Substrate Range of the Titanium TADDOLate Catalyzed Asymmetric Fluorination of Activated Carbonyl Compounds

Abstract

The substrate range of the [TiCl2(TADDOLate)] (TADDOL=α,α,α′,α′‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol)‐catalyzed asymmetric α‐fluorination of activated β‐carbonyl compounds has been investigated. Optimal conditions for catalysis are characterized by using 5 mol‐% of TiCl2(naphthalen‐1‐yl)‐TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F‐TEDA (1‐(chloromethyl)‐4‐fluoro‐1,4‐diazoniabicyclo[2.2.2]octane bis‐[tetrafluoroborate]) at room temperature. A series of α‐methylated β‐keto esters (3‐oxobutanoates, 3‐oxopentanoates) with bulky benzyl ester groups (60–90% ee) or phenyl ester (67–88% ee) have been fluorinated readily, whereas α‐acyl lactones were also readily fluorinated, but gave lower inductions (13–46% ee). Double stereochemical differentiation in β‐keto esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5 : 3.5. For the first time, β‐keto S‐thioesters were asymmetrically fluorinated (62–91.5% ee) and chlorinated (83% ee). Lower inductions were observed in fluorinations of 1,3‐diketones (up to 40% ee) and β‐keto amides (up to 59% ee). General strategies for preparing activated β‐carbonyl compounds as important model substrates for asymmetric catalytic α‐functionalizations are presented (>60 examples).

Morita–Baylis–Hillman adducts as building blocks of heterocycles: a simple approach to 4-substituted pyrazolones, and mechanism investigation via ESI–MS(/MS)

“…Here, we prepared the 2-methylated b-ketoesters observing no issues regarding dialkylation. Our protocol avoids the use of strong bases and acylating reagents and leads to both, yields and scope, comparable or even better than those reported in literature [27,29,32,33,[55][56][57][58][59][60]. This was clearly shown for compound 3b, where different methodologies and their respective yields are presented (Scheme 6) [27,29,33,[55][56][57].…”

Modern Approaches for Asymmetric Construction of Carbon–Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs

“…When milder NFSI or NFPY-BF 4 was used as the fluorinating reagent instead of highly reactive Selectfluor, increased enantioselectivity was observed for such highly enolized substrates but not for nonenolized substrates, but the reactions using these reagents were very slow. 197–199…”

Asymmetric Preparation of α-Quaternary Fluorinated β-keto Esters. Review

“…From this report until 2010 a range of metal catalysed fluorination reactions have been developed and previously reviewed [43]. Some years later, in 2012, Togni's group in a remarkable paper mainly dedicated to acyclic 1,3-dicarbonyl compounds, reported that using the same Ti/TADDOL complex the cyclic tetralone 16 (Scheme 1), gave the α-fluorinated product in 20% ee (entry 20, Table 1) [44]. We will comment on these results on acyclic 1,3-dicarbonyl later on.…”

“…Regarding the enantioinduction they are not so rigid and have more degrees of conformational freedom in comparison with cyclic 3-oxo esters. In 2012, Togni's group reported [44] that using the Ti/TADDOL complexes (1, Figure 2) and Selectfluor ® ( Figure 1) a series of alkyl α-methyl 3-oxobutanoates were fluorinated giving excellent yields (44-96%) and moderate ee (10 examples, 45-81% ee). In addition, alkyl α-methyl 3-oxopentanoates could be fluorinated with moderate to high selectivities (7 examples, 30-90% ee).…”

“…Fluorinated acyclic β-keto esters prepared by Togni's research group[44].Molecules 2020, 25, x FOR PEER REVIEW 8 of 28…”