Lithium Aluminum Hydride-Titanium(IV) Chloride1

LiAlH4-TiCl4
(LiAlH4)

[16853-85-3]  · AlH4Li  · Lithium Aluminum Hydride-Titanium(IV) Chloride  · (MW 37.96) (TiCl4)

[7550-45-0]  · Cl4Ti  · Lithium Aluminum Hydride-Titanium(IV) Chloride  · (MW 189.68)

(generation of dihalocarbenes;2,3 hydrogenolysis of allylic alcohols;4 deoxygenation of oxygen-bridged compounds9,10 and N-oxides;12 preparation of alkenes;15 reducing agent for sulfoxides,17 alkenes, alkynes,18 and 3-amido ketones;20 catalyst for hydroaluminations of alkenes and alkynes22)

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

Solubility: see Lithium Aluminum Hydride and Titanium(IV) Chloride; reactions using the mixture are run in anhydrous THF or diethyl ether.

Form Supplied in: for most applications, the reagent is prepared in situ from commercially available components.

Preparative Method: for applications involving the initial formation of low-valent titanium, lithium aluminum hydride (1 equiv) is added under nitrogen to a cooled (0 °C) solution of titanium(IV) chloride (1 equiv) in anhydrous THF, resulting in a black suspension with gas evolution.13 The molar ratio of LiAlH4 and TiCl4 can vary and the addition of various organic tertiary amine bases following the addition of LiAlH4 is also common.

Handling, Storage, and Precautions: see Lithium Aluminum Hydride and Titanium(IV) Chloride. Use in a fume hood.

Generation of Dihalocarbenes.

Carbon tetrachloride reacts with LiAlH4-TiCl4 in the presence of alkenes to provide gem-dichlorocyclopropanes (eq 1).2 The reaction conditions are slightly acidic, in contrast to other methods that require strongly basic conditions. 1-Chloro-1-fluorocyclopropanes can be prepared in good yields using CFCl3 and low-valent titanium (eq 2).3 Other methods of generating chlorofluorocarbene in the presences of alkenes give lower yields.

Deoxygenations.

Secondary allylic alcohols react with LiAlH4-Aluminum Chloride and LiAlH4-TiCl4 in a similar fashion to provide hydrogenolysis products in fair yields.4 However, upon reaction with LiAlH4-AlCl3, tertiary allylic alcohols undergo dehydration whereas LiAlH4-TiCl4 gives the expected hydrogenolysis product (eq 3). In some cases, double bond migration occurs via a reductive SN2 reaction. In a related reaction, reductive demethoxylation of allyl methyl ethers using low-valent titanium is accompanied by double bond migration, providing predominantly the (Z)-alkene from either the (E)- or (Z)-allyl ethers (eq 4).5

Photooxygenation of (-)-b-pinene followed by reduction of the resulting peroxide to the corresponding alcohol and then treatment with low-valent titanium provides a simple route to (-)-a-pinene via hydrogenolysis of the allylic alcohol (eq 5).6 The peroxide also provides (-)-a-pinene upon treatment with low-valent titanium.

Alkenes can be prepared from epoxides with low-valent titanium generated from Titanium(III) Chloride and LiAlH4.7 The same reduction with TiCl4 in the presence of Triethylamine has been used to prepare a key intermediate in the synthesis of trans-g-irone (eq 6).8

Low-valent titanium has been used to deoxygenate furan cycloadducts in the preparation of arenes (eq 7).9 Substituted furan adducts provide substituted benzenes with LiAlH4-TiCl4 in the presence of triethylamine, while in the absence of triethylamine, 1,3-cyclohexadienes are obtained (eq 8).10

A third pathway involves the presence of small amounts of triethylamine and results in reduction of the enedicarboxylate portion of the molecule without deoxygenation (eq 9).11 Isolated double bonds are not reduced using low-valent titanium, but LiAlH4-TiCl4 does reduce diethyl maleate to diethyl succinate in 59% yield.

Aromatic N-oxides, typically resistant to deoxygenation, can be reduced under mild conditions using low-valent titanium.12 These conditions have been used to reduce heteroaromatic N-oxides with labile halogen atoms ortho and para to the ring nitrogen (eq 10).13 These compounds do not undergo dehalogenation, but it has been reported that 1-chloronaphthalene is reduced to naphthalene in 83% yield under similar conditions.14

Reductive Couplings.

Upon treatment with low-valent titanium in the presence of tertiary amines, carbonyl compounds undergo reductive dimerization in high yields to produce symmetrical alkenes (eq 11).15 Acetals of aromatic aldehydes and ketones couple to provide pinacol ethers or alkenes in high yields (eq 12), while dialkyl acetals derived from aliphatic aldehydes and ketones provide ethers as a result of reductive dealkoxylation (eq 13).16

Miscellaneous Reductions.

Lithium aluminum hydride/titanium(IV) chloride provides a mild method for the reduction of sulfoxides to the corresponding sulfides (eq 14).17 Yields are generally higher than when LiAlH4 is used alone and reductions are complete within 2 h at or below room temperature. Complex formation between the metal ion and the sulfinyl oxygen has been invoked to explain the effect that TiCl4 has in facilitating this reduction.

Sulfides are reduced to the corresponding hydrocarbons in good yield with TiCl4-LiAlH4 in THF at reflux.14 Terminal alkenes and alkynes are reduced to the corresponding alkanes in good yields using equamolar quantities of LiAlH4 and TiCl4.18 Disubstituted double bonds are only partially reduced, while internal alkynes give predominately the cis-alkene in good yield.

Stereoselective Reductions.

Reduction of 1,3-dicarbonyl compounds with lithium aluminum hydride in the presence of chelating agents such as TiCl4 provides 1,3-diols with good diastereoselectivity (eq 15).19 Cyclic models have been used to explain the course of reductions (eq 16). It has been suggested that the major isomer is formed via addition of hydride to both carbonyls from the least hindered side.

Chelation control with TiCl4 has been applied to the stereoselective synthesis of 1,3-amino alcohols from anti-3-amido ketones (eq 17).20,21 Again the stereochemical results are explained by a rigid cyclic transition state.

Hydroaluminations.

Titanium(IV) chloride catalyzes the addition of lithium aluminum hydride to alkenes to provide the corresponding organoaluminates in high yields under mild conditions.22 The relative rates of reaction decrease with increased substitution on the alkene, and with nonconjugated alkenes, LiAlH4 selectively adds to the least hindered double bond. Organoaluminates provide a convenient route to primary acetates,23 alkyl halides (eq 18),22,24 and alcohols,22 terminal allenes25 and alkynes,26 alkanes,22 and trialkenylboranes.27 Coupling reactions between organoaluminates and allylic halides can be accomplished in the presence of copper(I) salts.28

Methylenation of Carbonyl Compounds.

b-Elimination of 2-(phenylthio)ethanols, prepared via reaction of ketones with phenylthiomethyllithium, occurs with TiCl4/LiAlH4 in the presence of a tertiary amine to provide the terminal alkene in high yield.29

Related Reagents.

Titanium(III) Chloride-Lithium Aluminum Hydride.


1. (a) McMurry, J. E. ACR 1974, 7, 281. (b) Mukaiyama, T. AG(E) 1977, 16, 817.
2. Mukaiyama, T.; Shiono, M.; Watanabe, K.; Onaka, M. CL 1975, 711.
3. Dolbier, W. R., Jr.; Burkholder, C. R. TL 1988, 29, 6749.
4. Fujimoto, Y.; Ikekawa, N. CPB 1976, 24, 825.
5. Ishikawa, H.; Mukaiyama, T. CL 1976, 737.
6. Min, Y-F.; Zhang, B-W.; Cao, Y. S 1982, 875.
7. McMurry, J. E.; Fleming, M. P. JOC 1975, 40, 2555.
8. Takazawa, O.; Kogami, K.; Hayashi, K. BCJ 1985, 58, 389.
9. Xing, Y. D.; Huang, N. Z. JOC 1982, 47, 140.
10. Huang, N. Z.; Xing, Y. D.; Ye, D. Y. S 1982, 1041.
11. Hung, C. W.; Wong, H. N. C. TL 1987, 28, 2393.
12. Malinowski, M. S 1987, 732.
13. Malinowski, M.; Kaczmarek, L. S 1987, 1013.
14. Mukaiyama, T.; Hayashi, M.; Narasaka, K. CL 1973, 291.
15. Ishida, A.; Mukaiyama, T. CL 1976, 1127.
16. Ishikawa, H.; Mukaiyama, BCJ 1978, 51, 2059.
17. Drabowicz, J.; Mikolajczyk, M. S 1976, 527.
18. Chum, P. W.; Wilson, S. E. TL 1976, 17, 15.
19. Barluenga, J.; Resa, J. G.; Olano, B.; Fustero, S. JOC 1987, 52, 1425.
20. Barluenga, J.; Aguilar, E.; Olano, B.; Fustero, S. SL 1990, 463.
21. Barluenga, J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. L. JOC 1992, 57, 1219.
22. Sato, F.; Sato, S.; Kodama, H.; Sato, M. JOM 1977, 142, 71.
23. Sato, F.; Mori, Y.; Sato, M. TL 1979, 20, 1405.
24. (a) Sato, F.; Mori, Y.; Sato, M. CL 1978, 833. (b) Sato, F.; Sato, S.; Sato, M. JOM 1977, 131, C26.
25. Sato, F.; Oguro, K.; Sato, M. CL 1978, 805.
26. Sato, F.; Kodama, H.; Sato, M. CL 1978, 789.
27. Sato, F.; Haga, S.; Sato, M. CL 1978, 999.
28. Sato, F.; Kodama, H.; Sato, M. JOM 1978, 157, C30.
29. Watanabe, Y.; Shiono, M.; Mukaiyama, T. CL 1975, 871.

Daniel Kuzmich

The Ohio State University, Columbus, OH, USA



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