Novel applications of the hypervalent iodine chemistry. Synthesis of thiazolo-fused quinolinones

A synthesis of thiazolo[5,4-c ]quinolinone derivatives featuring the use of two different hypervalent iodine reagents has been achieved starting from ethyl benzoylacetate in an efficient way. Hydroxy(tosyloxy)phenyliodine (


Introduction
In recent years our group has been concerned with the development of the hypervalent iodine chemistry.In particular, we have reported the superior behavior of PIFA as a biaryl coupling reagent, over other metallic oxidants, in the preparation of polycyclic heterocycles such as phenanthrenes, 1 phenanthrenoids 2 and benzo[c]phenanthridines. 3 The clean transformations achieved, the mild conditions employed, and the low toxicity associated to it, prompted us to include PIFA in our synthetic plans.
Thus, we next focused our attention in the known ability of PIFA to generate Nacylnitrenium ions from N-alkoxyamides 4 which, eventually, could be trapped, intramolecularly in our case, by arene rings to afford the quinoline skeleton in a simple way (see Scheme 1).In this context, we considered that the pharmacological versatility of quinoline derivatives 5 could be modified, or even enhanced, in their heterocycle-fused analogues. 6In fact, the synthesis and the activity of a number of natural products with fused quinoline heterocyclic skeletons have been reported. 7In particular, we considered that the thiazole moiety, which is present in a number of important natural products (epothilone, 8 althiomycin, 9 bistramide C, 10 sulfomycin I 11 ), in antibiotics (cystothiazole 12 ) and, notably, in thiamine (vitamin B) inter alia, would be an interesting and promising substructure to be included in our target molecules. 13hus, in this paper we want to show a simple and efficient synthesis of thiazolo [5,4c]quinolin-4-ones of type 1 from β-ketoesters 3 following the retrosynthetic analysis depicted in Scheme 2.

Results and Discussion
The construction of the substituted thiazole ring started, as shown in Scheme 3, with the HITBmediated oxytosylation of commercially available β-ketoester 4 14 followed by application of the Hantzsch conditions on the resulting ester 5. α-Tosyloxy substituted ketones, as 5, have encountered a wide application in organic synthesis as alternative precursors to the corresponding halo-derivatives but without their unpleasant lachrymose properties. 15

Scheme 3
At this point (see Scheme 4), basic hydrolysis of the ester groups and subsequent activation of the resulting free carboxylic acids 7 and 12 with thionyl chloride afforded the corresponding acyl chlorides 8 and 13 which, without isolation, were treated following standard procedures with methoxylamine to yield the required N-methoxyamides 9 and 14, respectively.Kikugawa had previously employed this kind of precursor in an electrophilic aromatic substitution reaction, which involved a N-chlorination step with t-BuOCl and oxidative cyclization using silver or zinc salts. 16Similarly, Cherest and Lusinchi employed ferric chloride with the same purpose. 17Later, it was found 4 that limitations associated with these protocols (i.e. solubility of silver salts or undesired aromatic chlorination) could be overcome by using PIFA as the cyclization reagent in a single step.Following this strategy, the prepared amides 9 and 14 were treated with the cyclization reagent under optimized experimental conditions to afford the desired thiazoloquinolinones 10 and 15 in 90% and 97% yield, respectively.The same products were obtained when TFA was employed as an alternative to boron trifluoride but with lower yields and longer reaction times.In conclusion, the iodine (III)-mediated preparation of thiazolo [5,4-c]quinolin-4-ones has been described.The validity of the employed protocol in the synthesis of other quinolinone fused heterocycles, as well as the scope of substituents in the aromatic moiety of the quinolinone nucleus ring is currently under study.

Typical procedure for the synthesis of amides 9 and 14. Synthesis of 5-(Nmethoxycarbamoyl)-2-methyl-4-phenylthiazole (9)
Thionyl chloride (0.15 mL, 2.05 mmol) was added to a solution of the carboxylic acid 7 (0.3 g, 1.37 mmol) in CH 2 Cl 2 (10 mL).The mixture was heated at reflux for 4 h.Removal of solvent in vacuo gave the corresponding aroyl chloride 8 as a residue which, without isolation, was dissolved again in CH 2 Cl 2 (15 mL).To this solution, hydroxylamine (HCl salt) (0.12 g, 1.51 mmol) and pyridine (0.27 mL, 3.30 mmol) was added at 0 ºC, and the mixture was stirred at rt until the conversion was complete.Then, the solution was washed with saturated CuSO 4 , the organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo.The residue was column chromatographed (Hex/EtOAc, 3/7) and the resulting amide 9 was crystallized from hexanes as a pale brown solid.mp 154-155 o C (Hexanes); Scheme 1 Scheme 2 Scheme 4