John A. Wendt, Jeffrey Aubé. A notable development, that greatly extends the power of the reaction, has been the discovery that the intramolecular Schmidt reaction of organic azides with ketones (Scheme 1),3 or with carbocations derived from alkenes or alcohols,4 can give a wide range of bicyclic products bearing nitrogen at one of the ring fusion positions.

Reduction of the azido ester 11 with DIBAL-H in DCM at −78 °C afforded the azido aldehyde 12 in 88% yield. The Claisen-Schmidt condensation is what happens when you have an enolizable aldehyde plus ketone. Generally, intramolecular Schmidt reactions are more useful than their intermolecular counterparts, which are limited by poor site selectivity and sensitivity to steric hindrance. Toward the synthesis of sparteine: Intramolecular Schmidt reactions on a norbornanone platform. 3 115, 10183 – 10194 (1993). Am. For example, the Robinson annulation reaction sequence features an aldol condensation; the Wieland–Miescher ketone product is an important starting material for many organic syntheses. The intramolecular Schmidt reaction was first described at the beginning of the 1990s and rapidly proved to be a powerful tool for the fast assembly of complex nitrogen-containing heterocycles.

, Intramolecular Schmidt reactions of azides with carbocations: Synthesis of bridged-bicyclic and fused-bicyclic tertiary amines.

Chem. J. Total synthesis of (±)-antofine. The resulting tricyclic intermediate was readily transformed into a known intermediate en route to stenine, thus completing the formal synthesis. This means that we're kind of breaking the rules. Soc. 2 These cyclic nitrogen-containing species abound in biological systems and the drugs that target them, making the intramolecular Schmidt reaction relevant for the construction of useful molecules.

Now we're going to talk about a very specific type of crossed aldol reaction called the Claisen-Schmidt reaction. doi: 10.1021/ja00075a038 The intramolecular Schmidt reaction is a useful tool for the construction of polycyclic lactams 1 as well as their corresponding amines via subsequent reduction. Intramolecular and intermolecular Schmidt reactions of alkyl azides with aldehydes. This review focuses on the application of this reaction in the synthesis of natural products and other biologically relevant compounds. Intramolecular vs. Intermolecular Reaction In some reactions, two pathways present themselves: one via an intramolecular reaction (reacting groups both within the same molecule), one via an intermolecular reaction (reacting groups in different molecules). Tetrahedron 1996, 52 (10) , 3403-3408. The intramolecular reaction of azides and aldehydes, like the version using azidoketone substrates, is a useful tool for the synthesis of nitrogenous heterocycles.

Generally intramolecular reactions are entropically favoured. This key reaction cascade consists of an intramolecular Diels–Alder reaction followed by an intramolecular Schmidt reaction.