Titanium tetrachloride Mukaiyama reaction

An exceptionally mild procedure for the cross-condensation of aldimines and enolsilanes has been described (eq. [67]) (80). This titanium tetrachloride-mediated reaction is predicated on the previous analogies provided by Mukaiyama for related aldol condensations (73a). Depending on aldimine structure and reaction time, either -lactams or their penultimate amino esters may be isolated from the reaction. The authors postulate that these reactions are proceeding via titanium enolates derived from ligand exchange by... 

Both 2- and 3-aryl-P-alanine derivatives have been prepared by the Mukaiyama reaction of imines when catalyzed by titanium tetrachloride. The reaction of ketene silyl acetals with 0-alkyl imines is another source of aryl-substituted P-alanines.20 O-Substituted hydroxylamines (an "0-imine") have been used in this type of reaction. When 4.28 reacted with O-silylketene acetal 4.29, in the presence of... 

There are several strategies that involve the use of transition metal catalysts in addition to the Mukaiyama reaction. Reaction of leucinal with 1,3-butanediol gave a mixture of 6.115 (in 9% yield) and 6.116 (in 71% yield). After the chromatographic separation of 6.116, the titanium tetrachloride catalyzed reaction with 3-trimethylsilyl-l-propene gave 6.117. Ozonolysis and oxidation gave lactam 6.118, which was converted to 6.101a in five steps (overall yield was 32% from 6.117). 

Oppolzer s sultams also provided a solution to the problem of the asymmetric acetate aldol addition based upon a Mukaiyama reaction of sUyl ketene N,0-acetal 276, derived from N-acetylsultam 92 (R = H). In the titanium tetrachloride-mediated reaction with various aldehydes, the diastereoselectivity is not particularly high - as typical for aldol additions of a-unsubstituted enolates. 

However, the analogous reactions of 1-Me with various enol silyl ethers 23 in the presence of titanium tetrachloride at - 78 °C, led directly to the products 21 a - c [26 a, 33] of Mukaiyama-type reactions [34] in moderate yields (Scheme 6). 

Mukaiyama, T., Banno, K., Narasaka, K. New cross-aldol reactions. Reactions of silyl enol ethers with carbonyl compounds activated by titanium tetrachloride. J. Am. Chem. Soc. 1974, 96, 7503-7509. 

The Mukaiyama version of the aldol reaction is well known a carbonyl-titanium tetrachloride complex reacts with a trimethylsilyl enol ether. Under these conditions there is no titanium enolate involved. Another procedure has been reported a trimethylsilyl enol ether reacts with titanium tetrachloride to give the titanium enolate addition of the carbonyl compound generates the aldol product (although with slightly lower diastereoselectivity than with Mukaiyama s procedure). (Z)-Enolsilanes from acyclic ketones react rapidly and stereospecifically with TiCU to form (Z)-configured CbTi enolates, while the ( )-isomers react slowly to afford low yields of mixtures of ( )- and (Z)-Cl3Ti enolates (Scheme 41). 

The titanium tetrachloride (TiCl4)-mediated aldol reaction of silyl enol ethers with aldehydes was first reported by Mukaiyama and co-workers [22]. Following this report, several other Lewis acids such as BF3 Et20, and SnCl4, or fluoride anions such as BU4F were found to be effective promoters or catalysts in this reaction. 

Group 4 Titanium and Zirconium. The titanium tetrachloride mediated aldol reaction of silyl enol ethers with aldehydes was first reported in early of 1970s (16,17). It proceeds in a highly regioselective manner for cross or direct aldol reactions in high yields (18-20). Since the pioneer contribution by Mukaiyama s group, numerous synthetically useful procedures were developed in titanium- and zirconium-catalyzed aldol reaction of broad substrates (21-23). 

An interesting approach reacted a cyclopropylcarbinolamine such as 7.157 with titanium tetrachloride to generate iminium salts such as 7.158. When this salt was generated in the presence of a silyloxy ethylene derivative such as 7.159, an amino-ester was formed. This Mukaiyama reaction 3 (see chapter four, section 4.2) generated 2-(l-N,N-dibenzoylaminocyclopropyl)ethanoate, 7.260.92... 

In previous investigations we could show that carbohydrate enones with the electrophilic terminus of the unsaturated carbonyl system at the anomeric carbon react with silyl enol ethers under catalysis of titanium tetrachloride, i. e. in a Mukaiyama-type reaction, to give the corresponding C-glycosides in high diastereoselectivity. The high stereocontrol observed could be explained in terms of a strongly adjusted cycloaddition-like transition state. This... 

Although the direct generation of titanium enolates is typically the most useful method of generating titanium enolates for aldol reactions, other methods have been described. Grubbs and Stille reported that titanium enolates could be generated by reaction of biscyclopentadienyltitanium al-kylidene complexes and acyl halides [93]. Oshima and coworkers reported the formation of titanium enolates from a-iodoketones with allylsilane and titanium tetrachloride [94]. Mukaiyama and coworkers reported the generation of titanium enolates from a-bromoketones on treatment with TiCh and copper powder [95]. 

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