Synthesis via Cycloaddition Reactions

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. 

The Boger pyridine synthesis involves an inverse-electron demand hetero-Diels-Alder [4 + 2] reaction of the electron-deficient 1,2,4-triazine 

208 with an electron-rich dienophile such as enamine 209 followed by a facile retro-Diels-Alder of the unstable intermediate bicyclic species 210 to liberate nitrogen gas and aromatization via loss of pyrrolidine to afford the appropriately substituted pyridine derivative 211. The pyrrolidine enamine 

209 can be generated in situ from the corresponding ketone with pyrrolidine. There is a strong preference for the nucleophilic carbon of the dienophile to add to C-3 of the triazine. 

Boger initially developed the aforementioned methodology to construct penta-substituted pyridine 216 in the formal total synthesis of antitumor antibiotic streptonigrin 217. The requisite 1,2,4-triazene 214 was generated via a Diels-Alder/retro-Diels-Alder sequence between nitrogen-containing dienophile 212 and 1,2,4,5-tartazine 213. Exposure of enamine 214 to 215 resulted in the formation of 216. Similar chemistry was also applied in the synthesis of the structurally related lavendamycin 217.  

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Chapters 9, 10 and 11 describe methods for substitution directly on the ring with successive attention to Nl, C2 and C3. Chapters 12 and 13 are devoted to substituent modification as C3. Chapter 12 is a general discussion of these methods, while Chapter 13 covers the important special cases of the synthesis of 2-aminoethyl (tryptaminc) and 2-aminopropanoic acid (tryptophan) side-chains. Chapter 14 deals with methods for effecting carbo cyclic substitution. Chapter 15 describes synthetically important oxidation and reduction reactions which are characteristic of indoles. Chapter 16 illustrates methods for elaboration of indoles via cycloaddition reactions. 

Summary N-Silylation is a crucial prerequisite for the synthesis of interesting nonnatural amino acids via cycloaddition reactions of unsaturated amines. 

CEJ4035>. Diastereospecific synthesis of r-/3-lactams can be effected via cycloaddition reaction of bisimines and the ketene derived from 582 (R = CH2CO2H) (Staudinger reaction) <2000T8555>. Ruthenium-catalyzed [2-1-2] cycloaddition of norbornene and ynamide 582 (R = C=CPh) <2006T3823> was reported. 

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