mixtures of regioisomers (Scheme 35). 

The application of Diels-Alder methodology to pyridine formation can take different approaches. The heteroatom can be sourced from the diene or the dienophile and by varying its position in the starting materials can lead to strategies for different substitution patterns in the pyridine product. While such approaches are well documented, recent reports have both extended the range of derivatives available and incorporated new technology to assist in the optimization of reactions. 

The [4+2] discoimection is a common approach for the synthesis of pyridines. Lipihska has presented an extensive report of Diels-Alder-retro-Diels-Alder reactions of 1,2,4-triazines with enamines to produce cycloalkylpyridines 05T8148>. Triazines have been used as efficient... 

Two novel protocols have been developed for the direct conversion of 1,2,4-triazines 27 into highly substituted pyridines 28 via the inverse-electron demand Diels-Alder reaction a microwave-assisted solvent-free route and a tethered irnine-enarnine approach <05JOC10086>. 

Koyama et al. reported that various kinds of enamines react with the parent or 4-substituted triazines to afford many pyridine derivatives (90) via Diels-Alder reactions (Equation (25)), and the approach was applied to the total syntheses of pyridine alkaloids such as fabianine (91) and fusaric acid (92) (Scheme 14) <85H(23)2789, 86H(24)29, 89H(29)1809, 92MI 610-01, 94H(38)1595>. 

An entirely new approach to the synthesis of ellipticine (267) has been reported by Kozikowski and Havan (315). Crucial in this synthesis is the Diels-Alder addition of an acrylic acid moiety to an oxazole followed by elimination of the oxygen bridge to give a pyridine. Thus, heating the oxazole 738 in acetic acid-acrylonitrile at 145° gave the indolyl-ethyl pyridine 739 in 16% yield (Scheme 59). The iV-acetyl derivative of this intermediate had previously been converted to 267 (266). 

The initially reported structure of the cyctotoxic ascidian alkaloid 2-bromolep-toclinidinone 105 was amenable to a synthesis approach using an intramolecular oxazole-alkene Diels-Alder reaction, as shown in the retro-synthetic analysis in Figure 3.29. In a model system, the A-benzyl-substituted amide 106 afforded a 50% yield of pyridine 107 after refluxing in benzene for 18 h with 0.75 equivalent of DMAP. The analogous NH-carboxamide faded to provide any of the desired tricyclic pyridine. This was attributed to a conformational preference that allows an internal hydrogen bond between the amide-NH and the oxazole, rather than the conformation that allows efficient overlap of the oxazole and olefin. The yield of 107 could be increased to 87% if the reaction was performed in the presence of the Lewis acid europium(hfc)3. This was not further elaborated since the structure of 2-bromoleptoclinidinone was subsequently revised in 1989. 

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