Novel Syntheses of Variably Substituted Pyrrolo[2,3-d]thiazoles

Abstract

Pyrrolo[2,3-d]thiazoles are conveniently derived from the corresponding o-aminoalkynylthiazoles via microwave assisted 5-endo-dig cyclization. Methylene-bridged substituents in the 6-position are directly obtained from 5-exo-Heck cyclization based on the same iodoaminothiazole precursor. Further structural variety is accessible via Suzuki reaction of 2-chloroaminothiazoles prior to cyclization or post-cyclization modifications.

thiazoles - pyrroles - heterocycles - microwave irradiation

References

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The 2,5-diiodothiazole as a side-product in the synthesis of thiazole 2a could only be observed in traces via mass spectrometry. When scaling this reaction up to a 35 mmol, CH₂Cl₂ as solvent and a reaction time of 18 h at r.t. were used to achieve comparable yields.

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See supporting information for a detailed reaction parameter diagram.

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<A NAME="RT07810SS-18">18</A>

The low yield can be attributed to decomposition processes due to the considerably intense and long-lasting irradiation of the reaction mixture.

<A NAME="RT07810SS-19">19</A> The formation of a black slurry residue is observed, probably due to polymerization.

<A NAME="RT07810SS-20">20</A>

Several conditions were tested for the Boc cleavage of 6a: TFA in CH₂Cl₂, ethanolic HCl in CH₂Cl₂ and heating with SiO₂, with the latter being the superior method. In all cases partial decompostion occurred and oxidation of the alkyne appeared as the major side reaction.

<A NAME="RT07810SS-21">21</A>

All tried standard halogenation conditions for thiazoles affected the alkyne, or led to decomposition: iodination with NIS in CH₂Cl₂, DME, or MeCN with or without addition of K₂CO₃ at ambient or elevated temperatures. Best yields were obtained with N-chlorosuccinimide as electrophile compared to CCl₄ and quenching the reaction mixture with n-BuOH compared to H₂O, respectively.

<A NAME="RT07810SS-22">22</A>

Attempted Suzuki-couplings after cyclization to the unprotected pyrrolothiazoles only led to traces of product after prolonged reaction times, probably due to the influence of the free pyrrole NH group.

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<A NAME="RT07810SS-24">24</A>

Products resulting from 6-endo-cyclization could not be detected in any case.