Chlorotitanium Triisopropoxide1


[20717-86-6]  · C9H24ClO3Ti  · Chlorotitanium Triisopropoxide  · (MW 260.62)

(mild Lewis acid used for the preparation of organotitanium derivatives1 and titanium enolates;1,2 alkyl, 3-5 allyl,3,4,6 aryl,3-5 alkenyl,7 allenyl,8 and alkynyl9,10 titanium triisopropoxides exhibit reduced basicity and add to carbonyl compounds with enhanced chemo-, regio-, and stereoselectivity;1b-f titanium enolates2 react with aldehydes and imines11 with high levels of syn selectivity12 and greatly enhanced diastereofacial selectivity;13 titanium isopropoxides mediate the regioselective opening of epoxides14,15 and serve as a titanium source for the preparation of chiral titanium complexes16)

Alternate Names: chlorotitanium tris(isopropoxide); chlorotriisopropoxytitanium; chlorotris(2-propanolato)titanium.

Physical Data: mp 45-50 °C; bp 61-65 °C/0.1 mmHg; d 1.091 g cm-3.

Solubility: sol most nonprotic organic solvents, e.g. Et2O, THF, CH2Cl2, toluene, hexanes.

Form Supplied in: syrupy liquid; 1.0 M solution in CH2Cl2 or hexanes.

Preparative Method: available commercially, but can be easily made from a 3:1 mixture of Titanium Tetraisopropoxide and Titanium(IV) Chloride,3 which can be distilled to give the pure reagent or used in situ.17

Handling, Storage, and Precautions: corrosive; moisture sensitive; flammable liquid; can be stored under nitrogen, in pure form or in solution, for months.

Organotitanium Reagents.

The conversion of a variety of readily available organomagnesium (RMgX, Grignard) or organolithium reagents (RLi) to organotitanium derivatives of the general type RTiX3 (X = Cl, OR´, or NR2´´) often results in significant improvements in chemo-, regio-, diastereo-, and enantioselectivity.1 Similar effects are also possible with the titanation of enolates. The synthetic advantages of the organotitanium species 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.

Among the various titanium alkoxides, the isopropoxy derivatives are most synthetically useful because they exist in a monomeric form while retaining adequate titanium reactivity. Although less bulky alkoxide ligands (e.g. MeO, EtO) are expected to form more reactive titanium species, these derivatives are, overall, less reactive because they exist as oligomers.

Titanation of Organomagnesium and Organolithium Reagents.

The widely used 1,2-additions of organometallic reagents to aldehydes and ketones often take place with low stereoselectivity and without significant discrimination among different carbonyl groups. Treatment of these carbon nucleophiles with ClTi(O-i-Pr)3 (1) can have a dramatic effect in their chemo- and stereoselectivity. The resulting alkyltitanium triisopropoxide reagents are usually employed in carbonyl additions in situ, although some, such as Methyltitanium Triisopropoxide, can also be isolated in a pure form. An important advantage of these reagents is that they generally react much faster with aldehydes than with ketones (eq 1).1b-f,3,5,9,18 They also tolerate a variety of other electrophilic functional groups, such as halides, esters, cyano, and nitro groups.

The addition of the RTi(O-i-Pr)3 reagents to aldehydes and ketones often proceeds with significant diastereofacial selectivity, which varies with the R group (eq 2).4

Addition of these reagents to a- or b-alkoxy carbonyl compounds proceeds with a variable extent of chelation.19 Thus while methyltitanium triisopropoxide adds to aldehydes without chelation, it adds to similar ketones with chelation.4 The nature of the R group can also have a dramatic effect on the outcome of these carbonyl additions (eq 3).20

Titanation of functionalized organozinc nucleophiles21 results in highly stereocontrolled additions to aldehydes (eq 4).22

Titanation of lithiated allyl or crotyl carbamates allows a highly stereoselective homoaldol6 addition to aldehydes in an SN2´ fashion. Titanation with Titanium Tetraisopropoxide or Chlorotris(diethylamino)titanium, however, is often a more stereocontrolled process than titanation with (1) (eq 5).23

Although vinyltitanium reagents dimerize rapidly (eq 6),7 they can be efficiently added to aldehydes at low temperatures.7 The diastereoselectivity of these additions can be opposite to that observed for the lithium reagents (eq 7).24

Titanated alkynyl and aryl derivatives add regioselectively to pyridinium salts and pyrimidinones (eq 8).25

Titanation of phosphonate- or phosphinoxide-stabilized carbanions improves their aldehyde selectivity26 and can affect the stereoselectivity of their additions to aldehydes.27 With phosphonate acetate, titanation results in a stereoselective Knoevenagel condensation (eq 9).28

Titanation of Enolates.2

The conversion of lithium enolates to the corresponding titanium derivatives often results in enhanced chemo-, regio-, and stereoselectivities during the aldol reactions with aldehydes. Due to their suppressed Lewis acidity, the titanium enolates add selectively to aldehydes in the presence of ketones, while the reverse selectivity can be achieved via the in situ protection of the aldehyde moiety with Titanium Tetrakis(diethylamide) (eq 10).29

Regardless of their enolate geometry and substitution pattern,30 titanium enolates undergo aldol reactions with high levels of syn selectivity (eq 11).12

Addition of titanium enolates to chiral aldehydes, including a-alkoxy derivatives, takes place with no chelation19 and with high diastereoselectivity (eq 12).31

A complete reversal of diastereoselectivity upon titanation is possible during addition of ester enolates to chiral imines (eq 13).11

Titanation of chiral enolates often has a dramatic effect on their diastereofacial selectivity; examples include the enolates of chiral amides,32 chiral imides,33 chiral a´-silyloxy ketones,34 and chiral a´-benzoyloxy ketones (eq 14).13

A complete reversal of regioselectivity is observed in the reactions of enedithiolates with a,b-unsaturated ketones in the presence of (1). Although the lithium enedithiolates react by 1,4-addition, the titanium derivatives afford only 1,2-addition products, while the corresponding aluminum species give 1,4-addition through the sulfur atom (eq 15).35

Enolization of the imines of a-amino esters generates N-metalated azomethine ylides, which react with a,b-unsaturated carbonyl compounds to form pyrrolidine derivatives. The use of titanium intermediates,36,37 formed with a base and (1) or Dichlorotitanium Diisopropoxide, results in an increase of the regio- and stereoselectivity of this process (eq 16).37

Regioselective Epoxide Opening.

Titanium alkoxides promote the regioselective opening of asymmetric epoxides and epoxy alcohols with a variety of nucleophiles. Although Titanium Tetraisopropoxide is used more often for this purpose,14,15 (1) is used in the formation of titanium acetylide nucleophiles,9 or as a source of the Cl- nucleophile (eq 17).15

Preparation of Chiral Titanium Complexes.16

Chiral ligands on titanium can lead to significant enantioselectivities in various titanium-mediated reactions. For this purpose, numerous chiral alkoxytitanium complexes have been investigated.16 A common titanium source for many of these derivatives is (1), although dichlorotitanium diisopropoxide and titanium(IV) isopropoxide are also often used. One successful application is the enantioselective addition of alkyl groups to aldehydes (eq 18).38

1. (a) Bottrill, M.; Gavens, P. D.; Kelland, J. W.; McMeeking, J. In Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Pergamon: Oxford, 1982; Vol. 3, pp 433. (b) Reetz, M. T. Top. Curr. Chem. 1982, 106, 1. (c) Seebach, D.; Weidmann, B.; Widler, L. In Modern Synthetic Methods; Scheffold, R., Ed.; Wiley: New York, 1983; Vol. 3, pp 217-353. (d) Weidmann, B.; Seebach, D. AG(E) 1983, 22, 31. (e) Reetz, M. T. Organotitanium Reagents in Organic Synthesis; Springer: Berlin, 1986. (f) Ferreri, C.; Palumbo, G.; Caputo, R. COS 1991, 1, 139.
2. Paterson, I. COS 1991, 2, 301.
3. Reetz, M. T.; Westermann, J.; Steinbach, R.; Wenderoth, B.; Peter, R.; Ostarek, R.; Maus, S. CB 1985, 118, 1421.
4. Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.; Wenderoth, B. CB 1985, 118, 1441.
5. Weidmann, B.; Widler, L.; Olivero, A. G.; Maycock, C. D.; Seebach, D. HCA 1981, 64, 357.
6. (a) Hoppe, D. AG(E) 1984, 23, 932. (b) Hoppe, D.; Krämer, T.; Schwark, J.-R.; Zschage, O. PAC 1990, 62, 1999.
7. Boeckman, R. K., Jr.; O'Connor, K. J. TL 1989, 30, 3271.
8. Hoffmann, R. W.; Lanz, J. W.; Metternich, R. LA 1988, 161.
9. Krause, N.; Seebach, D. CB 1987, 120, 1845.
10. Krause, N.; Seebach, D. CB 1988, 121, 1315.
11. Fujisawa, T.; Ukaji, Y.; Noro, T.; Date, K.; Shimizu, M. T 1992, 48, 5629.
12. Reetz, M. T.; Peter, R. TL 1981, 22, 4691.
13. Choudhury, A.; Thornton, E. R. T 1992, 48, 5701.
14. (a) Caron, M.; Sharpless, K. B. JOC 1985, 50, 1557. (b) Kirshenbaum, K. S.; Sharpless, K. B. CL 1987, 11. (c) Caron, M.; Carlier, P. R.; Sharpless, K. B. JOC 1988, 53, 5185. (d) Urabe, H.; Aoyama, Y.; Sato, F. T 1992, 48, 5639.
15. Raifel'd, Y. E.; Nikitenko, A. A.; Arshava, B. M. TA 1991, 2, 1083.
16. Duthaler, R. O.; Hafner, A. CRV 1992, 92, 807.
17. Imwinkelried, R.; Seebach, D. OS 1989, 67, 180.
18. Weidmann, B.; Seebach, D. HCA 1980, 63, 2451.
19. (a) Reetz, M. T. AG(E) 1984, 23, 556. (b) Reetz, M. T. ACR 1993, 26, 462.
20. Mulzer, J.; Angermann, A. TL 1983, 24, 2843.
21. Knochel, P.; Singer, R. D. CRV 1993, 93, 2117.
22. Ochiai, H.; Nishihara, T.; Tamaru, Y.; Yoshida, Z. JOC 1988, 53, 1343.
23. Krämer, T.; Hoppe, D. TL 1987, 28, 5149.
24. Schick, H.; Spanig, J.; Mahrwald, R.; Bohle, M.; Reiher, T.; Pivnitsky, K. K. T 1992, 48, 5579.
25. Gundersen, L.-L.; Rise, F.; Undheim, K. T 1992, 48, 5647.
26. Kauffmann, T.; Schwartze, P. CB 1986, 119, 2150.
27. Birse, E. F.; McKenzie, A.; Murray, A. W. JCS(P1) 1988, 1039.
28. Reetz, M. T.; Peter, R.; Von Itzstein, M. CB 1987, 120, 121.
29. Reetz, M. T.; Wenderoth, B.; Peter, R. CC 1983, 406.
30. Yamago, S.; Machii, D.; Nakamura, E. JOC 1991, 56, 2098.
31. Reetz, M. T.; Kesseler, K.; Jung, A. T 1984, 40, 4327.
32. Devant, R.; Braun, M. CB 1986, 119, 2191.
33. Nerz-Stormes, M.; Thornton, E. R. JOC 1991, 56, 2489.
34. Siegel, C.; Thornton, E. R. TL 1986, 27, 457.
35. Kpegba, K.; Metzner, P. TL 1990, 31, 1853.
36. Barr, D. A.; Dorrity, M. J.; Grigg, R.; Malone, J. F.; Montgomery, J.; Rajviroongit, S.; Stevenson, P. TL 1990, 31, 6569.
37. Kanemasa, S.; Uchida, O.; Wada, E.; Yamamoto, H. CL 1990, 105.
38. Seebach, D.; Beck, A. K.; Imwinkelried, R.; Roggo, S.; Wonnacott, A. HCA 1987, 70, 954.

Nicos A. Petasis

University of Southern California, Los Angeles, CA, USA

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