Mild Deprotection of Dithioacetals by TMSCl / NaI Association in CH3CN

We showed for the first time, the fundamental role of CH 3 CN associated to TMSCl/NaI combination to deprotect S,S-ethylene- and S,S-propylene-ketals into ketones. Indeed, if the TMSCl/NaI association leads to the reduction of dithioketals in CH 2 Cl 2 , we have demonstrated that this association can be used to deprotect a large variety of various dithioketals into ketones in CH 3 CN. Otherwise, under mild experimental conditions, O,O-acetals as well as O,S-oxathianes were cleanly deprotected with high yields. It is also possible to easily regenerate the carbonyl function of various hydrazones and imines using this novel protocol. We believe that this metal-free process is a good alternative to other known methodologies used to deprotect dithioketals into ketones. Abstract. A mild process using a combination of TMSCl and NaI in acetonitrile is used to regenerate carbonyl compounds from a variety of dithiane and dithiolane derivatives. This easy to handle and inexpensive protocol is also efficient to deprotect oxygenated and mixed acetals as 1,3-dioxanes, 1,3-dioxolanes and 1,3-oxathianes quantitatively. As a possible extension of this method, it was also showed that nitrogenated-substrates as hydrazones, N -tosylhydrazones and ketimes reacted well under these conditions to give the expected ketones in high yields. The methodology proposed herein is a good alternative to the existing methods since it does not use metals, oxidants, reducing agents, acidic or basic media, and keto-products were obtained in high to excellent yields. Abstract. A mild process using a combination of TMSCl and NaI in acetonitrile is used to regenerate carbonyl compounds from a variety of dithiane and dithiolane derivatives. This easy to handle and inexpensive protocol is also efficient to deprotect oxygenated and mixed acetals as 1,3-dioxanes, 1,3-dioxolanes and 1,3-oxathianes quantitatively. As a possible extension of this method, it was also showed that nitrogenated-substrates as hydrazones, N -tosylhydrazones and ketimes reacted well under these conditions to give the expected ketones in high yields. The methodology proposed herein is a good alternative to the existing methods since it does not use metals, oxidants, reducing agents, acidic or basic media, and keto-products were obtained in high to excellent yields.


Introduction
Dithianes are commonly used in organic chemistry to mask the electrophilic nature of carbonyl groups [1] in elaborated molecules but also serve as acyl anions in syntheses according to the Umpolung concept. [2 ]The main advantages of dithianes are their easy access from a carbonyl compound by using propane-1,3dithiol and a Lewis acid and their stabilities in alkaline and acid conditions notably permitting their purification on silica columns. In counterparts to this stability, many procedures have been developed for their deprotection but generally require drastic conditions. [3] Most of the time, toxic metal salts as Hg(II), [4] Ag(I), [5] Zn(II), [6] Ga(III), [7] Cu(II), [8] Tl(V) [9] and others are used in excess in harsh conditions with some success. The use of hypervalent-iodine reagents for the removal of dithianes has been also reported as an efficient process using periodic acid, [10] diacetoxyiodobenzene, [11] bis(trifluoroacetoxy)iodobenzene (BTI), [12] Dess-Martin periodinane [13] and Nhalosuccinimides. [14] However, a large variety of the aforementioned methods require the use of toxic metals, the need of oxidizing species in large amounts sometimes accompanied with co-oxidants mainly in harsh reaction conditions. In this context, we believe that an alternative milder process is still needed using for example inexpensive and soft reagents to achieve this transformation at room temperature in the presence of various functional groups.
Recently, we reported the interesting reducing properties of the TMSCl/NaI association in CH2Cl2 towards various functional groups as unsymmetrical -diketones, [15] -ketoesters, [16] and hydrazones [16] derivatives. Under similar reaction conditions, we next demonstrated that a variety of dithioacetals were cleanly desulfurized at room temperature [17] in CH2Cl2 using this metal-free process in a Mozingo-type reaction. [18] By replacing CH2Cl2 by CH3CN as the reaction solvent, we surprisingly observed that dithianes derivatives were not reduced into methylene substrates but were totally and cleanly deprotected into ketones. It seemed interesting to study in detail this method for the deprotection of thioacetals which does not use metal salts, nor oxidants, nor toxic or expensive reagents ( Figure 1). Herein, we wish to report the mild deprotection conditions of a range of dithianes, dithiolanes and oxygenated derivatives using the TMSCl/NaI association in CH3CN.

Scheme 1. Deprotection of cyclic ketals 3,4 and oxathiane 5 by TMSCl/NaI in MeCN
As it could be seen in Scheme 1, by using TMSCl/NaI in CH3CN under conditions A (seen in entry 7 of Table 1), we observed a clean and complete deprotection of ketals 3 and 4 as well as 1.3oxathiane 5 into ketones (93 to 97%). For comparison, Jung reported that TMSI in CHCl3 deprotected ethylene ketals into ketones but with very low yields (20 %) and that TMSI did not react with thioketals after 24 h of mixing at 75 °C. [22] Encouraged by these results and by the simplicity of this process, the deprotection of a variety of thioacetals 1 was carried out with the TMSCl/NaI association in CH3CN for 24 h. Table 2 summarizes the results of this study achieved using 10 eq of TMSCl/NaI at rt (conditions A) or 20 eq of TMSCl/NaI at 60 °C (conditions B) for less cooperative substrates.  a) Dithioacetals were prepared from the corresponding ketones with dithiols in the presence of BF3-Et2O. [23] b) All purified ketones had 1 H and 13 C NMR data identical to those of authentic samples. c) 1-Benzyl-4methoxybenzene (40%) resulting from the dithioketal reduction was also isolated. d) NaBr replaced NaI.
As observed 1,3-dithianes and 1,2-dithiolanes of acetophenones 1a-g were deprotected into their parent ketones with good yields ranging from 54 to 94%. It is of note that, 1,3-dithianes 1b,c, and 1f,g were more cooperative substrates than our model substrate 1a since the deprotection reaction required half quantity of TMSCl/NaI and was achieved at rt under conditions A. Examination of these results also shows that 1,3-dithianes seem easier to deprotect using TMSCl/NaI in CH3CN than their 1,2-dithiolane counterparts (compare 1c and 1d) and that electrondonating groups on the aromatic nucleus allowed more efficient deprotection reactions (compare 1c and 1g). As expected, 1,3-dithianes prepared from aliphatic aryl (cyclic or not) ketones 1h-l reacted well with the TMSCl/NaI combination and furnished ketones 2h-l in good to excellent isolated yields (64 to 91%). The case of dialkyldithiane derivatives was next examined with compounds 1m-p and showed that these compounds were also cooperative substrates as they were rapidly and cleanly deprotected to give the desired ketones 2m-p with satisfactory yields (76 to 95%). When -bromo dithiane 1q was reacted with TMSCl/NaI, acetophenone 2q was obtained indicating that, besides the expected deprotection reaction, a debromination reaction occurred too in agreement with a previous report of Olah. [24] Then, the case of diaryldithianes was examined. Under A classical conditions (TMSCl/NaI 10 equiv, rt, 24 h), we observed that 1,3-dithiane 1r having no H, reacted with TMSCl/NaI to give a mixture composed in almost equal parts of the expected ketone 2r (43%) accompanied by the reduction [17] product 1-benzyl-4methoxybenzene (40%). To avoid the formation of the reduction by-product, we successfully replaced NaI by NaBr, increased the quantity of TMSCl/NaBr and heated the solution at 60 °C for a prolonged time (TLC monitoring). By using these conditions, diarylketones 2r and 2s were then obtained with acceptable yields and without any traces of the reduced diarylmethane by-products. Next, 1,3dithianes of aldehydes were also studied with compounds 1t and 1u. It is of note that these 1,3dithianes reacted rapidly under A mild conditions to give the corresponding aldehydes in variable yields. For the deprotection of dithioketals of aldehydes, it is very important to examine carefully the course of the deprotection reaction by TLC monitoring because prolonged reaction times resulted in a severe decrease in yields. Indeed, it has been reported that, at rt, aldehydes reacted rapidly with TMSI to give iodosilyl ethers and diiodoethers. [25] This suggests that, as soon as aldehydes are formed after thioacetal deprotection, they add nucleophilic iodides which may arise from TMSI very slowly generated in the media according to an exchange Finkelstein reaction. [26] To show the interest of this process with respect to other previously reported methods using for examples HgO associated with BF3-Et2O, [27] 2,6-dicarboxy pyridinium chlorochromate (DCPCC) [28] or SbCl5 [29] we have deprotected dithiolanes 1v and 1w by TMSCl/NaI in CH3CN (Scheme 2). The comparison of the yields obtained using the TMSCl/NaI mild association in CH3CN vs toxic oxidizing agent as HgO (86 % vs 65%), DCPCC (93% vs 70%) or SbCl5 (93% vs 77%) supports well that this novel metal-free process is welcome since the yields in desired ketones are significantly higher and the reagents used for the deprotection are inexpensive, not toxic and very easy to handle. Scheme 2. Deprotection of dithianes 1v and 1w by TMSCl/NaI in CH3CN.
Next, as dithioacetals, the regeneration of carbonyl compounds from nitrogen-derivatives as hydrazones, N-tosylhydrazones, ketimines and oximes required most of the time harsh reaction conditions including oxidative or reducing process, acidic or alkaline media, expensive reagents or hazardous experimental protocols. [30] In order to find a milder process, we next examined if the TMSCl/NaI combination in CH3CN process could be applied successfully to these robust nitrogen substrates. In Scheme 3 were presented the results of the regeneration of carbonyl functions of diphenylhydrazone 6, N-tosylhydrazone 7, Nbenzylimine 8, ketimine 9 and diphenylmethanone oxime 10, using TMSCl/NaI in CH3CN. We were pleased to observe that the TMSCl/NaI combination in CH3CN was able to transform imines and hydrazones into ketones with good yields (90 to 100%) as well as N-tosylhydrazone 7 which required the use of stronger reaction conditions. On the contrary, imine 8 and ketimine 9 were easily transformed into their ketones with high yields using the TMSCl/NaI association in CH3CN at rt. When diphenylmethanone oxime 10 was reacted with the TMSCl/NaI association (10 eq), we isolated, after 24 h of reaction achieved at rt, 4-methoxy-N-(4methoxyphenyl)benzamide 11 in a good yield (84%) accompanied by only 4 % of the bis(4methoxyphenyl)methanone 2r. The scope of this interesting Beckmann rearrangement, using the TMSCl/NaI combination, is currently under investigation in our lab with a range of oxime substrates. [31] Scheme 4. Plausible mechanism A plausible reaction mechanism is indicated in (Scheme 4). First, CH3CN activates the TMSCl/NaI association as mentioned previously by Olah [20] to promote intermediate I and II after halide exchange in the presence of NaI. Then, II reacts with a sulfur atom of dithiolane 1c to give a sulfonium species of type III. Further assistance from the neighboring dithiane sulfur atom possibly leads to a fragmented sulfonium intermediate IV which added H2O (from reagents, CH3CN or during hydrolysis) to promote hemithioketal V which is then activated into a sulfonium intermediate VI (having or not H. With no H as in 1r or 1s, VI finally rearranges into the desired ketone 2d. [32] For dithiolanes prepared from enolizable ketones as 1c, the same (a) pathway could be followed but it is also reasonable to consider an additional pathway (b) in which an iodide deprotonates intermediate VI to furnish an enol species which tautomerizes into ketone 2d. Since dithioacetals having H can evolve according to two different pathways, this can explain that these entities are easier to deprotect than diarylthioketals counterparts. It is of note that a similar mechanism has been previously proposed by Nicolaou for the deprotection of S,S-acetals and ketals using IBX. [33]

Conclusion
In this article we showed for the first time, the fundamental role of CH3CN associated to TMSCl/NaI combination to deprotect S,S-ethylene-and S,Spropylene-ketals into ketones. Indeed, if the mild TMSCl/NaI association leads to the reduction of dithioketals in CH2Cl2, we have demonstrated that this association can be used to deprotect a large variety of various dithioketals into ketones in CH3CN. Otherwise, under mild experimental conditions, O,O-acetals as well as O,S-oxathianes were cleanly deprotected with high yields. It is also possible to easily regenerate the carbonyl function of various hydrazones and imines using this novel protocol. We believe that this metal-free process is a good alternative to other known methodologies used to deprotect dithioketals into ketones.

Experimental Section
A general experimental procedure is described as following: a mixture of thioketal (100 mg) and NaI (10 eq) was stirred in MeCN for 5 min. Then, 10 eq of TMSCl were added to the solution which was stirred for 24 h at rt. The reaction was then hydrolyzed for 5 min. with H2O (5 mL) and extracted with CH2Cl2. Organic layers were dried over MgSO4 and concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel to give the expected carbonyl compound which have identical NMR spectra with starting ketones.

Introduction
Dithianes are commonly used in organic chemistry to mask the electrophilic nature of carbonyl groups [1] in elaborated molecules but also serve as acyl anions in syntheses according to the Umpolung concept. [2 ]The main advantages of dithianes are their easy access from a carbonyl compound by using propane-1,3dithiol and a Lewis acid and their stabilities in alkaline and acid conditions notably permitting their purification on silica columns. In counterparts to this stability, many procedures have been developed for their deprotection but generally require drastic conditions. [3] Most of the time, toxic metal salts as Hg(II), [4] Ag(I), [5] Zn(II), [6] Ga(III), [7] Cu(II), [8] Tl(V) [9] and others are used in excess in harsh conditions with some success. The use of hypervalent-iodine reagents for the removal of dithianes has been also reported as an efficient process using periodic acid, [10] diacetoxyiodobenzene, [11] bis(trifluoroacetoxy)iodo-benzene (BTI), [12] Dess-Martin periodinane [13] and N-halosuccinimides. [14] However, a large variety of the aforementioned methods require the use of toxic metals, the need of oxidizing species in large amounts sometimes accompanied with co-oxidants mainly in harsh reaction conditions. In this context, we believe that an alternative milder process is still needed using for example inexpensive and soft reagents to achieve this transformation at room temperature in the presence of various functional groups.
Recently, we reported the interesting reducing properties of the TMSCl/NaI association in CH2Cl2 towards various functional groups as unsymmetrical -diketones, [15] -ketoesters, [16] and hydrazones [Error! Bookmark not defined.] derivatives. Under similar reaction conditions, we next demonstrated that a variety of dithioacetals were cleanly desulfurized at room temperature [17] in CH2Cl2 using this metal-free process in a Mozingo-type reaction. [18] By replacing CH2Cl2 by CH3CN as the reaction solvent, we surprisingly observed that dithianes derivatives were not reduced into methylene substrates but were totally and cleanly deprotected into ketones. It seemed interesting to study in detail this method for the deprotection of thioacetals which does not use metal salts, nor oxidants, nor toxic or expensive reagents (Figure 1). Herein, we wish to report the mild deprotection conditions of a range of dithianes, dithiolanes and oxygenated derivatives using the TMSCl/NaI association in CH3CN.
Next, we were interested to evaluate this mild protocol with 1.3-dioxolane 3, 1,3-dioxane 4, and with 1,3-oxathiane 5. Scheme 1. Deprotection of cyclic ketals 3,4 and oxathiane 5 by TMSCl/NaI in MeCN As it could be seen in Scheme 1, by using TMSCl/NaI in CH3CN under conditions A (seen in entry 7 of Table 1), we observed a clean and complete deprotection of ketals 3 and 4 as well as 1.3-oxathiane 5 into ketones (93 to 97%). For comparison, Jung reported that TMSI in CHCl3 deprotected ethylene ketals into ketones but with very low yields (20 %) and that TMSI did not react with thioketals after 24 h of mixing at 75 °C. [22] Encouraged by these results and by the simplicity of this process, the deprotection of a variety of thioacetals 1 was carried out with the TMSCl/NaI association in CH3CN for 24 h. Table 2 summarizes the results of this study achieved using 10 eq of TMSCl/NaI at rt (conditions A) or 20 eq of TMSCl/NaI at 60 °C (conditions B) for less cooperative substrates.  a) Dithioacetals were prepared from the corresponding ketones with dithiols in the presence of BF3-Et2O. [23] b) All purified ketones had 1 H and 13 C NMR data identical to those of authentic samples. c) 1-Benzyl-4methoxybenzene (40%) resulting from the dithioketal reduction was also isolated. d) NaBr replaced NaI.
As observed 1,3-dithianes and 1,2-dithiolanes of acetophenones 1a-g were deprotected into their parent ketones with good yields ranging from 54 to 94%. It is of note that, 1,3-dithianes 1b,c, and 1f,g were more cooperative substrates than our model substrate 1a since the deprotection reaction required half quantity of TMSCl/NaI and was achieved at rt under conditions A. Examination of these results also shows that 1,3-dithianes seem easier to deprotect using TMSCl/NaI in CH3CN than their 1,2-dithiolane counterparts (compare 1c and 1d) and that electrondonating groups on the aromatic nucleus allowed more efficient deprotection reactions (compare 1c and 1g). As expected, 1,3-dithianes prepared from aliphatic aryl (cyclic or not) ketones 1h-l reacted well with the TMSCl/NaI combination and furnished ketones 2h-l in good to excellent isolated yields (64 to 91%). The case of dialkyldithiane derivatives was next examined with compounds 1m-p and showed that these compounds were also cooperative substrates as they were rapidly and cleanly deprotected to give the desired ketones 2m-p with satisfactory yields (76 to 95%). When -bromo dithiane 1q was reacted with TMSCl/NaI, acetophenone 2q was obtained indicating that, besides the expected deprotection reaction, a debromination reaction occurred too in agreement with a previous report of Olah. [24] Then, the case of diaryldithianes was examined. Under A classical conditions (TMSCl/NaI 10 equiv, rt, 24 h), we observed that 1,3-dithiane 1r having no H, reacted with TMSCl/NaI to give a mixture composed in almost equal parts of the expected ketone 2r (43%) accompanied by the reduction [Error! Bookmark not defined.] product 1-benzyl-4-methoxybenzene (40%). To avoid the formation of the reduction by-product, we successfully replaced NaI by NaBr, increased the quantity of TMSCl/NaBr and heated the solution at 60 °C for a prolonged time (TLC monitoring). By using these conditions, diarylketones 2r and 2s were then obtained with acceptable yields and without any traces of the reduced diarylmethane by-products. Next, 1,3-dithianes of aldehydes were also studied with compounds 1t and 1u. It is of note that these 1,3-dithianes reacted rapidly under A mild conditions to give the corresponding aldehydes in variable yields. For the deprotection of dithioketals of aldehydes, it is very important to examine carefully the course of the deprotection reaction by TLC monitoring because prolonged reaction times resulted in a severe decrease in yields. Indeed, it has been reported that, at rt, aldehydes reacted rapidly with TMSI to give iodosilyl ethers and diiodoethers. [25] This suggests that, as soon as aldehydes are formed after thioacetal deprotection, they add nucleophilic iodides which may arise from TMSI very slowly generated in the media according to an exchange Finkelstein reaction. [26] To show the interest of this process with respect to other previously reported methods using for examples HgO associated with BF3-Et2O, [27] 2,6-dicarboxy pyridinium chlorochromate (DCPCC) [28] or SbCl5 [29] we have deprotected dithiolanes 1v and 1w by TMSCl/NaI in CH3CN (Scheme 2). The comparison of the yields obtained using the TMSCl/NaI mild association in CH3CN vs toxic oxidizing agent as HgO (86 % vs 65%), DCPCC (93% vs 70%) or SbCl5 (93% vs 77%) supports well that this novel metal-free process is welcome since the yields in desired ketones are significantly higher and the reagents used for the deprotection are inexpensive, not toxic and very easy to handle. Scheme 2. Deprotection of dithianes 1v and 1w by TMSCl/NaI in CH3CN.
Next, as dithioacetals, the regeneration of carbonyl compounds from nitrogen-derivatives as hydrazones, N-tosylhydrazones, ketimines and oximes required most of the time harsh reaction conditions including oxidative or reducing process, acidic or alkaline media, expensive reagents or hazardous experimental protocols. [30] In order to find a milder process, we next examined if the TMSCl/NaI combination in CH3CN process could be applied successfully to these robust nitrogen substrates.
In Scheme 3 were presented the results of the regeneration of carbonyl functions of diphenylhydrazone 6, N-tosylhydrazone 7, Nbenzylimine 8, ketimine 9 and diphenylmethanone oxime 10, using TMSCl/NaI in CH3CN. We were pleased to observe that the TMSCl/NaI combination in CH3CN was able to transform imines and hydrazones into ketones with good yields (90 to 100%) as well as N-tosylhydrazone 7 which required the use of stronger reaction conditions. On the contrary, imine 8 and ketimine 9 were easily transformed into their ketones with high yields using the TMSCl/NaI association in CH3CN at rt. When diphenylmethanone oxime 10 was reacted with the TMSCl/NaI association (10 eq), we isolated, after 24 h of reaction achieved at rt, 4-methoxy-N-(4methoxyphenyl)benzamide 11 in a good yield (84%) accompanied by only 4 % of the bis(4methoxyphenyl)methanone 2r. The scope of this interesting Beckmann rearrangement, using the TMSCl/NaI combination, is currently under investigation in our lab with a range of oxime substrates. [31] Scheme 4. Plausible mechanism A plausible reaction mechanism is indicated in (Scheme 4). First, CH3CN activates the TMSCl/NaI association as mentioned previously by Olah [Error! Bookmark not defined.] to promote intermediate I and II after halide exchange in the presence of NaI. Then, II reacts with a sulfur atom of dithiolane 1c to give a sulfonium species of type III. Further assistance from the neighboring dithiane sulfur atom possibly leads to a fragmented sulfonium intermediate IV which added H2O (from reagents, CH3CN or during hydrolysis) to promote hemithioketal V which is then activated into a sulfonium intermediate VI (having or not H. With no H as in 1r or 1s, VI finally rearranges into the desired ketone 2d. [32] For dithiolanes prepared from enolizable ketones as 1c, the same (a) pathway could be followed but it is also reasonable to consider an additional pathway (b) in which an iodide deprotonates intermediate VI to furnish an enol species which tautomerizes into ketone 2d. Since dithioacetals having H can evolve according to two different pathways, this can explain that these entities are easier to deprotect than diarylthioketals counterparts. It is of note that a similar mechanism has been previously proposed by Nicolaou for the deprotection of S,S-acetals and ketals using IBX. [33] In this article we showed for the first time, the fundamental role of CH3CN associated to TMSCl/NaI combination to deprotect S,S-ethyleneand S,S-propylene-ketals into ketones. Indeed, if the mild TMSCl/NaI association leads to the reduction of dithioketals in CH2Cl2, we have demonstrated that this association can be used to deprotect a large variety of various dithioketals into ketones in CH3CN. Otherwise, under mild experimental conditions, O,O-acetals as well as O,S-oxathianes were cleanly deprotected with high yields. It is also possible to easily regenerate the carbonyl function of various hydrazones and imines using this novel protocol. We believe that this metal-free process is a good alternative to other known methodologies used to deprotect dithioketals into ketones.

Experimental Section
A general experimental procedure is described as following: a mixture of thioketal (100 mg) and NaI (10 eq) was stirred in MeCN for 5 min. Then, 10 eq of TMSCl were added to the solution which was stirred for 24 h at rt. The reaction was then hydrolyzed for 5 min. with H2O (5 mL) and extracted with CH2Cl2. Organic layers were dried over MgSO4 and concentrated under reduced pressure to give a residue which was purified by chromatography on silica gel to give the expected carbonyl compound which have identical NMR spectra with starting ketones.