Carbocations, Schmidt reactions

Amyes, T. L., Richard, J. P. Kinetic and thermodynamic stability of -azidobenzyl carbocations putative intermediates in the Schmidt reaction. J. Am. Chem. Soc. 1991, 113, 1867-1869. 

Pearson, W. H., Walavalkar, R., Schkeryantz, J. M., Fang, W. K., Blickensdorf, J. D. Intramolecular Schmidt reactions of azides with carbocations synthesis of bridged-bicyclic and fused-bicyclic tertiary amines. J. Am. Chem. Soc. 1993,115,10183-10194. 

Under the conditions of the Schmidt reaction the azide group in (81) was captured intermolecularly by a carbocation, producing an aminodiazonium ion intermediate which subsequently rearranged yielding indolizidine 167B (82) <93JA10183>. 

Schmidt reaction. Nascent carbocations generated from alcohols (using TfOH or SnCl ) are trapped by the added alkyl azides. ... 

Use of carbocations to initiate the Schmidt reaction has been the subject of several investigations during the last two decades. The cationic intermediate can be generated from secondary or tertiary alcohols or from olefins. The first example was described by the Pearson group for the synthesis of a bicyclic enamine. However, various drawbacks still remain when carbocations are involved limited stability of the intermediates, low selectivity, and the need... 

As with alkene precursors, there is often a lack of selectivity in Schmidt reactions of carbocations generated from alcohols under acidic reaction conditions. However, the Renaud group reported the first example of an intramolecular Schmidt reaction involving a primary electrophilic carbon center for the synthesis of (-)-indolizidine under nonacidic conditions fScheme 4.1 liP After activation of the alcohol 31 via triflation, alkyl migration and extrusion of molecular N2 occurred smoothly. After subsequent reduction of 32, the desired structure 33 was obtained in high yield and excellent optical purity (98% ee). This concise approach enabled the synthesis of (-)-indolizidine in seven linear steps and 27% overall yield. 

There were very few reports of Schmidt reactions involving alkyl azides for almost 40 years after Boyer s papers appeared. Some papers described sequences that resembled the bona fide Schmidt reaction in that azides ultimately afforded lactams, but were thermally enacted and mechanistically distinct from the classical Schmidt reaction (see Section 7.5). hi the early 1990s, a series of disclosures finally established synthetically useful versions of the Schmidt reaction using various kinds of alkyl azides as the key substrates. The following discussion of this chemistry will concentrate first on those reactions in which the electrophilic partner is a carbonyl group or carbonyl equivalent. Later sections will describe processes in which an alkyl azide attacks a carbocation derived from an alkene, alcohol, or a related precursor. Finally, the ways in which these reactions have been used to construct natural products or other compounds of interest will conclude this chapter. 

Schmidt Reactions of Alkyl Azides with Carbocations... 

Scheme 7.23 Intermolecular Schmidt reactions of alkyl azides with carbocations...

The lack of regioselectivity, the limitation that tertiary or benzylic alcohols must be used as precursors to Schmidt reactions with carbocations, and the harsh Lewis acidic... 

Traditionally, relative stabilities of carbocations have been derived from the comparison of the rates of solvolysis reactions following the SN1 mechanism, for which the designation Dm + An has recently been proposed [36], The comparison of solvolytic rate constants for substrates of a large structural variety is hampered by the fact that the published solvolysis rates refer to different solvents, different temperatures, and precursors with different leaving groups. Dau-Schmidt has, therefore, converted solvolysis rates of a manifold of alkyl chlorides and bromides to standard conditions, i.e., soiv of RC1 in 100% EtOH at 25° C (Scheme 6) [37]. Although from a theoretical point of view, ethanol is not an ideal solvent for observing unassisted SN 1-type reactions (nucleophilic solvent participation), it has been selected as the reference solvent because most available experimental data have been collected in solvents of comparable nucleophilicity, a fact which made conversions to 100% ethanol relatively unproblematic [38],... 

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