Comparison of different Lewis acids supported on natural phosphate as new catalysts for chemoselective dithioacetalization of carbonyl compounds under solvent-free conditions

Various carbonyl compounds can be efficiently converted to their corresponding dithioacetals in the presence of catalytic amounts of ZnCl 2 , NiCl 2 or CuCl 2 supported on natural phosphate. The best catalytic activities were observed with the zinc catalysts. In addition, by employing these catalysts, highly chemoselective dithioacetalization of carbonyl compounds has been achieved


Introduction
The use of heterogeneous catalysts under solvent-free conditions is becoming very popular as it has many advantages: reduced pollution, reusability, high selectivity, low cost, and simplicity in process and in handling.These factors are especially important in industry.
Recently, an informative review 1 by Toda et al. clearly pointed out the superiority of the solvent-free or the use of dry reaction conditions in chemical synthesis.
Thioacetalization of carbonyl compounds plays an important role in organic synthesis.Since the introduction of 1,3-dithianes as nucleophilic acylating reagents by Corey and Seebach 2 , dithioacetals have become widely used tools for C-C bond formation.Furthermore, the stability exhibited by 1,3-dithiolanes under acidic and basic conditions has led to their synthetic utility as ISSN 1424-6376 Page 32 © ARKAT carbonyl protecting groups and as intermediates for the conversion of carbonyl compounds to their parent hydrocarbons 3 .Recently, several acid catalysts have been used in the preparation of thioacetals such as Zn or Mg(OTf) 2 4 , BF 3 .Et 2 O 5 , ZrCl 2 /SiO 2 6 , titanium tetrachloride 7 , SOCl 2 /SiO 2 8 , Zeolite 9 , WCl 2 10 , 5 M LiClO 4 /Et 2 O(LPDE) 11 , TaCl 5 /SiO 2 12 , MoO 2 (acac) 2 13 and Yttrium triflate 14 and other catalysts with more or less success 15 .Many of these methods require long reaction times and reflux temperatures and result in unwanted side reactions, whilst offering poor selectivity when applied to mixtures of aldehydes and ketones.Although some recent methods employing LiBr 16 , InCl 3 17 , and LiBF 4 18 have been reported to show chemoselectivity, these Lewis acids are destroyed in the work-up procedure and cannot be recovered and reused.
On the other hand, we have used natural phosphate (NP) 19 alone and doped as the new heterogeneous catalysts for several reactions such as Knoevenagel condensation 20 , construction of carbon-carbon 21 , carbon-sulfur 22 and carbon-nitrogen 23 bonds, epoxidation of alkenes 24 , Claisen-Schmidt condensation 25 and synthesis of unsaturated arylsulfones 26 .NP has been used also as a Lewis acid catalyst or support in Friedel-Crafts alkylation 27 , 1,3-dipolar cycloaddition 28 and acyclonucleoside synthesis 29 .
In continuation of our interest to develop environmentally safe methods, herein we wish to report an efficient method for the thioacetalization of carbonyl compounds in good to high yields, as well as the chemoselective protection of various carbonyl compounds by employing ZnCl 2 supported on natural phosphate (Scheme 1, Table 1 , SO 4 2-, CO 3 2-or MnO 4-, and F -by HO -or Cl -.These different substitutions cause distortions of the structure which depends on the nature and the radii of the ions involved.This solid presented a very low surface area (BET) at ca. 1-1.43 m 2 g -1 .
The preparation of MCl 2 /NP (M = Zn, Cu or Ni) was as follows: 10 mmol of MCl 2 and 10g of NP were mixed in 100 ml of water and then evaporated to dryness and dried for 2h at 150°C before use.
The modification of the apatite structure solid by MCl 2 impregnation does not change the crystalline structure of the solid material [30].It should be noted that no MCl 2 phases were detected on the doped materials in all cases, indicating that MCl 2 were highly dispersed in the solid material.Interestingly, some changes of structure of doped catalysts were observed in scanning electron micrographs (SEM).Thus, the comparaison of the images of ZnCl 2 /NP with NP (Figure 1) shows some modification in the particle morphology of doped materials.This result suggests that ZnCl 2 interacted with the surface of NP.So, we can reasonably suspect that the modification of the surface morphology of the apatites was responsible for the enhancement of the catalytic activity observed with the doped materials.(2 mmol) and di-or mono-thiol (2.1 or 4.2 mmol, respectively) was added and the mixture was stirred until completion of the reaction, as monitored by thin layer chromatography (TLC).The reaction mixture was filtered and the catalyst washed with dichloromethane.After concentration of the filtrate under reduced pressure the residue was subjected to chromatography leading to the respective thioacetal (2 to 5, Scheme 1, Table 1).The product structure was analysed by 1 H, 13 C-NMR, IR spectrometry and melting points.

Results and Discussion
First of all, we have tested the natural phosphate alone (0.1, 0.3, 0.5, 0.7, 1g) as the acidic catalyst in the thioacetalization of carbonyl compounds (Figure 2).Thus, various amount of NP alone have been used to catalyse the thioacetalization of p-chlorobenzaldehyde by thiophenol.A low yield of 4d was obtained with NP alone (Figure 2).The yields seem to be limited even if the time of the reaction is prolonged.However, the reaction time is very long (30 hours).In view of the established beneficial effects of solid supports, we have investigated the use of the NP impregnated with metal halides for the thioacetalization of carbonyl compounds under mild conditions.These impregnation catalysts have been prepared as indicated before.
Firstly, we have tested the NP impregnated with ZnCl 2 as the solid catalyst for the thioacetalization of p-chlorobenzaldehyde by thiophenol.The best weight of ZnCl 2 /NP is 300 mg (Figure 2).In a blank reaction in the presence of 40 mg (quantity present in ZnCl 2 /NP catalyst) of ZnCl 2 alone without NP the thioacetal 4d was obtained with low yields (25%, 70 min).
Furthermore, the metal halide effect was also examined.Thus, we have tested CuCl 2 and NiCl 2 alone and supported on NP.The thiocetalization of p-chloro benzaldehyde by thiophenol with CuCl 2 , CuCl 2 /NP, NiCl 2 and NiCl 2 /NP are 21, 83, 18, and 40, respectively, after 70 min of reaction time.The results obtained with product 4d using impregnated catalysts are regrouped in Figure 3.Among these catalysts, satisfactory results have been obtained with ZnCl 2 supported on the NP.The NP was the preferred choice as support to keep the reaction medium under mild and neutral conditions (Figure 3).The best conditions for the thioacetalization of p-chlorobenzaldehyde by thiophenol are generalized to other carbonyl compounds.Accordingly, dithioacetals and 1,3-dithiolanes have been obtained by the reaction of thiols (ethanethiol and thiophenol) and dithiols (1,2ethanedithiol, 1,2-propanedithiol), respectively, in the presence of catalytic amounts of ZnCl 2 /NP (Scheme 1); the results are illustrated in Table 1.

ARKAT
Because the conversion of aldehydes is faster than that of ketones, as shown in Table 1, the present method can be used for the chemoselective protection of aldehydes in the presence of a ketone function [31].For example, when an equimolar mixture of aldehyde and ketone was allowed to react with 1,2-ethanedithiol in the presence of a catalytic amount of ZnCl 2 /NP, only the 1,2-dithiane derivative of the corresponding aldehyde was obtained; ketone was recovered quantitatively (Scheme 2).Furthermore, the thioacetalization of ethyl acetoacetate also exhibited splendid selectivity towards the acetyl group (Scheme 2).In addition, this method is free from the problem of Michael addition encountered in some cases of α,β-unsaturated systems with some reagents [32] (entry 8, Table 1).

Scheme 2
To evaluate the effect of the presence of an electron acceptor or donor on the aromatic ring of benzaldehyde, the reaction was carried out between thiophenol and substituted benzaldehyde derivatives using ZnCl 2 /NP as catalyst (Scheme 1).Results in Table 1 show that the presence of electron-withdrawing groups on the aromatic ring of the aldehydes (entry 19-20, Table 1) decreases the yields proportionally to the value of Hammet constant.Meanwhile, the presence of electron-donating groups (entry 16-18, Table 1) increases the yields, demonstrating the participation of both the aldehydes and the thiol in the rate controlling step of the reaction.The activity of ZnCl 2 /NP seems to be higher than other known catalysts (

Conclusions
We have developed a simple and efficient method for the chemoselective protection of carbonyl compounds as dithioacetals, dithiolanes and dithianes using a catalytic amount of a Lewis acid supported on natural phosphate in solvent-free conditions at room temperature.Further, the natural phosphate of non-toxic and inexpensive catalysts can be readily recovered and reused, thus making this procedure more environmentally acceptable.

Figure 2 .
Figure 2. Weight effect of the catalyst NP alone and doped with ZnCl 2 in the thioacetalization of p-chlorobenzaldehyde by thiophenol.

Table 1 .
ZnCl 2 /NP catalysed protection of carbonyl compounds as dithioacetals, 1,3-dithiolanes and 1,3-dithianes a Yields refer to isolated in pure products.b Yields based on thiol as reagent, as the acetone is volatile.

Table 2
Comparison of ZnCL 2 /NP with several heterogeneous homogeneous catalysts in the synthesis of products 3a and 3g a Yields refer to isolated and chromatographically pure compounds; b Reaction carried out solventfree conditions; c Reaction carried at 90-110 °C.