Microwave-assisted safe and efficient synthesis of α-ketothioesters from acetylenic sulfones and DMSO

ABSTRACT α-Ketothioesters are safely and efficiently synthesized from arylacetylenic sulfones and dimethyl sulfoxide (DMSO) in the presence of equivalent of water and catalytic amount of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) under microwave irradiation. Arylacetylenic sulfones and dimethyl sulfoxide first form arenecarbonyl sulfonyl dimethylsulfonium methylides via nucleophilic addition, ring closure, and 4e ring opening. The methylides undergo a radical process to generate α-methylthio-α-sulfonylacetophenones, which further convert to α-ketothioesters through the Pummerer oxidation. Compared to the previous methods, the current method is safer and more efficient. GRAPHICAL ABSTRACT


Introduction
α-Ketothioesters are a class of important and active organic compounds consisting of an α-keto group adjacent to a thioester moiety. The simplest S-ethyl 2-oxopropanethioate (EOP) has been shown to be a promising therapeutic agent for treating inflammation observed in neurodegenerative disorders [1]. A chiral bicyclic piperazinone-containing αketothioester has been reported to be a potent thrombin inhibitor in the nanomolar range [2] (a, Scheme 1).
Acetylenic sulfones are readily available electron-deficient alkynes and have been applied in various transformations [21,22]. In our previous work, they produced αketosulfonium ylides and α-ketothioethers in the reaction with DMSO [23,24]. In this work, direct, safe, and efficient synthesis of α-ketothioesters was realized by adding catalytic amount of DBDMH in the microwave-assisted reaction of acetylenic sulfones and DMSO, showing diverse reactivities of acetylenic sulfones and DMSO (Scheme 2).

Results and discussion
1-Methyl-4-((phenylethynyl)sulfonyl)benzene (1a) was first employed as the model substrate to react with DMSO to optimize reaction conditions (Table 1). In the absence of any haloid reagents, 2a was not detected ( The reaction also occurred violently, the pressure increased sharply and generated a large amount of paraformaldehyde appeared on the neck of the reaction tube and on the inside surface of its cap. All reactions were conducted in a commercial CEM microwave reactor and the pressure can be observed and set at a safe concern threshold ( < 4 bar). 75% Yield of 2a was obtained when shortening the reaction time to 8 min ( Table 1, entry 8). Finally, inexpensive and readily available 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) was tested, 2a was generated in 67% yield when the reaction was conducted at 130°C with addition of 10 mol% DBDMH (Table 1, entry 9). However, the reaction occurred violently and partial product decomposed under these conditions. Then the reaction temperature and time were further screened ( Table 1, entries [10][11][12][13][14]. The yield increased slightly to 69% when the reaction was carried out at 120°C (Table 1, entry 10). However, it decreased to 45% and 39%, respectively, when the reaction temperature was further lowered to 110 and 100°C (Table 1, entries 11 and 12). Lengthening the reaction time to 25 min resulting in the increase of the yield to 75% at 120°C (Table 1, entry 13) and further lengthening the reaction time led to decomposition of product 2a. By contrast, when the reaction was conducted in an oil bath at 120°C for 25 min, affording the product 2a in only 2% yield ( Table 1, entry 14). The results indicated that the reaction was greatly accelerated under microwave irradiation because microwave heats polar substance selectively [25,26], leading to reactants to reach the desired reaction temperature soon. Thus, microwave accelerates some organic reactions involving polar reactants [27,28] With the optimal reaction conditions in hand, the reaction scope was then evaluated (Table 2). First, the reactions of different substituent groups on the alkyne side were examined. The substrates 1b-g with different weak electron-donating and withdrawing groups on the aryl group or in different positions of the aromatic ring in the acetylene side afforded the corresponding products 2b-g in moderate to good yields (57-83%). Strong electrondeficient substrates 1h-k produced the corresponding products 2h-k in 70-76% yields. However, it should be noted that the strong electron-donating substrates 1l-n gave the corresponding products 2l-n in only 19-59% yields under standard conditions. The product 2 m was obtained in 19% yield with byproducts 3 m in 39% yield and 4 m in 24% yield under standard conditions. The yield was further improved to 53% for 2 m when DBDMH was increased to 20 mol%. Both heteroaryl thiophen-3-yl and fused-arene naphthylen-2-yl substrates 1o and 1p proceeded well under standard conditions. However, none of 2q-s was detected when alk-1-ynyl 4-methylphenyl sulfones 1q-s were attempted under the standard reaction conditions possibly due to their low electrophilic reactivity at the first nucleophilic attack step of DMSO because alkyl groups are electron-donating substituents (vide post, Scheme 4).
The reactions of different substituent groups on the sulfone side were examined as well (Table 3). Weak electron-withdrawing 4-chlorophenyl sulfone 1t gave product 2a in 81% yield, while strong electron-withdrawing 4-nitrophenyl sulfone 1u generated 2a in 56% yield. However, only a trace amount of 2a was observed for methyl sulfone 1v under standard conditions. The yield was improved to 54% when DBDMH was increased to 20 mol%.
To understand the reaction mechanism, some control experiments were conducted (Scheme 3). The reaction of 1-methyl-4-((phenylethynyl)sulfonyl)benzene (1a) and anhydrous DMSO-d 6 gave rise to products 2a-d 3 in 84% yield (a, Scheme 3). When the reaction of 1a and dry DMSO was conducted only for 10 min, generating the product 2a in 13% yield, accompanying with 2-(dimethyl-4-sulfanylidene)−1-phenyl-2-tosylethan-1-one (3) in 24% yield and 2-(methylthio)-1-phenyl-2-tosylethan-1-one (4) in 61% yield (b, Scheme 3). Replacing 1a with 3 as starting material, 2a and 4 were obtained in 19% and 76%  yields, respectively, when the reaction was conducted only for 10 min (c, Scheme 3), and 2a was obtained in 57% yield for the 25 min. reaction (d, Scheme 3). When compound 4 was applied as starting material under standard reaction conditions, product 2a generated in 65% yield (e, Scheme 3). The above experiments results indicated that both 3 and 4 were the reaction intermediates and 3 generated first, then 4 followed by. To examine whether the transformation still involves a radical stage like our previously reported formation of compound 4 [24], the reactions of 1a, 3, and 4 were conducted under the standard conditions with the radical scavenger TEMPO. Only the reaction involving 4 as starting material gave the desired product 2a in 78% yield and no product 2a was detected for the other two reactions (f-h, Scheme 3). However, the captured product 1-methoxy-2,2,6,6tetramethylpiperidine was detected (at m/z = 171) by GC-MS analysis in the reaction of 3 (g, Scheme 3). The results revealed that the formation of compound 4 indeed involved a similar radical process as previous one [24], but the last step was unrelated with radical mechanism. Besides, a small amount of 1-phenyl-2-tosylethan-1-one (5) was observed or isolated as a decomposed product of 4. Last, we designed an experiment to verify the oxidation of bromide into bromine with DMSO under the optimal conditions because only 10 mol% of DBDMH was enployed. Equivalents of KBr and anisole were mixed in DMSO and the reaction was conducted under optimal conditions (i, Scheme 3). Despite of the violent reaction and grievous carbonization, 4-bromoanisole was monitored (at m/z = 186) by GC-MS analysis, illustrating that bromide was oxidized into bromine under optimal conditions. However, in our synthetic reaction system, brimide generated gradually and was converted to bromine and further to DBDMH by DMSO. Thus, the reaction proceeded smoothly because bromide existed always in a low concentration.
Based on our previous work [23,24], and the above control experiments, the reaction mechanism with 1a as an exmple substrate can be proposed as presented in Scheme 4. Initially, dimethyl sulfoxide nucleophilically attacks the acetylenic sulfone 1a, producing a zwitterionic intermediate A, which cyclizes into a four-membered ring intermediate B.
It further undergoes a 4e ring opening to generate sulfonium ylide 3 [22]. After the formation of the sulfonium ylide 3, dimethyl sulfide is generated through the decomposition of dimethyl sulfoxide with the aid of the ylide 3 under heating [24]. Dimethyl sulfide dissociates into the methylthiyl and methyl radicals. The methyl radical further reacts with the ylide 3 to form a new radical intermediate C, which abstracts a hydrogen atom from dimethyl sulfide to afford the intermediate 4. It shows a silightly different radical process from our previously reported one [24] because the current reaction is perfomed at lower reaction temperature (120°C) than previous one (160°C) and the corresonding dimethyl disulfide and dimethylthiomethane were not observed in the current GC-MS anaylsis.
For the tranformation from 4 to product 2a, the sulfur atom of thioether in intermediate 4 attacks the bromine in DBDMH to form 1-bromo-4,4-dimethyl-5-oxo-4,5-dihydro-1Himidazol-2-olate (D) and a sulfonium intermediate E, which undergoes an elimination of HBr to generate another sulfonium F. DMSO nucleophilically attacks sulfonium F, generating intermediate G. Finally, H 2 O attacks G [29], resulting in eliminations of pmethylbenzenesulfinic acid, DMSO, and a proton to afford the desired product 2a (the Pummerer oxidation). Simultaneously, DMSO oxidizes bromide into bromine, which reacts with 1H-imidazol-2-olate D to regenerate DBDMH and bromide anion under optimal conditions. Both DBDMH and bromide participate in the next reaction cycle.

Conclusion
In summary, we successfully developed an efficient and safe method to synthesize αketothioesters from acetylenic sulfones under microwave irradiation with DMSO as an oxidant and methanesulfenylating reagent. The reaction requires a catalytic amount of DBDMH and equivalent amount of water to achieve the efficient synthesis. The mechanistic investigations indicate that arylacetylenic sulfones and DMSO first generate arenecarbonyl sulfonyl dimethylsulfonium methylides via nucleophilic addition, ring closure, and 4e ring opening. The methylides undergo a radical process to form α-methylthio-αsulfonylketones, which further transform to final α-ketothioesters via the Pummerer oxidation. Compared to the previous methods, the current method realizes a convenient and safe transformation from arylacetylenic sulfones and DMSO to α-ketothioesters by use of a catalytic amount of brominium reagents under microwave assistance and also shows diverse reactivities of acetylenic sulfones and DMSO.

General
Unless otherwise noted, all starting materials were purchased from commercial suppliers. DCM was refluxed over CaH 2 ; Et 3 N was refluxed over TsCl and P 2 O 5 , DMSO was stirred overnight with CaH 2 at RT. All the solvents and reagents were freshly distilled prior to use. Column chromatography was performed using silica gel (normal phase, 200-300 mesh) from Branch of Qingdao Haiyang Chemical, with a mixture of petroleum ether (PE) (b.p. 60-90°C) and ethyl acetate (EtOAc) as eluent. Reactions were monitored by TLC on GF254 silica gel plates (0.2 mm) from Institute of Yantai Chemical Industry. The plates were visualized under UV light. Melting points were determined on a Yanaco MP-500 melting point apparatus and are uncorrected. 1 H, 19 F, and 13 C NMR spectra were Alkynyl sulfone compounds 1a-1q and 1t-1v were prepared in our previously reported literature [23,24].

General procedure of the synthesis of alk-1-ylyl sulfones 1r and 1s
Following a modified procedure described in the literature [30], to a solution of ((prop-2yn-1-yloxy)methyl)benzene (0.45 g, 3 mmol) in THF (12 mL) cooled to -78°C was added n-BuLi (2.1 mL, 3.3 mmol, 1.6 M in hexane) dropwise. The resulting solution was stirred for 1 h and then warmed to RT, to which was added a premixed solution of phenyl disulfide (672 mg, 3 mmol) and MeI (437 mg, 3 mmol). The reaction was monitored by TLC. Upon completion, Et 3 N (1 mL) was added to quench the reaction. After addition of water (10 mL) and removal of THF under reduced pressure with a rotary evaporator, the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined extracts were washed with brine and dried over Na 2 SO 4 . After rotary evaporation, the residue was further condensed under high vacuum to remove thioanisole and then purified by silica gel column chromatography using PE/EtOAc (100:1, v/v) as eluent to afford the crude alk-1-ynyl sulfide.
mCPBA (414 mg, 2.4 mmol) was added into a solution of the sulfide (1.1 mmol) in dichloromethane (6 mL) at 0°C. The reaction mixture was stirred for 1 h at 0°C and then for 3.5 h at room temperature. After finished the reaction monitored by TLC, the reaction mixture was washed with saturated aqueous NaHCO 3 , dried over Na 2 SO 4 , and concentrated. The residue was purified by silica gel column chromatograph (PE/EtOAc 10:1, v/v) to afford the desired sulfone 1r as colorless crystals (230 mg, 71% yield) and 1s as colorless oil (170 mg, 74%).

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).