Methyltitanium reagents

The methyltitanium reagents 37 modified by the chiral 2-pyrrolidinemethanols 36 also did not show satisfactory enantioselectivities in addition reactions to aromatic aldehydes35. Noteworthy, however, is the fact that the enantioselectivity substantially increases with the change from A-methyl to A-acyl substituents. 

With the chiral methyltitanium reagents 39, modified by the bidentate ligands A-sulfonyl-norephedrine 38, a pronounced enantioselectivity is observed in reactions with aromatic aldehydes. Considerably lower enantiosclcction is obtained with aliphatic aldehydes36. 

Addition of the analogous methyltitanium reagent to bcnzaldchydc afforded the addition product with only 59% ee34. Use of the methyltitanium reagent obtained via chiral modification by the tartaric acid derived diol 43, did not lead to an improvement of the enantioselectivity42. 

Chiral methyltitanium reagents.1 The N-sulfonamides (1) formed from norephedrine have been used as chiral ligands for a methyltitanium reagent. Thus addition of 1 to TiCl4 and CH3Li (1 4) and then to isopropanol provides a reagent... 

The BIPOLato-Ti-TADDOLato catalysts prepared by addition of BIPOL and TADDOL to Ti(0 Pr)4, catalyze methylation with an achiral methyltitanium reagent to give highly enantiomerically pure methylcarbinol. Since the sterically bulky 3,3 -substituents leads to an increase in enantioselectivity, the chirality of BlPOLato-Ti(0 Pr)2 catalyst 30 can be dynamically controlled by the chiral TADDOL moiety (Scheme 8.25). 3,3 -Dimethoxy derivative affords complete enantioselectivity (100% ee), while the moderate enantioselectivity is obtained with the parent BIPOL (73% ee). 

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... 

Surprisingly, aromatic nitriles were found not to yield 1-arylcyclopropylamines under these conditions. However, this deficit is compensated for by a complementary method developed by de Meijere et al. using diethylzinc in the presence of methyltitanium triiso-propoxide and lithium isopropoxide (Scheme 11.40). While aliphatic nitriles 152 gave primary cyclopropylamines 155 in only 12—16% yield with this reagent mixture, aromatic nitriles 156 and 158 furnished 1-arylcyclopropylamines 157 and 159 in moderate (28—40% for substituted benzonitriles 156) to good (70% for 3-cyanopyridine 158) yields (Scheme 11.40) [138],... 

Dichloro(cyclopentadienyl)methyltitanium, CpTi(CH3)Cl2 (1). The reagent is prepared by reaction of CpTiCl3 with (CH3)2Zn (71% yield).15 Unlike many organotitanium reagents, 1 is heat-stable. As expected, 1 forms adducts with aldehydes at room temperature but reacts only slowly with ketones even at 50°. The reaction with benzoyl chloride is slow and requires 2 equiv. of 1 to afford 2-phenyl-2-propanol (50% yield).16... 

The electronic configuration of titanium is [Ar] 3d24s2, which means that Ti(IV) compounds are d° species with free coordination sites 1-27,28). H-NMR and 13C-NMR data are known and have been occasionally discussed in terms of bond polarity 19), but such interpretations are obviously of limited value. The electronic structure of methyltitanium trichloride 17 and other reagents have been considered qualitatively 52) and quantitatively S3 56> using molecular orbital procedures. It is problematical to compare these calculations in a quantitative way with those that have been carried out for methyllithium 57> since different methods, basis sets and assumptions are involved, but the extreme polar nature of the C—Li bond does not appear to apply to the C—Ti analog. Several MO calculations of the w-interaction between ethylene and methyltitanium trichloride 17 (models for Ziegler-Natta polymerization) clearly emphasize the role of vacant coordination sites at titanium 58). 

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). 

The first system to be studied involved the addition of methyltitanium tri-isopropoxide 6 (one part) to a 1 1 mixture of hexanal 74 and 2-ethylbutanal 75 21). The product ratio 76 77 turned out to 92 8 (95 % conversion), showing that reactions of organotitanium reagents are very sensitive to the steric environment around the reaction center. It is interesting to note that in Grignard reactions a reversed mode of addition is required, i.e., the aldehyde is added to the very basic organometallic reagent, otherwise rapid aldolization sets in. For competition experiments this is unsuitable 21). 

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). 

As already shown in Section B.I, certain organotitanium reagents readily form isolable, octahedral 1 2 adducts with such donor molecules as THF, glyme, thio-ethers, amines and diamines1,19) (Equation 47). In case of methyltitanium trichloride 17, structural data show the methyl group to occupy the equatorial position 96). In order to test whether such molecules undergo stereoselective addition to aldehydes (Equation 47), we reacted 134, 135 and 136 (prepared from TMEDA, glyme and THF, respectively) with 2-phenylpropanal 12491. The 125 126 ratios of 80 20, 82 18 und 85 15 show that the Cram product is preferred in all cases... 

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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