Fluorination of ketones

G.A. Olah, M. Nojima, I. Kerekes, Synthetic methods and reactions. I. Seleniuum tetrafluoride and its pyridine complex. Convenient fluorinating agents for fluorination of ketones, aldehydes, amides, alcohols, carboxylic acids, and anhydrides, J. Am. Chem. Soc. 96 (1974) 925-927. 

The fluorination of nitriles is successful only if the resulting trifluoromethyl derivatives are low-boiling compounds (bp < IOC). Butyronitrile and isobutyronitrile give a mixture of products. The same trend is observed in the fluorination of ketones. Acetone is converted into 2,2-difluoropropane (90%) but other ketones, such as ethyl methyl ketone, undergo fragmentation.126... 

The fluorination of ketones with DAST may result in the formation of vinyl fluorides, e.g. 5, in addition to gew-difluoro compounds. If vinyl fluorides are the desired product, this reaction can be promoted by carrying out the fluorination procedure in 1,2-dimethoxyethane in the presence of fuming sulfuric acid.51... 

Table 10. Direct a-Fluorination of Ketones Using l-Fluoro-4-hydroxy-l,4-dia-zoniabicyclo[2.2.2]octane Bis(tetrafluoroborate) (NFTh, 21)96...

Various chiral amines can catalyze the direct enantioselective a-fluorination of aldehydes. Enders and Hiittl have focused on the use of Selectfluor for the a-fluorination of aldehydes and ketones [24a], For the aldehydes, no enantiomeric excess was reported using L-proline as the catalyst. In an attempt to perform direct enantioselective a-fluorination of ketones, cyclohexanone was used as the model substrate and a number of chiral amines were tested for their enantioselective properties however, the enantiomeric excess was rather low and in the range of 0 to 36% ee. 

Fluorination of Ketone Enolates. (+)-lV-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) reacts with ketone enolates to give a-fluoro ketones. For example, reaction of the sodium enolate of propiophenone 2 gives a-fluoropropiophenone 3 in 41% isolated yield (eq 1). No enantioselectivity, however, is observed due to racemization of the product under the reaction conditions. When a tertiary substituted ketone such as a-methyltetralone (4) is employed, the desired a-fluorinated product (S)-(-)-S is obtained in 76% ee and 53% isolated yield (eq 2). In this reaction, (+)-l was found to be more reactive, affording higher yields and better enan-tioselectivities than its parent (-)-N-fluoro-2,10-camphorsultam i.e., 35% ee, < 5% yield. ... 

A -Fluoro-dihydrobenzo[l,2-i isothiazole is an efficient agent for electrophilic asymmetric fluorination of enolates <1999JOG5708>. A -Fluoro-2,10-camphorsulfonamide 237 (see Section 4.05.6.4.2) is a good asymmetric reagent for a-fluorination of ketones <1998JOG9604>. 

Halogenations. Fluorination of ketones can make use of 7, although the enantioselectivity is only moderate. Of the active methylene compounds, fluorination in the presence of dihydroquinine esters is adequate. A synthesis of p-amino-a-hydroxy acids involves iodination of substrates such as 8, which is attended by spontaneous cyclization. ... 

Fluorination of ketones. Direct fluorination with reagent (1) often proceeds in... 

SCHEME 13.11. Enatnine-catalyzed asymmetric a-fluorination of ketones. 

An enamine-catalyzed asymmetric a-fluorination of ketones, which are notoriously challenging substrates for this reaction, was reported by MacMillan and coworkers in 2011 [27]. After exhaustive automated screening of over 250 organo-catalysts, a Cinchona alkaloid-derived primary amine organocatalyst was identified as the optimal catalyst for this transformation (Scheme 13.11). Only cyclic ketones provided fluorinated products in high yields and enantiomeric excesses. 

The first highly enantio-selective a-fluorination of ketones using organocatalysis has been accomplished. " The optimal catalytic system, a primary amine-functionalized cinchona alkaloid (24), allows the direct and asymmetric a-fluorination of a variety of carbo- and hetero-cyclic substrates. Furthermore, this protocol also provides diastereo-, regio-, and chemo-selective catalyst control in fluorinations involving complex carbonyl systems (up to 98 2 dr, 99% ee, and >99 1 regiocontrol). 

The first investigation on continuous geminal fluorination of carbonyl groups vhth dialkylaminosulfur trifluoride derivatives in micro- and minifluidic devices vas reported by Lovis et al. [3]. In 2007, they described the fluorination of ketone functionalities vith DAST as the second step in steroid synthesis (Figure 6.2) [3b]. 

A safety-related assessment of the described geminal fluorination of ketones with DAST was also performed 4]. Considering the overall process including pumps, reservoirs for substrates, products/quench solution, process analysis, predetermined breaking points, and so on, the continuous process with minifluidic devices is technically feasible and reasonable. 

Stavber S, Jereb M, Zupan M. Direct a-fluorination of ketones using N-F reagents. Synthesis 2002 17 2609-2615. 

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