Alkyltitanium reagents

A clear limitation of titanium chemistry has to do with the observation that such sterically hindered ketones as 58 do not react well with the less reactive n-alkyltitanium reagents 77). Of course, this does not apply to sterically non-hindered steroidal C22-aldehydes, which react smoothly and with high degrees of asymmetric induction 77). 

In the alkylation of a-chiral aldehydes with no ability to chelate with organometal-lic compounds such as Grignard reagents, erythro alcohols are usually obtained preferentially according to the Cram s rule [127], and high Cram selectivity can be achieved with alkyltitanium reagents developed by Reetz [128]. In contrast, application of amphiphilic alkylation to a-chiral aldehydes enables one to achieve the hitherto difficult anti-Cram selectivity, affording threo alcohols selectively as shown in Sch. 91 [125]. 

Ti complexes have been extensively used for the stereoselective introduction of side chains in steroidal molecules, e.g. pregnenolone acetate and the steroidal C-22 aldehyde (73 equation 29). In these cases satisfactory results are only obtained by using Ti reagents, like methyl, ds-methyl and allyl derivatives, due to the strong steric hindrance that affects the position to be attacked. 1,3-Anti dia-stereoselecdon in the addition of alkyltitanium reagents to chirally -substituted aldehydes having a dithioacetal group at the a-position (75) was also observed (equation 30). ... 

Addition to carbonyl groups. These alkyltitanium(IV) compounds (and related reagents) add readily to both aldehydes and ketones to form alcohols in high yield. Addition to aldehydes is so much faster than addition to ketones that selective addition to an aldehyde is possible. Diastereoselective addition to ketones is a useful feature. Thus the reaction affords an excellent route to the axial alcohol (2). 

Review. Reetz1 has reviewed newer published reactions of these reagents as well as numerous unpublished results from his own research. The review emphasizes the chemo-, diastereo-, and enantioselective reactions that can be achieved. Drawbacks are that secondary and tertiary alkyltitanium compounds generally are not available, owing to /1-hydride elimination, and that ready ligand exchange makes the preparation of derivatives chiral at titanium difficult. The review includes useful suggestions for experimental techniques. 

These reactions can be explained by the following mechanism. At first, isopropyltitanocene (521) is formed by transmetallation and its -elimination generates Cp2Ti-H and propylene. Insertion of the alkene to Ti-H affords the alkyltitanium 522. Then the alkyl Grignard reagent 523 is formed by transmetallation... 

Alkyltitanium(IV) complexes having N -dialkylamino ligand systems, RTi(NR 2)3, fail to give nucleophilic additions to carbonyl compounds (Section 1.5.3.1.1). Their reaction with aldehydes leads instead to tertiary amines by addition of both the alkyl moiety of the reagent and one of the N, -dialkylamino ligands (equation 59). The synthetic interest of the reaction is restricted to noneno-lizable aldehydes, since enolizable carbonyl compounds lead to enamines. ... 

The amido ligand is isoelectronic with the alkyl and alkoxo groups and has the possibility to exhibit N-M ir-interactions in order to stabilize the systems they form. Different synthetic reactions are used to prepare mono-Cp titanium derivatives containing amido ligands. These compounds are normally synthesized by (i) the action of the corresponding amide salt on Cp TiCl3, (ii) displacement of amine from a homoleptic amido titanium compound by a Cp reagent, (iii) dehalosilylation reactions, and (iv) elimination of alkane by reaction of an alkyltitanium compound with amine. 

The asymmetric alkylation additions of the prochiral aldehydes and ketones with organometallic reagents have been studied extensively during the last several decades. Alkyltitanium complexes can be obtained from metal carbanions via titanation. Introduction of chirality at the titanium center or on the ligand (or a combination of both) enables the possibility of asymmetric induction in the carbonyl addition reaction. Since the alkyllithiums and Grignard reagents are... 

In further studies on nucleophilic alkylation of aldehydes and ketones (to give secondary and tertiary alcohols, respectively) using alkyltitanium(iv) compounds, the e lier work on methyl tri-isopropoxytitanium (5,155) has been extended to other alkyl tri(alkoxy)titanium reagents. The observed chemoselec-tive addition to the aldehyde in benzaldehyde-acetophenone mixtures [equation (2)] illustrates that these systems are less reactive but more selective... 

---