Thiazole A-oxidation

Oxidation of thiazoles 137 with HOF MeCN provides easy access to the family of thiazole A-oxides 138 <06CC2262>. The readily made HOF MeCN complex, considered to be one of the best oxygen transfer agents in chemistry, transfers an oxygen atom directly to thiazole-containing compounds without affecting the double bonds of the thiazole moiety. A small amount of /V,SVS -trioxide 139 is also formed in this oxidation. 

Thiazole A-oxides may result from the direct oxidation of thiazoles with hydrogen peroxide or with tungstic acid or peracetic acid. These products are unstable and break down by autoxidation 2,4-dimethylthiazole 3-oxide rearranges in acetic anhydride into... 

Thiazole A -oxides, A -imides, and A -ylides are formally betaines derived from A -hydroxy-, A -amino-, and A -alkyl-azolium compounds. Where the cation is involved, reactivity is similar to that of thiazolium ions. 

Thiazole A -oxides can easily be alkylated on the oxygen. For example, Ar-(alkoxy)-5-(p-methoxyphenyl)-4-methylthiazole-2(377)-thiones were prepared from Ar-(hydroxy)-5-( -methoxyphenyl)-4-methylthiazole-2(3//)-thione tetraethylammonium salt and an appropriate alkyl chloride or tosylate in moderate to good yields <20060BC2313>. A -Methoxythiazole-2(377)-thiones were synthesized from the A -hydroxythiazole-2(3//)-thiones by treatment first with a tetraalkylammonium hydroxide in methanol and then methyl ra-toluenesulfonate in DMF <2005EJ0869>. 

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>. 

Although earlier warnings concerning the instability of thiazole-A-oxides have been reported, Begtrup and Hansen <92ACS372> have found that these compounds are stable for months when stored in a cool and dry atmosphere. 

Although they have not found extensive utility in drug discovery, a few examples do exist where thiazole A-oxides were prepared as target molecules. One such case is shown below where these compounds were... 

Scheme 15 Sequential direct arylation of thiazole A/-oxide (a) versus thiazole (b) with aryl halides.

Hammer and co-workers used the Hantzsch thiazole synthesis to prepare thiazole and thiazole-A -oxide nucleobases with the goal of producing nucleobase analogs with pronounced directional dipoles and the capacity to base pair. Their overall goal was to use these compounds as models to explore the biochemical and biophysical properties of DNA. Treatment of... 

Figure 1.18 Computed free energy activation barriers (kcaimoi" ) for C-H activation at Pd(Ph)(K -OAc)(PMe3) for A/-methylimidazoie and oxazoie (with and without bound CuCi), thiozole, and thiazole A/-oxide [37c].

Thiazole-N-oxides are prepared by the action at low temperature (-10°C) of hydrogen peroxide in acetic acid (474). 4-MethyIthiazole and 2,4-dimethylthiazole afforded the corresponding N-oxides with yields of 27 and 58%, respectively (Scheme 88). Thiazole-N-oxides without a methyl group in the 2-position are so unstable that they have a tendency to form 2-hydroxythiazoles and are decomposed by oxidation, whereas a 2-methyl group would prevent such rearrangement (474). 

Little work has been carried out on thiazole N-oxides. These products are unstable and breakdown by autoxidation to give thiazolium-A -oxide sulfates and other decomposition products (264). They are prepared by direct oxidation with hydrogen peroxide, or by tungstic acid (264, 265) or peracetic acid (265-267). 

Only one reaction of thiazole N-oxides has been studied in detail. The rearrangement in acetic anhydride of 2,4-dimethylthiazoIe-3-oxide gave 2-acetoxy-4-methylthiazole and 4-acetoxymethyl-2-methylthiazole in a ratio of about 4.5 to 1(264). 

The oxidation of thiazoles by peroxy acids leads to the corresponding A-oxides. Peracetic, MCPBA, permaleic, and trifluoroperacetic acid have been employed for this reaction. Chemical yields range from 4% to 50%, the more basic thiazoles producing higher yields. Thus, thiazole, 2,4-dimethyl- and 4,5-dimethylthiazoles, and 2-phenylthiazole can be oxidized in moderate to good yields. However, neither 4-chloro-2-phenylthiazole nor 5-chloro-2-phenylthiazole could be oxidized. 3-Oxides were also obtained by oxidation of 1,2,3-thiadiazoles and 5-phenylthiatriazole (121—>122) (75T1783). 

Of the substituted pyridines, the halogenated derivatives have been the most intensively studied.144,145 Treatment of 3,5-dichloropyridine A-oxide at 74° with 0.1 A NaOD led to exchange in three positions of the molecule, whereas with 3-chloropyridine iV-oxide relative rates of exchange were position 2>6>4>5. In l-methyl-4-pyridone, 1,3,5-trimethyl-4-pyridone, and 3,5-dibromo-l-methyl-4-pyridone, deuteration in basic D20 at 100° gives 2- and 6-substitution.146 With the poly-azaindenes (45) -(47) already discussed in the acid exchange section,141 base-catalyzed deuteration occurs in the positions indicated 45 3 and 5 46 2, 3, 5, and 6 and 47 2, 5, 6, and 7. In other isolated heterocycles some selectivity is observed in base-catalyzed exchange, e.g., certain imidazoles,147 thiazole,148 isothiazole,148 benzothiazole,149 and benzoxazole.149... 

The formation of A-oxides by peroxy acid oxidation of thiazoles has been reported. Reagents used and typical yields have been discussed elsewhere <1996CHEC-II(3)373>. N-Oxidation of epothilones A-C with w-chloroperbenzoic acid (MCPBA) has been reported in yields from 20% to 48%, which are typical for this type of transformation. Oxidation was confirmed to have occurred exclusively on the nitrogen atom by X-ray crystallography <1999AGE1971>, controverting an earlier report that treatment of epothilone A with MCPBA resulted in sulfoxide formation < 1997JA7960>. 

Thiazole iV-oxides are easily deoxygenated to the parent thiazoles by a variety of reagents such as phosphorus trichloride <55JPJ12l>, sodium dithionite <85CPB618>, dimethylformamide at reflux <82JHC77>, or triethyl phosphite <91JMC108>. 

Abstract Azines, diazines or thiazole (V-oxides are highly reactive substrates in palladium-catalyzed direct arylation reaction. For these reactions, the results are inconsistent with an SEAr reaction pathway and may best fit with a concerted metalation-deprotonation-like (CMD) mechanism. 

Thiazole /V-oxides are also highly reactive substrates in direct arylation [80]. For example, the direct arylation of several thiazole /V-oxides with arylbromides in the presence of a palladium catalyst and a Buchwald ligand can be achieved at 25 °C,... 

Imidazole /V-oxide substrates may be used in a similar fashion. Initial investigations revealed that the use of palladium acetate in conjunction with an electron deficient 4-fluorophenylphosphine in acetonitrile at 70 °C provides C2 arylation in high yields. With the goal of achieving the same reactivity at or near room temperature it was determined that the use of palladium acetate in conjunction with a Buchwald ligand, catalytic copper bromide and 30 mol% pivalic acid in acetonitrile could also achieve high yields of C2 arylation at 25 °C. As was the case with thiazole V-oxides. if the C2 and C5 positions of the imidazole are blocked C4 arylation may also be achieved in synthetically useful yield (Scheme 15). 

When a 2-su phinyl-carboxamide is warmed with hydrazoic acid, a 3-iminoiso-thiazole I-oxide is formed. 

Resistance to oxidative breakdown falls off in the order thiazoles > imidazoles > oxazoles. 2-Substituted thiazoles can be converted into A-oxides, ° however peracids bring about degradation of imidazoles oxazole A-oxides can only be prepared by ring synthesis. Substituted oxazoles are converted into imides, with loss of C-5. ... 

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