8-hydroxyquinoline vs 4,7-dimethoxy-1,10-phenantroline

I always read paper from Buchwald, not because it is interesting, but it can be useful, and in particular the last JOC dealing with N-arylation of imidazoles and benzimidazoles. I jumped directly to the support. info. to see the synthesis of the phenantroline ligand.

The author indicates that the ligand has been synthesized according to a combination of procedures, but the most relevant is the following one: Tetrahedron 2002, 58, 9095.

The first step consists in the synthesis of the methoxyalkylidene derivative of meldrum's acid with trimethylorthoformate, and a subsequent double Michael addition of phenylene diamine to perform the disubstituted aminobenzene in 77% yield. After, a thermal decarboxylation/cyclization in diphenylether at 250°C, the 4,7-dihydroxyphenantroline is isolated in 86%. The end of the reaction is quite classical, a chlorination in refluxing POCl3 followed by a nucleophilic substitution with NaOMe in 74% over 2 steps.

Nice way to synthesize phenantrolines...

Nevertheless, if you read quickly this publication (abstract and conclusion), it seems this phenantroline is the best ligand for the N-arylation of imidazoles and benzimidazoles. According to me, it is not. Of course this ligand is excellent. But my first choice will be 8-hydroxyquinoline. Because, first, the regioselectivity concerning the 4-methylimidazole is better (63:1), otherwise in almost all the cases the yields are quite the same, and finally (the best reason) it is cheaper....

Copper-Catalyzed N-Arylation of Imidazoles and Benzimidazoles

Ryan A. Altman, Erica D. Koval, and Stephen L. Buchwald

J. Org. Chem.; 2007

Synthesis of Alprazolam

In reading about Synthesis of Essential Drugs, I have found in my lab (not a very good book, from a chemical point of view, a lot of mistakes), I have come upon a very strange way to synthesize benzodiazepines (actually triazolobenzodiazepines).
This synthesis starts by a nucleophilic substitution of hydrazine on a 2-chloroquinoline (2,6-dichloro-4-phenylquinoline), boiling this hydrazinoquinoline with orthoacetate in xylene affords triazoloquinoline intermediates.



This intermediate undergoes the key step of the synthesis, a oxidative ring opening of the quinoline with sodium periodate and ruthenium oxide, leading to the triazolobenzophenone.



The 1,3,4-triazole is treated with formaldehyde to provide hydroxymethyl intermediate, subsequent bromination using phosphorous tribromide gives bromomethyltriazole which after spontaneous cyclization with ammonia produces the Alprazolam.



Sorry for the lack of informations, I don't have the two patents concerning this molecule.

3-arylquinoline

Side reactions in organic chemistry can be considered as a failure in a target oriented synthesis, but it can be a valuable source a inspiration for the design of new methodologies.
In 2004, Baldwin and coll. tried to synthesize the 5,5',6,6'-tetrahydroxy-3,3'-biindolyl, a potent antioxidant, he proposed as key step a bis-cyclization of the two 2-aminoaryl substituents on the furan (as 1,4-dialdheyde precursor).


Cyclization was attempted with para-toluenesulfonic acid in benzene, and lead to the formation of a 3-arylquinoline in poor 25% yield along with the starting material.


Finally, the 3,3'-biindole has been synthesized by a palladium catalyzed homocoupling reaction from the corresponding 3-iodoindole.

For the mechanism of the quinoline formation and other informations see:

Tetrahedron 60 (2004) 3695–3712

SYNTHESIS OF 3-HydroxyCinchoninic acid

The synthesis of the 3-hydroxycinchoninic acid has been performed with the reaction a commercially available isatin in presence of chloropyruvic acid (previously synthesized from pyruvic acid and sulfuryl chloride in 95-98% Yield.) in a aqueous potassium hydroxyde solution. After the workup the 3-hydroxycinchoninic acid is isolated as a yellow solid(60-71%).

For more information:

Organic Syntheses, Coll. Vol. 5, p.635 (1973); Vol. 40, p.54 (1960).

James Cason and James D. Willett.