K2S2O8-Promoted Aryl Thioamides Synthesis from Aryl Aldehydes Using Thiourea as the Sulfur Source

Thiourea as a sulfur atom transfer reagent was applied for the synthesis of aryl thioamides through a three-component coupling reaction with aryl aldehydes and N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMAC). The reaction could tolerate various functional groups and gave moderate to good yields of desired products under the transition-metal-free condition.


Results and Discussion
Initially, we treated the reaction of 4-chlorobenzaldehyde 1a in DMF and H 2 O at 125 • C in the presence of thiourea using the benzoyl peroxide (BPO) as an oxidant. After 24 h, the desired thioamide product 3a was isolated in 58% yield ( After establishing the optimized conditions, this procedure was applied to access a variety of aryl thioamide derivatives. Several different aryl aldehydes could undergo this transformation smoothly in a mild condition to give the desired products 3a-r (Scheme 1). The results indicated that many popular functional groups were well tolerated, such as methyl, methoxyl, chloro, bromo, fluoro, trifluoromethyl, and tert-butyl. Furthermore, the substrate bearing a sensitive hydroxy group, which was generally protected in the presence of an oxidant could be also tolerated in this transformation, and afforded the desired product 3o in 83% yield. A substituted amino was suitable as well, and gave 88% yield of 3p. The substituents on aromatic aldehydes had a certain influence on this transformation. When the substituents were strong electron-withdrawing groups, either lower yield of desired products, or no desired products were obtained (3j and 3r). The desired product 3m was not afforded possibly due to the steric hindrance. Moreover, our experiments demonstrated that 2naphthaldehyde was a suitable substrate for this transformation, and gave the desired product 3q a good yield.
We attempted to explore the different N-substituted formamides for this transformation in additional solvent. No good results were provided when the normal solvents such as N-methyl-2- After establishing the optimized conditions, this procedure was applied to access a variety of aryl thioamide derivatives. Several different aryl aldehydes could undergo this transformation smoothly in a mild condition to give the desired products 3a-r (Scheme 1). The results indicated that many popular functional groups were well tolerated, such as methyl, methoxyl, chloro, bromo, fluoro, trifluoromethyl, and tert-butyl. Furthermore, the substrate bearing a sensitive hydroxy group, which was generally protected in the presence of an oxidant could be also tolerated in this transformation, and afforded the desired product 3o in 83% yield. A substituted amino was suitable as well, and gave 88% yield of 3p. The substituents on aromatic aldehydes had a certain influence on this transformation. When the substituents were strong electron-withdrawing groups, either lower yield of desired products, or no desired products were obtained (3j and 3r). The desired product 3m was not afforded possibly due to the steric hindrance. Moreover, our experiments demonstrated that 2-naphthaldehyde was a suitable substrate for this transformation, and gave the desired product 3q a good yield.
We attempted to explore the different N-substituted formamides for this transformation in additional solvent. No good results were provided when the normal solvents such as N-methyl-2-pyrrolidone (NMP), 1,4-dioxane, 1,2-dichloroethane (DCE), toluene, chlorobenzene (PhCl), dimethyl sulfoxide (DMSO), ethylene glycol, were used (see Supporting Information). Unexpectedly, N,N-dimethylacetamide (DMAC), which was seldom used as an amine source by the acyl C-N bond activation [37], could replace DMF to give the same desired product in good yield. Subsequently, the reactions of aryl aldehydes with thiourea in DMAC were examined under the similar reaction condition ( Table 2). The results demonstrated that various groups were tolerated well, such as methyl, chloro, and bromo, and the good yields of the desired products were isolated.
Molecules 2018, 23, x FOR PEER REVIEW 3 of 9 pyrrolidone (NMP), 1,4-dioxane, 1,2-dichloroethane (DCE), toluene, chlorobenzene (PhCl), dimethyl sulfoxide (DMSO), ethylene glycol, were used (see Supporting Information). Unexpectedly, N,Ndimethylacetamide (DMAC), which was seldom used as an amine source by the acyl C-N bond activation [37], could replace DMF to give the same desired product in good yield. Subsequently, the reactions of aryl aldehydes with thiourea in DMAC were examined under the similar reaction condition ( Table 2). The results demonstrated that various groups were tolerated well, such as methyl, chloro, and bromo, and the good yields of the desired products were isolated.  In addition, extremely small amounts of amide products were observed, along with the generation of thioamide products under the optimal condition. So, two control experiments were conducted to explain the tentative reaction mechanism (see Supporting Information). First, no thioamide product was formed in the absence of thiourea, and only trace amounts of amide product were observed. Second, when the N,N-dimethylbenzamide replacing the benzaldehyde was manipulated under the standard condition, no desired thioamide was observed.    In addition, extremely small amounts of amide products were observed, along with the generation of thioamide products under the optimal condition. So, two control experiments were conducted to explain the tentative reaction mechanism (see Supporting Information). First, no thioamide product was formed in the absence of thiourea, and only trace amounts of amide product were observed. Second, when the N,N-dimethylbenzamide replacing the benzaldehyde was manipulated under the standard condition, no desired thioamide was observed. Based on our experimental results and previous reports [35], a proposed reaction mechanism for this transformation is described in Scheme 3. First, an aryl aldehyde undergoes a nucleophilic attack by a dimethylamine, which is from the hydrolysis of DMF, to generate iminium intermediate A. The iminium A then is directly attacked by thiourea to form the intermediate B, together with the release of urea [43,47,49]. Finally, intermediate B is oxidized by K2S2O8 to afford the desired thioamide product. In addition, extremely small amounts of amide products were observed, along with the generation of thioamide products under the optimal condition. So, two control experiments were conducted to explain the tentative reaction mechanism (see Supporting Information). First, no thioamide product was formed in the absence of thiourea, and only trace amounts of amide product were observed. Second, when the N,N-dimethylbenzamide replacing the benzaldehyde was manipulated under the standard condition, no desired thioamide was observed.
Based on our experimental results and previous reports [35], a proposed reaction mechanism for this transformation is described in Scheme 3. First, an aryl aldehyde undergoes a nucleophilic attack by a dimethylamine, which is from the hydrolysis of DMF, to generate iminium intermediate A.

Materials and Methods
Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers, and were used without further purification. Reactions were monitored by thin layer chromatography (TLC) analysis on silica gel 60 F254, and visualization was accomplished by irradiation with short wave UV light at 254 nm. 1 [35]. 1

Materials and Methods
Unless otherwise stated, all reagents and solvents were purchased from commercial suppliers, and were used without further purification. Reactions were monitored by thin layer chromatography (TLC) analysis on silica gel 60 F254, and visualization was accomplished by irradiation with short wave UV light at 254 nm. 1