Experimental and Theoretical Studies of Bromination of Diethyl 2,4,6‐Trimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate

Abstract

A reaction of diethyl 2,4,6‐trimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate with 1, 2, and more equivalents of N‐bromosuccinimide (NBS) in methanol was investigated by NMR spectroscopy at a temperature interval ranging from 25 to 40°C. The reaction was found to proceed through several steps. The structures of the intermediates diethyl 3‐bromo‐2,4,6‐trimethyl‐3,4‐dihydropyridine‐3,5‐dicarboxylate, diethyl 3‐bromo‐2‐methoxy‐2,4,6‐trimethyl‐1,2,3,4‐tetrahydropyridine‐3,5‐dicarboxylate, and diethyl 3,5‐dibromo‐2‐methoxy‐2,4,6‐trimethyl‐2,3,4,5‐tetrahydropyridine‐3,5‐dicarboxylate were identified by multinuclear (1H, 13C, and 15N) NMR spectral data. The optimal structures of all species participating in the reaction as well as changes in their relative energies along with the proposed pathway of the reaction were analyzed by quantum‐chemical calculations. The mechanism of bromination of diethyl 2,4,6‐trimethyl‐1,4‐dihydropyridine‐3,5‐dicarboxylate with NBS in methanol was found to favor the bromination in the 2,6‐methyl side chains as the only products in full agreement with experimental observations.

Intramolecular hydrogen bonds in 1,4-dihydropyridine derivatives

“…The necessary 2-bromomethyl-1,4-DHP 2 and 2,6-bis-bromomethyl-1,4-DHP 4 were obtained by our elaborated method including the bromination of the methyl groups in the position 2- (or 2,6-) with N-bromosuccinimide (NBS) in methanol according to the literature [ 8 , 9 ]. The further reaction of appropriate monobromomethyl-1,4-dihydropyridine (DHP) 2 or bis-bromomethyl-1,4-DHP 4 with dry potassium acetate in dry dimethylformamide (DMF) lead to target compounds 3 and 5 in medium-to-good yields ( figure 1 ).…”

Development of Self-Assembling bis-1,4-Dihydropyridines: Detailed Studies of Bromination of Four Methyl Groups and Bromine Nucleophilic Substitution

“…It has been proposed that after NBS addition to the double bond of 1,4-DHP, followed by succinimide elimination, methoxide addition to the second position of 1,4-DHP takes place. Such an intermediate has been identified by NMR [ 41 ]. The reaction with DBDMH for 20 h in the same solvent system—EtOAc/MeOH (1:3) ( 6 , Table 1 , entry 8)—gave product 11b, with a yield of 48%.…”

Highly Efficient Electrocarboxylation Method to Synthesize Novel Acid Derivatives of 1,4-Dihydropyridines and to Study Their Antimicrobial Activity

“…moles of NBS using methanol as the solvent at room temperature 41 as with a lesser amount of NBS and lower temperature a monosubstituted product is formed. 42 , 43 This step produced diethyl 2,6-bis(bromomethyl)-4-substituted-1,4-dihydropyridine-3,5-dicarboxylate ( 8a – k ) and a mechanism of the transformation is also reported; 44 the synthesis was confirmed by two methyl groups disappearing from δ 2.25 and two methylene protons appearing from δ 3.96, also the shift of the singlet peak for a proton of N–H at δ 8.80 ppm, to δ 10.6. Results were verified with existing literature.…”