Dichloromethane as an Unusual Methylene Equivalent. A New Entry of Highly Nucleophilic and Selective Titanium−Methylene Complexes for Ester Methylenation

Abstract

[reaction: see text] The successful application of CH2Cl2-Mg-TiCl4-system mediated methylenation of various esters such as tert-butyl ester and 2,5-cyclohexadiene-1-carboxylate highlights the extraordinary reactivity, selectivity, and the nonbasic nature of this new methylene-carbenoid, which serves as a practical reagent applicable to large-scale synthesis.

A New Entry of Highly Selective and Nucleophilic BrH2C‐ and ClH2C‐Titanium Complexes for Carbonyl Coupling

“…We previously demonstrated the impact of electron‐pair‐donor (EPD) additives on this TiCl 4 , Mg mediated protocol . On similar grounds, we found the most prominent effect of EPD additives on this process.…”

“…This necessity has actuated resurgence to devise a new chemoselective protocol to achieve chloromethyl and bromomethyl carbinols, which should be suitable to sterically hindered and enolizable aldehydes as well as ketones. Earlier studies in our laboratory proved the feasibility of CHnXm‐TiCl 4 ‐Mg system to prepare highly nucleophilic halo‐methylene and methylene carbenoids . Recently, we demonstrated an efficient strategy to circumvent the preparation of dibromo‐ and tribromomethyl titanium reagents through the oxidative addition of C–Br bond to Ti‐Mg bimetallics.…”

“…Recently, we demonstrated an efficient strategy to circumvent the preparation of dibromo‐ and tribromomethyl titanium reagents through the oxidative addition of C–Br bond to Ti‐Mg bimetallics. [9k] In light of that, we envisioned to develop a highly selective and scalable protocol, herein, whereby the TiCl 4 ‐Mg mediated direct coupling of dihalomethane with carbonyl compounds can be directed not only to bromomethyl carbinol but also to chloromethyl carbinol in good to excellent yield.…”

New, General, and Practical Preparation of Methyl Ketones via the Direct Coupling of Amides with CH2Cl2 Promoted by TiCl4/Mg

“…However, the direct acylation of methyl-metal reagents is often complicated by accompanying overaddition, leading to the formation of tertiary alcohols, and suffers from one or more experimental drawbacks such as use of expensive or potentially unstable reagents, delicate reaction conditions, and complicated procedures. In searching for a new and practical strategy based upon the concept of simple carbonyl-methylenation, , we turned our attention to the methylenation of amides since the resultant enamines would be expected to react with water quite readily to give methyl ketones (Scheme ). Our development of a CH 2 Cl 2 −TiCl 4 −Mg system for carbonyl-methylenation led to our consideration of such a system for this process .…”

“…In searching for a new and practical strategy based upon the concept of simple carbonyl-methylenation, , we turned our attention to the methylenation of amides since the resultant enamines would be expected to react with water quite readily to give methyl ketones (Scheme ). Our development of a CH 2 Cl 2 −TiCl 4 −Mg system for carbonyl-methylenation led to our consideration of such a system for this process . Effecting such methylenations by use of a highly nucleophilic methylene equivalent derived from the CH 2 Cl 2 −TiCl 4 −Mg system may have the advantage of (1) enhancing synthetic efficiency by not requiring expensive or potentially unstable reagents and (2) extending the preparation to deuterated methyl ketones via Ti−Mg-promoted CD 2 -transfer reactions of CD 2 Cl 2 .…”