Di-2-methoxyethyl Azodicarboxylate (DMEAD): An Inexpensive and Separation-friendly Alternative Reagent for the Mitsunobu Reaction

Abstract

Di-2-methoxyethyl azodicarboxylate (DMEAD) was prepared as an alternative of DEAD or DIAD for the Mitsunobu reaction. Removal of the hydrazinedicarboxylate generated from DMEAD becomes much easier owing to the polar and water-soluble property.The Mitsunobu reaction is popular in organic synthesis to introduce an acidic nucleophile (carboxylic acid, phenol, imide, etc.) to an alcoholic function under mild conditions.2 The notable property of this reaction is complete inversion of stereochemistry at the alcoholic function. The original procedure consists of mixing an alcohol and a nucleophile with diethyl azodicarboxylate (DEAD) and triphenylphosphane at ambient temperature.3 This oxidant-reductant combination to cause dehydration in the Mitsunobu reaction is still widely used although diisopropyl azodicarboxylate (DIAD) is also conveniently employed as a more stable analogue of DEAD. A major drawback of this process is formation of two co-products, hydrazinedicarboxylate and phosphane oxide, which must be removed from the reaction mixture to isolate a target compound. Many efforts have been undertaken to solve this issue: e.g., one of the reagents is supported by polymer or solid to perform the separation by filtration, or is attached to an acidic, basic, or fluorous function to allow the separation by extraction into a basic or acidic aqueous layer or into fluorous solvent. These modifications of the original oxidant or reductant are considered to intend a separation-free or separation-friendly process. 4,5 Formation of triphenylphosphane oxide is practically insignificant matter in the separation process due to its facile crystallization in non-polar solvents. In contrast, separation of the other co-product, diethyl or diisopropyl hydrazinedicarboxylate requires highly capable column chromatography to isolate a target compound. One also often faces a problem that several side products of the hydrazinedicarboxylate cannot be removed completely from the product. In situ recycling of DEAD that makes it a catalyst is one of the solutions. 6 Total removal of the hydrazinedicarboxylate and the side-products can be performed by polymerization of norbornene units incorporated in the reagent as to be called impurity annihilation.7 Very recently, di-4-chlorobenzyl analogue was reported, 8 where the hydrazinedicarboxylate can be removed by the crystallization. We have made another approach to this issue by molecular design to enable the separation of a hydrazinedicarboxylate by extraction with neutral water. The preparation cost and handling were also considered to compete with DEAD and DIAD in the commercial source. Di-2-methoxyethyl azodicarboxylate (DMEAD) is a new reagent, which will be detailed in this report.Di-2-dimethoxyethyl hydrazinedicarboxylate (1) was prepared by mixing hydrazine hydrate and 2-methoxyethyl chloroformate in ethanol in the presence of sodium carbonate (72% yield after recrystallization, Scheme 1).9,10 Solubility of 1 is good in chloroform (0.25 g/mL) and ethyl acetate (0.1), but very poor (<0...

Redox Divergent Synthesis of Fawcettimine‐Type Lycopodium Alkaloids

“…An azonane ring of tricyclic compounds 21 a – d was constructed by intramolecular amination between primary alcohols and nosyl amides of compounds 20 a – d under Mitsunobu conditions with di‐2‐methoxyethyl azodicarboxylate (DMEAD, 1.5 equiv) 25. 28, 29…”

“…Elimination of tertiary hydroxyl groups of compounds 19 a-d readily proceeded by treatment with p-toluenesulfonic acid (20 mol %) or Amberlyst 15 to give cyclopentene derivatives 20 a-d. [27] An azonane ring of tricyclic compounds 21 a-d was constructed by intramolecular amination between primary alcohols and nosyl amides of compounds 20 a-d under Mitsunobu conditions with di-2-methoxyethyl azodicarboxylate (DMEAD, 1.5 equiv). [25,28,29] End games to lead to each alkaloid from four azonane compounds 21 a-d are shown in Schemes 4-7. Alcohol 22 produced by hydrolysis of compound 21 a was subjected to Sharpless epoxidation conditions to give b-epoxide 23 exclusively (Scheme 4).…”

Applications of Mitsunobu Reaction in total synthesis of natural products

“…After several steps, fragment 235 transformed into 236a‐d . Intermediate alkaloids, compounds 237a–d were constructed via Mitsunobu reaction of compounds 236a‐d in the presence of DMEAD and PPh 3 in THF at room temperature and lead to desired natural product Lycopodium alkaloids in several steps via different functional group transformations.…”

Radiosynthesis and bioconjugation of [18F]FPy5yne, a prosthetic group for the 18F labeling of bioactive peptides

“…23 Unfortunately, 2 was found to elute closely with reaction by-product diisopropyl hydrazine-1,2-dicarboxylate, and the two compounds could not be separated in our hands using silica gel chromatography. Presumably, alternative Mitsonubu reagents with water-soluble by-products such as di-tertbutyl azodicarboxylate (DBAD) 24 and di-2-methoxyethyl azodicarboxylate (DMEAD) 25 could be employed. In our case, however, use of these expensive reagents proved unnecessary.…”