Robinson-Schopf condensation

The final step to 46 is cyclocondensation of 3,7-diazabicyclo[3.3.1]nonane (51), bispidine70, with formaldehyde. There are two different approaches to 51 (i) a pyridine is converted to a piperidine and (ii) the double Mannich or Robinson-Schopf condensation of ketone 52 with formaldehyde and primary amines affords 1,5-disubstituted 3,7-dazabicyclo[3.3.1]nonan-9-one (53), bispidone, from which 5,7-disubstituted l,3-diazaadamantan-6-one (61) is derived. Route (i) is adopted by Galinovsky and Langer,71 Stetter and... 

Another representative example is the preparation of (3A,5/ ,7a/ )-5-(benzotriazol-l-yl)-3-phenyl[2,l-A oxazolopyr-rolidine 238 that was synthesized from benzotriazole, (A)-phenylglycinol, and 2,5-dimethoxy-tetrahydrofuran at room temperature. This reaction entailed the formation of two heterocyclic rings and two new chiral centers in one step (Equation 33) by double Robinson-Schopf condensation of the dialdehyde with the amino group and benzotriazole intercepting the initially formed iminium ion (Equation 36) <1999JOC1979>. 

The advantages of Robinson s concept was confirmed in numerous total syntheses of alkaloids. One of the most illustrative examples is served by Stevens synthesis of the tricyclic compound coccinelline 45 (Scheme 3.10), the pheromone of the ladybug (ladybird). As was acknowledged in Stevens review article, in less time than it took to write this paragraph, we had developed on paper an attractive approach that relies on one of the oldest reactions known in alkaloid synthesis, namely the classical Robinson-Schopf condensation . This approach involved the retrosynthetic transformation of 45 into the ketopiper-idine derivative 46, which is amenable to disconnection in accordance with the same logic as used by Robinson in the analysis of tropinone. 

The preparation described here is an improvement of the previous procedure. The double condensation of glutaraldehyde with the amino group of (R)-(-)-phenylglycinol (related to the Robinson-Schopf condensation) probably leads to the expected product via the formation of an intermediate of type and/or B. 

Rhodium(ll) acetate dimer, 70,93 Robinson-Schopf condensation, 70, 56... 

This reaction is related to the Betti Reaction and Robinson-Schopf Condensation. 

This reaction was first reported by Robinson in 1917 and subsequently improved by Schopf in 1935. It is an ingenious one-pot multicomponent synthesis of tropinone from succindialdehyde, acetonedicarboxylic acid and methylamine in aqueous solution involving a double Mannich Reaction This reaction is thus known as the Robinson tropinone synthesis," Robinson synthesis, " Robinson-Schopf reaction,Robinson-Schopf condensation, or Robinson condensation." It has been reported that the Robinson tropinone synthesis can take place without any racemization at the stereogenic center adjacent to the aldehyde group, as demonstrated by the formation of L-a/to-teloidinone from D-tartaraldehyde, and c-a/to-teloidinone from i-tartaraldehyde respectively." ... 

The Robinson-Schopf condensation is a tandem process most notably recognized as the reaction between one molecule of succinaldehyde (1), methyl amine (2), and acetone dicarboxylic acid 3 to give the bicyclic product tropinone (4) in a one-pot procedure. 

Due to its remarkable simplicity, many early approaches to tropane alkaloids utilized the Robinson-Schopf condensation. As pointed out by Sheehan, the... 

The conditions of the Robinson-Schopf condensation allow for a wide breadth of nucleophilic amines. In addition to alkyl amines, hydroxyalkyl, benzylic, aromatic, heterocyclic amines, as well as a-amino acids and esters are sufficiently reactive to participate in this reaction. ... 

As shown before vida supra), the seminal application of the Robinson-Schopf condensation to natural product synthesis was the concise preparation of tropinone (4). In pondering the biogenesis of tropane alkaloids, Robinson put forth a bold hypothesis By imaginary hydrolysis at the points indicated by the dotted lines, the substance may be resolved into succindialdehyde, methyl amine, and acetone, and this observation suggested a line of attack of the problem which has resulted in a direct synthesis. ... 

Later, Robinson s approach was improved substantially by Schopf in the early 1930s when he realized that only slight changes of the pH affect the yield of the reaction. After in-depth studies concerning the optimal reaction conditions, buffered conditions using a citrate buffer (pH=5) where found to double the initial yield of the reaction [133]. Therefore, the synthesis of tropinone from sncci-ndialdehyde, Af-methylamine, and acetonedicarboxylate is nowadays commonly referred to as Robinson-Schopf condensation. 

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