Titanium-Catalyzed Stereoselective Geminal Heterodihalogenation of β-Ketoesters

Abstract

[reaction: see text] beta-Ketoesters can be effectively monofluorinated with F-TEDA using CpTiCl(3) as a catalyst. With the use of this catalyst, the extent of the competing difluorination does not reach 10%. [TiCl(2)(TADDOLato)] complexes catalyze the one-pot enantioselective heterodihalogenation of beta-ketoesters with F-TEDA and NCS to afford alpha-chloro-alpha-fluoro-beta-ketoesters in moderate to good yields. The sequence of addition of the halogenating agents determines the sense of chiral induction.

Expanding the scope of asymmetric electrophilic atom-transfer reactions: Titanium- and ruthenium-catalyzed hydroxylation of β-ketoesters

“…1 (2)(3)(4)(5). Our work inspired further developments involving chiral Pd catalysts (6) and chiral phase transfer catalysts for the same type of fluorination (7).…”

“…The ␣-functionalization of carbonyl compounds most often relies on the reaction of enolate anions, or enol derivatives with electrophiles. The direct activation of the enol form of keto derivatives has recently been introduced as a new synthetic methodology to achieve ␣-amination (9) or, as already mentioned, ␣-halogenation (2)(3)(4)(5). So far, the only straightforward enantioselective ␣-hydroxylation is the reaction of enolate salts with enantiopure N-sulfonyloxaziridines, acting as electrophilic oxygen sources, as developed by Davis (10,11).…”

Catalytic Enantioselective Fluorination of α‐Chloro‐β‐keto Esters in the Presence of Chiral Nickel Complexes

“…The absolute configuration of 3b was determined to be S by comparing chiral HPLC data to the published values of ref. [13] On the other hand, ethyl 2-chloro-3-oxobutanoate (1g) could not be fluorinated under identical conditions (Table 4, entry 7). [a] Isolated yields.…”

“…[12] Togni has recently reported the first catalytic enantioselective synthesis of a-chloro-a-fluoro-b-keto esters using chiral titanium complexes with up to 65% enantiomeric excess. [13] Recently, we have developed Pd(II)-catalyzed enantioselective fluorination of achloro-b-keto esters with up to 77% enantioselectivity. [14] As part of a research program related to the development of synthetic methods for the enantioselective construction of stereogenic carbon centers, [15] we recently reported the catalytic enantioselective amination and Michael-type reaction of active methines in the presence of chiral nickel(II) complexes developed by the Evans group.…”

Recent Advances in Catalytic Enantioselective Fluorination Reactions

“…[15] By using their Ti-TADDOL complex as a catalyst they examined one-pot sequential chlorination-fluorination and fluorination-chlorination reactions, and a,a-chlorofluoro-b-keto esters were obtained with up to 65% ee. Kim and co-workers later reported the same reaction using cationic aqua palladium complexes 22 [16] closely related to the palladium complexes 11 described previously by Sodeoka.…”