Cook–Heilbron thiazole synthesis
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The Cook–Heilbron thiazole synthesis highlights the formation of 5-aminothiazoles through the chemical reaction of α-aminonitriles or aminocyanoacetates with dithioacids, carbon disulphide, carbon oxysulfide, or isothiocyanates at room temperature and under mild or aqueous conditions.[1][2] Variation of substituents at the 2nd and 4th position of the thiazole is introduced by selecting different combinations of starting reagents.[2]
This reaction was first discovered in 1947 by Alan H. Cook, Sir Ian Heilbron, and A.L Levy, and marks one of the first examples of 5-aminothiazole synthesis with significant yield and diversity in scope.[1] Prior to their discovery, 5-aminothiazoles were a relatively unknown class of compounds, but were of synthetic interest and utility.[1][3] Their premier publication illustrated the formation of 5-amino-2-benzylthiazole and 5-amino-4-carbethoxy-2-benzylthiazole by reacting dithiophenylacetic acid with aminoacetonitrile and ethyl aminocyanoacetate, respectively.[1] Subsequent experiments by Cook and Heilbron, detailed in their series of publications titled “Studies in the Azole Series” describe early attempts to expand the scope of 5-aminothiazole synthesis, as well as employ 5-aminothiazoles in the formation of purines and pyridines.[3][4][5][6]
| Cook-Heilbron thiazole synthesis | |
|---|---|
| Named after | Alan H. Cook Ian Heilbron |
| Reaction type | Ring forming reaction |
Mechanism
Summarize
Perspective
In the first step of the reaction mechanism for the synthesis of a 5-aminothiazole from an α-aminonitrile and carbon disulphide, a lone pair on the nitrogen of the α-aminonitrile[7] performs a nucleophilic attack on the slightly electropositive carbon of carbon disulfide. This addition reaction pushes electrons from the carbon-sulfur double bond onto one of the sulfur atoms. Acting as a Lewis Base, the sulfur atom donates its electrons to the carbon atom of the nitrile, forming a sulfur-carbon sigma bond in an intramolecular 5-exo-dig cyclization. This cyclization forms a 5-imino-2-thione thiazolidine compound that undergoes a tautomerization when a base, such as water, abstracts the hydrogens at positions 3 and 4. The electrons from the carbon-hydrogen sigma bond are pushed back into the thiazole ring, forming two new double bonds with the adjacent carbon atoms, and catalyzing the formation of two new nitrogen-hydrogen, and sulfur-hydrogen sigma bonds. This tautomerization occurs because it is thermodynamically favourable, yielding the aromatic final product: 5-aminothiazole.
Applications
Summarize
Perspective
Few instances of applications of the Cook–Heilbron thiazole synthesis are found in literature.[2] In recent years, modifications of the Hantzsch thiazole synthesis are the most common, partly because of its ease in introducing R- group diversity.[8]
However, in 2008 Scott et al. employed a Cook-Heilbron synthesis in their approach to synthesize novel of pyridyl and thiazolyl bisamide CSF-1R inhibitors for use in novel cancer therapeutics.[9] A couple of the compounds that were analysed for in vivo anti-cancer activity contained thiazole derivatives that had been synthesized using a Cook-Heilbron approach. For instance, 2-methyl-5-aminothiazoles were prepared via condensation and cyclization of aminoacetonitrile and ethyldithioacetate as part of the synthesis of thiazolyl bisamines:[9]
Relevance
Thiazoles are essential components of many biologically active compounds making them important features in drug design.[10] Thiazoles are found in a number of pharmacological compounds such as tiazofurin and dasatinib (antineoplastic agents), ritonavir (an anti-HIV drug), ravuconazole (antifungal agent), meloxicam and fentiazac (anti-inflammatory agents) and nizatidine (anti-ulcer agent).[10]
Consequently, understanding and applying a range of approaches to synthesize thiazoles facilitates greater flexibility in both designing drugs as well as optimizing synthetic routes.
References
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