The piperidine alkaloid (–)-cassine present in the flowers of Senna spectabilis can significantly influence the activity of cholinesterase, which is related to Alzheimer’s disease. In addition, these alkaloids presented sedative and anticonvulsant, effects related to the central nervous system. They also presented antimalarial and schistosomicidal activities. These results stimulated us to prepare a series of substituted aromatic esters from the alkaloid (–)-cassine, a major metabolite isolated from Senna spectabilis flowers, aiming to discover new compounds with antimalarial activity. To prepare the semisynthetic derivatives, initially (–)-cassine was converted into hydrochloride by a stream of hydrogen chloride gas generated in a modified Kipp’s apparatus (30 min) that was bubbled through a solution of alkaloid (–)-cassine in chloroform. Additionally, substituted benzoyl chlorides were added to a solution of the hydrochloride of 1 (1:5) in chloroform, and the mixture was refluxed under nitrogen atmosphere. The reaction was monitored for 8 h by TLC, time required to consume all the starting material. Further, the products were purified by CC and submitted to HRESIMS and 1D and 2D NMR analysis. Molecular weight of derivative (–)-3-O-(2-bromobenzoyl)cassine was measured by HRESIMS, and the molecular formula was established as C25H39BrNO3+. The protonated molecular ion was observed at m/z 480.2103 [M + H]+ and was close to the calculated value for C25H39BrNO3+, 480.2108 (Δ 1.0 ppm). Furthermore, the semisynthetic derivatives were confirmed by the 1D and 2D NMR data with the acyl group linked to oxygen at C-3 evidenced by the HMBC correlation between H-3 (δH 4.14) and C-1’’ (δC 168.1), as exemplified for the derivative (–)-3-O-(2-bromobenzoyl)cassine. The synthetic methodology used was efficient for preparation of the derivatives (2–13) (conversion rate >90%, GC-FID). The HRESIMS-(+), 1D and 2D NMR analysis were important tools to confirm the structures of the semisynthetic derivatives.