Inherent Oxygen Preference in Enolate Monofluoromethylation and a Synthetic Entry to Monofluoromethyl Ethers

Abstract

The control of regioselectivity in the alkylation of enolates is one of the oldest research areas in organic chemistry. [1] The ratio of regioisomers formed by C/O-alkylation is sensitive to the extent of substrate enolization, which is highly dependent on the structure of the carbonyl compound, but also on the nature of the alkylating reagent and the reaction conditions, in particular the solvent and base. It has been shown that more C-alkylation tends to be observed with softer nucleophiles, whereas O-alkylation is favored with harder electrophiles. [2,3] However, the complete control of C/O regioselectivity is still a challenge, for example, the regioselective Omethylation of b-ketoesters 1. [3, 4] In 2008, we reported that the trifluoromethylsulfoxinium salt 2 was very effective for the electrophilic trifluoromethylation of carbon-centered nucleophiles. [5] As an extension of our interest in the synthesis of organofluorine compounds, [6] we reveal herein that the electrophilic monofluoromethylation of 1,3-dicarbonyl compounds by the novel monofluoromethylsulfoxinium salts 3 occurs selectively at the oxygen atoms of enolates, rather than at the corresponding carbon atoms, to provide 4, whereas trifluoromethylation by enolate alkylation with 2 takes place at the carbon centers. The resulting previously unknown monofluoromethyl enol ethers 4 of b-ketoesters [7] can be conveniently transformed into monofluoromethyl ethers 5 in high yield by a reduction system based on Pd/C catalysis (Scheme 1). As a consequence, the approach not only constitutes one of the scarce examples of the selective Oalkylation of enolates, but also provides a new synthetic entry to biologically relevant monofluoromethyl ethers, which are of interest to the pharmaceutical and agrochemical industries, and which are difficult to obtain by the direct electrophilic fluoromethylation of alcohols. [8,9] We also described the monofluoromethylation of other oxygen-centered nucleophiles, such as carboxylic acids, phenols, naphthols, alcohols, and sulfonic acids, with the self-stable monofluoromethylating reagents 3. Thus, this approach provides access to a great number of biologically relevant monofluoromethyl esters, ethers, and sulfonates.The novel electrophilic monofluoromethylation reagents 3 were synthesized by the procedure shown in Scheme 2. Phenyl monofluoromethyl sulfoxide (7), [10a,b] prepared from thioanisole (6) in three steps, including nucleophilic substitution of chloride with KF, was converted into sulfoximine 8 under conventional conditions by treatment with NaN 3 / H 2 SO 4 . (Caution! This step involves the generation of explosive hydrogen azide). The stepwise methylation of 8 with Me 3 OBF 4 /K 2 CO 3 followed by methyl trifluoromethanesulfonate gave N,N-(dimethylamino)-S-phenyl-Smonofluoromethyloxosulfonium trifluoromethanesulfonate (3 a) via 9 [10c] as a viscous oil. The trifluoromethanesulfonate 3 a was transformed into the hexafluorophosphate 3 b as colorless crystals with KPF 6 in CH 2 Cl 2 in 88 % yield.We began our inves...

Einführung von Fluor und fluorhaltigen funktionellen Gruppen

“…Da das Reagens 2.1 durch Alkylierung von Natriumthiophenolat mit Chlorfluormethan hergestellt wird, ist eine Fluormethylierung mit Chlorfluormethan effizienter und kann mit reaktiven Substraten wie Phenolen, Thiophenolen und Imidazolen ähnliche Ausbeuten liefern. [ [176] Eine elektrophile Fluormethylierung von Arylnucleophilen wurde unseres Wissens bisher noch nicht beschrieben.…”

“…Die nucleophile Fluormethylierung von Elektrophilen basiert auf der Verwendung von Fluormethidäquivalenten, die normalerweise mesomere stabilisierende Gruppen, beispielsweise Sulfone, enthalten. [ [176] Eine elektrophile Fluormethylierung von Arylnucleophilen wurde unseres Wissens bisher noch nicht beschrieben. Auch das seltene Beispiel einer radikalischen Fluormethylierung wurde beschrieben.…”

Cation versus Radical: Studies on the C/O Regioselectivity in Electrophilic Tri‐, Di‐ and Monofluoromethylations of β‐Ketoesters

“…They concluded that the enolate ion of 1 a attacks at the methyl carbon atom of the sulfonium salts through an ionic S N 2 process after the formation of a S—O sulfurane intermediate (Scheme 2). [10] In this context, our findings of complete C selectivity in trifluoromethylation5c and O selectivity in monofluoromethylation3h are of great interest not only for the synthesis of fluorinated compounds but also for the mechanistic aspect of alkylations. The number of fluorine atoms should have an effect on C and O selectivities.…”

“…It has been shown that C-alkylation tends to be observed more frequently with softer electrophiles, while O-alkylation is preferred with harder electrophiles. [8, 9] However, the complete control of C/O regioselectivity is still a challenge, for example, in the O-regioselective methylation of β-ketoesters 3h,. [9, 10] Matsuyama and co-workers carefully examined the methylation of methyl 1-indanone-2-carboxylate ( 1 a ) using two types of methyl sulfonium salts A and B in the presence of K 2 CO 3 in dichloromethane.…”

Efficient Difluoromethylation of sp3 Carbon Nucleophiles by Bromodifluoromethylation Reagents with Organic Bases

“…[8–10] Electrophilic difluoromethylation through difluorocarbene species has attracted considerable attention, and several methods have been reported 8a–h, j, l. Although the difluoromethylation of heteroatom-centered nucleophiles such as oxygen, sulfur and nitrogen nucleophiles is well studied,[11], 8g, j, l mild and efficient difluoromethylation methods for carbon-centered nucleophiles are relatively scarce 8i, k–m, 12d. In 2007, Prakash and co-workers developed a new electrophilic difluoromethylating reagent, S -(difluoromethyl)diarylsulfonium tetrafluoroborate 8i.…”