Oxidative rearrangement of alkyl aryl/heteroaryl ketones by 1,2-aryl/heteroaryl shift using iodic acid

A method for synthesis of α-aryl/heteroaryl alkanoic acids involving oxidative rearrangement of alkyl aryl/heteroaryl ketones by 1,2-aryl/heteroaryl shift using iodic acid is described.


Introduction
Improvements in reaction methodologies are yielding useful and simplified new variants. 1eplacement of hazardous and expensive reagents by safer, cheaper and off-the-shelf reagents is an attractive option towards improved methodologies.α-Aryl/heteroaryl alkanoic acid derivatives have commercial importance as NSAIDs, such as naproxen, ibuprofen, flurbiprofen, diclofenac and indomethacin.Many of them are known for their analgesic, and antipyretic properties too. 2 There are quite a large number of methods available for their synthesis, 3 which include arylation of esters using transition metal catalysed reactions, 4 carbonylation/carboxylation reactions that includes aryl halides, α-aryl alcohols as counterpart of α-aryl/heteroaryl alkanoic acids.3b,5 Another useful and widely followed approach is oxidative rearrangement of alkyl aryl/heteroaryl ketones as shown in Scheme 1.

Scheme 1. Oxidative rearrangement of alkyl aryl/heteroaryl ketones.
This approach is attractive because parent ketones are readily accessible through Friedel-Crafts reactions.Another procedure to synthesise α-aryl/heteroaryl alkanoic acid derivatives is alkylation of corresponding acetic acids; however, selectivity in getting mono substituted product is a major concern.
Early methods reported for this oxidative rearrangement were based on use of lead(IV) acetate, 6 silver nitrate 7 and thallium nitrate. 7,8Toxicity factor of these metal reagents 9 lead to the development of other methods, which include iodine, iodine monochloride and iodine trichloride mediated transformations. 10ypervalent iodine reagents have also made their entry into this transformation because of their popularity as mild oxidising agents and similar reactivity pattern as of lead and thallium. 11ydroxy(tosyloxy)iodo]benzene (HTIB, Koser's reagent) and iodosobenzene, 12 diacetoxyiodobenzene (DIB), 13 1H-1-hydroxy-5-methyl-1,2,3-benziodoxathiazole 3,3-dioxide (HMBI), 14 have been used effectively to perform the transformation.Scope still exists to improve the methodology using other hypervalent iodine reagents especially those which are safer and readily available off-the-shelf, such as iodic acid.Our group is actively working on hypervalent iodine mediated oxidative transformations 15 and recently on iodic acid. 16In this paper we report successful application of iodic acid for oxidative rearrangement.

Results and Discussion
An initial experiment was performed on acetophenone 1a with 1.1 equiv of HIO3 in the presence of methanol: trimethylorthoformate (TMOF) (9:1) and a catalytic amount of conc.H2SO4, at 65 °C.The rearranged product, methyl phenylacetate 2a, was found in 92 % yield within 2h.Reaction conditions were studied and the results are given in Table 1.
When the reaction was carried out in absence of sulfuric acid as catalyst at room temperature as well as at 65 °C reaction did not occur (Table 1, entries 1&2).Reaction in the presence of the acid catalyst at room temperature was very slow, and rearranged product 2a was obtained in 40% in 6 h.When the reaction temperature was raised to 65 °C, reaction was accelerated and 2a was found in 92% yield in 2 h (Table 1, entry 4).To understand the role of TMOF a reaction was performed in its absence.H NMR and IR analysis data, yields presented are after column chromatography.b In some runs even after prolonged heating conversion was incomplete and ≤ 5% of unreacted starting material was recovered.
With these encouraging results in hand we went to check the generality and usefulness of the reaction, by performing the reaction on various substrates including aryl/heteroaryl methyl ketones and other alkyl aryl ketones and the results are summarised in Table 2 and Table 3 a Products were characterized by 1 H NMR and IR analysis data, yields presented are after column chromatography.b α-methoxylated products were formed (≤5%) however these did not pose any problem during isolation.
Other alkyl aryl ketones such as propiophenones 3a-c, butyrophenone 3d, valerophenone 3e and 3-benzoylpropanoic acid 3f were subjected to the transformation.All these substrates underwent the transformation readily and gave good yields of the corresponding rearranged products (Table 3, entries 1-5).In the case of 3-benzoylpropanoic acid under the reaction condition diesterified product 4f was isolated (Table 3, entry 6).

Conclusions
Iodic acid, a readily available, safer and off-the-self reagent, was found to be suitable for synthesis of α-aryl/heteroaryl alkanoic acids starting from alkyl aryl/heteroaryl ketones through oxidative rearrangement by 1,2-aryl/heteroaryl shift and is superior to iodine-mediated methods.

Experimental Section
General. 1 H NMR spectra were recorded on JEOL MY-60 operating at 60 MHz, chemical shifts are expressed in parts per million downfield from TMS in δ units.IR spectra were recorded on

Table 1 .
Study of reaction conditions a,b a Products were characterized by

Table 2 .
, respectively.Products of oxidative rearrangement of aryl/heteroaryl methyl ketone derivatives a

Table 3 .
Oxidative rearrangement of higher alkyl aryl ketones a Products were characterized by1H NMR and IR analysis data, yields presented are after column chromatography Comparative results of our method with iodine-mediated methods from the literature, with some examples, are given in Table4.Our method is superior with respect to yield and stoichiometry (Table4, entry 1), or no requirement of co-oxidant AgNO3 (Table4, entries 2-4). a

Table 4 .
Comparison of our method with iodine mediated methods