2.4- Disubstituted thiazoles

Another modification of the Hantzsch thiazole synthesis afforded C-4 thiazolylmethyl phosphonium salts (49). These ylids could then undergo Wittig condensations to furnish a wide variety of 2,4-disubstituted thiazoles <96TL983>. 

Disubstituted thiazoles are readily obtained by the action of a-mercapto ketones (278) on nitriles (279). The reaction is carried out in benzene solution at 0°C by passing a current of dry hydrogen chloride through the mixture (Scheme 199). In a variation of this reaction, by refluxing a-mercapto ketones (278) with aldoximes (280) for 2 hours at 100 °C, 2,4-di- or 2,4,5-tri-substituted thiazoles are obtained in good yields (Scheme 200). 

Bromination 2,4-disubstituted thiazoles at C(5) in good yields utilizes Br2, AcOH <1999T1977>. Isothiazoles with electron-releasing substituents such as amino, hydroxy, or alkoxy in the 3- or 5-positions are brominated in high yield at the 4-position. Alkyl-isothiazoles give lower yields, but 3-methylisothiazole-5-carboxylic acid can be brominated efficiently. Thiazoles with an electron-releasing substituent at the 2- or 4-position are brominated at C(5). 

Conversely, a-haloketones have been immobilized on resin and reacted with a range of thioamides and thioureas to form 2,4-disubstituted thiazoles in good to excellent yields <2002TL3193>. 

In a solid-phase combinatorial approach, resin-bound esters 151 underwent Tebbe-mediated methylenation, followed by bromination with Bt2 to give the corresponding dibromides 152. These were reacted in turn with a range of thioamides in a large excess to give the 2,4-disubstituted thiazoles 153 (Scheme 57). The product was easily separated from the remaining thioamide by treatment with 5-(4 -chloromethylphenyl)pentylpolystyrene resin (CMPP resin) <1998CC2019>. 

Thiazoles may also be intermediate in some other imidazole syntheses <87CJC282>. Dimroth rearrangement of 5-aminothiazoles ((255), (256)) gives hydantoin analogues <86BSBll29>. While 2,4-disubstituted thiazole A(-oxides are converted by aryl isocyanates into imidazoles, the 2,5-isomers are unreactive (Scheme 191) <82CPB1722>. 

Reaction of 1-alkynyl thiocyanates (300) with alcohols, phenols, thiols, or secondary aliphatic amines in the presence of a Lewis acid (anhydrous zinc chloride or boron trifluoride diethyl etherate) affords 2,4-disubstituted thiazoles (301) in good yields (Equation (52)) <82RTC310>. 

When subjected to acids or suitable electrophiles 3-mono- and 3,6-disubstituted thiazolo[3,2-c][l,2,3]triazoles (50) suffer ring opening yielding 2-mono- and 2,4-disubstituted thiazoles (79)-(81) (Equation (5) and Table 16) <91X2851,9lT286i>. 

Taunton and co-workers have reported a one-step racemization free organolithium-mediated diversification of peptide thiazoles. A mild procedure for the C5 lithiation of 2,4-disubstituted thiazoles has been described in this report, and an example is shown below. The method is compatible with A-Boc, A-trityl, carboxylic ester, and carboxamide protecting groups and has been used to functionalize directly the thiazole ring of cyclopeptide natural products. 

The exhilarating outcomes of the 2,4-disubstituted thiazoles as a unique class of Src Homology 2 (SH2) inhibitors for the behavior of osteoporosis and breast cancer have also been reported [27], Selection of the 2,4-disubstituted thiazoles as concealed pharmacophores for diacylhy-drazine of SC-51089, a prospective PGE2 antagonist have also been described [28], With these results, the thiazole ring system proves to be a well-known structural motif that originate in several pharmaceutical agents and natural products extraded from various plants and marine systems. 

Rajan S G et al. [74] designed and S3mthesized a sequence of 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one 23 compounds. S3mthesized molecules were estimated for their inhibitory activity in the course of record factors, nuclear factor-kB (NF-kB) and activating factor (AP-1) interceded transcriptional activation in a cell line based in vitro assay as well as for their anti-inflammatory activity in vivo model of severe inflammation. 

HI El-Subbagh et al. [76] S3mthesized a sequence of 2,4-disubstituted thiazole compounds containing N-n-butyl or N-cyclohexyl thioureido synthon at position-2 and N-substituted thiosemicarbazone moiety 25 at position-4 and verified for antitumor activity. All of the established derivatives revealed antineoplastic activity at concentrations less than 10 pM. 

Rajan S, Hardik G, Thaker M, Tony G, Kamala K. V. Design, synthesis and characterization of novel 2-(2,4-disubstituted-thiazole-5-yl)-3-aryl-3H-quinazoline-4-one derivatives as inhibitors of NF-kB and AP-1 mediated transcription activation and as potential anti-inflammatory agents, Eur. J. Med. Chem. 2009. p. 2184 - 2189. DOI 10.1016/i.ejmech.2008.10.031... 

Kumar Y, Green R, Borysko K. Z, Wise D. S, Wotring L. L, Townsend L. B. Synthesis of 2,4-disubstituted thiazoles and selenazoles as potential antitumor and antifilarial agents. 1. Methyl 4-(isothiocyanatomethyl)thiazole-2-carbamates, -selenazole-2-car-bamates, and related derivatives, J. Med. Chem. 1993. p. 3843 - 3848. DOI 10.1021/ jm00076a012... 

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