No abstract

No abstract

The "bottom-up" approach to development of direct-drop processes is a powerful, yet simple, strategy that every process chemist should consider for the development of efficient, costeffective, and environmentally friendly processes. This approach is aided by a "parallel crystallization" technique, which allows for rapid identification of multiple solvent systems for the crystallization of the desired product using a minimal amount of material and solvent. This "bottom-up" approach is illustrated by several examples where the desired product is crystallized directly from the reaction mixture.

A practical, safe, and high-yielding process for the cyclopropanation of a chiral epoxide has been developed using the inexpensive and nonhazardous reagents triethylphosphonoacetate and sodium tert-butoxide. IntroductionCyclopropane ring systems are ubiquitous in nature and are contained in a large number of natural products, insecticides, and pharmaceutical drug candidates. 1 In conjunction with our work on the melatonergic agent 1 2 (Scheme 1), we needed to develop a cost-effective process for the large-scale preparation of the enantiomerically pure transcyclopropane carboxylic acid 2b.The reaction of epoxides with the anion of triethylphosphonoacetate (TEPA) in the synthesis of cyclopropane derivatives has been known for over four decades, 3 and there has been occasional additional application of the reaction between epoxides and phosphonates (either R-phosphono esters or phosphono ketones). 4 However, the utility of this reaction for the large-scale preparation of cyclopropane derivatives has not been explored. We were attracted toward developing the use of TEPA for the conversion of 3 to 2a due to its low cost, ease of availability and handling onscale. Most of the cited procedures use NaH as the base and afford the cyclopropane derivatives in fair yields (20-60%). Therefore, to make such a procedure scale-worthy, we needed to find a suitable substitute for NaH (dust hazard, hydrogen evolution, moisture sensitivity, etc.) and to identify reaction conditions to significantly improve the overall yield of the reaction.Herein, we wish to report the development of a safe, practical, and high-yielding process for the conversion of 3 to 2a by using the chemistry of TEPA anion and subsequent isolation of 2b.

No abstract