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19.5.14.1.9 Variation 9: Reaction with Nitriles (Thorpe–Ziegler Reaction)

DOI: 10.1055/sos-SD-019-00220

Murahashi, S.-I.Science of Synthesis, (200419356.

Addition of carbon nucleophiles to the CN bonds of nitriles is one of the most attractive transformations of nitriles. The reported methods are limited to strong-base promoted intramolecular cyclization reactions of dinitriles (ThorpeZiegler reaction). The reaction of nitriles with strong bases generates nitrile anions that attack the neutral nitrile to generate an intermediate imine, which undergoes isomerization and protonation to give the enaminonitrile.[‌80‌‌82‌] The ThorpeZiegler dinitrile cyclization provides a powerful method of assembling 5- to 33-membered rings.[‌11‌,‌80‌] Dinitrile cyclizations of five- and six-membered rings are particularly facile with analogous seven- or eight-membered rings being similarly efficient. Traditionally, dinitriles have been cyclized using sodium hydride, alkoxide, and amide bases,[‌83‌] although in some favorable instances very weak bases are effective for the cyclization.[‌84‌]

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MM(MM8)eMM, e=8, 8 MeMM(MMe8)8 8888 [‌88‌]
MMMM8MM8Me [MeM(MM)(MMe8)8] (eee.) >88 [‌88‌]
MMMM8MM8e-Me
+MeMMM8MM
[MeM(MM)(MMe8)8] (eee.) 88 [‌88‌]
MMMM8MM8Me
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[MeM(MM)(MMe8)8] (eee.) 88 [‌88‌]
[MeM8(M-eMe8)8] (eee.) 88 [‌88‌]
MeMM [MeM8(M-eMe8)8] (eee.) 88 [‌88‌]

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8-Meeee-8M-eeeeee-8-eeeeeeeeeeee (88); Meeeeee Meeeeeeee:[‌88‌]

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