Inverse Electron Demand Diels-Alder Reactions of Heterocyclic Azadienes: [4 + 2] Cycloaddition Reaction of Amidines with 1,3,5-Triazines

• Published in: Journal of organic chemistry Vol. 59; no. 17; pp. 4950 - 4955
• Main Authors: Boger, Dale L, Kochanny, Monica J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.08.1994; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; 1,2,4-TRIAZINES; ACID; THERMAL CYCLOADDITION; DIMETHYL "1,2,4,5-TETRAZINE-3,6-DICARBOXYLATE; STREPTONIGRIN; PYRIMIDINES; DIENOPHILES; CYCLO-ADDITION; FORMAL TOTAL SYNTHESIS; METHYL-ESTER
• DOI: 10.1021/jo00096a044
• ISSN: 0022-3263

A detailed study of the scope of the amidine Diels-Alder reaction with 1,3,5-triazines is described. The thermal reaction of amidines with symmetrical 1,3,5-triazines proceeds with in situ amidine to 1,1-diaminoethene tautomerization, [4 + 2] cycloaddition with the 1,3,5-triazine, loss of ammonia from the initial Diels-Alder adduct with imine generation, imine to enamine tautomerization, and retro Diels-Alder loss of ethyl cyanoformate to provide substituted 4-aminopyrimidines in excellent conversions. The reaction proceeds best with the amidine hydrochloride salts at intermediate reaction temperatures (90-100 degrees C) in polar, aprotic solvents, is rather invariant to the ratio of dienophile-diene used (1:2 congruent to 1:1 congruent to 2:1), and is subject to triazine substitutent effects characteristic of an inverse electron demand Diels-Alder reaction (R = CO(2)Et > R = H >> R = SCH3). Notably, the generality of the amidine [4 + 2] cycloaddition reaction with 1,3,5-triazines which has been extended to include cyclic amidines effectively addresses the limitations of the alternative ynamine or N,O-ketene acetal dienophiles. A comparative examination of amidines, thioimidates, and imidates revealed that amidines are uniquely suited for use in this reaction cascade.