Titanium(III) Chloride-Lithium Aluminum Hydride1


[7705-07-9]  · Cl3Ti  · Titanium(III) Chloride-Lithium Aluminum Hydride  · (MW 154.23) (LiAlH4)

[16853-85-3]  · AlH4Li  · Titanium(III) Chloride-Lithium Aluminum Hydride  · (MW 37.96)

(reagent combination for the production of low-valent titanium which is used for the inter- and intramolecular reductive coupling of carbonyl and dicarbonyl compounds, as well as reductive elimination reactions)

Physical Data: see Titanium(III) Chloride and Lithium Aluminum Hydride.

Solubility: THF and DME are the favored solvents for reactions involving low-valent titanium.

Form Supplied in: a 4:1 ball-milled mixture of TiCl3 and LiAlH4 is available, which serves as a precursor to the McMurry reagent.

Handling, Storage, and Precautions: most commonly, low-valent titanium species are prepared, under an inert atmosphere (nitrogen or argon), immediately prior to use. Presumably the reagent is pyrophoric, although this property may be due to the residual reducing agent used in the preparation process rather than an inherent property of Ti0/TiI itself. The reagent is moisture sensitive.

Reductive Coupling Reactions.2-14

The combination of TiCl3 and LiAlH4 produces the McMurry reagent which has been one of the most popular of the low-valent titanium reagents (see Titanium) employed for reductive coupling of carbonyls to alkenes. Depending on the molar ratio of TiCl3 to LiAlH4 used, either TiI or Ti0 is produced. It has been suggested that the optimum ratio of TiCl3 to LiAlH4 for coupling is 2:1.3 Crossed intermolecular reductive couplings of two different carbonyl compounds are readily effected by this reagent if one of the components, often acetone, is used in excess (eq 1).4

The McMurry coupling reaction has provided a means for the synthesis of a range of novel hydrocarbons,1 including strained alkenes,5 and torsionally distorted systems (eq 2).6 When the illustrated reaction is carried out in a chiral solvent, the (±)-isomer is produced preferentially.

Intramolecular couplings of a wide range of a,o-diketones are readily effected by TiCl3/LiAlH4 and even highly strained cyclopropenes can be prepared (eq 3).7 However, it is generally found that the Titanium(III) Chloride-Zinc/Copper Couple reagent is more effective for such intramolecular processes.

These cyclocoupling processes have been extended to keto esters and keto acids,8 with the resulting formation of cycloalkanones. Such a conversion has been employed as the key step in the synthesis of a ring-fused cyclononanone (eq 4), a precursor to the natural product isocaryophyllene.9 Interestingly, accompanying the cyclization process is the (E) -> (Z) isomerization about the double bond. Such cyclizations presumably proceed through the intermediate enol ether which hydrolyzes to the product cycloalkanone on acidic workup. Such intramolecular keto ester couplings work particularly well for the formation of five- to seven-membered rings, but higher homologs are formed in lower yield. Often, a considerable amount of work is needed to optimize the yields in such reactions. The best results are obtained with a low-valent titanium reagent prepared by the reduction of TiCl3 with LiAlH4 in the presence of Triethylamine. For reasons not fully understood, neither the TiCl3/Zn(Cu) nor the TiCl3(DME)1.5/Zn(Cu) reagent works as well.

The reagent produced from a 3:1 mixture of TiCl3 and LiAlH4 effects reductive couplings of allylic and benzylic alcohols (eq 5);10 TiII alkoxides may be involved.11 In some cases (e.g. with farnesol), couplings lead to mixtures of regioisomeric products. Reduction of benzyl alcohols affords the corresponding 1,2-diphenylethane.10 Benzyl halides behave in a similar fashion, while a,a-dihalotoluenes react with the McMurry reagent to give stilbenes (eq 6).12

Intramolecular variants of such processes are also known. Thus reductive cyclization of certain 1,3-diols affords cyclopropanes (eq 7).13 In the example given, inversion of configuration is observed at one of the cyclization centers; this has been taken as evidence that an anionic intermediate is involved which cyclizes in the illustrated manner.

The bis-O-methyl ether derivative of the diol shown in eq 7 also cyclizes to give the same product, this time in 60% yield. In a presumably related process (eq 8), the reagent derived from a 4:1 mixture of TiCl3 and LiAlH4 effects the conversion of a,a-bis(trimethylsiloxy) sulfides into the corresponding alkenes. The reaction probably proceeds via an intermediate episulfide.14

Reductive Elimination Reactions.12,15-18

The conversion of b-ionone into vitamin A involves, in the later stages, reaction of the low-valent titanium species produced from a 2:1 mixture of TiCl3 and LiAlH4 with an allylic diol (either the (E)- or (Z)-isomer) (eq 9). The result is the formation of an (E,E)-diene.15

Analogous reduction of the primary acetate (as opposed to the primary silyl ether shown) gave a mixture of the (E,E)- and (E,Z)-dienes.15 A similar reduction process has been employed in a synthesis of 13-cis-retinoic acid.16 The McMurry reagent has also been used to prepare alkenes from the corresponding bromohydrin,17 epoxide,18 and vic-dibromide.12 In the latter two cases, at least, the reaction is not stereospecific. For example, reduction of either pure (Z)- or pure (E)-5-decene epoxide gives a 4:1 mixture of (E)- and (Z)-5-decene.18

1. (a) Robertson, G. M. COS 1991, 3, 583. (b) Betschart, C.; Seebach, D. C 1989, 43, 39. (c) McMurry, J. E. CRV 1989, 89, 1513. (d) Lenoir, D. S 1989, 883. (e) Pons, J.-M.; Santelli, M. T 1988, 44, 4295. (f) McMurry, J. E. ACR 1983, 16, 405.
2. McMurry, J. E.; Fleming, M. P. JACS 1974, 96, 4708.
3. Dams, R.; Malinowski, M.; Westdorp, I.; Geise, H. Y. JOC 1982, 47, 248.
4. McMurry, J. E.; Krepski, L. R. JOC 1976, 41, 3929.
5. (a) Langler, R. F.; Tidwell, T. T. TL 1975, 777. (b) Bomse, D. S.; Morton, T. H. TL 1975, 781.
6. Feringa, B.; Wynberg, H. JACS 1977, 99, 602.
7. Baumstark, A. L.; McCloskey, C. J.; Witt, K. E. JOC 1978, 43, 3609.
8. McMurry, J. E.; Miller, D. D. JACS 1983, 105, 1660.
9. McMurry, J. E.; Miller, D. D. TL 1983, 24, 1885.
10. McMurry, J. E.; Silvestri, M. JOC 1975, 40, 2687.
11. van Tamelen, E. E.; &AAring;kermark, B.; Sharpless, K. B. JACS 1969, 91, 1552.
12. Olah, G. A.; Prakash, G. K. S. S 1976, 607.
13. Walborsky, H. M.; Murari, M. P. JACS 1980, 102, 426.
14. Chan, T. H.; Li, J. S.; Aida, T.; Harpp, D. N. TL 1982, 23, 837.
15. (a) Solladié, G.; Girardin, A. TL 1988, 29, 213. (b) Solladié, G.; Hamdouchi, C. SL 1989, 66. (c) Walborsky, H. M.; Wüst, H. H. JACS 1982, 104, 5807.
16. Solladié, G.; Girardin, A.; Métra, P. TL 1988, 29, 209.
17. McMurry, J. E.; Hoz, T. JOC 1975, 40, 3797.
18. McMurry, J. E.; Fleming, M. P. JOC 1975, 40, 2555.

Martin G. Banwell

University of Melbourne, Parkville, Victoria, Australia

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