[6607-37-0]  · C12H30ClN3Ti  · Chlorotris(diethylamino)titanium  · (MW 299.72)

(efficient transmetalating agent useful in the conversion of reactive and nonselective organolithium or -magnesium compounds into organotitanium reagents for chemo- and stereoselective Grignard-type,2,3 aldol,4-6 homoaldol,7,8 and Michael additions9)

Alternate Name: chlorotitanium tris(diethylamide).

Physical Data: bp 94-96 °C/0.02 mmHg.

Solubility: sol ether, THF, CH2Cl2, toluene.

Form Supplied in: liquid.

Preparative Methods: the reaction of Lithium Diethylamide, prepared by the reaction of HNEt2 with BuLi10a or Li/styrene,10b with a stoichiometric amount of Titanium(IV) Chloride affords ClTi(NEt2)3 (eq 1). The reaction of TiCl4 with Titanium Tetrakis(diethylamide) also leads to ClTi(NEt2)3.10c ClTi(NMe2)3 is accessible via similar routes.10a

Handling, Storage, and Precautions: moisture-sensitive; should be handled and stored under an inert gas atmosphere (e.g. N2). Syringe techniques are adequate.

Traditional carbanions such as alkyllithium reagents, lithium enolates, and other deprotonated CH-acidic compounds, as well as some organomagnesium reagents, are so basic and reactive that carbonyl addition and substitution reactions often show low degrees of chemo- and stereoselectivity. In many of these cases, titanation using ClTiX3 (X = Cl, OR, NR2) increases carbanion selectivity dramatically.1,11 Control of chemoselectivity is best achieved by titanating with Titanium(IV) Chloride or Chlorotitanium Triisopropoxide, the alternative and less readily available ClTi(NEt2)3 not being necessary. However, in stereoselective reactions the nature of the ligands on titanium play a pivotal role. The transmetalating agents ClTi(NMe2)3 and ClTi(NEt2)3 (or their Br analogs) have been used in a number of such cases.1 All of them involve resonance stabilized ambident carbanions, e.g. enolates, allylic, and heteroallylic species. In contrast, saturated titanium compounds of the type RTi(NEt2)3 (R = alkyl), although readily available from RLi and ClTi(NEt2)3, do not undergo Grignard-type reactions, aminoalkylation being the preferred reaction mode.1,11

The aldol addition of titanium enolates generally affords the syn configured aldols, irrespective of the geometry of the enolate.1,4 This property is of particular synthetic interest in the case of cyclic ketones (eq 2),4 because the boron analogs afford the anti-aldols in a complementary manner.12

Cram selectivity in the reaction of chiral aldehydes with the very reactive allylmagnesium chloride can also be increased dramatically by prior titanation, CH2=CHCH2Ti(NEt2)3 being most selective.2 This reagent is also useful in axially selective allyl additions to cyclohexanone derivatives.3

The tris(diethylamino)titanium enolate of ethyl acetate reacts with chiral a-siloxy ketones to afford the aldol adducts with >99% nonchelation control.5 Simple diastereoselectivity in the addition of crotyltitanium reagents to ketones is of particular synthetic interest because other metal reagents fail. MeCH=CHCH2Ti(NEt2)3 is best suited for prochiral aliphatic ketones (ds > 90%),3 whereas aromatic ketones require reagents with alkoxy ligands at titanium.3,11

Racemic aminotitanium homoenolate equivalents react stereoselectively with achiral7 and chiral aldehydes.13 For example, of eight possible diastereomers from g-attack on 2-phenylpropanal, only two are formed in a ratio of 93:7 (eq 3).13 The results obtained by employing ClTi(NEt2)3 in related cases are similar or better, as in the synthesis of D- and L-3,6-dideoxy-3-C-methylhexofuranosides.13 Enantiomerically pure analogs react with achiral aldehydes enantio- and diastereoselectively.14

Several other chiral titanium compounds having amino ligands have been reported,1 including one of the most stereoselective reagents for homoaldol additions currently available.8

Lithiated bis-lactim ethers do not react stereoselectively with aldehydes, but can be titanated with ClTi(NR3)3 (R = Me, Et) to form highly selective reagents for the synthesis of enantio- and diastereomerically pure a-amino-b-hydroxy acids (eq 4).6 These reagents also undergo enantioselective Michael additions to nitro alkenes and a,b-unsaturated esters.9

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. Reetz, M. T.; Steinbach, R.; Wenderoth, B.; Westermann, J. CI(L) 1981, 541.
3. Reetz, M. T.; Steinbach, R.; Westermann, J.; Peter, R.; Wenderoth, B. CB 1985, 118, 1441.
4. (a) Reetz, M. T.; Peter, R. TL 1981, 22, 4691. (b) Reetz, M. T. AG 1984, 96, 542; AG(E) 1984, 23, 556.
5. Reetz, M. T.; Hüllmann, M. CC 1986, 1600.
6. (a) Schöllkopf, U.; Nozulak, J.; Grauert, M. S 1985, 55. (b) Grauert, M.; Schöllkopf, U. LA 1985, 1817. (c) Beulshausen, T.; Groth, U.; Schöllkopf, U. LA 1991, 1207.
7. Hanko, R.; Hoppe, D. AG 1982, 94, 378; AG(E) 1982, 21, 372.
8. Roder, H.; Helmchen, G.; Peters, E. M.; Peters, K.; v. Schnering, H. G. AG 1984, 96, 895; AG(E) 1984, 23, 898.
9. (a) Busch, K.; Groth, U. M.; Kühnle, W.; Schöllkopf, U. T 1992, 48, 5607. (b) Schöllkopf, U.; Pettig, D.; Busse, U. S 1986, 737.
10. (a) Bradley, D. C.; Thomas, I. M. JCS 1960, 3857. (b) Reetz, M. T.; Urz, R.; Schuster, T. S 1983, 540. (c) Benzing, E.; Kornicker, W. CB 1961, 94, 2263.
11. (a) Schiess, M.; Seebach, D. HCA 1982, 65, 2598. (b) Weidmann, B.; Seebach, D. AG 1983, 95, 12; AG(E) 1983, 22, 31.
12. Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
13. Hoppe, D. AG 1984, 96, 930; AG(E) 1984, 23, 932.
14. Krämer, T.; Hoppe, D. TL 1987, 28, 5149.

Manfred T. Reetz

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

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