Tiffeneau

TiFFENEAU Aminoalcohoi rearrangement Cationic rearrangement (nng enlargement) of 1,2-aminoalcohois by diazotizatlon... 

To establish the structure of A-homo ketone (3b) Nelson and Schut repeated the TifFeneau ring enlargement of 5a-cholestanone [(Ib) (6a) (6b) -> (7)] and obtained a ketone identical with A-homo ketone (3b). 

It is recommended that Nelson and Schut s diazomethane procedure be considered first for preparing saturated A-homo-4-ketones, or enlarging cyclic ketones in general, rather than the Tiffeneau procedure, because fewer steps are involved, isolation and purification are operationally simpler, and the overall yield is often better. 

A. Saturated B-Homo Ketones and Hydrocarbons 1. Tiffeneau Ring Enlargement... 

B-Homosteroids were first reported by Ringold in the course of an investigation of the relationship of structural changes to biological activity of anabolic agents. The Tiffeneau rearrangement sequence described earlier for the preparation of A-homosteroids was used to synthesize 17/ -hydroxy-B-homo-5a-androstan-3-one (56a). 

Tiffeneau ring enlargement of 5a-deuterio ketone (59) gives the required 3yS-hydroxy-B-homo-5a-deuteriocholestan-7-one acetate (60). The 6a-bromo-3 -hydroxy-B-homo-5a-deuteriocholestan-7-one acetate (61) obtained by bromination is then treated with lithium bromide in dimethylformamide to give the deuterium free a,j5-unsaturated ketone (62). The loss of deuterium bromide proves that bromination takes place at C-6 and that the carbonyl group must therefore be located at C-7. 

Tiffeneau ring enlargement is a route to D-homosteroids. Goldberg and Monnier" treated the 17i5-hydroxy-20-amine (91) prepared by hydrogenation of 17a-cyano-5a-androstane-3)3,17j5-diol (90a) with nitrous acid and obtained 3i5-hydroxy-5a-D-homo-androstan-17a-one (92). 

Goldberg and Wydler have shown that the 17a-ketone is not the only product of the Tiffeneau ring enlargement sequence. Careful examination of the products derived from nitrous acid deamination of 17a-aminomethyl-5a-androstane-3/l,17j6-diol 3-acetate (91) showed the presence of a minor amount of isomeric D-homo-17-one (98). 

An advantage of Tiffeneau ring enlargement and rearrangement of 17a-hydroxy-20-keto steroids for preparing of D-homosteroids is the ready availability of the starting 17-ketones. Both procedures involve mild conditions which allow a wide variety of suitably protected functional groups to be present. 

B-homo-estr-5(10) -en-17-one, 381 Ring enlargement by the Tiffeneau procedure... 

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 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 procedure was carried out by the checkers and compared with Tiffeneau s procedure. Tiffcneau s directions seem preferable for the following reasons. There was much less tendency to form an emulsion when the sodium salt was extracted with ether. The emulsion in Hibbert s methods was frequently persistent and the solution became warm before the aqueous solution could be separated from the ether, thus causing decomposition. A 10 per cent solution of sodium ethylate is difficult to handle for it crystallizes and cannot be added from a separatory funnel. If more alcohol is added the tendency toward formation of the emulsion is increased. 

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

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