Titanium Tetrakis(diethylamide)1


[4419-47-0]  · C16H40N4Ti  · Titanium Tetrakis(diethylamide)  · (MW 336.48)

(for the in situ protection of aldehydes and ketones,2 for the formation of enamines from ketones;3 for conjugate diethylamino addition to a,b-unsaturated ketones and esters;4 and for diethylamino transfer to carboxylic5 and phosphonic acid esters6)

Physical Data: bp 112 °C/0.3 mmHg; d204 0.931 g cm-3; 13C NMR (benzene-d6): d = 45.5, 15.7 ppm.

Solubility: sol THF, ether, CH2Cl2.

Form Supplied in: not commercially available.

Preparative Methods: a number of syntheses of Ti(NEt2)4 have been described,7 the following affording a very pure product (eq 1).8

It is likely that the parent compound Ti(NMe2)4 is accessible via the analogous route, although this has not been demonstrated. Ti(NMe2)4 is best synthesized by reacting LiNMe2, prepared from HNMe2 and n-butyllithium, with TiCl4.7

Handling, Storage, and Precautions: is moisture sensitive and should be handled and stored under an inert gas atmosphere (e.g. N2); nonprotic solvents need to be used; syringe techniques are adequate. Use in a fume hood.

In Situ Protection of Aldehydes and Ketones.

Classical reagents such as alkyllithium reagents and Li enolates derived from esters generally do not react chemoselectively with dicarbonyl compounds or other polyfunctional substrates. In many cases, titanation of such reactive reagents using Titanium(IV) Chloride, Chlorotitanium Triisopropoxide, or Titanium Tetraisopropoxide solves such problems, as in aldehyde-selective addition reactions of keto aldehydes.1 However, if the less reactive site is required to undergo C-C bond formation, a three-step sequence involving protection, reaction, and deprotection is necessary. Since the introduction of protective groups is not always completely regioselective, difficulties arise. In such cases the in situ protection of carbonyl functionalities using Ti(NR2)4 (R = Me, Et) may solve the problem.2 Aldehydes readily react with Ti(NEt2)4 at -78 °C to form amide adducts which are stable in solution (eq 2), whereas ketones require temperatures above -30 °C at which the corresponding adducts begin to fragment. The less bulky reagent Ti(NMe2)4 forms stable adducts with aldehydes and ketones at low temperatures.2

Consequently, complete chemoselective in situ protection of the aldehyde function of keto aldehydes is possible. Addition of a reactive carbon nucleophile such as CH2=CHCH2MgCl, PhSO2CH2Li, or CH2=CH(OEt)OLi then occurs at the less reactive ketone site. Since deprotection at the aldehyde function occurs quantitatively during aqueous workup, the one-pot procedure constitutes a simple way to enforce ketone selectivity (eq 3).2

This protocol for in situ protection has been applied in the regioselective alkenation of keto aldehydes (eq 4).9

Site selectivity in diketones is also possible, in such cases the parent compound Ti(NMe2)4 being the reagent of choice. Here again, the direction of chemoselectivity is reversed with respect to the reaction of organotitanium reagents in the absence of Ti(NR2)4. In situ protection allows for reactions at the sterically more hindered site, e.g. (eq 5).2

The above in situ methodology has limitations in that very reactive carbon nucleophiles need to be employed following the protection step, i.e. rapid reactions below -30 °C need to be carried out at which temperature the protected forms maintain stability. Indeed, refluxing ketones with Ti(NEt2)4 is a method of enamine formation.3 A related protocol based on the in situ protection of aldehydes by TiCl4/PPh3 is also easy to perform, but its synthetic scope remains to be established.10 Lithium morpholide likewise adds to aldehydes in situ (mainly aromatic aldehydes), but the basic nature of the reagent causes undesired enolization in the case of ketones.11

Michael Additions to a,b-Unsaturated Carbonyl Compounds.

Titanium amides such as Ti(NEt2)4 readily add to a,b-unsaturated esters and ketones in a Michael fashion.4 The intermediate tris(amino)titanium enolates can be intercepted with aldehydes, the overall process being a tandem conjugate addition-aldol reaction sequence.4 a,b-Unsaturated aldehydes were not tested, but an earlier publication reports the reaction of cinnamaldehyde with Ti(NMe2)4, leading to the corresponding aminal via 1,2-addition.5

Dialkylamino Group Transfer to Carboxylic and Phosphonic Acid Esters.

Carboxylic acid esters react with Ti(NMe2)4 to form the corresponding amides.5 Similar exchange reactions have been used extensively in phosphorus chemistry, as in the selective diethylamino group transfer to phosphoryl centers (eq 6).6

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) Reetz, M. T.; Wenderoth, B.; Peter, R. CC 1983, 406. (b) Reetz, M. T.; Wenderoth, B. TL 1982, 23, 5259.
3. Weingarten, H.; White, W. A. JOC 1966, 31, 4041.
4. Hosomi, A.; Yanagi, T.; Hojo, M. TL 1991, 32, 2371.
5. Chandra, G.; George, T. A.; Lappert, M. F. JCS(C) 1969, 2565.
6. (a) Froneman, M.; Modro, T. A.; Qaba, L.; Vather, S. M.; TL 1987, 28, 2979; see also (b) Vather, S. M.; Modro, T. A. PS 1986, 26, 383. (c) Froneman, M.; Modro, T. A. S 1991, 201.
7. (a) Bradley, D. C.; Thomas, I. M. JCS 1960, 3857. (b) Bürger, H.; Neese, H. J. Z. Anorg. Allg. Chem. 1969, 370, 275. (c) Reetz, M. T.; Urz, R.; Schuster, T. S 1983, 540.
8. Steinborn, D.; Wagner, I.; Taube, R. S 1989, 304.
9. Okazoe, T.; Hibino, J.; Takai, K.; Nozaki, H. TL 1985, 26, 5581.
10. Kauffmann, T.; Abel, T.; Schreer, M. AG 1988, 100, 1006 AG(E) 1988, 27, 944.
11. Comins, D. L.; Brown, J. D.; Mantlo, N. B. TL 1982, 23, 3979.

Manfred T. Reetz

Max-Planck-Institut für Kohlenforschung, Mülheim, Germany

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