Tiffeneau-Demjanov ring expansion

What is Tiffeneau-Demjanov ring expansion?

The Tiffeneau-Demjanov ring expansion, a multi-step extension of the Demjanov rearrangement, was first documented in 1937 by Tiffeneau et al. This process elongates carbonyl compounds by one carbon atom via conversion of the carbonyl compound into a β-amino alcohol, followed by diazotization with nitrous acid HNO2. This reaction is also known as the Tiffeneau-Demjanov rearrangement, Tiffeneau-Demjanov  reaction, or Tiffeneau-Demjanov homologation, and is frequently used to expand the ring of cyclic ketones.

Tiffeneau-Demjanov ring expansion - general reaction scheme - Tiffeneau-Demjanov rearrangement - Tiffeneau-Demjanov  reaction - Tiffeneau-Demjanov homologation
Tiffeneau-Demjanov ring expansion

β-amino alcohols are typically prepared by reducing cyanohydrins or β-nitro alcohols, which are derived from ketones and sodium nitromethane. The migrating aptitudes of functional groups during Tiffeneau-Demjanov ring expansion correspond with their electron density, and a general migrating aptitude trend of:

methylenecyclopropyl > methine

has been observed.

However, this trend does not account for steric hindrance or ring strain, which can impact the migration of functional groups. It is noteworthy that the stereochemistry of the migrating carbon is generally retained after rearrangement, and the yield of rearrangement in cyclic ketones decreases as ring size increases.

Although Tiffeneau-Demjanov ring expansion is valuable for cyclic ketones, it is limited by the availability of β-amino cyclic alcohols, the stability of cyanohydrin, and the steric strain factors of ketones.

References

Tiffeneau, M.; Weill, P. and Tchoubar, B., “Isomérisation de l’oxyde de méthylène cyclohexane en hexahydrobenzaldéhyde et désamination de l’aminoalcool correspondant en cycloheptanone” [Isomerization of cyclohexane methylene oxide to hexahydrobenzaldehyde and deamination of the corresponding aminoalcohol to cycloheptanoneComptes rendus de l’Académie des Sciences, 1937, 205, 54-56

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