Lithium (3,3-Diethoxy-1-propen-2-yl)(phenylthio)cuprate1

[57428-24-7]  · C13H18CuLiO2S  · Lithium (3,3-Diethoxy-1-propen-2-yl)(phenylthio)cuprate  · (MW 308.87)

(a-bromoacrolein-derived heterocuprate capable of nucleophilic additions and substitutions;2 useful in the preparation of a-methylene-g-butyrolactones3)

Alternate Name: lithium [(a-diethoxymethyl)vinyl](phenylthio)cuprate.

Solubility: prepared as a solution in ether; presumably can also be prepared in THF.

Analysis of Reagent Purity: an assay to determine relative thermal stabilities4 can be used to estimate reagent quality and concentration: a sample of known volume and temperature is quenched with excess PhCOCl. The yield of phenyl ketone is measured by GC, the response of which is calibrated using authentic product and n-dodecane as internal standard.

Preparative Methods: preparation of the heterocuprate5 requires synthesis of 2-bromo-3,3-diethoxypropene,6 which can be obtained from the widely available diethyl acetal of acrolein via bromination-dehydrobromination. Under an inert atmosphere of nitrogen or argon, a 0 °C solution of distilled Thiophenol in anhydrous ether is treated with 1 equiv of n-Butyllithium. The resultant solution is transferred to a room-temperature suspension of 1 equiv of Copper(I) Iodide in anhydrous ether under nitrogen or argon, to provide a yellow suspension of Phenylthiocopper(I); this suspension is cooled to -78 °C. In a separate flask under nitrogen or argon at -78 °C, 1 equiv of 2-bromo-3,3-diethoxypropene in anhydrous ether is treated dropwise with 1 equiv of n-BuLi; the 3,3-diethoxy-2-lithiopropene7 that results is added dropwise to the -78 °C solution of PhSCu. The heterocuprate that forms is typically reacted with electrophiles at -78 °C with subsequent warming to -40 °C. Modifications using other sources of PhSCu may be acceptable.8

Handling, Storage, and Precautions: best results are obtained with high purity copper(I) salts,9 dry, oxygen-free solvents, and alkyllithium solutions free of contaminating alkoxides or hydroxides.10 n-BuLi is used to prepare the intermediate reagents lithium thiophenoxide and 3,3-diethoxy-2-lithiopropene, and is pyrophoric;11 due care must be exercised in its handling. Thermal decomposition occurs at &egt;-40 °C. Use in a fume hood.


This vinylic organometallic reagent is representative of the heterocuprate class of organocopper reagents. The vinylic group is reactive as a nucleophile, whereas the SPh group is not. Such nontransferable groups are called dummy ligands;12 the SPh dummy ligand in particular is typically found to provide enhanced thermal stability and solubility compared to the analogous homocuprate. Heterocuprates generally exhibit less nucleophilic reactivity than the corresponding homocuprates; however, increased thermal stabilities coupled with greater efficiency in use of the transferable ligand make them reasonable alternative reagents. This is particularly true when relatively high reaction temperatures are required, or when the organolithium used to form the cuprate is difficult or expensive to prepare.

Lithium (3,3-diethoxy-1-propen-2-yl)(phenylthio)cuprate can be used to prepare a variety of 2-substituted propenoic acid derivatives, especially a-methylenelactones. The reagent, along with cognate mixed homocuprate reagents, is generally considered to be superior to analogous (ethoxycarbonyl)vinylcuprate reagents. These latter reagents usually undergo 1,2- as opposed to expected 1,4-additions to a,b-unsaturated carbonyl compounds.13

Nucleophilic Substitutions of Halides.

Although unreactive with benzyl bromide and vinyl iodides, lithium (3,3-diethoxy-1-propen-2-yl)(phenylthio)cuprate undergoes clean substitutions with allylic bromides5 to afford 1,4-dienes (eq 1). The mixed homocuprate Lithium (3,3-Diethoxy-1-propen-2-yl)(3,3-dimethyl-1-butynyl)cuprate provides similar results.14

1,4-Additions to 2-Alkenones.

The reagent undergoes 1,4-addition to cyclohexenone, cyclopentenone, and 3-penten-2-one in 50-80% chemical yields in diethyl ether; the use of THF greatly diminishes formation of 1,4-adducts.5 A comparative study indicates that mixed homocuprates, especially lithium (3,3-diethoxy-1-propen-2-yl)(3,3-dimethyl-1-butynyl)cuprate, are the reagents of choice in 1,4-additions (eq 2).14

1,4-Adduct (1) has been used to prepare a-methylene-d-valerolactones (eq 3),5 common structural motifs in marine cembranolides.3a If a 4-trimethylsilyloxy- or 4-t-butyldimethylsilyloxy-2-cycloalkenone is used as substrate for the 1,4-addition, trans-a-methylene-g-butyrolactones can be prepared;14 this strategy utilizes the steric control effect of the 4-silyloxy substituent, which causes the nucleophile to attack at the opposing face of the double bond.

Additions to Epoxides.

Although the phenylthiocuprate is reported to be unreactive with cyclohexene epoxide, the homocuprate Lithium Bis(3,3-diethoxy-1-propen-2-yl)cuprate and mixed homocuprate lithium (3,3-diethoxy-1-propen-2-yl)(3,3-dimethyl-1-butynyl)cuprate undergo both 1,2- and 1,4-additions to cycloalkadiene monoepoxides (eq 4).15 1,4-Addition is distinctly favored when diethyl ether is used as solvent. The hydroxyacetal adducts can be used in the stereospecific construction of a-methylene-g-butyrolactones of 1,3-diols. For example, when (2) is isolated from (3) by vacuum distillation, transacetalization affords a cyclic mixed acetal. Upon oxidation with Jones reagent, the corresponding trans-a-methylene-g-butyrolactone is isolated (eq 5). If 1,4-adduct (3) is hydrolyzed, the resultant aldehyde can be oxidized to its corresponding acid; iodolactonization provides a cis-a-methylene-g-butyrolactone (eq 6).

Other potential methods to prepare 2-substituted propenoic acid derivatives include Pd-catalyzed formylation of vinyl iodides and vinyl triflates16 and hydrocupration of alkyl propiolates using Hexa-m-hydrohexakis(triphenylphosphine)hexacopper.17

Related Reagents.

3,3-Diethoxy-1-propen-2-ylcopper; Lithium Bis(3,3-diethoxy-1-propen-2-yl)cuprate; and Lithium (3,3-Diethoxy-1-propen-2-yl)(3,3-dimethyl-1-butynyl)cuprate; for related heterocuprates, see Lithium Methyl(phenylthio)cuprate; for discussion of lithium dialkylcuprates, see Lithium Dimethylcuprate.

1. (a) Lipshutz, B. H.; Sengupta, S. OR 1992, 41, 135. (b) Posner, G. H. An Introduction to Synthesis Using Organocopper Reagents; Wiley: New York, 1980.
2. (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon: New York, 1992. (b) Kozlowski, J. A. COS 1991, 4, 169. (c) Hulce, M.; Chapdelaine, M. J. COS 1991, 4, 237. (d) Chapdelaine, M. J.; Hulce, M. OR 1990, 38, 225. (e) Posner, G. H. OR 1975, 22, 253. (f) Posner, G. H. OR 1972, 19, 1.
3. For a recent review: Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. S 1986, 157. As components in total syntheses of natural products: (a) Marshall, J. A. In Studies in Natural Products Chemistry; Rahman, A.-u., Ed.; Elsevier: New York, 1992; Vol. 10, p 3. (b) McMurray, J. E.; Dushin, R. G. In Studies in Natural Products Chemistry; Rahman, A.-u., Ed.; Elsevier: New York, 1991; Vol. 8, p 15.
4. Bertz, S. H.; Dabbagh, G. CC 1982, 1030.
5. Grieco, P. A.; Wang, C.-L. W.; Majetich, G. JOC 1976, 41, 726.
6. Claisen, L. CB 1898, 31, 1015.
7. Ficini, J.; Depezay, J.-C. TL 1969, 4797.
8. (a) For preparation of PhSCu in THF, see Corey, E. J.; Boger, D. L. TL 1978, 4597. (b) PhSCu in purities of 95->98% is commercially available.
9. Purification methods: (a) Posner, G. H.; Sterling, J. J. JACS 1973, 95, 3076. (b) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: New York, 1988; p 322. (c) Lipshutz, B. H.; Whitney, S.; Kozlowski, J. A.; Breneman, C. M. TL 1986, 27, 4273.
10. Corey, E. J.; Naef, R.; Hannon, F. J. JACS 1986, 108, 7114.
11. Wakefield, B. J. Organolithium Methods; Academic: New York, 1988; pp 11-15.
12. Lipshutz, B. H. SL 1990, 119.
13. Marino, J. P.; Floyd, D. M. TL 1975, 3897.
14. Boeckman, R. K. Jr.; Ramaiah, M. JOC 1977, 42, 1581.
15. Marino, J. P.; Farina, J. S. JOC 1976, 41, 3213.
16. (a) Baillargeon, V. P.; Stille, J. K. JACS 1986, 108, 452. (b) Schoenberg, A.; Heck, R. F. JACS 1974, 96, 7761.
17. Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. JACS 1988, 110, 291.

Martin Hulce

Creighton University, Omaha, NE, USA

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