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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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Finally, in order to demonstrate the importance of running these reactions under the strict exclusion of water, the thioesterification of BDT 2a with N-Boc-phenylalanine was studied by 31 P NMR. The respective NMR spectra are shown in Figure 6. Clean conversion of triethylphosphite to triethylphosphate can be seen in the top spectrum, corresponding to the reaction under dry conditions. Likewise, a number of phosphorous containing products that are not triethyl phosphate can be seen in the bottom spectrum, corresponding to the reaction run open to air. These results further support the conclusion that water is detrimental to the reaction and can give rise to non-productive conversion of the phosphite into a range of undesired side products.

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Taken together, the results suggest that the dehydration of carboxylic acids in the presence of either triphenylphosphine or triethylphosphite can be optimized to give good yields of BDT-derived thioesters. In the case of aromatic carboxylic acids, thioesters could only be obtained when triphenylphosphine was the reducing agent, while aliphatic acids gave suitable yields with triphenylphosphine and the entire series of BDTs tested as well as with triethylphosphite and less reactive BDT 2a. As previously discussed, the ideal conditions for thioesterification were in toluene, at room temperature and under a dry, inert atmosphere and reactions are complete within minutes. Having confirmed that BDTs can react to give thioesters in a manner analogous to BiTs, our attention was next turned to the study of the final two steps of the catalytic cycle, namely reaction of BDT-derived thioester to give an acylated product (i.e.

amides, esters, ketones) and oxidation of the resulting thiol back to the BDT.

Reaction of BDT-Derived Thioesters The second step in BDT-catalyzed redox dehydrations (step 2, Figure 2) is the reaction of BDT-derived thioester with a nucleophile to give the desired product by generating a new acyl bond as well as the reduced form of the BDT (o-mercaptobenzene sulfonamides will be referred to as “thiol”). As previously discussed, boronic acids, amines and alcohols have all been utilized as nucleophiles with both catalytic and stoichiometric BiT to give ketones, amides and esters respectively. In order to compare the reactivity between BDTs and BiTs and assess the potential of BDTs as organocatalysts, we next examined the reaction of BDT-derived thioesters with both boronic acid and amine.

We first sought to study the ketonization of thioester and boronic acid in the presence of a

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generation Liebeskind-Srogl coupling16 as follows: A dry test tube was charged with thioester 6a, pyrimidine-5-boronic acid (2.5 equiv), copper(I)-3-methylsalicylate (CuMeSal, 5 mol %) and activated molecular sieves. The solids were taken up in dry DMF (0.10 M) and the reaction was heated in an oil bath at 50 oC until TLC indicated complete consumption of the starting thioester.

Reaction workup involved a basic wash with saturated NaHCO3 to remove unreacted boronic

acid and thiol. Products were isolated by column chromatography in a 2:1 mixture of hexanes:

ethyl acetate.

The results of the reaction are shown in Scheme 15. As indicated, no ketone was generated during the course of the reaction and the only major product isolated was S-arylated BDT derived from the reaction between thiol and boronic acid. This outcome is noteworthy because it demonstrates a major difference in reactivity between BiTs and BDTs. As described above and reported in the literature16, BiT-derived thioesters react with boronic acid to give the desired ketone and the S-arylated BiT. These results suggest that BDTs do not give ketone under the same conditions.

As previously discussed, the addition of NMI as a ligand for copper was effective in

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BDT, the above reaction was run in the presence catalytic NMI (Scheme 16). However, even with added ligand no ketone formation was observed and again the major product isolated was Sarylated BDT. Finally, since oxygen in air was thought to be necessary for regeneration of the copper catalyst in Liebeskind-Srogl coupling, the same reaction was run under argon with stoichiometric CuMeSal to see if ketone formation was even possible. Surprisingly, even under an inert atmosphere the only product observed was S-arylated BDT (Scheme 17). Coupling of aryl thiols with aryl boronic acids is a known reaction that is typically catalyzed by higher oxidation state copper complexes (CuII/CuIII)26. Presumably then, under our reaction conditions disproportionation of CuI occurs27 to give a higher oxidation state copper that is capable of catalyzing the coupling reaction, resulting in the formation of S-arylated BDT. Based on these results, BDT-derived thioesters do not react with boronic acids to give ketone, but rather S

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Following the unsuccessful ketonization attempts, we instead turned our attention to amidation by reacting BDT-derived thioesters with amine. Our investigation began by simply taking up thioester in toluene and adding glycine ethyl ester hydrochloride (1.1 equiv) and N,Ndiisopropylethylamine (DIPEA, 1.05 equiv) as shown in Scheme 18. Unfortunately at room temperature and 50 oC no reaction occurred and the thioester was quantitatively recovered after acidic workup. Next, in order to facilitate amide formation, the same reaction was run with the addition of a copper catalysts and the result is shown in Scheme 19. As shown, under the same copper catalyzed conditions used for amidation of BiT-derived thioesters, the desired amide was not obtained after running at 50 oC overnight. Instead, only hydrolysis of the thioester was observed. Further, in the presence of copper catalyst the thiol, generated by loss of the acyl group on the thioester, was completely oxidized to disulfide. While no amide was formed, the

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possible and under appropriate conditions the BDT might be regenerated during the reaction.

Further work is needed to find appropriate conditions for the generation of amides from BDTderived thioesters.

Oxidative Recycle of Thiol to BDT After observing oxidation of the BDT-derived thiol to disulfide under the very mild conditions required for amidation, we next studied conditions for the final step in the catalytic cycle (step 3, Figure 2), the oxidative recycle of the BDT. Since the BiT recycle is believed to occur first by oxidation of thiol to disulfide followed by disproportionation of the disulfide to give BDT and thiol28, we began our study by simply heating disulfide 1a in DMF to various temperatures in the presence of a molybdenum catalyst (5 mol %). The molybdenum catalyst used has been previously studied and found to be an excellent catalyst for the oxidation of thiols

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very little reaction was seen and the disulfide was recovered in near quantitative yield in each case. However, at 100 oC disproportionation begins to occur and after heating for 6 hours at this temperature the BDT was obtained in excellent yield (entry 4). An even faster reaction was observed at 120 oC and again the BDT was obtained in high yield in only 2 hours (entry 5).

In an effort to lower the temperature of disproportionation, a variety of catalysts were tested under the conditions described in Table 6. Unfortunately, no significant disproportionation took place at temperatures below 100 oC with any of the catalyst tested, and BDT was only obtained when the reaction was run at high temperature. The best yields were obtained with Mo and CuI/NMI catalysts (entries 1 and 2), but both Pd/C and charcoal also gave good yield of BDT (entries 3 and 4). Finally, to see if there is any difference in the rate and temperature of disproportionation for the more reactive BDTs, 1b (the disulfide of BDT 2b) was reacted in the presence of the Mo catalyst at 100 oC as shown in entry 5. The rate of BDT formation was increased and complete conversion was achieved in only 2 hours with the more reactive BDT.

Taken together these results suggest that oxidation under BiT-like conditions only occurs at higher temperature and different conditions or chemical additives may be needed to make the

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Amidation Using Stoichiometric or Catalytic BDT We completed our examination of BDTs by attempting a catalytic amidation under the optimal conditions based on our previous results. The catalytic procedure is shown in Scheme 20 and was performed as follows: A dry test tube was charged with BDT 1a, N-Boc-phenylalanine, glycine ethyl ester hydrochloride, DIPEA, CuI, NMI and activated molecular sieves. The solids were taken up in dry toluene and stirred for 10 minutes before triethyl phosphite (1.0 equiv) was added. The reaction was heated to 100 oC and monitored by TLC. After 8 hours, toluene was evaporated and the crude reaction mixture was analyzed by 1H NMR. Unfortunately, no amidation was observed, and the crude 1H NMR and TLC both show a complex mixture of

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Following the unsuccessful catalytic reaction, the potential for amidation through a batch recycle was assessed as shown in Scheme 21. The BDT-derived thioester was made first, and in a one-pot reaction the thioester was exposed to the appropriate amine and CuI/NMI and then heated to 100 oC. However, after reacting overnight again no amide formation was observed but some BDT could be isolated by column chromatography, albeit in poor yield. These results suggest that more work is needed, particularly on the amidation and BDT recycle step, in order to develop a mild catalytic reaction that can be applied to a variety of dehydrative, acylative chemistry.

Conclusion A series of BDTs were synthesized through a reaction 2-(benzylthio)benzene sulfonamide with sulfuryl chloride. In a typical reaction, the product yields was moderately high and BDTs could be easily purified by precipitation from the reaction and recrystallization where necessary. The purified BDTs could also be converted to thioesters through a redox dehydration with carboxylic acids and triphenylphosphine or triethyl phosphite. BDT-derived thioesters were synthesized from both aryl and alkyl carboxylic acids. However, the aryl acids gave poor very poor yields with phosphite, and only modest yields with phosphine while aliphatic acids gave modest to good yields with both phosphorus sources. The BDT-derived thioesters could undergo

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Further, no amidation with amines was observed under the conditions tested in this study.

Finally, BDTs could be synthesized from their corresponding disulfide through a disproportionation/oxidation procedure. While attempts to use BDTs in place of BiTs for catalytic dehydrative bond construction were unsuccessful, future work may uncover the conditions necessary to develop a fully catalytic system or delve into other interesting

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relative to tetramethylsilane in deuterated chloroform (CDCl3: 1H = 7.26 ppm, 13C = 77.16 ppm), or deuterated DMSO (DMSO-d6: 1H = 2.50 ppm, 13C = 39.52 ppm), as noted. Spectral data are reported in the following order: chemical shift (δ); multiplicities are indicated as s (singlet), d (doublet), t (triplet), q (quartet), sext (sextet), sept (septet), m (multiplet); coupling constants, J (Hz); integration. Infrared spectra were recorded on a Nicolet 510 FT-IR spectrometer. Uncalibrated melting points were taken on a Thomas-Hoover melting point apparatus in open capillary tubes. ESI or APCI high resolution mass spectrometry was carried out on new compounds. Solvents for reactions and chromatography were reagent grade and used as received. Where indicated, dry solvents were obtained via drying with 4 Å molecular sieves overnight. Reactions requiring inert atmospheres were carried out in flame-dried glassware under argon.

Reagents chlorosulfonic acid, pyridine, triethylamine, benzyl thiol, sodium hydroxide, potassium hydroxide, sulfuryl chloride, sodium borohydride, triphenylphosphine and triethyl phosphite were purchased from Alfa Aesar or Sigma-Aldrich. Starting materials 1-chloro-4nitrobenzene, 2-bromobenzenesulfonyl chloride, isopropylamine, aniline, 2,6-dimethylaniline, N-Boc-Phe, pyrimidine-5-boronic acid and glycine ethyl ester hydrochloride were purchased

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2-chloro-5-nitrobenzenesulfonyl chloride. To a 250 mL round-bottomed flask equipped with a magnetic stir bar was charged 1-chloro-4-nitrobenzene (20.0 g, 127 mmol) and chlorosulfonic acid (85 mL, 1.27 mol). The flask was equipped with a reflux condenser and carefully heated to 125 oC for 24 hours while open to air. Then the reaction mixture was cooled to room temperature, poured onto ice, and extracted with DCM (3 x 50 mL). The combined organic layers were dried with MgSO4 and concentrated to give a dark brown oil. The oil was taken up in EtOAc (100 mL) and decolorized with activated carbon to give a yellow solution. The product was isolated by crystallization upon addition of hexanes. Yellow solid (20.83 g, 81.0 mmol, 64 % yield); m.p. 88 - 89 oC (lit 89 - 90 oC)21; 1H NMR (400 MHz, CDCl3) δ 8.99 (dd, J = 2.6, 0.6 Hz, 1H), 8.51 (ddd, J = 8.8, 2.6, 0.6 Hz, 1H), 7.89 (dd, J = 8.8, 0.6 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 146.0, 142.0, 139.6, 134.2, 129.9, 125.7

General procedure for sulfonamide synthesis:

Method A via excess amine:

To a round-bottomed flask equipped with a magnetic stir bar was added sulfonyl chloride (1.0 equiv) and DCM (0.50 M) followed by the appropriate amine (3.0 equiv). The reaction was stirred at room temperature until completion as indicated by TLC. Upon completion the reaction was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was then dried with MgSO4 and concentrated to give product. When necessary, product was purified by recrystallization from appropriate solvent.

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