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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12

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.

The syntheses of azaindoles via DBN-mediated cyclization of Boc-protected o-aminoalkynylpyridines are reported in:

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16

See supporting information for a detailed reaction parameter diagram.

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18

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

19 The formation of a black slurry residue is observed, probably due to polymerization.

20

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.

21

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.

22

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.

23 Wensbo D. Gronowitz S. Tetrahedron  1995,  51:  10323 

24

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