Methyltitanium Triisopropoxide1


[18006-13-8]  · C10H24O3Ti  · Methyltitanium Triisopropoxide  · (MW 240.22)

(nonbasic nucleophilic reagent;1 adds to aldehydes and ketones with very high chemo-1,2 and stereoselectivity;1,3 adds to lactols stereoselectively4,5)

Alternate Names: methyltriisopropoxytitanium; methyltitanium tris(isopropoxide); methyltris(2-propanolato)titanium; triisopropoxymethyltitanium.

Physical Data: bp 50 °C/0.01 mmHg; mp 10 °C.

Solubility: miscible with most nonprotic organic solvents, e.g. Et2O, THF, CH2Cl2, toluene. In dilute solutions it is mainly monomeric, while in more concentrated solutions some degree of aggregation occurs.

Form Supplied in: bright yellow liquid; not available commercially.

Analysis of Reagent Purity: 1H NMR in C6D6: 4.61 (m, 3H); 1.26 (d, 18H); 0.98 (s, 3H).

Preparative Methods: pure reagent can be prepared by the addition of a solution of Methyllithium in Et2O to an equimolar amount of Chlorotitanium Triisopropoxide or Titanium Tetraisopropoxide in Et2O at -40 °C followed by warming to rt.2 It can be isolated in excellent yields by removal of the solvent in vacuo and distillation. For carbonyl additions6 the reagent can be prepared in situ from MeLi and ClTi(O-i-Pr)3 (which can be prepared in situ from a 3:1 mixture of Ti(O-i-Pr)4 and Titanium(IV) Chloride). The yields from these in situ methods are essentially the same as when purified reagent is employed.

Handling, Storage, and Precautions: moisture and air sensitive. Under N2 it can be kept in the refrigerator for weeks; at rt it decomposes into a deep blue-green liquid over 12 h.

Organotitanium Reagents.

The nucleophilic addition of alkyl groups to aldehydes and ketones to give alcohols is traditionally performed with organomagnesium (RMgX, Grignard) or organolithium reagents (RLi). The conversion of these carbanion equivalents to derivatives of the general type R1TiX3 (X = Cl, OR2, or NR32) often results in significant improvements in the chemo-, regio-, diastereo-, and enantioselectivity of these processes.1 Consequently, these organotitanium compounds have found widespread synthetic utility, beyond their traditional use as components of Ziegler-Natta polymerization catalysts.1a,1b The synthetic advantages of these reagents are derived not only from the modulation of their nucleophilicity and Lewis basicity, but also through their improved solubility in organic solvents and their increased steric and electronic requirements. In the case of MeTi(O-i-Pr)3, the three bulky alkoxy substituents on the titanium prevent oligomerization and dramatically reduce its Lewis acidity, which decreases in the following order: Methyltitanium Trichloride > MeTiCl2(O-i-Pr) > MeTiCl(O-i-Pr)2 > MeTi(O-i-Pr)3. Similarly to other organotitanium reagents, MeTi(O-i-Pr)3 exhibits much higher chemo- and stereoselectivity than MeLi or Methylmagnesium Bromide.

Chemoselective Additions to Aldehydes and Ketones.2,7

MeTi(O-i-Pr)3 adds readily to aldehydes in a 1,2-fashion, under mild conditions (-50 °C to 22 °C, over 2-3 h), forming methyl addition products in high yields. It also has low basicity and tolerates a wide variety of functional groups. While the reagent does not add to the carbonyl group of esters, it can promote transesterification to the isopropyl esters. Surprisingly, a similar reaction takes place with acyl chlorides, which are also converted to isopropyl esters. Other functional groups, such as epoxides, alkyl halides, amides, cyano or nitro substituents, do not interfere with the carbonyl addition process (eq 1).6 The use of MeLi or MeMgBr in these cases gives complex mixtures and low yields of the alcohols.

The reagent reacts with aldehydes at much faster rates than with ketones (up to 105:1) and it can be used for the selective addition to aldehydes in the presence of ketones7 (eq 2).2

The reagent is highly regioselective and is sensitive to both steric and electronic effects. Among two aldehydes or two ketones, it adds to the least hindered one with a high degree of preference.2 The order of relative reactivity for selected carbonyls is shown in eq 3.8

Other reagents of the general type RTi(O-i-Pr)3, exhibit analogous selectivities, adding preferentially to the least hindered carbonyls.9 The reverse selectivity can be achieved via the in situ protection of the least hindered group with a bulky organoaluminum reagent (eq 4).10

Stereoselective Additions to Aldehydes and Ketones.

The addition of MeTi(O-i-Pr)3 to carbonyl groups proceeds according to Cram's rule (Felkin-Anh model), but with enhanced stereoselectivities. Although other reagents can be slightly more selective, overall MeTi(O-i-Pr)3 is often the reagent of choice (eq 5).1c,1f,3

Although the addition of several organometallics (particularly MeTiCl3) to chiral a- or b-alkoxy aldehydes often proceeds via chelation control,1h,11 the reactions of MeTi(O-i-Pr)3 tend to take place without chelation8 and with high diastereoselectivity in the opposite sense (eq 6).12

Despite its low Lewis acidity, however, the additions of MeTi(O-i-Pr)3 to ketones with neighboring chelating substituents proceed with rate-accelerating chelation,1h,8,11 giving tertiary alcohols with a high degree of stereocontrol (eq 7),13 including remote asymmetric induction.14

Additions to cyclohexanones take place preferentially from the equatorial direction, even with conformationally labile substrates (eq 8).3

Stereoselective Additions to Lactols.

MeTi(O-i-Pr)3 is the reagent of choice for the stereoselective addition to lactol derivatives (eqs 9 and 10).4,5 These reactions presumably involve chelated alkoxytitanium intermediates.4,5,15,16

Copper-Catalyzed SN2 Alkylations.

Although the RTi(O-i-Pr)3 reagents generally behave as poor nucleophiles, in the presence of catalytic amounts of copper salts they react with allyl halides or phosphonates exclusively in an SN2 manner (eq 11).17

1. (a) Wailes, P. C.; Coutts, R. S. P.; Weigold, H. Organometallic Chemistry of Titanium, Zirconium and Hafnium; Academic: New York, 1974. (b) Bottrill, M.; Gavens, P. D.; Kelland, J. W.; McMeeking, J. In Comprehensive Organometallic Chemistry; Wilkinson, G.; Ed.; Pergamon: Oxford, 1982; Vol. 3, p 433. (c) Reetz, M. T. Top. Curr. Chem. 1982, 106, 1. (d) Seebach, D.; Weidmann, B.; Widler, L. In Transition Metals in Organic Synthesis; Scheffold, 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.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek, R.; Maus, S. CB 1985, 118, 1421.
3. Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.; Wenderoth, B. CB 1985, 118, 1441.
4. Tomooka, K.; Okinaga, T.; Suzuki, K.; Tsuchihashi, G. TL 1987, 28, 6335.
5. Tomooka, K.; Okinaga, T.; Suzuki, K.; Tsuchihashi, G. TL 1989, 30, 1563.
6. (a) Imwinkelried, R.; Seebach, D. OS 1989, 67, 180. (b) Imwinkelried, R.; Seebach, D. OSC 1993, 8, 495.
7. Weidmann, B.; Seebach, D. HCA 1980, 63, 2451.
8. Reetz, M. T.; Maus, S. T 1987, 43, 101.
9. Weidmann, B.; Widler, L.; Olivero, A. G.; Maycock, C. D.; Seebach, D. HCA 1981, 64, 357.
10. Maruoka, K.; Saito, S.; Concepcion, A. B.; Yamamoto, H. JACS 1993, 115, 1183.
11. Reetz, M. T. AG(E) 1984, 23, 556.
12. Mead, K.; MacDonald, T. L. JOC 1985, 50, 422.
13. Ukaji, Y.; Yamamoto, K.; Fukui, M.; Fujisawa, T. TL 1991, 32, 2919.
14. Takahashi, H.; Tanahashi, K.; Higashiyama, K.; Onishi, H. CPB 1986, 34, 479.
15. Fujisawa, T.; Watai, T.; Sugiyama, T.; Ukaji, Y. CL 1989, 2045.
16. Ukaji, Y.; Kanda, H.; Yamamoto, K.; Fujisawa, T. CL 1990, 597.
17. Arai, M.; Lipshutz, B. H.; Nakamura, E. T 1992, 48, 5709.

Nicos A. Petasis & Irini Akritopoulou-Zanze

University of Southern California, Los Angeles, CA, USA

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