ABSTRACT
We report the syntheses of 1,4-diazacycles by diol-diamine coupling, uniquely made possible with a (pyridyl)phosphine-ligated ruthenium(II) catalyst (1). The reactions can exploit either two sequential N-alkylations or an intermediate tautomerization pathway to yield piperazines and diazepanes; diazepanes are generally inaccessible by catalytic routes. Our conditions tolerate different amines and alcohols that are relevant to key medicinal platforms. We show the syntheses of the drugs cyclizine and homochlorcyclizine in 91% and 67% yields, respectively.
ABSTRACT
We report a pyridyl-phosphine ruthenium(II) catalyzed tandem alcohol amination/Pictet-Spengler reaction sequence to synthesize tetrahydro-ß-carbolines from an alcohol and tryptamine. Our conditions use a Lewis acid cocatalyst, In(OTf)3, that is compatible with typically base catalyzed amination and an acid catalyzed Pictet-Spengler cyclization. This method proceeds well with benzylic alcohols, heterocyclic carbinols, and aliphatic alcohols. We also show how combining this reaction with a subsequent cycloamination enables a direct synthesis of tetracyclic alkaloids like harmicine.