Metalation of Heterocyclic Aromatic Aldehydes Directed by Alpha-Amino Alkoxides

摘要

The addition of certain lithiated secondary amines to various heteroaromatic aldehydes forms alpha - amino alkoxides which are stable to substitution by lithium reagents. The in situ formed alpha -amino alkoxide is used as both an aldehyde protecting group and as a directing group for ring-lithiation. The alpha -amino alkoxides are metalated with alkyllithium, alkylated, and hydrolyzed to provide substituted heterocyclic aldehydes via one-pot reactions. The ability to vary the site of metalation on the heteroaromatic ring by changing the amine component of the alpha - amino alkoxide from the strong ortho directing N,N,N' -trimethyl-ethylenediamine to the much weaker coordinating N-methlypiperazine is discussed. The heterocyclic aromatic aldehydes studied include: 6-methyl-2-pyridinecarboxaldehyde, 2-thiophenecarboxaldehyde, 3-thio phenecarboxaldehyde, 2-furaldehyde, 3-furaldehyde, 1-methyl- 2-pyrrolecarboxaldehyde, 1-methlindole-3-carboxaldehyde, N-protected indole-3-carboxaldehydes, and 1-methylindole-2-carboxaldehyde.