Titanium reagents, coupling with aldehydes

Preparation Essentially this reaction involves the preparation of a low-valent titanium reagent that then couples carbonyl groups, including esters to aldehydes/ketones. Generally, TiCLt is reduced with some reducing agent (LiAIH4, Zn, Mg). 

The bifunctional cyclopropane 156 was also prepared by modified Simmons-Smith cyclopropanation 85) of 2-trimethylsilyl-2-propen-l-ol 157 84) followed by oxidation of the cyclopropylcarbinol 158 with activated manganese dioxide 88 >, in 72% overall yield, Eq. (50) 86,89). Coupling of the aldehyde 156 with 2,6-dimethylcyclohexenone 159 90) induced by the low valent titanium reagent from TiCl3 and zinc-copper couple (or lithium metal) provided the silylated cyclopropyldiene 160, in 50-60% yield, Eq. (51) 89 91>. 

It is advantageous to utilize either titanium isopropoxide or trimethylaluminum complexes with aldehydes in general, because pinacol-coupled diols form with the Zn/CH2Br2/riG4 systems as minor side products. No evidence of Simmons-Smith-type side products was observed with any of the methylena-tion reagents. Additional examples of the reaction with aldehydes are presented in Table 11. 

Several ADAM (alkenyidiarylmethane) II non-nucleoside reverse transcriptase inhibitors were prepared by M. Cushman and co-workers. The McMurry reaction was the key transformation that enabled the coupling of the diaryl ketone with a variety of aldehydes in good yield. The commercially available TiCU-THF (2 1) and zinc dust was used to prepare the low-valent titanium reagent in refluxing THF. To this suspension was added the diaryl ketone and the aldehyde successively. 

Alkenes can be obtained from aldehydes or ketones on reductive dimerization by treatment with a reagent prepared from titanium(III) chloride and zinc-copper couple (or L1A1H4), or with a species of active titanium metal formed by reduction of titanium(III) chloride with potassium or lithium metal. This McMurry coupling reaction is of wide application, but in intermolecular reactions generally affords a mixture of the E- and Z-alkenes (2.99). 

A combination of alkali metal salts, particularly potassium chloride, with low-valent titanium reagents generated from titanium chlorides with lithium or magnesium in either THF or DME are effective reagents for stereoselective McMurry coupling reactions of aldehydes and ketones to substituted alkenes (Figure 1.11). 

More work has been reported on the inter- and intra-molecular pinacolic coupling of aldehydes and ketones, e.g. cycloheptanone and acetone gave (220) on treatment with a magnesium-mercury-titanium(iv) chloride reagent. ... 

Lewis acid promoted reactions of silicon enolates, /.e., silyl enol ethers and ketene silyl acetals with various electrophiles have yielded a wealth of novel and selective synthetic methods. This combination of reagents has been used in the past to perform such reactions as aldol-condensations with aldehydes and acetals, imine-condensations, conjugate additions to a,P-enones, alkylations, electrophilic aminations, and Diels-Alder/cyclocondensations. Our own interest in this field has involved the use of titanium tetrachloride to promote the reaction of ketene silyl acetals with non-activated imines as an efficient route to P-lactams. This reaction has been applied to the asymmetric synthesis of P-lactams via a chiral imine-titanium tetrachloride template. We have also found that both ketene silyl acetals and vinylketene silyl acetals oxidativelly dimerize or cross-couple, in the presence of titanium tetrachloride to conveniently yield various diesters . Our present study concerns reactions of vinylketene silyl acetals with non-activated imines and vinylimines promoted by titanium and zirconium tetrachlorides. 

McMurry reactions will be presented in the following order intermolecular, intramolecular, mixed (tandem) couplings of aldehydes and ketones, and finally keto ester, oxoamide, and acetal couplings. All the compounds which serve as illustrations are listed in Tables 6.1-6.10, along with the titanium reagents and solvents used for their preparation and the yields of isolated products where not specified, the reactions were performed at solvent reflux temperature. 

Reduction of aromatic aldehydes to pinacols using sodium amalgam is quite rare. Equally rare is conversion of aromatic aldehydes to alkenes formed by deoxygenation and coupling and accomplished by treatment of the aldehyde with a reagent obtained by reduction of titanium trichloride with lithium in dimethoxyethane. Benzaldehyde thus afforded /ra/is-stilbene in 97% yield [206, 209]. 

Coupling reactions of aldehydes or ketones to 1,2-diols proceed with low-valent metals such as magnesium, zinc, and aluminum.Because it is not easy to control the stereoselectivity (diastereoselectivity and/or enantioselectivity) of the reactions with such main group metals, low-valent species of early transition metals are frequently employed with electron-donating ligands. The representative reagents are low-valent titanium and samarium species. 

Titanium(iv) iodide" " or a combination of a titanium(iv) salt and an iodide source promotes pinacol coupling reactions of aromatic aldehydes. The combination of the reagents is considered to generate titanium(m) species along with U. 

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