Methyltitanium triisopropoxide

The best titanium mediator appears to be methyltitanium triisopropoxide, yet good yields are also obtained with titanium tetraisopropoxide and chlorotitanium triisopropoxide. The methyl group on titanium serves as a dummy alkyl ligand which is eliminated as methane after hydride transfer from the... 

Improved yields of cyclopropylamines 47 could be obtained by using methyltitanium triisopropoxide (53) instead of titanium tetraisopropoxide [108], as well as by adding the Grignard reagent to the mixture of the amide and the titanium reagent at ambient rather than low temperature (Schemes 11.15 and 11.16, and Table 11.9) [67,69]. In principle, methyltitanium triisopropoxide requires only one equivalent of the alkylmagnesium halide to generate a dialkyltitanium diisopropoxide intermediate 55, and in this particular case P-hydride elimination can only occur at the non-methyl substituent so that methane... 

Table 11.9. /V,/V-Dialkylcyclopropylamines 47 from /V,/V-dialkylcarboxamides 44 and ethyl- as well as substituted ethylmagnesium bromides 27 in the presence of methyltitanium triisopropoxide.

The reaction of the racemic lactol, 5-(ten-butyldiphenylsilyloxymethyl)tetrahydro-2-furanol, with methyltitanium triisopropoxide yielded two racemic nucleophilic addition products in a 12 1 ratio syn vs. anti configuration had to be determined104 (see p 469). 

It was not until the pioneering studies of Bestian, Clauss and Beermann at Farbwerke Hoechst, that a number of methyltitanium alkoxides and chlorides were prepared in high yields, isolated and characterized 31). Later, additional examples and improvements were reported 1,19,28 32). Methyltitanium triisopropoxide 6 is readily prepared by quenching methyllithium with 5, decanting from the inorganic precipitate and distilling at 0.01 torr/50 °C (95% yield)31b,32). 

Aldehydes 39a-g — 54 react smoothly with methyltitanium triisopropoxide 6 (the numbers in parentheses refer to yields of isolated adducts). Generally, a 10-15% excess of titanium reagent is used, except in compounds containing HO-groups (100% excess). In case of a, P-unsaturated carbonyl compounds, the 1,2-addition mode is observed 22,76,82). 

A final point regards the effect of lithium salts. Methyltitanium triisopropoxide 6, prepared from methyllithium and 3, reacts in situ with carbonyl compounds lightly slower than the distilled compound. However, this has no effect on chemoselectivity6. The only exception noted so far concerns allyl derivatives, as discussed in the following Section C.VII. 

In the first reported example of asymmetric induction using organotitanium reagents, methyltitanium triisopropoxide 6 was reacted with 124 (0 °C/2 h, THF) 72). The ratio of Cram to anti-Cram product 125 126 turned out to be 88 12 (Table 6) which is higher than that observed for CH3MgX (66 34 = or CH3Li (65 35) 9S). 

Finally, the first case of 1,4 asymmetric induction in the addition of organo-titanium reagents to carbonyl compounds has been reported 83). O-Phthalic-dicarb-oxaldehyde 164 reacts with one equivalent of methyltitanium triisopropoxide 6 to form the mono-adduct 165 in high yield (>90% conversion 71% isolated)13. If two equivalents of 6 are employed, smooth dimethylation occurs, providing an 83 17 mixture of d, 1 and meso diols 166 and 167, respectively (Equation 56)83),... 

Michael additions of organotitanium or zirconium reagents remain to be explored systematically. Recently, Stork described an interesting stereoselective intramolecular Michael addition in which zirconium enolates appear to be involved113). In another Michael type process, methyltitanium triisopropoxide 6 was added enantioselectively to a chiral a, p-unsaturated sulfoxide, but CH3MgCl was more efficient114). 

Consequently, various Grignard reagents have been shown to be effective for the intramolecular cyclopropanation reactions with insignificant differences in yields. Whereas several titanium alkoxides and aryloxides can also be employed, chlorotitanium triisopropoxide and methyltitanium triisopropoxide have often been found to be the titanium reagent of choice. Ether, THE, toluene, or even dichloromethane are generally appropriate reaction solvents. 

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