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«Signature: _ Stephen Wilson Date Synthesis and Reactivity of Benzo[1,3,2]dithiazole 1,1-dioxides: Implications in Acylative Redox Dehydration By ...»

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This method will begin with the synthesis of 2-(chlorosulfonyl)phenyl hypochlorothioite. From here, condensation with the appropriate amine should give BDT. Other potential methods are those described for the synthesis of BiTs, and all potential methods are outlined in Figure 4.

Benzo-1,3,2-dithiazole-1,1-dioxide Synthesis Our studies began with the development of a new procedure for the synthesis of benzodithiazole-1,1-dioxides (BDTs). In the only reported literature procedure, a variety of Naryl BDTs were synthesized by the reaction of 2-(chlorosulfonyl)phenyl hypochlorothioite with the respective amine in the presence of a tertiary amine base.7 This method is similar to the condensation of 2-(chlorocarbonyl)phenyl hypochlorothioite to form the corresponding BiT (Figure 1a) and the proposed reaction is shown in Figure 4A. However, there is no literature procedure available for the synthesis of the starting sulfonyl/sulfenyl chloride, and obtaining this reagent proved difficult leading us to quickly abandon this route.

Next, we turned our attention to known procedures for the synthesis of benzisothiazolinone (BiT). In a reaction analogous to one described by Srogl,14 cyclization of 2tert-butylthio)- N-isopropyl-5-nitrobenzenesulfonamide using DMSO in the presence of trimethylsilyl chloride (Figure 4B) was also unsuccessful in producing the desired BDT. At room temperature, no reaction was seen and the starting sulfonamide was re-isolated in quantitative yield. Upon heating the reaction to reflux in chloroform, the only product observed after 2 hours was 2-isopropyl-7-nitro-2,3-dihydrobenzo[e][1,4,2]dithiazine 1,1-dioxide (Scheme 6). This product could arise from the trapping of a thionium intermediate in a reaction Pummerer-like rearrangement. And in fact, the Pummerer rearrangement has been observed as a minor product

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Cyclization of tert-butyl sulfoxides via heating in a pyridine/toluene mixture (Figure 4C) was also unsuccessful. The major product observed upon heating of 2-(tert-butylsulfinyl)-Nisopropyl-5-nitrobenzenesulfonamide with toluene and pyridine was disulfide 1a (Scheme 7), presumably arising from the rapid disproportionation of an intermediate sulfenic acid formed by loss of isobutene.9,22 The thermal cyclization of the related benzyl sulfoxide was also unsuccessful and only quantitative recovery of starting material was observed.

Oxidation of N-isopropyl-2-mercapto-5-nitrobenzenesulfonamide, the reduced form of BDT, in the presence of copper iodide (CuI) while open to air resulted in formation of disulfide 1a in quantitative yield at room temperature and at 50 oC (Scheme 8). Attempts at bis(trifluoroacetoxy)iodobenzene-mediated nitrenium formation followed by subsequent ring

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After many failed attempts at synthesizing any BDT, we instead decided to focus on procedures that would generate a sulfenyl halide that could then react in a condensation with the NH of the adjacent sulfonamide. Past research has shown that benzyl thioethers are readily converted to sulfenyl chlorides by chlorination with sulfuryl chloride (SO2Cl2).13 Based on this observation, 2-(benzylthio)-N-isopropyl-5-nitrobenzenesulfonamide was reacted with SO2Cl2 as shown in Scheme 9. Gratifyingly, upon cooling of the reaction to 0 oC a yellow precipitate was obtained and readily recrystallized from ethanol to give clean BDT in 72 percent yield. The reaction was also attempted with other halogenating reagents used in place of SO2Cl2, but no

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With a successful synthesis of the BDT in hand, a library of six BDTs with different structural variations was proposed to study as potential organocatalysts (Figure 5). A general procedure for the synthesis 2a-2c, is shown in Scheme 10. Starting from 1-chloro-4nitrobenzene, chlorosulfonation by heating overnight in the presence of chlorosulfonic acid furnished the desired sulfonyl chloride. While chlorosulfonic acid was used in this procedure, the same product can be obtained using a variety of sulfonating reagents described in the literature.24,25 The desired sulfonamides were obtained by condensation of sulfonyl chloride and the appropriate amine in the presence of base. Triethylamine, pyridine or excess of the reactant amine are all good potential bases, but for the more acidic sulfonamides (i.e. those derived from aryl amines) pyridine gave the highest yields, presumably due to its slightly less basic nature.

Next, aromatic substitution by benzyl thiol in the presence of either sodium or potassium hydroxide at low temperature gave the desired benzyl thioethers in good yield. Finally, oxidative ring-closure was achieved by heating in the presence of SO2Cl2 for one hour. As shown in Scheme 10, all of the BDTs were obtained in 66 -72 percent yield from benzyl thioether with formation of disulfide as the only major side reaction. Conducting the ring closure under a dry,

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open to air the major product in those reactions was the disulfide with very little BDT formation observed.

Synthesis of aromatic ring-unsubstituted BDTs 2d-2f was achieved under similar conditions (Scheme 11). Starting from commercially available 2-bromobenzenesulfonyl chloride, the desired sulfonamides were obtained by condensation with the appropriate amine and base.

The optimal base in this reaction follows the same trend noted above with BDTs 2a-2c. Next, aromatic substitution with benzyl thiol was achieved by heating to temperatures above 100 oC overnight in the presence of sodium hydroxide. As might be anticipated, the yield of the desired benzyl thioether was lower under these conditions than it was for the 4-nitro BDTs. However, the yield could be improved in some cases by first generating the copper benzyl thiolate by heating benzyl thiol in the presence of copper oxide, then performing the aromatic substitution using the copper salt without any added base. Finally, in the same manner as the 4-nitro BDTs, ring-closure was achieved by heating with SO2Cl2 under an inert atmosphere. All BDTs were purified by recrystallization in ethanol with the exception of parent N-isopropyl BDT (2f) which

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Due to the low purity of 2f, it was excluded from further studies. Yields of BDT from benzyl thioether are also reported in Scheme 11.

Thioesterification of BDT with Triphenylphosphine The first step in the catalytic cycle using BiTs as organocatalysts for redox dehydration reactions is the formation of thioester from carboxylic acid, BiT and a phosphorous(III) reducing agent (step 1, Figure 2). In order to compare the reactivity of BDTs with that of BiTs, we first studied thioesterification of BDT 2a with p-toluic acid (3) and triphenylphosphine as shown in Scheme 12. Triphenylphosphine was used in preliminary tests in place of the triethylphosphite because the potential for side reactions with the R groups on phosphorus is eliminated with the

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The reaction was conducted as follows: the solids (BDT, triphenylphosphine and the carboxylic acid) were added to a small test tube and the tube was capped with a rubber septum and purged with argon. To the solids at room temperature was added toluene and the reaction was stirred and monitored by thin layer chromatography. Upon addition of solvent, an immediate change in color from yellow to orange was noted and within 2 minutes all of the starting materials were consumed. Purification by column chromatography gave the desired thioester in 32 percent yield, with the remainder of the BDT being converted to its reduced thiol form. The significant amount of thiol generated suggested the presence of enough water to quench the phosphonium intermediate that forms during the reaction. And indeed, when the reaction was run with dry toluene (less than 100 ppm water) in the presence of activated molecular sieves, the yield of 4 improved to 54 percent.

Since it was demonstrated that BDTs can react to generate thioester, we next varied solvent and temperature in order to improve the overall yield. The results of this study are shown

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solvents, with the best yield being obtained in toluene and modest to poor yields reported in ethyl acetate and DMF. However, no significant trend was seen in the range of temperatures tested.

These results suggest that the best conditions for the reaction are toluene as solvent at room temperature.

With only modest success using aryl carboxylic acid to obtain thioesters, our interest turned to aliphatic carboxylic acids. Previous results with BiT chemistry suggest that aliphatic acids, and in particular amino acids, are better substrates for thioesterification. With this in mind, 2a was reacted with Boc-protected phenylalanine as shown in Scheme 13. Gratifyingly, the reaction in toluene at room temperature gave an excellent yield of thioester. Consistent with the observations using p-toluic acid, the reaction was complete almost immediately upon addition and still had a corresponding color change from yellow to orange. Further, as noted in Scheme 13, the reaction could be performed with no additional drying precautions without a significant

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In order to study the reactivity of BDTs, 2a was compared to 2b, 2c and 2f. Each one was subjected to the best conditions for thioesterification using triphenylphosphine and Bocprotected phenylalanine. The results are shown in Table 2. There is a clear difference in reactivity between the 4-nitro BDTs and the corresponding unsubstituted BDTs. The reaction time for every BDT in the 4-nitro series (2a and 2c) is under 2 minutes, with the N-aryl BDT 2c giving an almost instantaneous reaction. But, the corresponding parent BDTs (2d and 2e) are much less reactive. Further, there is a clear trend in reactivity based on the nature of the group on nitrogen. Alkyl groups are less reactive than aryl, with the 2,6-dimethylaniline giving the fastest reaction time.

Another interesting result was observed when the reaction was run open to air versus under a dry, inert atmosphere. For the more reactive BDTs, the presence of water seems to have little effect on the yield of thioester, as the yields were unchanged when the reaction was run under dry conditions instead of open to air. However, the less reactive BDTs required dry reaction conditions to optimize the yield. This observation might be explained by the reactivity

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more reactive BDTs go on almost immediately upon forming to give the desired product while the less reactive BDTs give more stable intermediates, allowing more time for water to quench the reaction. This explanation is consistent with the observation that thiol was the major side product from thioesterification of less reactive BDTs.

Thioesterification of BDT with Triethyl Phosphite With the success of triphenylphosphine as a terminal reductant for the dehydration of carboxylic acids to form BDT-derived thioesters, our attention turned to organophosphites as terminal reductants to replace triphenylphosphine. There are a number of advantages to using phosphites in place of phosphines, including atom economy, cost, and ease of removal. Ease of removal is perhaps the greatest advantage of reagents such as triethylphosphite, since they are oxidized during the reaction to phosphates which are water soluble and easily separated from the reaction by aqueous work-up.

The reaction of p-toluic acid and 2a was studied first with triethylphosphite as the

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toluic acid and BDT in various solvents (0.1 M in BDT). The reaction was performed at room temperature, both with and without dry conditions. The results are shown in Table 3. Similar to the reactions with triphenylphosphine, a trend in yield with varying solvent was observed. While some product was observed under dry conditions in toluene, the yield in ethyl acetate was poor and almost no product was observed when run in DMF. Further, yields were significantly lower in all cases when the reaction was run open to air.

Unlike the reactions run with triphenylphosphine, when triethylphosphite was used as reductant, a variety of side products were observed in the crude 1H NMR. Among these products were thiol, disulfide, and a range of products derived from loss of an ethyl group from the phosphite. Based on these results, the best conditions for making BDT-derived thioester from aryl carboxylic acid were in dry toluene under an inert atmosphere. This result is consistent with observations using a triphenylphosphine reductant. However, the yields are much lower with triethylphosphite due to the reactive ethyl groups, and even with dry conditions the yield of desired thioester never exceeded 50 percent.

Next, in order further illuminate the cause for such low yields, phosphorous NMR was used to study the reaction of BDT 2a and triethylphosphite in toluene without any carboxylic acid present (Scheme 14). Amazingly, even without any acid present a rapid color change was observed upon mixing BDT and triethylphosphite with toluene in an NMR tube, and the signal for triethyl phosphite was no longer evident in the 31P NMR. The 31P NMR spectrum instead

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the products giving rise to each signal proved difficult so no characterization was performed, but even so the study still highlights a number of non-productive degradation pathways for the triethylphosphite that can explain the lowered yield of thioester.

While we were able to successfully isolate BDT-derived thioester from aromatic carboxylic acids, the best yields were still very modest and prohibitive for use in the catalytic cycle envisioned in Figure 2. So, with the overall goal being to demonstrate the use of BDTs as organocatalysts in redox dehydration reactions, we next turned to the dehydration of aliphatic carboxylic acids in an effort to improve product yield.

As a direct comparison to triphenylphosphine mediated thioesterification of aliphatic carboxylic acids, we next studied thioesterification of N-Boc-phenylalanine with triethylphosphite. The outcomes from thioesterification of the series of BDTs with N-Bocphenylalanine are shown in Table 4. As expected, the yield of thioester when the reaction was run open to air was only modest. However, under dry conditions yields were improved for all thioesters although the yields are still considerably better when the reaction is run with

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