Regioselective Addition of Mesitol to a 2,4-Dichloropyridine

Abstract

The regioselectivity of the addition of 2,4,6-trimethylphenol to 2,4dichloro-3,6-dimethylpyridine can be controlled by the proper choice of catalyst and solvent. The use of catalytic copper(I) salts and pyridine as solvent results in exclusive addition at C-2. In their absence, a mixture of regioisomers is obtained in which addition at C-4 is dominant.

Convergent Kilo-Scale Synthesis of a Potent Renin Inhibitor for the Treatment of Hypertension

“…We found that complete conversion could be achieved within 20 h with reduced catalyst loading (2 mol %) if the reaction was run more concentrated (1.0 M) and with a larger excess of sodium methoxide (1.7 equiv). These optimized conditions maintained a good ratio (100:1) of 13 : 13a and afforded good isolated yield (70%) of the desired regioisomer after distillation (eq ) …”

“…20 Reaction run in toluene afforded a good ratio of 13:13a, albeit with low conversion. Inspired by a recent report that copper salts catalyze this type of displacement whilst improving the isomeric ratio, 21 we screened various copper catalysts and identified CuI and N,N 0 -dimethylethylenediamine as an effective catalyst/ligand combination to improve the rate of reaction. We found that complete conversion could be achieved within 20 h with reduced catalyst loading (2 mol %) if the reaction was run more concentrated (1.0 M) and with a larger excess of sodium methoxide (1.7 equiv).…”

“…These optimized conditions maintained a good ratio (100:1) of 13:13a and afforded good isolated yield (70%) of the desired regioisomer after distillation (eq 4). 21 4-Chloro-2-methoxypyridine was then used in the Suzuki reaction with vinyl boronÀpinacol ester 14. Optimization of the Suzuki-coupling conditions revealed that a combination of 1 mol % Pd(OAc) 2 , 2 mol % X-Phos, 22 and aqueous K 3 PO 4 in 2-methyltetrahydrofuran (2-MeTHF) at 50 °C afforded complete conversion of the chloropyridine starting material to the desired product 15 in a 75% assay yield.…”

Preparation of a Corticotropin-Releasing Factor Antagonist by Nucleophilic Aromatic Substitution and Copper-Mediated Ether Formation

“…Unfortunately, while addition of amine 7 provided some selectivity for the 4-position, bis-addition proceeded at a competitive rate (entry 2). A selective nucleophilic aromatic substitution at the 2-position of 2,4-dichloro-3,6-dimethylpyridine had been demonstrated at Pfizer with mesitol . This protocol was evaluated, and although it provided good selectivity, it led to only 29% of the desired product (entry 3).…”

“…In conclusion, several synthetic approaches involving nucleophilic aromatic substitutions of 2,4-dichloropyridine derivatives were studied for the preparation of a CRF drug candidate ( 1 ). It was noted that changing the 3-position of the substrate from a methyl group to a methyl ester drastically changed the reaction conditions required for the introduction of the aryl ether. While the approach utilizing the pyridine N -oxide provided high levels of regioselectivity in the formation of the aryl ether, it was avoided for safety reasons due to the low onset temperature of both N -oxides.…”