Boger reaction

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 Boger pyridine synthesis involves the reaction of triazine 1 with activated alkene 2 in a hetero-Diels-Alder fashion. The intermediate bicyclic species 3 is unstable and a facile cycloreversion takes place due to the loss of nitrogen gas to afford the appropriately substituted pyridine derivative 4. 

Prior to the delineation of the concept of conservation of orbital symmetry by Woodward and Hoffmann, Bachmann and Deno reported that all Diels-Alder reactions 

Independently, Kondrat eva reported that oxazoles 7 would undergo reactions with alkenes to afford pyridine derivatives 8. 

An example of this methodology was its use in the synthesis of vitamin Be, pyridoxine 12. Cycloaddition of oxazole 9, prepared from ethyl A-acetylalanate and P2O5, with maleic anhydride initially gave 10. Upon exposure to acidic ethanol, the oxabicyclooctane system fragments to afford pyridine 11. Reduction of the ester substituents with LiAlIU generated the desired product 12. 

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Galatsis, P. Boger Reaction In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2005, 323-339. (Review). 

Pyridines can be achieved by the [4 + 2] hetero Diels-Alder cycloaddition of i) an alkene dienophile and an 3-azadiene such as 1,2,4-triazine (the Boger reaction), oxazole (Kondrat eva pyridine synthesis), oxazinone, pyrimidine, or ii) an alkene and a 4-azadiene or iii) a butadiene and an azadienophile. 

Several examples of intramolecular Boger reactions toward the synthesis of pyridine-containing heterocyclic systems were reported by the Taylor group and the Snyder group, For instance, intramolecular cyclization of triazine 219, after loss of nitrogen, afforded 220. Alternatively, triazine 221 generated bicyclic systems 222, which was then oxidized to 223. ... 

Boger et al. prepared Duocarmycin SA via asymmetric epoxidation of a cyclic olefin 54." The stereochemistry set by the epoxidation step was used for subsequent C-C bond forming reactions. Epoxidation of olefin 54 was carried at -78°C to provide... 

In an approach to the AB rings of rubrolone 65, Boger examined the use of oxazinones as a replacement for triazines. Reaction of l,3-oxazin-6-one 66 with enamines 67 produced the corresponding pyridines 70. The reaction proceeds in a manner analogous to the triazines however, instead of losing nitrogen, these systems lose CO2 via the intermediate bicyclo[2.2.2]octanes 68. The resultant 69 then loses pyrrolidine as in the triazine example. 

For examples of Diels-Alder reactions involving 2-azadienes, see (a) Boger, D.L. Weinreb, S.M. In Hetero Diels-Alder Methodology in Organic Synthesis, Academic Press San Diego, 1987, p. 255 (b) Boger, D. L. Tetrahedron 1983, 39, 2869. 

Boger D. L. Heterocyclic and Acyclic Azadiene Diels-Alder Reactions Total Synthesis of Nothapodytine B. J. Heterocycl. Chem. 1998 35 1003-1011 Keywords inverse electron-demand Diels-Alder reactions, acyclic azadienes, synthesis of natural products... 

Having an efficient total synthesis of the indole alkaloid vindoline in mind, the Boger group [47] developed a facile entry to its core structure using a domino [4+2]/[3+2] cycloaddition. Reaction of the 1,3,4-oxadiazoles 4-139 led to 4-140 in high yield and excellent stereoselectivity via the intermediates 4-141 and 4-142 (Scheme 4.29). 

A few stoichiometric reactions that formed aromatic carbon nitrogen bonds in the presence of stoichiometric amounts of Pd(PPh3)4 had been reported by Boger and co-workers (Equation (3)).24-26 In the absence of base, the palladium(0) was apparently not regenerated. Pd(PPh3)4 failed to catalyze these reactions when used in a 1 mol.% quantity, but it did induce cyclization in good yield when it was used in stoichiometric amounts 24-26... 

In contrast to the failure of Diels-Alder reactions, dipolar cycloadditions of indoles are much more successful, and the Boger group has reported a fascinating [4+2]/l,3-dipolar cycloaddition cascade involving indole as the dipolarophile in their impressive synthesis of vindoline (Scheme 4.8) [26]. After the initial... 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

The Boger group synthesis commences with a Stille coupling of a stannyl acetylene with two equivalents of a highly oxygenated bromobenzene to yield a symmetrical diarylalkyne (82). The subsequent reaction of this alkyne (82) with 3,6-dicabomethoxytetrazine under Diels-Alder/retrograde Diels-Alder... 

One of the earliest syntheses of lavendamycin methyl ester, however, did not employ either the Pictet-Spengler or the Bischler-Napieralski reactions for construction of the /J-carboline ring system. Instead, a palladium-promoted ring closure of aryl pyridine 36 (Fig. 12) was used to prepare /1-carboline 37 by Boger and coworkers [35]. Unfortunately, stoichiometric palladium was found to be necessary, in this case 1.5 equivalents of the tetrakis(triphenylphosphine)palladium(0) being used. Friedlander condensation with aldehyde 38 in the presence of benzyltrimethylammonium hydrox-... 

Applications of the cross-metathesis reaction in more diverse areas of organic chemistry are beginning to appear in the literature. For example, the use of alkene metathesis in solution-phase combinatorial synthesis was recently reported by Boger and co-workers [45]. They assembled a chemical library of 600 compounds 27 (including cisttrans isomers) in which the final reaction was the metathesis of a mixture of 24 oo-alkene carboxamides 26 (prepared from six ami-nodiacetamides, with differing amide groups, each functionalised with four to-alkene carboxylic acids) (Eq.27). 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

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