Efficient synthesis of Fluorinated Azaindoles
Introduction
Azaindoles and their derivatives have shown remarkable biological activity and have therefore received considerable attention in drug optimization strategies. The four azaindole positional isomers link together the pyridine and pyrrole rings by a fused C-C bond while having all the criteria required to be bioisosteres of an indole or purine system. The use of azaindoles instead of other bicyclic fused heterocycles allows the modulation and fine-tuning of the compounds' solubility, pKa and lipophilicity, target binding capacity, and toxicity, among other physicochemical and pharmacological properties.
Fig.1. Four azaindole positional isomers of azaindole
Synthesis
Fluorinated heterocyclic compounds have unique advantages suitable for use in medicine and agriculture, particularly their enhanced ability to penetrate membranes and tissues in living organisms, which facilitates the uptake, delivery and diffusion of fluorinated compounds. The challenge in the synthesis of fluorinated azaindoles is the selective aromatic fluorination which was previously achieved by Balz-Schiemann reaction or by electrophilic fluorination.
The disadvantage of electrophilic fluorination of neutral aromatic compounds is that it usually yields a mixture of mono- and poly-fluorinated products. On the other hand, the Balz-Schiemann fluorination reaction provides regioselective monofluorinated aromatic fluorinations via controlled thermal decomposition of the diazonium salt of tetrafluoroboronic acid.
In 2003, C. Thibault et al. reported two methods for the synthesis of 4-fluoro-1H-pyrrolo [2,3-b] pyridine, alias 4-fluoro-7-azaindole.
The first approach utilizes a regioselective Balz-Schiemann fluorination reaction, which requires the synthesis of an intermediate amine 1. The regioselective chlorination of 1H-pyrrolo [2,3-b] pyridine 7-oxide was carried out in DMF using methanesulfonyl chloride at C-4 2. Buchwald-palladium-catalyzed amination using the chloride and N-allylamine 3 was performed to produce allylamine. Subsequently, the alkenylation was carried out using carbopalladium in an acidic alcohol solution to give 1H-pyrrolo [2,3-b] pyridin-4-amine 4. It was then subjected to Balz-Schiemann fluorination reaction conditions 5 and pyrolyzed to give fluorinated aromatic compounds (Scheme 1).
Scheme 1. Synthesis of Fluorinated Azaindoles by the Balz-Schiemann reaction
The route of the Balz-Schiemann reaction described above provides a four-step synthesis of 4-fluoro-1H-pyrrolo [2,3-b] pyridines.
The second approach attempts to change the leaving group from a chloride to a bromide, using the bromide in a lithium-halogen exchange reaction followed by treatment with an electrophilic fluorine reagent to produce 4-fluoro-1H-pyrrolo [2,3-b] pyridine 6 (Scheme 2).
Scheme 2. Synthesis of Fluorinated Azaindoles by electrophilic fluorination reaction
Treatment of N-oxides with methanesulfonic anhydride and tetramethylammonium bromide in DMF gave 4-bromo-1H-pyrrolo[2,3-b]pyridine, which was then protected as N-triisopropylsilyl derivatives. Lithium-halogen exchange of bromides using tert-butyl lithium in THF at -78°C 7 followed by the addition of N-fluorobis(benzenesulfonamides) gave 4-fluoro-1H-pyrrolo[2,3-b]pyridine 8.
In conclusion, the above two routes for the synthesis of 4-fluoro-1H-pyrrolo[2,3-b]pyridines: the first synthetic method is characterized by the Balz-Schiemann reaction at room temperature. The second method is characterized by an effective lithium-halogen exchange of the corresponding bromide followed by quenching with an electrophilic fluorine source.
Applications
Azaindoles derivatives, especially fluorinated azaindoles have been recognized as superior structures in bioprocess regulation, medicinal chemistry and drug discovery programs. Their commercial availability is steadily increasing and synthetic innovations are constantly being updated. A number of fluoroazaindole derivatives have emerged from medicinal chemistry programs and some of them have been and are being developed as drug candidate molecules for the treatment of human diseases.
Reference
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2. Benoıˆt, S.; Gingras, S. Processes for the preparation of antiviral 7-azaindole derivatives. U.S. Provisional Patent 60/367,401, 2003.
3. Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.Org. Chem. 2000, 65, 1158.
4. (a) Jaime-Figueroa, S.; Liu, Y.; Muchowski, J. M.; Putman, D. G.Tetrahetron Lett. 1998, 39, 1313. Other deallylation conditions attempted did not improve yield; see other conditions in ref 9a and: (b) Garro-Helion,F.; Merzouk, A.; Guibe´, F. J. Org. Chem. 1993, 58, 6109.
5. On a larger scale, purification could also be done using Dowex 50W X 4 resin.
6. Differding, E.; Ofner, H. Synlett 1991, 187.
7. A >1.5 M solution of tert-butyllithium in pentane was used to avoid the precipitation of N-fluorobenzenesulfimide.
8. Barnes, K. D.;Hu, Y.; Hunt, D. A. Synth. Commun. 1994, 24, 1749.