Lithium Chloride-Diisopropylethylamine

LiCl-i-Pr2NEt
(LiCl)

[7447-41-8]  · ClLi  · Lithium Chloride-Diisopropylethylamine  · (MW 42.39) (i-Pr2NEt)

[7087-68-5]  · C8H19N  · Lithium Chloride-Diisopropylethylamine  · (MW 129.28)

(lithium salt-amine base combination for Horner-Wadsworth-Emmons alkenation; alkylation of b-keto esters; palladium-catalyzed cross-couplings)

Physical Data: see Lithium Chloride and Diisopropylethylamine.

Handling, Storage, and Precautions: the combination reagent is prepared in situ; use in a fume hood; see Lithium Chloride and Diisopropylethylamine for handling of each reagent.

Horner-Wadsworth-Emmons Alkenation.

The combination of LiCl and DIPEA (1:1 molar ratio) finds utility in the Horner-Wadsworth-Emmons alkenation involving base-sensitive compounds.1 Treatment of aliphatic, a,b-unsaturated, and aromatic aldehydes with Triethyl Phosphonoacetate and LiCl-DIPEA (or 1,8-Diazabicyclo[5.4.0]undec-7-ene) in acetonitrile leads to high yields of (E) isomeric unsaturated esters (eq 1).

Treatment of the base-sensitive phosphonate (1) and aldehyde (2) with LiCl-DIPEA in acetonitrile at rt for 24 h affords the ketone (3) in high yields, with no evidence of epimerization at the a-position or self-condensation of the aldehyde (eq 2). Use of Sodium Hydride or Potassium t-Butoxide leads to much lower yields (0-34%).

b-Keto Ester Alkylations.

Ethyl Acetoacetate and Diethyl Malonate are monoalkylated in high yields using a 1:2 mixture of LiCl-DIPEA with Benzyl Bromide (1 equiv) in refluxing THF (eq 3).2 The presence of the lithium cation is critical for a successful alkylation. Replacement of the lithium salt by NaCl or KCl leads to no alkylation products.3 O-Alkylation does not take place under these reaction conditions; however, dialkylation occurs using acetonitrile as solvent. Acetylacetone does not alkylate under these reaction conditions.

Cross-Couplings.

The optimal conditions for a successful palladium-catalyzed cross-coupling between aryl halides and unsaturated epoxides involve 10% Palladium(II) Acetate, n-Bu4NCl (1 equiv), lithium formate (3 equiv), and the combination of LiCl (1 equiv) and DIPEA (3 equiv) at 50 °C in DMF. Following these optimized reaction conditions, the cross-coupling of iodobenzene and 4,5-epoxy-1-hexene (4) leads to a 79:21 mixture of (E):(Z) allylic alcohols (5) in 78% yield (eq 4).4 The mechanism involves a palladium migration process.


1. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T. TL 1984, 25, 2183.
2. Yoo, S.-E.; Yi, K. Y. Bull. Korean Chem. Soc. 1989, 10, 112.
3. For the role played by the lithium cation see: (a) Bottin-Strzalko, T.; Corset, J.; Froment, F.; Pouet, M.-J.; Seyden-Penne, J.; Simonnin, M.-P. JOC 1980, 45, 1270. (b) Cambillau, C.; Bram, G.; Corset, J.; Riche, C.; Pascard-Billy, C. T 1978, 34, 2675.
4. Larock, R. C.; Leung, W.-Y. JOC 1990, 55, 6244.

Kirk L. Sorgi

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA



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