Microwave-induced, solvent-free transformations of benzoheteracyclanones by HTIB (Koser’s reagent)

The microwave-activated reactions of [hydroxy(tosyloxy)iodo]benzene (HTIB) with various chromanones, thiochromanones and dihydroquinolones under solvent-free conditions have been studied. In addition to the common dehydrogenation reaction, 2,3-migration also has been observed in the case of flavanone and 2,2-disubstituted chromanones. 3-Tosyloxychromanones were isolated from the reaction of chromanone and 2-methylchromanone for the first time. Substrates with nucleophilic heteroatoms such as thiochromanones and 2-phenyl-2,3-dihydro-4-quinolone reacted by electrophilic attack of the heteroatom.


Introduction
[Hydroxy(tosyloxy)iodo]benzene 1 (HTIB, Koser's reagent) and related hypervalent iodine derivatives have become widely used reagents for synthetic organic chemistry during the last decades, and excellent overviews of their chemistry have been forthcoming in several papers. 2he most frequently exploited reactions of HTIB and the other [(arylsulfonyloxy)(hydroxy)iodo]benzene analogues are the α-sulfonyloxylation of ketones (or their enol derivatives), sulfonyloxylation of double bonds, phenyliodination and oxidation, and all of these approaches have been utilized in the synthesis of various heterocyclic systems 2 .A survey of the literature reveals continuous efforts to develop these reagents and the conditions for their use.Some recent examples are preparation of isoflavones from 2'-hydroxychalcones by means of a polymer-supported reagent, 3 α-tosyloxylation in ionic liquids, 4 α-hydroxylation of ketones by HTIB in DMSO-water mixtures, 5 oxidative α-tosyloxylation of alcohols into αtosyloxy aldehydes and ketones 6 or the use of [hydroxy(2,4dinitrobenzenesulfonyloxy)iodo]benzene (HDNIB). 7icrowave (MW) irradiation is an efficient and environmentally-benign method to activate various organic transformations to afford products in higher yields in shorter reaction periods.In this class of MW-assisted reactions, solvent-free syntheses are of particular interest and importance in view of their simplicity, tunability and ease of work-up. 8MW activation was utilized advantageously in the α-tosyloxylation of acetophenones by HTIB in the presence of K10 clay and the generated tosylates were successfully transformed into thiazoles and imidazo[2,1-b]thiazoles. 9 In continuation of our studies in the field of cyclic α-(arylsulfonyloxy)ketones and oxygencontaining heterocycles, we decided to investigate the reaction of various chromanone derivatives and their sulfur or nitrogen-containing analogues with HTIB under MW irradiation and solvent-free conditions, and the most characteristic results are presented here.

Results and Discussion
First, we searched for the most efficient MW-inactive support for use of the highly sensitive 2,2dimethyl-7-methoxychromanone (5b) as a test molecule.MW irradiation and subsequent workup afforded the expected 2,3-dimethyl-7-methoxychromone (6b) in addition to some unidentified, highly polar products which could be removed easily by filtration through a short pad of silica or by short-column chromatography (Scheme 1, Table 1).The structure of the product was in accordance with literature data, Prakash and his coworkers 10 have observed the same 2,3-methyl migration and dehydrogenation in refluxing acetonitrile using ultrasound activation.The results summarized in Table 1 reveal a decisive role for the support.Surprisingly, poor conversion and low yield was found using Montmorillonite K10 and neutral alumina.Inorganic salts such as CaCO 3 or Na 2 SO 4 gave much better conversions.Good conversions also have been achieved without any support, but the yield was lower due to secondary reactions causing the decomposition of the product.Taking the length of the irradiation period, conversions and yields into consideration, we chose Na 2 SO 4 as the carrier for further experiments.
On the contrary, when flavanone (1c) was treated with HTIB no tosylate 2c was obtained and the reaction yielded a mixture of flavone (3c) and isoflavone (4c) (Table 2, Scheme 1).This result is in accordance with the literature data.According to Prakash et al., 3-tosyloxyflavanone was never observed using classical heating and the product ratio depended strongly on the conditions.In boiling acetonitrile or propionitrile, isoflavone (4c) was the major product accompanied with a small amount of flavone (3c) and methyl 2-phenyl-2,3-dihydrobenzofuran-3-carboxylate. 13The change of the solvent to methanol resulted in a dramatic shift as flavone (3c) became the major product, accompanied by some cis-3-methoxyflavanone and methyl 2phenyl-2,3-dihydrobenzofuran-3-carboxylate. 14The oxidative rearrangement of flavanone (1c) also has been performed using other reagents such as iodobenzene diacetate/p-toluenesulfonic acid in acetonitrile, iodosobenzene/methanesulfonic acid in methylene chloride or acetonitrile 2 or various thallium(III) reagents. 15The treatment of various substituted 2,2-dimethylchromanones 5a-c,e-g with HTIB under our MW conditions afforded the corresponding 2,3-dimethylchromones 6a-c,e-g (Table 3, Scheme 1).The use of higher amounts of HTIB resulted in an increase in the conversion in all cases, but the yields were significantly lower due to the decomposition of the primary products formed.This tendency is quite conspicuous in the case of 7-benzyloxy-2,2,5-trimethylchromanone (5g) where the aromatic ring is highly activated and, therefore, sensitive to the competitive attack of the electrophilic reagent (Table 3, Entries 9,10).For the same reason, the reaction of 2,2dimethyl-7-hydroxychromanone (5d) failed to give any desired rearranged product 6d.The latter was prepared by the acid-catalyzed debenzylation of the protected derivative 6c.The 2,3-alkyl migration and dehydrogenation also was observed in the reaction of the 2spirochromanones 8a-c to give the corresponding tricyclic products 9a-c in good-to-excellent yields.The same reaction had been observed previously from the treatment of the spirochromanones with HTIB in hot acetonitrile, with or without ultrasound activation, 10 or with thallium(III) trinitrate in hot acetonitrile. 16Based on the results, we can conclude that the rearrangement is expected only with 2,2-disubstituted chromanones or 2-substituted chromanones containing a group of high migrating capability (e.g.aryl).HTIB-induced dehydrogenation and migration of spirochromanones offers a useful method for the synthesis of various naturally-occurring and/or biologically active targets and some such molecules containing a tetrahydroxanthone moiety are shown in Figure 1.To the best of our knowledge, the only exploitation of this approach has been presented by Gabutt et al. 21who accomplished the synthesis of the rotenoid core.The obtained results can be integrated in a single mechanism.According to the literature, 2 the reacting species in the HTIB-mediated reactions is the 3-phenyliodonio intermediate 11 which has a trans relative configuration in the case of 2-substituted chromanones.The preferred formation of this diastereomer can be rationalized in terms of the optimized 22  The lack of an electron-donating 2-alkyl substituent in cation 12a makes it more unstable and hinders the migration in the case of 2-methylchromanone (1b).On the other hand, it seems very likely that the migration in the flavanone (1c) takes place via the phenonium intermediate 12c.
We have investigated also some heteroanalogs of chromanones.Treatment of 1thiochromanone 13a with HTIB under MW irradiation afforded the corresponding sulfoxide 14a, accompanied by a small amount of 1-thiochromone 15a.Surprisingly, the same product 14a was obtained in nearly the same yield without any MW activation simply by intimately mixing the reagents and the support.2-Substituted-1-thiochromanones 13b,c gave similar results, affording the sulfoxides 14b,c with low-to moderate diastereoselectivity (Scheme 3, Table 4).Oxidation of sulfides to sulfoxides without apparent overoxidation to sulfones by [methoxy(tosyloxy)iodo]benzene (MTIB), obtained from HTIB and trimethyl orthoformate, 23 or by HTIB or HCIB in methylene chloride, 24 or by in situ generated HTIB in acetonitrile 25 has been reported, but this is the first case where a heterogenous, solid-phase reaction has been observed.Our finding offers a new and easy entry to heterocyclic sulfoxides.Finally, the reactivity of 2,3-dihydro-4-quinonolones 16, 18 was tested since previously very little had been published on the reaction of dihydroquinolones with hypervalent iodine reagents.2-Aryl-2,3-dihydro-4-quinolones were reported to afford 4-alkoxy-2-arylquinolines in the presence of HTIB, trialkyl orthoformate and perchloric acid 26 and 2-aryl-4-quinolones upon treatment with iodobenzene diacetate and potassium hydroxide in methanolic solution. 27Under our conditions, both substrates reacted sluggishly and low conversions were found even by using higher amounts of HTIB.The substitution on the nitrogen plays a decisive role since 2-phenyl-2,3-dihydro-4-quinolone ( 16) gave the dehydrogenated 2-phenyl-4-quinolone (17) as the sole product while 1-acetyl-2-phenyl-2,3-dihydro-4-quinolone (18) yielded the migrated 3-phenyl-4quinolone (19) (Scheme 3, Table 4).Neither of these reactions has considerable synthetic value but each provides important mechanistic information.Similarly to the sulfur-containing substrates where the sulfoxidation proceeds by an electrophilic attack on the sulfur atom and runs via the intermediate 20, HTIB attacks the nucleophilic nitrogen atom in the dihydroquinolone 16 giving the phenyliodonium intermediate 21 and then finally the quinolone 22.This latter intermediate transforms into the final product, either by a hydrogen shift or by a protonationdeprotonation sequence (Scheme 3).The acylation of the nitrogen in compound 18 stops its nucleophilic character and directs the transformation to the enol mechanism shown in Scheme 2. This duality proves for the higher reactivity of nucleophilic heteroatoms toward HTIB in comparison with double bonds.
In conclusion, the reaction of 2-unsubstituted and 2-alkylchromanones with HTIB was found to give the corresponding, hitherto unknown 3-tosyloxy derivatives, in addition to dehydrogenation, whereas dehydrogenation and/or 2,3-migration was observed with other chromanones.Attack at the nucleophilic heteroatom was observed in the reactions of 1thiochromanones or 2-phenyl-2,3-dihydro-4-quinolone, giving the corresponding sulfoxides or the dehydrogenated product, respectively.

General procedure for the microwave-induced reactions
Benzoheteracyclanone 1a-c, 5a-c,e-g, 8a-c, 16, or 18 (1 mmol), HTIB (1.2 or 2.4 mmol) and anhydrous sodium sulfate (5 g) were mixed thoroughly and irradiated in a household microwave oven (2.45 GHz, 700 W) with a one-minute break between two exposures (for details see Tables 1-4).The mixture was washed with dichloromethane (4x30 mL), concentrated in vacuo and the residue was submitted to short-column chromatography.Conversion and yields are shown in the Tables.Known products 3a-c, 4c were identified by TLC comparison, m.p. and 1 H NMR spectra.

Table 1 .
Effect of the support on the MW-induced reaction of 2,2-dimethyl-7-methoxychromanone (5b) with HTIB a aAccording to the General Procedure (Experimental Part) by treating 1.00 mmol of 5b with 1.20 mmol of HTIB, elution with hexane-ethyl acetate (1:1, v/v).b Calculated on the basis of the recovered starting material.c Refers to pure isolated products, the values are normalized to 100% conversion.

Table 2 .
Reaction of chromanones 1a-c with HTIB under MW irradiation using Na 2 SO 4 support a A: dichloromethane, B: dichloromethane, components of low R f were eluted by ethyl acetate and re-chromatographed using hexane-ethyl acetate (1:1, v/v).b Calculated on the basis of the recovered starting material.c Refers to pure isolated products, the values are normalized to 100% conversion.

Table 4 .
Reaction of thiochromanones 13a-c and dihydroquinolones 16,18 with HTIB under MW irradiation using Na 2 SO 4 support a E: ethyl acetate, F: toluene-ethyl acetate (4:1, v/v), G: ethyl acetate-hexane (8:1, v/v) b Calculated on the basis of the recovered starting material.c Refers to pure isolated products, the values are normalized to 100% conversion.