Demjanov-Tiffeneau reaction

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 reaction of nitrous acid with the amino group of the /3-amino alcohol—e.g. 1-aminomethyl-cyclopentanol 1—leads to formation of the nitrosamine 4, from which, through protonation and subsequent loss of water, a diazonium ion species 5 is formed —similar to a diazotization reaction  

With diazonium species like 5, dinitrogen (N2) functions as a good leaving group. Loss of N2 from 5 generates a carbenium ion species 2, which rearranges by a 

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

2-migration of a ring-CHa group to give the more stable hydroxy-substituted carbenium ion 6. Loss of a proton from 6 yields a ring-enlarged ketone—e.g. cyclohexanone 3—as the final product  

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The starting material for the Tiffeneau-Demjanov reaction is available by various methods. A common route is the addition of nitromethane to a cyclic ketone—e.g. cyclopentanone 7—followed by a hydrogenation of the nitro group to give the /3-amino alcohol, e.g. 1 ... 

Various side-reactions may be observed with the Demjanov reaction the Tiffeneau-Demjanov reaction usually gives better yields of the ring-enlarged product. 

This reaction has been used to form ring-expanded cyclic ketones, a procedure known as the Tiffeneau-Demjanov reaction 1... 

Thiocarbonates, synthesis of, 17, 3 Thiocyanation of aromatic amines, phenols, and polynuclear hydrocarbons, 3, 6 Thiophenes, synthesis of, 6, 9 Thorpe-Ziegler condensation, 15, 1 31 Tiemann reaction, 3, 9 Tiffeneau-Demjanov reaction, 11, 2 Tin(n) enolates, 46, 1 Tin hydride method to prepare radicals,... 

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. 

Aminomethylcarbinols yield ketones when treated with nitrous acid. This reaction has been used synthetically to form ring-expanded cyclic ketones, a procedure known as the Tiffeneau-Demjanov reaction The diazotization procedure generates the same type of /3-hydroxycarbonium ion that is formed in the... 

Variations and improvements on the Demanjov and Tiffeneau-Demjanov reaction have been limited. Variations have come in different methods to generate diazonium salts using various acids containing non-nucleophilic counter ions. The use of weaker acids for the Demanjov rearrangement led to diminished amounts of olefmic by-products. Understanding how facile the reaction was at lower temperature also provided higher yield and fewer byproducts. 

Another example of the utility of this reaction is the formation of enantiopure cycloheptenones from optically pure natural products like R-carvone. Hydroxylaminomethylcyclohexene 72 derived from -carvone rearranged to provide two compounds resulting from selective rearrangement of the vinyl carbon. While the alkene migrated into conjugation under the reaction conditions providing 10% of 74, the Tiffeneau-Demjanov reaction provided entry into optically-enriched cycloheptenones. ... 

Because treatment of a primary aliphatic amine with HNO2 gives a mixture of products, it is generally not a useful reaction. An exception is the Tiffeneau-Demjanov reaction, in which a cychc 8-aminoalcohol is treated with nitrous acid to give a ring-expanded ketone, with evolution of nitrogen. 

A synthetically useful version of the reaction is the Tiffeneau-Demjanov reaction, which gives a one-carbon ring expansion of a cyclic j8-aminoalcohol and produces a cyclic ketone. 

The ring expansion reaction (methylene insertion) with diazomethane (CH2N2) appears to involve the same intermediate as that formed from the corresponding primary amine on treatment with nitrous acid (HONO) in the Tiffeneau-Demjanov reaction. ... 

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