Nonsymmetrical Azocarbonamide Carboxylates as Effective Mitsunobu Reagents

Abstract

A family of nonsymmetrical Mitsunobu reagents possessing both dialkyl amide and ester substituents was developed. These new reagents were readily prepared in a single pot from inexpensive, commercially available materials by using a scalable and environmentally friendly procedure. They were shown to exhibit activity parallel to that of diethyl azodicarboxylate/diisopropyl azodicarboxylate in a wide variety of Mitsunobu reactions. Importantly, the acyl hydrazine reaction byproducts were readily separable from the crude mixture by standard aqueous workup. In addition, the discovery of effective nonsymmetrical Mitsunobu reagents offers new directions for the ongoing development of this important reaction.

Synthesis and pharmacological characterization of the selective GluK1 radioligand (S)-2-amino-3-(6-[3H]-2,4-dioxo-3,4-dihydrothieno[3,2-d]pyrimidin-1(2H)-yl)propanoic acid ([3H]-NF608)

“…(11) was synthesized according to literature procedure. 13 (S)-3-(6-Bromo-2,4-dioxo-3,4-dihydrothienoij3,2-d]pyrimidin-1IJ2H)-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (12). A solution of 6-bromothienoij3,2-d]pyrimidine-2,4IJ1H,3H)-dione (11) (581 mg, 2.35 mmol) in anhydrous DMF (11.4 mL) was cooled to 0 °C and then sodium hydride (60% w/w in mineral oil, 85 mg, 2.14 mmol) was added.…”

The Goldilocks Principle in Phase Labeling. Minimalist and Orthogonal Phase Tagging for Chromatography-Free Mitsunobu Reaction

“…Alternatively, efforts have been made to modify both the azocarboxylate and phosphine reactants with phase labels to facilitate the removal of the excess and spent reagents in the purification process . Various approaches have been explored, including soluble and insoluble supports and fluorous and ionic tagging. − Despite promising advances in chromatography-free Mitsunobu methods, the relatively high cost of the modified reagents and/or their often tedious synthesis limit their widespread utility both at laboratory and industrial scales. The work we report herein was prompted by the desire to address this gap in practicality; thus, inexpensive and easily accessible phase-labeled Mitsunobu reagents were targeted.…”

Advances and mechanistic insight on the catalytic Mitsunobu reaction using recyclable azo reagents

“…Although it is predicted that Michael-type addition of triphenylphosphine to ethyl 2-arylazocarboxylates (an attack to N2) takes place to form betaines, 28 the formation of other intermediary structures should be considered. Unlike for the symmetric DEAD, 29 the issue of the regiochemistry of the triphenylphosphine attack to ethyl 2-arylazocarboxylates is raised as a consequence of their non-symmetric nature and the potential electrophilicity of the azo benzene derivatives toward triphenylphosphine. 30 , 31…”