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PhIO-Mediated oxidative dethioacetalization/dethioketalization under water- free conditions

Treatment of thioacetals and thioketals with iodosobenzene in anhydrous DCM conveniently afforded the corresponding carbonyl compounds in high yields under water-free conditions. The mechanistic studies indicate that this dethioacetalization/dethioketalization process does not need water and the oxygen of the carbonyl products comes from the hypervalent iodine reagent.


Introduction
The protection of carbonyl compounds as thioacetals and thioketals has been widely applied [1][2][3][4] in organic synthesis, as the approach can enable the synthesis of useful synthetic building blocks via a protection/deprotection protocol. For a representative example, the lithium anions of aldehyde 1,3-dithianes could be utilized as nucleophiles for the formation of new C-C bonds, providing a practical umpolung approach for further alkylating of the substrates. [5][6][7] Cyclic thioacetals and thioketals, such as 1,3-dithiolanes and 1,3dithianes, have been commonly used in various organic transformations due to their easy preparation and high stability against the acidic/basic conditions. 8 However, regeneration of the parent carbonyl species via removal of the thio moiety is often not an easy task. Generally, the existing deprotection can be achieved by using the traditional Hg(II)-based reagents 9,10 and other metal salts including AgNO3, 11 Fe(acac)3, 12 Cu(NO3)2, 13 SbCl5, 14 GaCl3 15 and ZnCr2O7. 16 It is obvious that most of the above methods are suffering from limits of potential environmental concerns caused by the metal pollution. With this context, the development of facile and 'greener' deprotection approaches for converting thioacetals and thioketals back to carbonyl compounds under convenient and environment-friendly conditions has been the increasing interest of organic chemists. Accordingly, the novel deprotection protocols continuously evolved and now the conversion can be realized by using hydrogen peroxide, 17 oxone, 18 selectfluor, 19 clay 20 and UV/visible light. 21 Furthermore, the electrophilicity of halonium ions also allows the oxidative cleavage of 1,3-dithianes by using halogenation reagents including NBS (N-bromosuccinimide) 22 and NCS (N-chlorosuccinimide). 23,24 It is worth noting that various oxidative systems involving the use of iodine reagents such as NH4I/H2O2, 25 NaI/1,4-benzoquinone (BQ), 26 MeI, 27 I2/H2O2 28 and IBr 29 have also been used for this dethioacetalization process.
Owing to their non-metallic and environment-benign characteristic as well as the moderate oxidizing property, hypervalent iodine compounds have also been explored for the oxidative dethioacetalization reactions. Until now, several of them have been attested to be efficient reagents for this deprotection process. In 1989, Stork and Zhao 30 reported a concise method for the deprotection of 1,3-dithianes by using bis(trifluoroacetoxy)iodobenzene (PIFA) as oxidant in acetonitrile/H2O or MeOH/H2O (Scheme 1a). During this transformation, the hypervalent iodine reagent can realize an efficient selective dethioacetalization as the functional groups including esters, alcohols, halides, secondary amides, acetals, alkenes and alkynes could be well tolerated under the conditions. The method has been widely applied in a series of organic transformations, including the synthesis of complicated naturally occurring compounds. 31,32 In 2002, Panek and coworkers reported that thioketals and thioacetals could be efficiently and chemoselectively deprotected by Dess-Martin periodinane (DMP) in mixed solvents containing acetonitrile, DCM and water (Scheme 1b). The method was equally compatible with a variety of functional groups involving nitriles, esters, lactones, aldehydes, ethers, and olefins. 33 In 2004, Nicolaou and colleagues reported that o-iodoxybenzoic acid (IBX) in DMSO/H2O was also a powerful system for the cleavage of dithiane (Scheme 1c). 34 It is worth noting that Nicolaou proposed that IBX could directly provide oxygen atoms for the newly generated carbonyl groups. However, water was also used as a component of the mixed solvent as the reaction could be greatly promoted with the introduction of water, possibly due to the improved solvalysis of IBX in aqueous solvent. It is evident that all of the above methods applied water in their respective reaction systems, possibly for introducing the oxygen of the carbonyl compound via a presumed hydrolysis process. As it is obvious that the above hypervlaent iodine-mediated approaches are not applicable to compounds bearing water-sensitive moieties, it is highly desirable to develop a novel dethioacetalization process that does not require the participation of water. In this communication, we reported that iodosobenzene (PhIO) is another efficient hypervalent iodine reagent that can realize dethioacetalization/dethioketalization of 1,3-dithiolanes or 1,3-dithianes by using DCM as sole solvent (Scheme 1d). One striking of the current approach is that, differing from the above existing approaches, the reaction does not require the presence of water and the oxygen atoms of the regenerated carbonyl groups has been proved to be from the hypervalent iodine reagent.

Results and Discussion
Based on previous research describing that PhIO could transfer oxygen atoms to ketene, 35 we were interested to investigate the feasibility of PhIO-mediated dethioacetalization as well as of the origin of the oxygen in the final carbonyl products. 2-Phenyl-1,3-dithiolane 1a was used as the model substrate which was deprotected with 1.0 equiv of PhIO in anhydrous acetonitrile at room temperature. To our delight, thioacetal 1a was converted to the corresponding aldehyde 2a in 82% yield (entry 1, Table 1). Encouraged by this result, we further screened the reaction conditions by using different anhydrous solvents. The results indicated that the deprotection could occur smoothly when ethyl acetate (EtOAc) and DCM was used as solvent, with DCM being the best choice as the desired aldehyde 2a was achieved in 85% yield (entries 2-3, Table 1). While the reaction using 1,2-dichloroethane (DCE), n-hexane, tetrahydrofuran (THF), N,N-dimethylformamide (DMF) or 1,4dioxane as solvent was proved to be less efficient since aldehyde 2a was obtained in relatively much lower yields (entries 4-8, Table 1). It was further observed that toluene and methanol (MeOH) were not appropriate solvents for this deprotection reaction because the yield of the target product 2a was fairly low for both cases, even after a prolonged reaction time (entries 9-10, Table 1). Next, the dosage amount of PhIO was investigated to further improve the outcome of the deprotection reaction. With an increased amount of oxidant from 1.0 to 1.2 equiv, the reaction rate was obviously enhanced and the product could be achieved in 92% yield (entry 11, Table 1). However, the further application of 1.5 equiv was not necessary as the reaction afforded the deprotected product in an even lower yield, possibly due to the formation of some unidentified byproducts (entry 12, Table  1).
With the optimized conditions (entry 11, Table 1) in hand, we went on investigating the scope of this novel dethioacetalization/dethioketalization method with a diverse range of dithioacetals substrates. It was demonstrated that the new deprotection pathway was suitable for a plethora of substrates possessing versatile electron-donating groups (EDG) or electron-withdrawing groups (EWG). Strikingly, the functional groups including ether, dimethylamino, ester, halogen atom, phenolic hydroxy and alkene were all well tolerated under the reaction conditions (Table 2). Specifically, electron-rich as well as neutral aromatic dithioacetals could be deprotected smoothly in anhydrous DCM within 30 min to afford the corresponding aldehydes in excellent yield (entries 1-7, Table 2). The method works equally well for dithioacetals bearing electron-deficient aromatic substituent as the corresponding products were obtained in good yield (entries 8-10, Table 2). It was further observed that dithioacetals derived from α, β-unsaturated, condensed-aromatic, heteroaromatic and aliphatic aldehydes were all converted to the corresponding deprotected aldehydes in good to excellent yields (entries 11-14, Table 2). Furthermore, the method was also well applicable to 1,3-dithianes, the six-membered analogue of the five-membered 1,3-dithiolanes, as the reaction delivered the parent aldehydes in equally good to excellent yields (entries 16-19, Table 2). It is worth noting that in all cases, no carboxylic acids, an-over oxidation product of aldehydes, was observed during this dethioacetalization process.    In addition, we explored the efficiency of this method on dithioketals involving aromatic, aliphatic and heteroaromatic substrates. The results indicated that all the reactions underwent a smooth deprotection to furnish the corresponding carbonyl compounds in good to excellent yields (entries 1-9, Table 3). It is worth noting that the amide moiety in dithioketal 1ab could be well tolerated (entry 2, Table 3). Furthermore, dithioketal-protected estrone 1aj also underwent facile deprotection to regenerate the parent carbonyl product, without any influence on the phenolic hydroxyl group (entry 10, Table 3).
To verify the feasibility of this method for the dethioacetalization of compounds bearing water-sensitive groups, we carried out a control experiment by subjecting (4-(1,3-dithian-2-yl)phenoxy)trimethylsilane 1r to this PhIO-mediated water-free conditions. The result clearly showed that dithioacetal 1r could be conveniently converted to the parent aldehyde 2r, with the TMS group intact during the process. However, when substrate 1r was deprotected by the known hypervalent iodine reagent-mediated approaches using water as a co-solvent, the dethioacetalization as well as the desilylation both occurred to afford product 2p.  To understand the exact source of the oxygen atom in the newly generated carbonyl compounds, we conducted two control experiments. First, the deprotection of 2-phenyl-1,3-dithiolane 1a on a 5 grams scale in anhydrous DCM under N2 atmosphere was carried out and the corresponding benzaldehyde 2a was obtained in excellent yield (Scheme 3). This outcome could rule out the possibilities that the residual water in the solvent and the O2 from air participated the deprotection process. Second, PhI 18 O was prepared according to a literature procedure 36 and its reaction with 2,2-diphenyl-1,3-dithiolane 1aa under the optimized conditions did afford the corresponding 18 O-labelled carbonyl product 3aa (Scheme 4, eq. a), The outcome of this isotope-labelling experiment indicates that the oxygen atom of the carbonyl product could be originated from PhIO. Although the previous reports demonstrated that the thio moieties in the substrate was converted to disulfide during the deprotection process, 21,26 dithioacetal 1s was prepared and subjected to the standard conditions to make further corroboration. Unsurprisingly, the reaction of 1s with PhIO in DCM afforded disulfide 3s in 90% yield, with isolation of 4-methylbenzaldehyde 2s in 93% yield (Scheme 4, eq. b).

Scheme 4. Control experiments.
Based on the above experimental results and the conclusions from previous reports, 34,35 a possible mechanism was proposed for this novel PhIO-mediated dethioacetalization/dethioketalization (Scheme 5). First, the reaction of 1,3-dithianes І with PhIO generates the sulfonium intermediates II, which undergo ring-opening to form sulfonium intermediates III. Then following the similar pathway proposed by Nicolaou, 34 the oxygen anion nucleophilicly attacks the carbon center of sulfonium moiety in III, with the concomitant formation of disulfide bond and the cleavage of S-I bond, to furnish intermediates IV. Finally, eliminations occur in intermediate IV to afford the final carbonyl products V, with removal of phenyl iodide and the cyclic disulfide as byproducts.

Conclusions
In summary, we have developed a viable PhIO-mediated dethioacetalization/dethioketalization method by which 1,3-dithiolanes and 1,3-dithianes could be smoothly converted to the corresponding carbonyl products under water-free conditions. Significantly, differing from the existing hypervalent iodine mediated deprotection methods, the current approach does not require the participation of water and it is verified that PhIO can provide oxygen atoms for the regenerated carbonyl groups. This feature might render this method practical application to the dethioacetalization/dethioketalization of substrates that bear water-sensitive functional groups.

Experimental Section
General. Commercially available reagents and solvents were purchased as reagent grade and used without further purification. 1,3-Dithiolanes/dithianes substrates and PhIO were synthesized and purified according to the literature procedures. 37,38 All reactions were carried out at room temperature and stirred magnetically in anhydrous solvents. Thin layer chromatography (TLC) plates were visualized by exposures to the ultraviolet light (254 nm). Flash column chromatography was performed over silica gel (200-300 m) using a mixture of ethyl acetate (EtOAc) and petroleum ether (PE) as the eluent. Preparative high-performance liquid chromatography was conducted on a LC-20AP system and over a ZORBAX CN column (21.2 mm × 250 mm, 7 μm) using a mixture of dichloromethane (DCM) and hexane as the eluent. 1 H and 13 C NMR spectra were recorded on a 400 MHz spectrometer or a 600 MHz spectrometer at 25 °C. The values of chemical shifts are shown in ppm and referring to tetramethylsilane (TMS) as the internal standard whose chemical shift value is 0.00 ppm. The peaks are manifested as follows: chemical shift; s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; dd, doublet of doublets; and br, broad. The coupling constants (J) are reported in Hertz (Hz). Melting points were measured with a Micromelting point apparatus. The data of high-resolution mass spectrometry (HRMS) were collected on a Q-TOF micro spectrometer.