Na2S-mediated thionation: an efficient access to secondary and tertiary α-ketothioamides via Willgerodt–Kindler reaction of readily available arylglyoxals with amines

The task of this paper is to provide an efficient process for synthesis of secondary and tertiary α-ketothioamides via Willgerodt–Kindler reaction of readily available arylglyoxals with amines using Na2S as an effective catalyst. A plausible role for Na2S in the reaction of arylglyoxals with primary amines is proposed. GRAPHICAL ABSTRACT


Introduction
Organosulfur compounds are valued not only for their rich and varied chemistry, but also for many important biological properties. [1] Thioamides are a class of organosulfur compounds that comprise a variety of derivatives that possess diverse physiological properties such as antigastric, antiulcer, antidiabetic, antitubercular, anti-inflammatory, antitumor, fungistatic, agricultural herbicides, antioxidant, molds and yeasts inhibitors. [2][3][4][5][6][7][8][9][10] The thioamide-NH is a stronger hydrogen bond donor than the amide NH, and the larger and less electronegative sulfur atom, relative to oxygen, is a weaker hydrogen bond acceptor. [11,12] These two factors combined may alter not only the hydrogen bonding ability at the receptor or enzyme level but also induce conformational changes and higher lipophilicity in the modified molecules. As a result, the substitution of thioamides for amides appears to be a promising and productive tool in drug discovery, inclusion chemistry, heterocycles synthesis and materials science. [13][14][15][16][17][18][19][20][21] On the other hand, α-ketothioamides have recently become a very important functional group in organic synthesis and medicinal chemistry. [22][23][24] These compounds have the potential to be converted into aryl glyoxalic acids.
Not surprisingly, one of the most exploited routes to thioamides involves the Willgerodt-Kindler reaction (W-K reaction). [25] In the original W-K reaction, ketones and aldehydes were found to react with sulfur and secondary amines to give terminal thioamides as a result of consecutive oxidations and rearrangements. Several recent reviews have rendered the W-K reaction as a more attractive reaction to the medicinal and organic chemist. [26][27][28][29][30][31][32] The first step of the W-K reaction is considered to involve cleavage of the S-S bond of elemental sulfur caused by nucleophilic attack of amine to form polysulfide anions in a reversible way. The less basic amines lead to only little formation of the polysulfide anions.
A number of limited approaches for the synthesis of α-ketothioamides have been developed, but these have disadvantages such as limited scope, expensive reagents or catalysts, and need for harsh reaction conditions. The addition of H 2 S onto acylcyanides according to Scheme 1 gave corresponding N-unsubstituted α-keto aryl thioamides. [33] However, the synthesis of αketothioamides is restricted to the N-unsubstituted derivatives. Recently, we have reported a procedure for the synthesis of α-ketothioamides from aryl thioacetamides using CuCl 2 ·2H 2 O as a heterogeneous catalyst (Scheme 3). [35] However, this method is restricted to the aryl thioacetomorpholide derivatives.
Reaction of diphenacyl sulfides under Gewald conditions unexpectedly resulted in a narrow variety of α-keto aryl thioamides formation with good yields (Scheme 4). [36] Arylglyoxals have been used as useful synthons in the organic synthesis. [37] Eftekhari and his co-workers have described a general synthesis of α-ketothioamides based on the W-K reaction of arylglyoxals with secondary cyclic amines and elemental sulfur. [38,39] The reaction was not worked with aliphatic amines such as dimethylamine and benzylamine as well as with primary aromatic amine such as aniline.
It is evident that the need for the development of new, a broad scope and flexible method is required to access α-ketothioamides without using toxic reagents and avoiding extreme conditions. Recently, Kanbara reported that the addition of a small amount of Na 2 S in the W-K reaction improved the reaction as shown in Scheme 4. [40] The W-K reaction between anilines and benzaldehyde proceeded in the presence of catalytic amount of Na 2 S to give thiobenzanilides in moderate to good yields (Scheme 5). This encouraged us to investigate the W-K reaction for comprehensive synthesis of αketothioamides from readily available arylglyoxals using catalytic amount of Na 2 S. To the best of our knowledge, this is the first demonstration for synthesis of secondary α-ketothioamides (Scheme 6).

Results and discussion
To find the optimal conditions, we conducted the W-K reaction of phenylglyoxal, morpholine and/or aniline under different conditions for the synthesis of tertiary α-ketothioamides and secondary α-ketothioamides, respectively (Tables 1 and 2). As shown in Table 1, 1-phenyl-2-(morpholin-1-yl)-2-thioxoethanone 2a was obtained in good yield (95%) when a mixture of phenylglyoxal 1a, morpholine and elemental sulfur were heated in the presence of Na 2 S at 60 • C under solvent-free condition for 10 min (Entry 10).
Our first experiment for optimization of reaction conditions of phenylglyoxal with aniline, showed that the presence of Na 2 S is required to achieve the synthesis of secondary α-ketothioamide 2g and no desired product was observed when the reaction was performed without Na 2 S (Table 2).
A polar solvent such as DMF was much better than H 2 O and solvent-free conditions. The effect of temperature was also studied by carrying out the model reaction at room temperature and 60 • C. It was observed that the yield was increased as the reaction temperature was raised to 60 • C.
The structures of the desired products were confirmed by MS (electron ionization (EI) and ESI), 1 HNMR and 13 CNMR spectra. It should be mentioned that the structures of tertiary αketothioamides were confirmed by a comparison with authentic samples prepared by reported methods. [34,37] The characteristic signal for 2e in the 1 HNMR spectrum was a broad resonance for the proton of the NH at 10.14 ppm. Intramolecular hydrogen bonding between the proton of amine and the ketone group, results in deshielding of the NH proton ( Figure 1).
The 1 H-decoupled 13 CNMR spectrum of 2e showed 10 distinct resonances in agreement with the proposed structure, with the ketone and thioamide carbons appearing at δ = 189.70 and 187.0 ppm, respectively, and 8 distinct resonances for the aromatic carbons between δ = 122.21 and 137.84 ppm. The MS (EI) mass spectrum of 2g clearly showed the presence of the molecular ion (241) [M + ]. MS (EI) analysis of α-ketothioamides revealed that their fragmentation followed a general pathway involving predominantly α-cleavage process from C-C bonds.
Using the optimized procedures (Tables 1 and 2), the reactions of arylglyoxals with various primary and secondary amines proceeded smoothly at 60 • C in the presence of 1 mol% of Na 2 S to afford α-ketothioamides. All the substrates consistently furnished the desired products in high yields and were not limited to aliphatic amines; aromatic amines also afforded the desired products in good yields (Table 3).
A plausible role for Na 2 S in the W-K reaction of arylglyoxals with primary amines such as aniline is shown in Scheme 7. The suspension of elemental sulfur in the DMF solution of aniline remained unreacted because of the poor nucleophilicity of aniline. The addition of a small amount of Na 2 S into the reaction mixture caused is considered to initiate the nucleophilic cleavage of the elemental sulfur ring to give the polysulfide anions as depicted in Scheme 6. The sulfur in polysulfides acts as a thiolating agent; the presence of small amounts of Na 2 S has a   Scheme 7. Plausible role for Na 2 S in the W-K reaction of arylglyoxals with primary amines.
In conclusion, we have reported an efficient Willgerodt-Kindler reaction for the synthesis of secondary and tertiary α-ketothioamides using Na 2 S as an inexpensive catalyst with benign and easy workup, which make it a useful and attractive strategy for the synthesis of αketothioamides. The reaction also proceeds very well with primary aliphatic and aromatic amines and corresponding α-ketothioamides were produced in high yields.

General procedure for the synthesis of arylglyoxals 1a-1c
The arylglyoxals were prepared according to reported procedure with some improvements. [42] To a solution of SeO 2 (25 mmol) in dioxane (30 mL) containing H 2 O (1 mL) was added an aryl methyl ketone (25 mmol). The solution was heated under reflux conditions for 6 h. Then the hot solution was decanted to remove the precipitated selenium. Distillation of dioxane was resulted a yellow liquid. Subsequently recrystallization of the liquid in hot H 2 O obtained the corresponding arylglyoxals 1a-1c.

General procedure for the synthesis of secondary and tertiary α-ketothioamides 2a-2q
Arylglyoxal 1 (1 mmol) was added to a mixture of amine (2 mmol), elemental sulfur (2 mmol) and Na 2 S (1 mol%) in DMF (2 mL) or solvent free for primary amine and secondary amine, respectively, then heated at 60 • C for 10 min-4 h (Tables 1 and 2). After completion of the reaction, monitored by TLC (n-hexane/EtOAc: 5/3), the obtained solid was removed by filtration. The unreacted sulfur and was removed by adding 5 ml EtOH, heating and then hot filtration. By cooling, corresponding α-ketothioamides were crystallized and separated by simple filtration. In the case of oily products, column chromatography was used for purification. Representative spectroscopic data of the α-ketothioamides 2a-2q: N-benzyl-2-oxo-2-phenylethanethioamide (2d) 1