Functionalization of 4-bromobenzo[ c][2,7]naphthyridine via regioselective direct ring metalation. A novel approach to analogues of pyridoacridine alkaloids

Abstract

Readily available 4-bromobenzo[c][2,7]naphthyridine undergoes regioselective direct ring metalation at C-5 with TMPMgCl∙LiCl at -40 °C. Quenching with various electrophiles gives a broad range of 5-substituted products, which are building blocks for the synthesis of heterocyclic natural products and analogues thereof. In combination with a Parham-type cyclization a novel approach to pyrido[4,3,2-mn]acridones has been worked out.

Keywords: alkaloids; cyclization; metalation; naphthyridine; pyridoacridine.

Figure 1

Marine pyridoacridine alkaloids amphimedine (1), ascididemin (2), kuanoniamine A (3), styelsamine D (4) and eilatin (5), as well as the two known tricyclic benzo[c][2,7]naphthyridine alkaloids perlolidine (6) and subarine (7) with the common benzo[c][2,7]naphthyridine moiety highlighted in bold.

Figure 2

A–C): Published methods for the synthesis of 4,5-disubstituted benzo[c][2,7]naphthyridines; D) New approach.

Scheme 1

Regioselective metalation of 4-bromobenzo[c][2,7]naphthyridine (9d) and subsequent conversion into secondary alcohols by reaction with (hetero)aromatic aldehydes.

Scheme 2

Outcome of a D₂O quenching experiment after metalation of 4-bromobenzo[c][2,7]naphthyridine (9d).

Scheme 3

Synthesis of 5-substituted 4-bromobenzo[c][2,7]naphthyridines via regioselective metalation of 9d using TMPMgCl∙LiCl and quenching with various electrophiles or cross-coupling reactions.

Scheme 4

Attempted synthesis of kuanoniamine A (3).

Scheme 5

Synthesis of pyrido[4,3,2-mn]acridone 22 starting from 20a via bromine–magnesium exchange reaction and subsequent intramolecular trapping of the methyl ester.