General, Robust, and Stereocomplementary Preparation of β-Ketoester Enol Tosylates as Cross-Coupling Partners Utilizing TsCl−N-Methylimidazole Agents

Abstract

We have developed a general, robust, and cost-effective method for the (E)- or (Z)-stereocomplementary enol tosylation of beta-ketoesters using TsCl- N-methylimidazole (NMI)-Et3N or LiOH. TsCl coupled with NMI formed a highly reactive N-sulfonylammonium intermediate. Stereocongested secondary alcohols were smoothly sulfonylated using Ts(Ms)Cl-NMI-Et3N. beta-Ketoesters underwent (E)-selective tosylation using TsCl-NMI-Et3N and (Z)-selective tosylation using TsCl-NMI-LiOH (total of 23 examples; 60%-99% yield). Stereoretentive Negishi and Sonogashira couplings using enol tosylates proceeded successfully to give trisubstituted alpha,beta-unsaturated esters.

Palladium-Catalyzed Regio- and Stereoselective Hydrosulfonation of Propiolate Esters

“…This observed reaction required Pd(OAc) 2 as a catalyst because a control experiment in the absence of catalyst produced no (Z)-3a (entry 12). The present reaction became less efficient with other oxidants such as KHSO 5 and Cu(OAc) 2 (entries [13][14][15]. However, reaction with p-benzoquinone as an oxidant produced an 84% yield (entry 16).…”

“…Finally, we found that other nucleophiles, ethanol, 2,4-dimethylbenzoic acid, and 4-methylbenzenesulfonamide, did not work under the standard conditions (entries 27-29). In short, the examples with electron-withdrawing functionality on sulfonic acids gave lower yields, such as 2,4-dinitrophenyl substitution (entry 13), and that with electron-donating moiety gave better yields, such as ethyl substitution (entry 21).…”

“…ed condition was used, which worked effectively with trisubstituted alkenes having an OTs group. 13 Because of the relatively higher reactivity of our prepared disubstituted alkenyl sulfonates, a new condition was optimized, as shown in Table S1 (Supporting Information). Alkyl (Z)-5phenylpent-2-en-4-ynoates (5) 22 were obtained in favor-able yields with 4-chlorophenyl-substituted sulfonate 3k and arylacetylenes 4 under Pd(0) catalysis in a combination of solvents, THF/i-Pr 2 NEt (4:1.5), at 90 °C for 24 hours (Table S2).…”

“…All reactions were carried out under N 2 , unless otherwise mentioned. All the obtained products were characterized by 1 H NMR, 13 C NMR, mass spectrometry, and IR spectroscopy. Melting points were measured on an Electrothermal MEL-TEMP melting point apparatus.…”

“…Alkenyl sulfonates are substantial building blocks for polymer syntheses 11 and metal-catalyzed coupling reagents. 12 Although alkenyl sulfonates can be prepared through robust stoichiometric tosylation of βketo esters with TsCl and appropriate bases, 13 metal-catalyzed synthesis of alkenyl sulfonates with regio-and stereoselective control is challenging. Previous approaches relied on cationic gold to achieve hydrosulfonation of alkynes.…”