[37494-03-4] · C7H15LiO2 · 3-(1-Ethoxyethoxy)propyllithium · (MW 138.14)
(nucleophilic organolithium reagent used as synthetic equivalent of 3-hydroxypropyl anion)
Solubility: normally prepared in diethyl ether and used in situ.
Handling, Storage, and Precautions: organolithium reagent sensitive to moisture; normally used immediately, but filtered 1 M solutions may be stored for months at -30 °C.
This reagent (referred to below as EEOPrLi), like the analogous Grignard reagent, is normally used in synthetic chemistry as a synthon for the 3-hydroxypropyl anion. The reagent, developed by Eaton for this purpose and first reported in 1972,1 is normally prepared in ca. 1 M ethereal solution by treatment of the bromide with Lithium wire or shot at ca. -5 to -15 °C after initiation at room temperature. The cloudy solution may be used immediately, or may be passed through a sintered glass funnel to give a crystal clear solution which may be stored at -30 °C for months. At room temperature, slow decomposition occurs to give cyclopropane, among other products. The 3-(1-ethoxyethoxy)propyl bromide starting material may be prepared on a large scale by the dichloroacetic acid catalyzed solvent-free addition of acid-free 3-bromopropanol to Ethyl Vinyl Ether.
Addition of the prepared reagent, unlike its Grignard counterpart,1 takes place readily to ketones and aldehydes at 0 °C or lower under typical conditions for organolithium reagents. Treatment with aqueous acid or Pyridinium p-Toluenesulfonate after simple workup readily induces hydrolysis to liberate the free alcohol together with the volatile byproducts ethanol and acetaldehyde and without affecting the newly introduced tertiary alcohol. Heating with acid causes cyclodehydration to produce the tetrahydrofuran, while simple oxidation, for example with Chromium(VI) Oxide, generates the g-lactone.1,2 These transformations are illustrated for cyclohexanone (eq 1).
Eaton has used the addition to 2-octanone followed by hydrolysis and oxidation to the g-lactone in his synthesis of dihydrojasmone (eq 2).1
The reagent has also been shown to add to lactones, addition to g-caprolactone followed by hydrolysis with HCl leading to cyclization to spiroacetals (eq 3).3
Addition to substituted pyridines takes place to give the 2-(3-hydroxypropyl) derivatives, both in rearomatized form after aerial oxidation (eq 4)4 and as the dihydropyridine by trapping with Ethyl Chloroformate (eq 5).5
Epoxides are also successful electrophiles,6 a reaction elegantly exemplified in a synthesis of brefeldin A in optically pure form. The synthesis involves addition of 3-(1-ethoxyethoxy)propyllithium to (S)-Propylene Oxide and trapping of the alkoxide with Benzyl Bromide (eq 6).7 Uncommonly for this reagent, the reaction is carried out in THF.
It is perhaps worth noting that 3-(1-ethoxyethoxy)propyllithium has also been used in the surface modification of poly(chlorotrifluoroethylene) films.8 These authors comment that generation of the reagent in heptane solution is much more rapid than in ether.
The related dialkyl lithium cuprate reagent, also developed by Eaton,1 undergoes efficient conjugate addition to a,b-unsaturated ketones at low temperature (e.g. eq 7).9 Eaton has used this reaction to prepare a key intermediate in his synthesis of peristylane.1,10 The cuprate reagent has also been shown to displace halide from primary alkyl iodides, as does the simple lithium reagent in the presence of catalytic quantities of CuI. This reaction was used to prepare gossyplure, the pink bollworm sex pheromone mixture (eq 8).11
Philip C. Bulman Page & Andrew Lund
University of Liverpool, UK