Convenient synthesis of N-sulfonyl α-hydroxyamides via DMSO oxidation of N-alk-1-ynylsulfonamides

ABSTRACT N-Arenesulfonyl α-hydroxyamides are conveniently synthesized from N-arylethynylsulfonamides (ynamides) via oxidation with dimethyl sulfoxide (DMSO) in the presence of equivalent of trifluoromethanesulfonic acid (TfOH) followed by treatment with water. In this reaction, ynamides are activated by protonation with TfOH and then undergo double DMSO nucleophilic addition and subsequent hydrolysis. Investigations on the substrate scope indicate N-arenesulfonyl and arylethynyl substituted ynamides proceed the oxidation well. Compared to the previous methods, the current method realizes the direct conversion from N-arylethynylsulfonamides to N-arenesulfonyl α-hydroxyamides with mild DMSO as a nucleophilic oxidant in the presence of strong acid trifluoromethanesulfonic acid. GRAPHICAL ABSTRACT


Introduction
α-Hydroxyamides are the crucial structural motifs in some bioactive molecules and also have been widely used as synthetic intermediates [1]. Many medicine molecules containing α-hydroxyamide fragments exhibit anticancer activities and analgesic effect [2,3]. For example, bicalutamide has been used in the treatment of the prostate cancer [4]. Hydroxyflutamide is a nonsteroidal antiandrogen drug [5]. Iopamidol is applied as a nonionic iodized contrast agent for cardiovascular disease clinically in the medical imaging [6]. Naproanilide has been utilized as herbicides in agriculture [7] (Figure 1). In organic synthetic chemistry, α-hydroxyamides have been utilized as the protective groups in the total synthesis of cyclotheonamide A [8], and synthetic intermediates for the preparation of α-substituted amides through acylation with acetic anhydride and deacetoxylative alkylation [9].
Recently, we realized a series of mild and convenient oxidations and functionalizations of alkynyl compounds with DMSO as mild oxidant or sulfur reagents and solvent [23][24][25][26]. We envisioned that N-alk-1-ynylsulfonamides should be oxidized to Nsulfonyl α-hydroxyamides conveniently with DMSO under acidic conditions. Herein, we present our direct conversion of N-alk-1-ynylsulfonamides into N-arenesulfonyl αhydroxyamides with DMSO as both nucleophilic oxidant and solvent under strong acidic conditions (Scheme 1d).

Results and discussion
N,4-Dimethyl-N-(phenylethynyl)benzenesulfonamide (1a) was first employed as the model substrate to react with DMSO to optimize reaction conditions ( Table 1). The effect of different acids were screened on the reaction at the beginning. In the presence of acetic acid and trifluoroacetic acid, no desired 2-hydroxyamide 2a was observed ( Table 1, entries 1 and 2). The desired product 2a was obtained in 54% yield with the corresponding Nmethyl-2-phenyl-N-tosylacetamide (3a) in 34% yield in the presence of CF 3 SO 3 H (TfOH) ( Table 1, entry 3). The results indicate that strong acid is required for the reaction due to weak basicity of the ynylsulfonamide. Thus, further optimizations were conducted in the presence of TfOH. The influence of the equivalent of TfOH on the reaction was explored. Both deficient and excessive amounts of TfOH resulted in the decrease of the yield because activation of 1a required equivalent of the acid and excessive acid would protonate DMSO, lowering its nucleophilicity with the protonated 1a (  Note: a Yield on the basis of 1 H NMR analysis of the reaction mixture with 1,3,5-trimethoxybenzene as an internal standard and the yield of the isolated product in the parentheses. With the optimal reaction conditions in hand, the substrate scope was then evaluated (Table 2). First, the substrates with different substituent groups on the alkyne side were examined. The substrates 1b-1 g with different weak electron-donating and withdrawing groups on the aryl group or on different positions of the phenyl ring in the acetylene side afforded the corresponding products 2b-2f in moderate to satisfactory yields of (47-67%). Strong electron-deficient substrate 1 g with the 4-trifluoromethylphenyl group produced the corresponding product 2 g in low 32% yield. However, strong electron-deficient substrates 2h-2i with the 4-cyano-and 4-nitrophenyl groups and strong electron-donation substrate 2j with the 4-methoxyphenyl group did not proceed the reaction. All of these three substrates possess Lewis-basic sites on their aromatic groups. In the reactions of 1 h, 1i, 1j, their Lewis-basic sites on the aromatic group might be protonated, resulting in messy products. Only trace amounts of the corresponding products 2 were observed on TLC analysis. The reactants were completely consumed, leading to large amounts of complex strong polar substances whose structures could not be determined in each of cases. A small amount of N-methyl-4-toluenesulfonamide was separated as a decomposed product during optimal conditions. Thus, the complex strong polar substances in the reaction mixture should be protonated sulphonamides and amides and they could not be separated. For heteroaryl substrate 1k with the thiophen-3-ylethynyl group, the desired product 2-hydroxy-N-methyl-2-(thiophen-3-yl)-N-tosylacetamide (2k) was obtained in only 10% yield. Furthermore, aliphatic N-hex-1-ynyl substrate 1 l did not proceed the desired reaction either. It produced N-methyl-N-tosylhexanamide (3 l) in 53% yield. N-Alkyl-N-phenylethynyl(4methylbenzene)sulfonamides 1m-1o worked well, affording the desired products Table 2. Scope of substrates 1 under optimal conditions. Note: a Messy products. b N-Methyl-N-tosylhexanamide (3 l) was obtained in 53% yield.
In our previous report [27], we found that DMSO showed stronger nucleophilicity than water in the NBS/DMSO-mediated synthesis of (2,3-dihydrobenzo[b] [1,4]oxathiin-3-yl)methanols from aryloxymethylthiiranes. To verify the hydroxyl group in the products 2 comes from water or DMSO, two control experiments were performed with methanol and thiophenol as additional nucleophiles, respectively, in the reaction of 1a. However, only product 2a was obtained in 60% yield in both cases, without the corresponding methoxy and phenylthio derivatives were observed (Scheme 2, top).
On the basis of our previous work [25,27] and control experiments, the reaction mechanism with 1a as an example substrate is proposed as presented in Scheme 2 (bottom). Ynamide 1a is activated via protonation with TfOH according to previous report [28], generating an intermediate A, which is easily attacked by DMSO to form an intermediate B. The intermediates B is further attacked by another DMSO and simultaneously loses a molecule of Me 2 S to generate an intermediate C. The intermediate C is further attacked by water followed by proton transfer and loss of DMSO and proton during treatment with water, affording to the final product 2a.
Generally, the yields are not so high in the reaction. It is attributed to that some unreacted intermediate A can be attacked by water followed by proton transfer and deprotonation during treatment with water through intermediates F and G, giving byproduct 3a.
On the other hand, the unreacted intermediate B can be also attacked by water and subsequent intramolecular proton transfer and loss of DMSO with proton via intermediate H to yield the byproduct 3a directly. This is the reason why byproduct 3a exists in the reaction.
Both strong electron-withdrawing and donating N-arylethynyl substrates did not work possibly because strong electron-deficient substrates hardly be protonated to form the corresponding intermediates A, while strong electron-donating substrates did not favor the nucleophilic attack of DMSO, leading to the difficult formation of the corresponding intermediates B.
The reaction mechanism for the reactions of 1a with N-butylbenzenesulfinamide and N-(diphenyl-λ 4   To show a practical application of the synthetic method, a gram-scaled reaction of N,4-dimethyl-N-(phenylethynyl)benzenesulfonamide (1a) (1.71 g, 6 mmol) in anhydrous DMSO was carried out, affording to the desired product 2a in 51% yield (1.02 g) and the product 2a was transformed to 2-((N,4-dimethylphenyl)sulfonamido)−2-oxo-1phenylethyl acetate (5) in the yield of 78% by treatment with acetic chloride in the presence of triethylamine. Because it usually required harsh reaction conditions to remove the tosyl group, benzyl methyl(phenylethynyl)carbamate (6) was prepared as a substrate with a readily removable protecting benzyloxycarbonyl (Cbz) group and subjected the reaction. However, 3-methyl-5-phenyloxazolidine-2,4-dione (7) was obtained in 58% yield (Scheme 5). The formation mechanism of 7 should be similar to that previously reported in the reaction of Selectfluor-catalyzed oxidative cyclization of alkynamides [31].

Conclusion
In summary, we successfully developed a new method to synthesize N-sulfonyl αhydroxyamides from ynamides with DMSO as a nucleophilic oxidant and solvent in equal amount of DMSO and chloroform as co-solvents in the presence of trifluoromethanesulfonic acid. The ynamides were first activated via protonation by the strong acid, and then doubly attacked by DMSO followed by treatment with water to realize the synthesis. The corresponding N-sulfonyl amides were generated simultaneously as byproducts due to the reactions of unreacted intermediates generated in the reaction with water during treatment with water. In comparison with the previous methods, the current method features a direct and mild conversion from ynamides to N-sulfonyl α-hydroxyamides under transition metal-free conditions.

General
Unless otherwise noted, all starting materials were purchased from commercial suppliers. DCM was refluxed over CaH 2 and distilled prior to use. Chloroform was dried over 4 Å molecular sieves and distilled prior to use. DMSO was stirred overnight with CaH 2 at RT.

General procedure of the synthesis of N-sulfonyl α-hydroxyamides 2
To a flame dried 10 mL reaction tube were added N-alk-1-ynylsulfonamide 1 (0.3 mmol) and anhydrous DMSO (0.25 mL) and 4 Å molecular sieves dried chloroform (0.25 mL). The solution was heated to 40°C and then was added TfOH (0.3 mmol, 27 μL). The resulting solution was stirred at the same temperature for 20 min. Upon completion, 2 mL of water was added into the reaction mixture under stirring. EtOAc (1 mL) was further added under stirring. After the two phases became clear, saturated brine (5 mL) was added. The mixture was separated and aqueous phase was extracted with EtOAc (5 × 5 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography with PE/EtOAc (5/1, v/v) as eluent to afford N-sulfonyl α-hydroxyamide 2.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The work was supported by the National Natural Science Foundation of China (grant number 21772010).