Demjanov rearrangement amino-alcohols

When a cyclic /3-amino alcohol—e.g. 1—is treated with nitrous acid, a deamination reaction can take place, to give a carbenium ion species 2, which in turn can undergo a rearrangement and subsequent loss of a proton to yield a ring-enlarged cyclic ketone 3. This reaction is called the Tiffeneau-Demjanov reactionit is of wider scope than the original Demjanov reaction ... 

The stabilization of the intermediate as a carhenium - oxonium ion in the diazotization of P-amino alcohols (Tiffeneau-Demjanov rearrangement) is responsible for the formation of 4-bromo-5,5-dimethylbicyclo[2.1.1]hexane-l-carbaldehyde (30) in the reaction of l-amino-4-bromo-7,7-dimethylbicyclo[2.2.1]heptan-2-ol with nitric acid.96... 

Fig. 14.21. Ring expansion of cyclic ketones via the Tiffe-neau-Demjanov rearrangement. The first step consists of the additions of HCN or nitromethane, respectively, to form either the cyanohydrin or the /J-nitroalcohol, respectively. The vicinal amino alcohol A is formed in the next step by reduction with LiAlH4. TheTiffeneau-Demjanov rearrangement starts after diazota-tion with the dediazotation.

Selectivity in rearrangement reactions is affected by the electronic nature of both the group that migrates and the group that is left behind. But there is more Stereochemistry is important too. The outcome of diazotization and semipinacol rearrangement (Tiffeneau-Demjanov rearrangement) of this amino-alcohol depends entirely on the diaster eoisomer you start with. There are four diastereoisomers, and we have drawn each one in the only conformation it can reasonably adopt, with the f-butyl group equatorial. 

Similar results were obtained on application of the related Tiffeneau-Demjanov reaction. This semipi-nacol-type reaction, an extension of the Demjanov rearrangement, involves the rearrangement of a diazonium ion (25 Scheme 7), which is generated by the diazotization of the corresponding amino alcohol (24).The amino alcohol is obtained from the ketone by reduction of a nitrome ane adduct (23a), cyanohydrin (23b) or trimethylsilyl cyanohydrin (23c). This procedure allows for a controlled addition-rearrangement sequence in cases where the use of diazomethane is complicated by the further reaction of the product ketone. 

Semipinacol rearrangements of diazonium salts derived from 2-amino alcohols are sometimes called TIffeneau-DemJanov rearrangements. 

Inversion of configuration is normally observed on rearrangement of cyclic 2-amino alcohol substrates. Collins et alP have examined in detail the stereochemical course of the Tiffeneau-Demjanov rearrangement in acyclic substrates. In a series of 2-amino-1,2-diaryl alcohols studied, variable amounts of inversion were observed, while in some cases retention of configuration predominated (equation 19). This complexity can be attributed to the flexibility of such acyclic substrates where several conformations are possible in the transition states. 

Tiffeneau-Demjanov ring expansion. Rearrangement of (i-amino alcohols on diazotization with nitrous acid to give ring-expanded carbonyl compounds. 

Diazotization of alkylamines represents the most direct conceivable route to diazoalkanes (2). However, isolation of non-stabilized diazoalkanes by this strategy is not feasible they fail to survive the strongly acidic conditions of the synthesis. If diazotization is performed on 1,2-amino alcohols with sodium nitrite at low pH, Tiffeneau-Demjanov rearrangement (TDR) [64, 65] occurs through a cationic (vs zwitterionic) intermediate to give a rearranged ketone (3). 

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