Dichlorodimethyltitanium1

Me2TiCl2

[35739-70-9]  · C2H6Cl2Ti  · Dichlorodimethyltitanium  · (MW 148.86)

(Lewis acidic reagent2 capable of geminal dimethylation of ketones3 and aromatic aldehydes,4 substitution reactions of tertiary alkyl halides and alcohols,5 and stereoselective Grignard-type additions to aldehydes and ketones6-9)

Physical Data: reliable data not available; dark violet in crystalline form (dec. at -10 °C); yellow in hydrocarbon solvents; violet in diethyl ether.

Preparative Methods: several methylmetal reagents such as Methyllithium, Methylmagnesium Bromide, Me2Zn, and Trimethylaluminum react stoichiometrically with Titanium(IV) Chloride to form Me2TiCl2.1-3 In the presence of ether, the Lewis acidic compound forms etherates. For a number of synthetic organic applications, ether-free solutions of Me2TiCl2 are required.1,3,5 In these cases, the preparation of choice is the reaction of Me2Zn with TiCl4 in dry CH2Cl2 (eq 1).3,5 Caution: Although Me2Zn is highly pyrophoric, CH2Cl2 solutions are less so and are easy to handle.3

Handling, Storage, and Precautions: although Me2TiCl2 can be crystallized, it is best not to isolate the compound (due to its thermal lability and light sensitivity). In situ reaction modes under an inert gas atmosphere (e.g. argon) in the absence of direct sunlight are recommended.

Methylation of Carbonyl Groups.

The most important synthetic applications of Me2TiCl2 pertain to carbonyl addition and SN1 substitution reactions, sometimes in a one-pot tandem process, as in the geminal dimethylation of ketones (eq 2).3 A two-fold excess of reagent is required which ensures Grignard-type reaction to a tertiary titanium alcoholate which then interacts with more Me2TiCl2 to form the final product via tertiary carbocations. The reactions need to be performed in nonethereal solvents such as CH2Cl2 at -30 to 0 °C (1-4 h).3 Me3Al/TiCl4 can also be employed.3 These reactions are milder and much more efficient than the previously reported reactions of ketones with an excess of Me3Al at 120-180 °C.10

A fairly wide range of ketones is amenable to such geminal dimethylation, but the yields are drastically lowered when sterically hindered ketones are used.3 The intermediacy of tertiary carbocations means that in relevant cases rearrangements may occur,3 as in the case of (+)-cuparenone which affords racemic (±)-cuparene.11

Another restriction concerns the use of highly functionalized substrates which bind the reagent and do not undergo geminal dimethylation. However, for simple systems, Me2TiCl2 is ideally suited3,5,12 and is to be preferred over multistep procedures such as Wittig alkenation of the ketone followed by Simmons-Smith cyclopropanation and ring-opening hydrogenation.13 Furthermore, aromatic (but not aliphatic) aldehydes are also geminal dimethylated.4

Ketones can be reacted with ether-free alkyllithium reagents in pentane or hexane, and the resulting insoluble tertiary lithium alcoholates treated with Me2TiCl2 to form the mixed geminal dialkylated products.14 This protocol allows for a simple access to synthetic tetrahydrocannabinoids (eq 3).14

Methylation of Tertiary Halides and Alcohols.

Me2TiCl2 prepared from Me2Zn/TiCl4 has also been used to methylate tertiary alkyl halides and tertiary alcohols.5 In the former case, Me2Zn and catalytic amounts of TiCl4 can also be employed.15 This method is also applicable to substitution reactions of chiral b-chloro sulfides which react with intermediate Me2TiCl2 stereospecifically with retention of configuration due to neighboring group participation.15c

Grignard-Type Additions to Carbonyl Compounds.

The above reactions all involve SN1 ionization, which means that a Lewis acidic medium is required, including nonethereal solvents. This precludes the use of MeLi or MeMgX because these reagents always contain ether. In the case of Grignard-type carbonyl addition reactions of Me2TiCl2, ether can usually be tolerated. This means that MeLi or MeMgX can be transmetalated with TiCl4 and the intermediate Me2TiCl2/etherate reacted with aldehydes or ketones. Interesting degrees of diastereoselectivities have been observed,1,7 as in the stereocontrolled reactions of chiral a-keto amides (eq 4).8 Nevertheless, Me2TiCl2/etherate has not been used often in the general area of stereoselective carbonyl addition reactions. Usually 1 equiv of MeLi or MeMgX per one part of TiCl4 has been employed, generating MeTiCl3/etherate which is a nonbasic, chemo- and stereoselective Grignard analog.16 Like MeLi/CeCl3, it is useful in addition reactions of enolizable ketones.17 Since carbonyl reactivity increases in the series MeTiCl3 < Me2TiCl2 < Me4Ti, the combination 2 MeLi/TiCl4 in ether is a viable alternative.1


1. (a) Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986. (b) Reetz, M. T. In Organometallics in Synthesis; Schlosser, M., Ed.; Wiley: New York, 1994.
2. (a) Gmelin Handbuch der Anorganischen Chemie; Springer: Berlin, 1977; Vol. 40, pp 74-75. (b) Schlegel, M.; Thiele, K.-H. Z. Anorg. Allg. Chem. 1985, 526, 43.
3. Reetz, M. T.; Westermann, J.; Kyung, S.-H. CB 1985, 118, 1050.
4. Reetz, M. T.; Kyung, S.-H. CB 1987, 120, 123.
5. Reetz, M. T.; Westermann, J.; Steinbach, R. CC 1981, 237.
6. Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R. AG(E) 1980, 19, 1011.
7. Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.; Wenderoth, B. CB 1985, 118, 1441.
8. Fujisawa, T.; Ukaji, Y.; Funabora, M.; Yamashita, M.; Sato, T. BCJ 1990, 63, 1894.
9. Fujisawa, T.; Watai, T.; Sugiyama, T.; Ukaji, Y. CL 1989, 2045.
10. Meisters, A.; Mole, T. AJC 1974, 27, 1665.
11. Posner, G. H.; Kogan, T. P. CC 1983, 1481.
12. Häfelinger, G.; Marb, M. NJC 1987, 11, 401.
13. (a) Oppolzer, W.; Godel, T. JACS 1978, 100, 2583. (b) Trost, B. M.; Hiemstra, H. JACS 1982, 104, 886. (c) Gröger, C.; Musso, H.; Rossnagel, I. CB 1980, 113, 3621.
14. Reetz, M. T.; Westermann, J. JOC 1983, 48, 254.
15. (a) Reetz, M. T.; Westermann, J.; Steinbach, R. AG(E) 1980, 19, 900. (b) Reetz, M. T.; Wenderoth, B.; Peter, R.; Steinbach, R.; Westermann, J. CC 1980, 1202. (c) Reetz, M. T.; Seitz, T. AG(E) 1987, 26, 1028.
16. Reetz, M. T.; Kyung, S.-H.; Hüllmann, M. T 1986, 42, 2931.
17. Imamoto, T.; Takiyama, N.; Nakamura, K.; Hatajima, T.; Kamiya, Y. JACS 1989, 111, 4392.

Manfred T. Reetz

Max-Planck-Institut für Kohlenforschung, Mülheim an der Ruhr, Germany



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.