Lithium 1-Methyl-2-(2-methyl-1-(E)-propenyl)cyclopropyl(phenylthio)cuprate

(E)

[87084-08-0]  · C14H18CuLiS  · Lithium 1-Methyl-2-(2-methyl-1-(E)-propenyl)cyclopropyl(phenylthio)cuprate  · (MW 288.88)

(intermediate for the synthesis of natural products, terpenes, and substrates for Cope rearrangement, divinylcyclopropane and [3,3]-sigmatropic shift studies)

Preparative Methods: to a stirred solution of 1.03 g (5.4 mmol) of 1-bromo-1-methyl-2-(2-methyl-1-propenyl)cyclopropane in 50 mL of dry THF-ether (1:1) at -78 °C under nitrogen was added dropwise a solution of t-Butyllithium (10.8 mmol) in pentane. After the pale yellow solution had been stirred at -78 °C for 30 min, 0.93 g (5.4 mmol) of Phenylthiocopper(I) was added from a bent tube attached to the reaction flask. The suspension was warmed to -20 °C and stirred for 30 min, which gave a red brown solution of the cuprate. The solution was cooled to -78 °C for addition to the iodo enone.2

Handling, Storage, and Precautions: best used immediately following its preparation. THF and ether need to be anhydrous (distill from sodium benzophenone). Air and moisture should be excluded.

The title reagent (4m) and the related reagents (1-5) shown in Table 12-12 are generally used to prepare divinylcyclopropanes that undergo Cope rearrangements to form seven-membered rings (eq 1). Formation and rearrangement of (7) is nearly quantitative, yielding a single product (8), which was converted to (±)-b-himachalene. In this case, the trans cuprate gave excellent results, but in certain other cases a cis cuprate is desirable1,7 (see below).

Preparation of Vinylcyclopropyl Bromides and their Organolithium Derivatives.

The bromides corresponding to reagents (1h) and (4h) were prepared by adding the dibromocarbene to butadiene and then replacing one bromide (eq 2). Treatment of (9) with t-butyllithium and then either Hydrogen Bromide or Iodomethane gives mixtures of products with the trans isomer predominating4,5 (see Table 1 for ratios). The cis and trans bromides are separable by spinning band distillation. Dibromide reduction with Tri-n-butylstannane or Zinc-Acetic Acid gives mixtures with the cis isomer predominating.6 -9 The reaction of (10) with t-butyllithium produces (1h) and (4h) (M = Li) which can then be converted to the cuprate using CuBr2.SMe2 or PhSCu. Starting with 2-methylbutadiene leads to (3) in the same way.11 The lithium reagent (3) (M = Li) was converted to the more selective MgBr variant by treatment with Magnesium Bromide.

To obtain a substituted vinyl group,4,5 acrolein acetal (11) was converted to the dibromide (12), which reacts with ethylidenetriphenylphosphorane or Diethyl Phenylthiomethylphosphonate to form (13) (eq 3). Treatment with t-butyllithium followed by HBr formed the monobromide and then reaction with t-butyllithium produced (1m) or (1s).

A highly stereoselective synthesis7 of (2c) and (2t) starts with dibromocarbene addition to the THP derivative of 3-methyl-2-buten-1-ol to produce (14) (eq 4). Hydrolysis of the THP ether, Pyridinium Chlorochromate oxidation, and Wittig alkenation results in (15b), which undergoes Zn/acetic acid reduction to selectively form cis-bromide (16). Treatment of (14) with n-BuLi gives only trans-bromide (17), which was converted to trans-bromide (19) by hydrolysis, PCC oxidation, and Wittig reaction. Both (16) and (19) were converted to thiophenylcuprates in the same way as the title compound.

In a similar way (eq 5),2 acetal (20) was transformed into (21) which was treated with n-BuLi/MeI in HMPA-THF to selectively make (22). The mixture (ca. 90% trans) could be separated by chromatography and crystallization. Hydrolysis of the acetal in formic acid followed by Wittig reaction with Isopropylidenetriphenylphosphorane generated the bromide needed to produce the trans cuprate (4m) (M = PhSCuLi).

Bromoenone (23) and Me2SCH2CO2Et have been combined12 to form (24) (eq 6), which was elaborated to (25) by a five-step sequence. Bromide (25) was converted to (5) (M = Li) using t-butyllithium.

Stereochemistry of Divinylcyclopropane Rearrangements.

For reagents (1)-(5), the cis isomers lead to the cis-divinylcyclopropanes that are excellent substrates for the Cope rearrangement. However, in many cases the trans-divinylcyclopropane works sufficiently well that separating cis and trans isomers is not necessary.1 In certain compounds where the Cope rearrangement is disfavored by steric factors, cis to trans isomerization and 1,5-shifts compete with the Cope rearrangement.7 In one such case (eq 7), an ingenious simultaneous photolysis/thermolysis overcame these side reactions and gave a high yield of Cope product from a cis/trans mixture.13

Choice of Organometallic Reagent.

The cuprate reagents (1), (2), and (4) have been used effectively for coupling reactions with b-iodoenones,2,7,9,10 e.g. (6) or 2-iodomethylenecyclohexanone, acyl chlorides6,8 (followed by conversion to the silyl enol ether), propargyl ketones,5 and propargyl esters.5 The phenylthiocuprates are efficient for transfer of secondary and tertiary cyclopropyl compounds and are readily made from Phenylthiocopper(I).14 The lithium reagents add in 1,2-fashion to b-alkoxy enolates3,5,15 to form some of the same compounds available from the cuprate route exemplified in eq 1. For example (eq 8), 3-methoxy-2-methylcyclopentanone gives products similar to (7).

They can also be used to add to aldehydes or ketones (eq 9); the resultant alcohol group can then be used to form the second vinyl group. Scopadulcic acid-B has been prepared11 using this approach with (3) (M = MgBr). The lithium reagent (3) (M = Li) was found to attack the aryl iodide of the starting aldehyde. Some of the lithium reagents have also been used to prepare chromium carbene complexes.16


1. (a) Piers, E. COS 1991, 5, 971. (b) Hudlicky, T.; Fan, R.; Reed, J. W.; Gadamasetti, K. G. OR 1992, 41, 1.
2. Piers, E.; Ruediger, E. H. CJC 1983, 61, 1239.
3. Wender, P. A.; Filosa, M. P. JOC 1976, 41, 3490.
4. Marino, J. P.; Browne, L. J. TL 1976, 3241.
5. Marino, J. P.; Browne, L. J. TL 1976, 3245.
6. Piers, E.; Burmeister, M. S.; Reissig, H.-U. CJC 1986, 64, 180.
7. Piers, E.; Morton, H. E.; Nagakura, I.; Thies, R. W. CJC 1983, 61, 1226.
8. Piers, E.; Reissig, H.-U. AG(E) 1979, 18, 791.
9. Piers, E.; Nagakura, I. TL 1976, 3237.
10. Piers, E.; Nagakura, I.; Morton, H. E. JOC 1978, 43, 3630.
11. Overman, L. E.; Ricca, D. J.; Tran, V. D. JACS 1993, 115, 2042.
12. Wender, P. A.; Hillemann, C. L.; Szymonifka, M. J. TL 1980, 21, 2205.
13. Wender, P. A.; Eissenstat, M. A.; Filosa, M. P. JACS 1979, 101, 2196.
14. Posner, G. H.; Brunelle, D. J.; Sinoway, L. S 1974, 662.
15. Murata, I.; Sugihara, Y.; Sugimura, T.; Wakabayashi, S. T 1986, 42, 1745.
16. Tumer, S. U.; Herndon, J. W.; McMullen, L. A. JACS 1992, 114, 8394.

Richard W. Thies

Oregon State University, Corvallis, OR, USA



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