Chemistry of nitroquinolones and synthetic application to unnatural 1-methyl-2-quinolone derivatives

Abstract

The 1-methyl-2-quinolone (MeQone) framework is often found in alkaloids and recently attention was drawn to unnatural MeQone derivatives with the aim of finding new biologically active compounds, however, low reactivity of the MeQone framework prevents the syntheses of versatile derivatives. A nitro group is one of the useful activating groups for this framework that enables a concise chemical transformation. Among nitroquinolones, 1-methyl-3,6,8-trinitro-2-quinolone (TNQ) exhibits unusual reactivity favoring region-selective cine-substitutions that afford 4-substituted 1-methyl-6,8-dinitro-2-quinolones upon treatment with nucleophilic reagents. Contrary to this, 1-methyl-3,6-dinitro-2-quinolone (3,6-DNQ) does not undergo any reaction under the same conditions. The unusual reactivity of TNQ is caused by steric repulsion between the methyl group at the 1-position and the nitro group at the 8-position, which distorts the MeQone framework. As a result, the pyridone ring of TNQ loses aromaticity and acts rather as an activated nitroalkene. Indeed, the pyridone moiety of TNQ undergoes cycloaddition with electron-rich alkenes or dienes under mild conditions, whereby a new fused ring is constructed on the [c]-face of the MeQone. Consequently, TNQ can be used as a new scaffold leading to versatile unnatural MeQone derivatives.

Figure 1

(a) Tautomerism of 2-quinolone. (b) Resonance structures of 1-methyl-2-quinolone (MeQone).

Scheme 1

(a) Direct functionalization. (b) Built-in method. (c) Ring transformation.

Scheme 2

Preparation of MeQone from quinoline.

Scheme 3

Nitration of substituted MeQones.

Scheme 4

Preparation of nitroquinolones from methyl anthranilate.

Scheme 5

Ring transformation of aminophenyl-1,3-thiazine.

Scheme 6

Construction of the [c]-fused isoxazole ring.

Scheme 7

Reaction of nitroarene and aryl Grignard reagent.

Scheme 8

Tandem addition of ethanedithiol leading to a spiro compound.

Scheme 9

Chemical transformation of malonylquinolones.

Scheme 10

Activation of the acyl group of α-aryl-β-keto esters.

Scheme 11

Diels-Alder reactions of 3-nitroquinolones.

Scheme 12

cine-Substitution of TNQ.

Scheme 13

A plausible mechanism for the dimerization of TNQ.

Figure 2

(a) An ORTEP view of TNQ. (b) An ORTEP view of 3,6-DNQ. (30% probability ellipsoids).

Scheme 14

Reaction of α-quinolylated β-diketone and β-keto ester with methylhydrazine.

Scheme 15

Arylation of the MeQone framework.

Scheme 16

A plausible mechanism for the present arylation

Scheme 17

Dual reactivity of nitroalkene in the cycloaddition.

Scheme 18

Diels-Alder reaction of TNQ with cyclopentadiene.

Scheme 19

(a) Cycloaddition with ethoxyethene in the absence of NEt₃. (b) Cycloaddition with ethoxyethene in the presence of NEt₃.

Scheme 20

Cycloaddition of TNQ with α,β-unsaturated oxime.