TheCook–Heilbron thiazole synthesis highlights the formation of 5-aminothiazoles through thechemical reaction of α-aminonitriles or aminocyanoacetates with dithioacids, carbon disulphide, carbon oxysulfide, or isothiocyanates at room temperature and under mild oraqueous conditions.[1][2] Variation ofsubstituents at the 2nd and 4th position of thethiazole is introduced by selecting different combinations of startingreagents.[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 ofpurines andpyridines.[3][4][5][6]
| Cook-Heilbron thiazole synthesis | |
|---|---|
| Named after | Alan H. Cook Ian Heilbron |
| Reaction type | Ring forming reaction |
In the first step of thereaction mechanism for the synthesis of a 5-aminothiazole from an α-aminonitrile and carbon disulphide, alone pair on the nitrogen of the α-aminonitrile[7] performs anucleophilic attack on the slightlyelectropositive carbon of carbon disulfide. Thisaddition reaction pushes electrons from the carbon-sulfurdouble bond onto one of the sulfur atoms. Acting as aLewis Base, the sulfur atom donates its electrons to the carbon atom of the nitrile, forming a sulfur-carbonsigma bond in an intramolecular 5-exo-digcyclization. This cyclization forms a 5-imino-2-thione thiazolidine compound that undergoes atautomerization when abase, 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 isthermodynamically favourable, yielding thearomatic final product: 5-aminothiazole.
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 thiazolylbisamines:[9]
Thiazoles are essential components of many biologically active compounds making them important features indrug design.[10] Thiazoles are found in a number of pharmacological compounds such astiazofurin anddasatinib (antineoplastic agents),ritonavir (an anti-HIV drug),ravuconazole (antifungal agent),meloxicam andfentiazac (anti-inflammatory agents) andnizatidine (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.