Methyltitanium Trichloride1


[2747-38-8]  · CH3Cl3Ti  · Methyltitanium Trichloride  · (MW 169.27)

(nonbasic nucleophilic reagent with high Lewis acidity;1,2 adds to aldehydes, ketones, and acetals with high chemo- and stereoselectivity;1,2 reagent for the SN1 substitution of tertiary halides3 and the geminal dimethylation of carbonyl compounds4,5)

Alternate Names: trichloromethyltitanium; methyltitanium(IV) trichloride.

Physical Data: mp 29 °C; bp 37 °C/1 mmHg.

Solubility: sol most commonly used aprotic solvents, including pentane, Et2O, THF, CH2Cl2. Forms octahedral complexes with bidentate ligands such as glycol ethers, ethylenediamines, and diphosphines as well as with solvents such as Et2O and THF.

Form Supplied in: purple crystals; not available commercially.

Analysis of Reagent Purity: 1H NMR: 2.9 ppm (s).

Preparative Methods: MeTiCl3:6 ether-free reagent, suitable for chelation-controlled carbonyl additions and SN1 substitutions, can be prepared from a 2:1 mixture of Titanium(IV) Chloride and Me2Zn5 in CH2Cl2 at -78 °C. The resulting solution can be used as is or distilled under vacuum. A 1:1 mixture of TiCl4 and Me2Zn produces Dichlorodimethyltitanium, which is more effective for SN1 substitutions.5 MeLi-TiCl4-Et2O:2 solutions of MeTiCl3 in Et2O can be more conveniently prepared from Methyllithium and TiCl4. Other organometallics, such as Methylmagnesium Bromide, can also be used. In the workup, simple quenching with ice water is preferred. The use of Sodium Carbonate may lead to cumbersome emulsions of TiO2, which can be avoided with NH4F or Potassium Fluoride.

Handling, Storage, and Precautions: moisture sensitive; stable at low temperature in the dark. At rt, it decomposes over several hours. Me2Zn is very pyrophoric in a pure form.

Organotitanium Reagents.

While many titanium compounds are used widely as key components of Ziegler-Natta polymerization catalysts,1a,1c a variety of organotitanium derivatives have found great utility in organic synthesis as well. Compounds of the general type R1TiX3 (X = Cl, OR2, or NR32), studied extensively by Reetz and others,1 often add to carbonyl groups with a high degree of chemo-, regio-, diastereo-, and enantioselectivity as compared with organomagnesium (RMgX, Grignard) or organolithium reagents (RLi). The synthetic advantages of these organotitanium reagents arise from the modulation of their nucleophilicity and Lewis acidity and basicity, as well as their improved solubility in organic solvents, and their increased steric and electronic requirements. Among the various commonly used derivatives, MeTiCl3 is the most Lewis acidic, while Methyltitanium Triisopropoxide is the least acidic. Other homologs of type RTiCl3 are more difficult to prepare and have found only limited synthetic use. The similar reagent Me2TiCl2 is more nucleophilic than MeTiCl3 and is more effective for SN1 substitutions.5

Chemoselective Addition to Aldehydes and Ketones.

MeTiCl3 reacts quickly with aldehydes at low temperatures, while similar reactions with ketones require higher temperatures. Among other related organometallics, MeTiCl3 exhibits one of the highest levels of aldehyde selectivities (eq 1).2 In the presence of phosphines, however, an in situ blocking of the aldehyde group allows the reagent to react selectively with ketones in the presence of aldehydes.7

In general, MeTiCl3 shows higher reactivity towards ketones than MeTi(O-i-Pr)3. Discrimination between different ketones is also most effective with this reagent (eq 2).2

A wide variety of functional groups are tolerated under the reaction conditions, including ester, cyano, or nitro groups (eq 3).2

Being the least basic, MeTiCl3 is the reagent of choice for the addition of methyl groups to highly enolizable ketones (eq 4).2

Stereoselective Additions to Aldehydes and Ketones.

The reagent, formed in situ from the combination of MeLi and TiCl4 in Et2O, adds to chiral aldehydes according to Cram's rule with higher stereoselectivity than ether-free preformed MeTiCl3 or even MeTi(O-i-Pr)3 (eq 5).2,8

The addition of ether-free MeTiCl3 to a-alkoxy aldehydes proceeds with chelation control9 and high diastereofacial selectivity, while MeTi(O-i-Pr)3 exhibits the opposite selectivity (eq 6).10,11 The postulated titanium chelates have been observed directly by 13C NMR spectroscopy.11

Similar chelation control with 1,3-asymmetric induction takes place with b-alkoxy aldehydes (eq 7).12

Although preformed MeTiCl3 and the combination of Me2Zn-TiCl4 often behave similarly, in some cases they exhibit significantly different diastereofacial selectivities (eq 8).13

Chelation of MeTiCl3 with neighboring sulfur groups is also possible (eq 9).

MeTiCl3 adds efficiently and stereoselectively to the carbonyl group of b-keto sulfoxides, despite the facile enolization of these compounds. Presumably this process involves chelation with the sulfoxide oxygen (eq 10).14

Additions to Acetals.

MeTiCl3 reacts readily with acetals at low temperature even in the presence of ketones. With chiral acetals, the reaction is highly stereoselective (eq 11).15

SN1 Methylation of Tertiary Alkyl Halides.

The high Lewis acidity of MeTiCl3 and the related derivative Me2TiCl2, obtained from MeTiCl3 or Me2Zn and 1 equiv of TiCl4, makes them suitable for the SN1 substitution of tertiary chlorides (eq 12)3 or bromides (eq 13). Primary or secondary halides do not undergo this reaction, which presumably proceeds via a carbocation.

Geminal Dimethylation of Carbonyl Compounds.

Reaction of ketones with MeTiCl3, or more effectively with Me2TiCl216,17 or Me2Zn-TiCl4,5 gives the corresponding geminal dimethyl derivatives directly4 (eq 14).16 This process presumably involves an initial addition to the carbonyl followed by ionization and SN1 substitution by a second methyl group.

When a combination of Me2Zn and TiCl4 is used in this reaction, the geminal dimethylation products are maximized when at least 2 equiv of each is utilized.5 Otherwise, the corresponding tertiary alcohol or tertiary chloride are obtained as major products (eq 15).5

The reaction works well with a variety of aliphatic and aromatic ketones, with the exception of a,b-unsaturated derivatives, which give a mixture of products. It is even possible to generate adjacent quaternary carbons in this manner (eq 16).5

Although aliphatic aldehydes give alcohols under these reaction conditions, aromatic aldehydes undergo geminal dimethylation to form isopropyl derivatives (eq 17).17

Similarly, acid chlorides undergo a direct geminal trimethylation (eq 18).5

1. (a) Wailes, P. C.; Coutts, R. S. P.; Weigold, H. Organometallic Chemistry of Titanium, Zirconium and Hafnium; Academic: New York, 1974. (b) Reetz, M. T. Top. Curr. Chem. 1982, 106, 1. (c) Bottrill, M.; Gavens, P. D.; Kelland, J. W.; McMeeking, J. In Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Pergamon: Oxford, 1982; Vol. 3, p 433. (d) Seebach, D.; Weidmann, B.; Widler, L. In Transition Metals in Organic Synthesis; Schaffold, R., Ed.; Wiley: New York, 1983, Vol. 3, pp 217-353. (e) Weidmann, B.; Seebach, D. AG(E) 1983, 22, 31. (f) Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986. (g) Ferreri, C.; Palumbo, G.; Caputo, R. COS 1991, 1, 139. (h) Reetz, M. T. ACR 1993, 26, 462.
2. Reetz, M. T.; Kyung, S. H.; Hüllmann, M. T 1986, 42, 2931.
3. Reetz, M. T.; Westermann, J.; Steinbach, R. AG(E) 1980, 19, 901.
4. Reetz, M. T.; Westermann, J.; Steinbach, R. AG(E) 1980, 19, 900.
5. Reetz, M. T.; Westermann, J.; Kyung, S.-H. CB 1985, 118, 1050.
6. Clark, R. J. H.; Coles, M. A. Inorg. Synth. 1976, 16, 120.
7. Kauffmann, T.; Abel, T.; Schreer, M. AG(E) 1988, 27, 944.
8. Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R. AG(E) 1980, 19, 1011.
9. Reetz, M. T. AG(E) 1984, 23, 556.
10. Reetz, M. T.; Kesseler, K.; Schmidtberger, S.; Wenderoth, B.; Steinbach, R. AG(E) 1983, 22, 989.
11. Reetz, M. T.; Raguse, B.; Seitz, T. T 1993, 49, 8561.
12. Reetz, M. T.; Jung, A. JACS 1983, 105, 4833.
13. Baldwin, S. W.; McIver, J. M. TL 1991, 32, 1937.
14. Fujisawa, T.; Fujimura, A.; Ukaji, Y. CL 1988, 1541.
15. Mori, A.; Maruoka, K.; Yamamoto, H. TL 1984, 25, 4421.
16. Reetz, M. T.; Westermann, J.; Steinbach, R. CC 1981, 237.
17. Reetz, M. T.; Kyung, S.-H. CB 1987, 120, 123.

Nicos A. Petasis & Irini Akritopoulou-Zanze

University of Southern California, Los Angeles, CA, USA

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