硫代酰胺作为重要的功能分子骨架, 在农药、医药领域具有广泛的应用价值, 同时也是合成含硫精细化学品的关键中间体. 本研究开发了一种以环脒(CA)、苯甲醛和H₂S为原料合成新型硫代酰胺的高效方法, 该方法以H₂S为硫源替代传统试剂, 成功合成了多种新型硫代酰胺类衍生物. 此外, 通过原位红外光谱监测了反应过程, 揭示了其反应机理: 首先环脒吸收H₂S生成CAH⁺HS⁻中间体, 随后HS⁻作为亲核硫源进攻苯甲醛的醛羰基, 发生亲核加成形成含O⁻的活性中间体, 然后该中间体亲核进攻CAH⁺生成C—O—C关键中间体, 继而通过分子内重排转化为内酰胺和硫代苯甲醛, 最终通过串联反应高效构建了一系列新型硫代酰胺类衍生物. 本研究首次提出并证实苯甲醛中的氧原子具有双重功能, 既作为亲核试剂进攻CAH⁺引发环脒开环, 又通过分子内重排定向迁移至产物, 为含硫精细化学品的分子设计提供了新思路.

Thioamides, an important functional molecular skeleton, have wide application in the fields of pesticides and pharmaceuticals. They also serving as key intermediates for synthesizing sulfur-containing fine chemicals. This study has developed an efficient method for synthesizing novel thioamide derivatives using cyclic amidines (CA), benzaldehyde, and H₂S as starting materials. Notably, H₂S was utilized as the sulfur source instead of traditional sulfur reagents, enabling the successful synthesis of a variety of novel thioamide derivatives. In addition, the reaction mechanism was elucidated through in situ infrared spectroscopy, which revealed a multi-step reaction process. Initially, the cyclic amidine reacts with H₂S to form a CAH⁺HS⁻ intermediate. Subsequently, the HS⁻ anion nucleophilically attack the carbonyl group of benzaldehyde to form an active intermediate containing an oxygen anion. This intermediate then nucleophilically attacks CAH⁺, generating a C—O—C key intermediate, which undergoes intramolecular rearrangement to produce lactam and thiobenzaldehyde. Ultimately, a series of novel thioamide derivatives were efficiently constructed through this tandem three-component reaction. This study demonstrates for the first time that the oxygen atom in benzaldehyde exhibits a dual function. It serves as a nucleophile to attack CAH⁺ and initiate ring-opening reaction of cyclic amidines, while simultaneously promoting oxygen atom migration to the lactam through intramolecular rearrangement. This discovery provides a novel approach for the design and synthesis of sulfur-containing fine chemicals. A typical general procedure for the synthesis of thioamides is described as follows: As an example, the procedure for the synthesis of thioamides from the starting matiarials H₂S, 1,8-diazabicyclo[5.4.0]- 7-undecene (DBU, 1a) and benzaldehyde (2a) is described, and similar methods are applied to other substrates. 1a (0.1520 g, 1.0 mmol), 2a (0.2120 g, 3.0 mmol), and tetrahydrofuran (THF, 2 mL) were loaded into a 15 mL stainless-steel autoclave equipped with a magnetic stirrer. Subsequently, the reactor was charged with H₂S (89.6 mL, 4.0 mmol). The reactor was placed in a constant-temperature sand bath, and the reaction mixture solution was stirred for 24 h. After the reaction was completed, a saturated NaCl aqueous solution was added to the reaction mixture solution, followed by extraction with EtOAc three times. The combined organic layer was washed with brine and dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The crude product was then purified by silica gel column chromatography (V(petroleum ether)/V(ethyl acetate)=1/1) to give the desired product N-(3-(2-oxoazepan-1-yl)propyl)benzothioamide (3a).