[75-24-1]  · C3H9Al  · Trimethylaluminum-Dichlorobis(h5-cyclopentadienyl)zirconium  · (MW 72.10) (Cl2ZrCp2)

[1291-32-2]  · C10H10Cl2Zr  · Trimethylaluminum-Dichlorobis(h5-cyclopentadienyl)zirconium  · (MW 292.32)

(regioselective and stereoselective methylalumination of alkynes; regioselective carbometallation of metallated alkynes)

Physical Data: Me3Al: bp 125 °C; d 0.752 g cm-3. Cl2ZrCp2: mp 245 °C.

Form Supplied in: Me3Al: liquid, available neat or as solution in hexanes or toluene. Cl2ZrCp2: colorless crystals. Both are commercially available.

Preparative Method: obtained simply by mixing the two components.

Handling, Storage, and Precautions: Me3Al is extremely pyrophoric and must be used and stored under an inert atmosphere of N2 or Ar. Cp2ZrCl2 may be handled in air, but it appears advisable to avoid extensive exposure to air, moisture, and light. Use in a fume hood.

NMR Behavior.

The 1H NMR spectrum of a mixture of Trimethylaluminum and Dichlorobis(cyclopentadienyl)zirconium (2:1 ratio) in 1,2-dichloroethane at 30 °C, the usual conditions under which its reactions are carried out, exhibits two broad signals (half width = 4 Hz) at d -0.31 and 6.40 ppm. When this mixture is quenched with THF (2 equiv), the high-field Me signal splits into three, at d 0.25, -0.75, and -0.95, while the downfield Cp signal splits into two, at d 6.45 and 6.22. Analysis of these signals indicates that the THF-quenched mixture consists of Cl2ZrCp2, Cl(Me)ZrCp2, Me3Al.THF, and Me2AlCl.THF.1-3 Thus, under the reaction conditions, Me3Al and Cl2ZrCp2 undergo Me-Cl exchange, which is rapid on the NMR timescale, to form Cl(Me)ZrCp2 (eq 1).

Controlled Methylalumination of Alkynes.

Controlled carbometallation of alkynes provides a very selective and efficient route to trisubstituted alkenes, many of which are important building blocks of a wide variety of natural products, especially those of terpenoid origin.4 Alkynes react with organoalanes to give carbometallation products. However, with terminal alkynes, metallation of the terminal carbon atom is the major pathway, and the regioselectivity of the carbometallation product, obtained in generally poor yields, is low.5,6 With internal alkynes the reaction requires higher temperatures, at which the product of initial carbometallation competes with the trialkylalane for the alkyne.6,7 The use of transition metal complexes in conjunction with the organoalane reagent leads to a dramatic improvement of the chemo- and regioselectivity of the carboalumination reaction. Negishi and co-workers have reported that alkynes react with an organometallic reagent obtained by mixing Me3Al and Cl2ZrCp2 to give alkenyl metals in high yields.1 The reaction is not complicated by the known hydrogen abstraction of terminal alkynes with organozirconium8 or organoaluminum5,6 compounds. Studies by NMR spectroscopy have indicated that the product of carbometallation is largely an organoalane. Therefore the reaction is catalytic with respect to zirconium. Indeed, the reaction of 1 equiv of phenylacetylene with 2 equiv of Me3Al in the presence of 0.1 equiv of Cl2ZrCp2 for 12 h at 25 °C produces, after hydrolysis, a-methylstyrene in high yield.1 The stereoselectivity of the reaction is excellent (>98 % cis addition) (eq 2), as is the regioselectivity in the cases of terminal alkynes (eqs 2 and 3).1 A recent modification of the reaction conditions by using a stoichiometric amount of H2O leads to a remarkable acceleration of the reaction.9 Internal alkynes can also be stereoselectively methylaluminated in high yields (eq 4).1

The Zr-catalyzed methylalumination can accommodate various heterofunctional groups such as OH, OTBDMS, SPh, I, and TMS.10 Of particular synthetic utility are those alkynes containing heterofunctional groups in the propargylic or homopropargylic position. Interestingly, and in marked contrast with some other known carbometallation reactions of propargyl and homopropargyl derivatives,11 this reaction is very highly stereoselective (>98%) and regioselective (92-100%, except for the case of homopropargyl phenyl sulfide with which the reaction is 83% regioselective), the regioselectivity being essentially the same as that observed with simple terminal alkynes (eq 5). The yields of methylalumination products are generally in the 50-90% range. Table 1 illustrates the scope of this methylalumination reaction.

From the viewpoint of synthetic applications, alkenylalanes are very useful reagents. They react with a wide variety of electrophiles, and the C-Al bond can be readily converted into C-X (X = H, D, halogen, Hg, B, Zr, Cu, C, etc.) with essentially complete retention of stereochemistry via protonolysis,6 deuterolysis,6 halogenolysis,13 transmetallation,14 reactions with various carbon electrophiles such as ClCO2Et, CO2, (CH2O)n, ClCH2OMe,15 and epoxides16 (preferably after ate complexation), and Pd- or Ni-catalyzed cross-coupling reactions.12,17 Applications include syntheses of allylic or homoallylic alcohols,15,16 conjugated dienes or enynes,14c 1,4-dienes,12 and 1,5-dienes or enynes.18 This methodology has been applied to the synthesis of various natural products such as geraniol,15 farnesol,18 monocyclofarnesol,19 a-farnesene,12 dendrolasin,20 mokupalide,20 vitamin A,21 brassinolide,22 milbemycin,23 verrucarin,24 udoteatrial,25 and zoapatanol.26

The methylalumination of alkynes with Me3Al-Cl2ZrCp2 appears to involve direct addition of a Me-Al bond, rather than a Me-Zr bond, to alkynes via a four-centered process which is facilitated by a ZrCp2 species, as depicted in eq 6.2 However, the reaction of 1-pentynyldimethylalane with either this reagent system or preformed Cl(Me)ZrCp2 must involve direct addition of the Me-Zr bond, as depicted in eq 7.27

Methylalumination of 1-Metalloalkynes.

The methylmetallation reaction of 1-alkynes that are terminally metallated with AlMe2 or SiMe3 with Me3Al-Cl2ZrCp2 is a highly regioselective process, leading to the formation of 1,1-dimetalloalkenes (eqs 7 and 8).27,28 Whereas the reaction of alkynylsilanes gives the methylaluminated products (the reaction can proceed with a catalytic amount of Cl2ZrCp2),28 that of alkynyldimethylalanes is a methylzirconation reaction which can also be achieved by using preformed Cl(Me)ZrCp2.27 It is noteworthy that the methylalumination of 1,4-bis(trimethylsilyl)-1,3-butadiyne gives exclusively the product of trans addition.28

1,1-Dimetalloalkenes are of potential interest for the development of selective routes to tri- and tetrasubstituted alkenes through differentiation of the two metal groups. Some promising results have been obtained along this line. Thus, for example, treatment of (1) with Acetyl Chloride in the presence of Aluminum Chloride gives a 92:8 mixture of (Z)- and (E)-4-methyl-3-hepten-2-one in 61% yield.27

However, the most extensive synthetic application of these 1,1-dimetalloalkenes to date is the synthesis of cycloalkenylmetals. Treatment of 1-(trimethylsilyl)-4-bromo-1-butyne with Me3Al (2 equiv) in the presence of Cl2ZrCp2 (1 equiv) in (CH2Cl)2 at 25 °C gives a cyclobutene (2) in 92% yield after 6 h, rather than the expected methylmetallation product (eq 9).29

The reaction evidently involves the intermediacy of the methylalumination product shown in eq 9. A p-type cyclization involving the intermediacy of a cyclopropylcarbinyl species must be operating,29 since (1) alkylation of alkenylalanes with alkyl halides does not occur under comparable conditions, (2) the Zr-catalyzed methylalumination is known to give exclusively or predominantly cis addition products which are wrong isomers for a s-type cyclization, and (3) the reaction is regioselective but nonregiospecific (eq 10).30 These results are consistent with the mechanism shown in eq 11.

The reaction is not limited to the formation of four-membered rings. The methylalumination reaction of 1-(trimethylsilyl)-6-bromo-1-hexyne gives 1-(trimethylsilyl)-1-cyclohexene as the major product.31 On the other hand, the corresponding reaction of 1-(trimethylsilyl)-5-bromo-1-pentyne gives only the noncyclized methylalumination product.31

Synthetically more attractive is the reaction of o-halo-1-alkynylalanes (3) with Me3Al-Cl2ZrCp2, which gives the corresponding cycloalkenylmetals (4), readily convertible to a wide variety of cyclobutenyl derivatives (eq 12).30 The same method can be applied to the synthesis of cyclopentenyl or cyclohexenyl analogs of (4), such as (5) and (6), in good yields.32

Ziegler-Natta Polymerization of Alkenes.

Some reagent systems consisting of methylaluminum and zirconocene derivatives have been used as homogeneous Ziegler-Natta polymerization catalysts. Satisfactory activity levels have been attained through the use of an additional component. For example, the use of Al2O3, MgCl2, or SiO2-supported Cl2ZrCp2 with Me3Al promotes the polymerization of propene with a fairly good activity.33 The most satisfactory Cl2ZrCp2-based system known to date makes use of methylaluminoxanes which are obtained by controlled hydrolysis of Me3Al.34

1. (a) Van Horn, D. E.; Negishi, E. JACS 1978, 100, 2252. (b) Negishi, E.; Van Horn, D. E. Organomet. Synth. 1986, 3, 467. (c) For a review see: Negishi, E. PAC 1981, 53, 2333.
2. Yoshida, T.; Negishi, E. JACS 1981, 103, 4985.
3. Negishi, E.; Van Horn, D. E.; Yoshida, T. JACS 1985, 107, 6639.
4. Devon, T. K.; Scott, A. I. Handbook of Naturally Occurring Compounds; Academic: New York, 1972 and 1975; Vols. 1 and 2.
5. Mole, T.; Surtees, J. R. AJC 1964, 17, 1229.
6. Mole, T.; Jeffrey, E. A. Organoaluminum Compounds; Elsevier: Amsterdam, 1972; Chapter 11.
7. Wilke, G.; Muller, H. LA 1960, 629, 222.
8. Wailes, P. C.; Weigold, H.; Bell, A. P. JOM 1971, 33, 181.
9. Wipf, P.; Lim, S. AG(E) 1993, 32, 1068.
10. (a) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. JOC 1981, 46, 4093. (b) Negishi, E.; Luo, F.-T.; Rand, C. L. TL 1982, 23, 27.
11. (a) Normant, J. F.; Alexakis, A. S 1981, 841. (b) Normant, J. F. JOM. Libr. 1976, 1, 219. (c) Brown, D. C.; Nichols, S. A.; Gilpin, A. B.; Thompson, D. W. JOC 1979, 44, 3457.
12. (a) Matsushita, H.; Negishi, E. JACS 1981, 103, 2882. (b) Negishi, E.; Matsushita, H. OS 1984, 62, 31.
13. (a) Negishi, E.; Van Horn, D. E.; King, A. O.; Okukado, N. S 1979, 501. (b) Zweifel, G.; Whitney, C. C. JACS 1967, 89, 2753.
14. (a) With HgCl2: Negishi, E.; Jadhav, K. P.; Daotien, N. TL 1982, 23, 2085. (b) With B-methoxy-9-borabicyclo[3.3.1]nonane or X2ZrCp2: Negishi, E.; Boardman, L. D. TL 1982, 23, 3327. (c) With ZnCl2: Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I. JACS 1978, 100, 2254. (d) To alkenylcopper: Wipf, P.; Smitrovich, J. H.; Moon, C.-W. JOC 1992, 57, 3178. (e) Ireland, R. E.; Wipf, P. JOC 1990, 55, 1425.
15. Okukado, N.; Negishi, E. TL 1978, 2357.
16. Kobayashi, M.; Valente, L. F.; Negishi, E.; Patterson, W.; Silveira, A., Jr. S 1980, 1034.
17. (a) Negishi, E.; Matsushita, H.; Okukado, N. TL 1981, 22, 2715. (b) Matsushita, H.; Negishi, E. JCS(C) 1982, 160. (c) Chatterjee, S.; Negishi, E. JOC 1985, 50, 3406.
18. Negishi, E.; Valente, L. F.; Kobayashi, M. JACS 1980, 102, 3298.
19. Negishi, E.; King, A. O.; Klima, W. L.; Patterson, W.; Silveira, A., Jr. JOC 1980, 45, 2526.
20. Kobayashi, M.; Negishi, E. JOC 1980, 45, 5223.
21. Negishi, E.; Owczarczyk, Z. TL 1991, 32, 6683.
22. (a) Fung, S.; Siddall, J. B. JACS 1980, 102, 6580. (b) Mori, K.; Sakakibara, M.; Okada, K. T 1984, 40, 1767.
23. Williams, D. R.; Barner, B. A.; Nishitani, K.; Phillips, J. G. JACS 1982, 104, 4708.
24. Roush, W. R.; Blizzard, T. A. JOC 1983, 48, 758; 1984, 49, 1772, 4332.
25. Whitesell, J. K.; Fisher, M.; Jardine, P. D. S. JOC 1983, 48, 1556.
26. Cookson, R. C.; Liverton, N. J. JCS(P1) 1985, 1589.
27. Yoshida, T.; Negishi, E. JACS 1981, 103, 1276.
28. (a) Kusumoto, T.; Nishide, K.; Hiyama, T. CL 1985, 1409. (b) Kusumoto, T.; Nishide, K.; Hiyama, T. BCJ 1990, 63, 1947.
29. Negishi, E.; Boardman, L. D.; Tour, J. M.; Sawada, H.; Rand, C. L. JACS 1983, 105, 6344.
30. Boardman, L. D.; Bagheri, V.; Sawada, H.; Negishi, E. JACS 1984, 106, 6105.
31. Negishi, E.; Boardman, L. D.; Sawada, H.; Bagheri, V.; Stoll, A. T.; Tour, J. M.; Rand, C. L. JACS 1988, 110, 5383.
32. Negishi, E.; Sawada, H.; Tour, J. M.; Wei, Y. JOC 1988, 53, 913.
33. Soga, K.; Kaminaka, M. Makromol. Chem. 1993, 194, 1745.
34. (a) Kaminsky, W.; Steiger, R. Polyhedron 1988, 7, 2375. (b) Kaminsky, W.; Miri, M.; Sinn, H.; Woldt, R. Makromol. Chem., Rapid Commun. 1983, 4, 417.

Ei-ichi Negishi & Danièle Choueiry

Purdue University, West Lafayette, IN, USA

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