Synthesis of Difluorinated Halohydrins by the Chemoselective Addition of Difluoroenolates to α-Haloketones

Abstract

α-Haloketones are valuable intermediates in the synthesis of pharmaceuticals and natural products because they display two electrophiles. Although chemoselective additions to each of these functional groups are known, the use of fluorinated nucleophiles has not been characterized, except for the dimerization of fluorohalomethyl ketones. Our studies demonstrate the use of difluoroenolates to create difluorinated bromohydrins and chlorohydrins from α-haloketones without any cyclization or rearrangement due to the mild conditions.

Graphical Abstract

The α-halocarbonyl group is an essential building block for assembling complex natural products^1–2 and creating other valuable organic structures.^3–8 Notable examples of the utility of the α-halocarbonyl group appeared in the total synthesis of batrachotoxin A¹ and palau’amine.² This functional group presents two electrophiles, and a typical goal of methodology development is the chemoselective manipulation of the carbonyl group^3,7,8 or the halogen.^4–6 Although the reactivity of many nucleophiles has been investigated with the α-halocarbonyl group, fluorinated nucleophiles have not been explored with this functionality.

Fluorinated organic molecules are attractive targets for pharmaceutical development, and many drugs display a fluorine atom.⁹ New methods for the synthesis of fluorinated compounds are of significant current interest;^3,10–13 however, the only examples in the literature of the addition of fluorinated nucleophiles to the α-halocarbonyl group are the unwanted reaction of difluorohalomethyl ketones (Figure 1).^14–16 In each of these three cases, a difluoroenolate is generated from a difluorohalomethyl ketone in the presence of a metal, but this intermediate is quickly consumed by dimerization with the starting material. Our laboratory has developed a mild method for the creation of difluoroenolates from highly α-fluorinated gem-diols.¹⁷ We hypothesized that this process could be exploited for the controlled addition of difluoroenolates to substrates displaying an α-haloketone. The highly α-fluorinated gem-diols are produced in two steps from ketones¹⁷ or aldehydes¹⁸ and have been shown to be useful starting materials for making fluorinated organic molecules.^19–22 We aimed to create difluorinated halohydrins from α-chloroketones or α-bromoketones and demonstrate the use of these intermediates in the synthesis of fluorinated organic molecules.

Figure 1.

Additions of difluoroenolates to α-haloketones to produce fluorinated halohydrins.

Our efforts to identify conditions for this transformation relied on the conditions from our prior study of the aldol reaction of aldehydes with the difluoroenolates from highly α-fluorinated gem-diols.¹⁷ After optimization (see Table S1), we determined that treatment of the gem-diol in the presence of an α-bromoketone with five equivalents of lithium bromide and 1.2 equivalents of triethylamine produced the bromohydrins 1–8 in 42–91% isolated yields (Scheme 1). Only bromohydrins were isolated in each of these cases, and the epoxides were not observed for these transformations. The scope of the gem-diols included aromatic, heteroaromatic, and alkyl groups, whereas the α-bromoketones displayed substituted phenyl rings. It is vital that the halogen of the lithium salt and the α-haloketone are the same, and in these cases, lithium bromide was only paired with α-bromoketones. Using other lithium salts, such as lithium chloride, with these examples produce chlorohydrins as inseparable side-products. We have previously reported the necessity of matching salts during halogenation of the difluoroenolate in the synthesis of α-halo-α,α-difluoromethyl ketones.²³

Scheme 1.

Additions of difluoroenolates generated from highly α-fluorinated gem-diols to α-bromoketones to produce difluorinated bromohydrins 1–8.

In order to synthesize chlorohydrins, lithium bromide was exchanged with lithium chloride and α-chloroketones were used as starting materials (Scheme 2). In a similar fashion, chlorohydrins 9–16 were isolated in good to excellent yields of 46–95%. By-products from the formation of an epoxide were not observed. The scope of the gem-diols included aromatic, heteroaromatic, and alkyl groups. Compatible α-chloroketones included substituted phenyl rings and α-chloroacetone (e.g., 11 and 14), which broadens the scope of the process. Again, the α-chloroketones must be paired with lithium chloride to prevent halogen exchange and the formation of unwanted by-products.

Scheme 2.

Additions of difluoroenolates generated from highly α-fluorinated gem-diols to α-chloroketones to produce difluorinated chlorohydrins 9–16.

In contrast to the prior reactions, when the fluorinated gem-diol 17¹⁷ was reacted with 2-bromo-4′-methoxyacetophenone 18, the epoxide 19 was isolated as the major product (Scheme 3). Additionally, we investigated the outcome of the reaction of the fluorinated gem-diol 20¹⁷ with the α-bromoketone 18, and the epoxide 21 was also obtained as the product. These examples demonstrate that the product can be dictated by the starting material in some cases. The fluorinated gem-diol 20¹⁷ was reacted with α-chlorocyclohexanone, and a single product (22) was isolated in 67% yield. The tertiary alcohol and secondary chloride on the product 22 display a syn-relationship. This stereochemical configuration is assigned by ¹H NMR data in which the proton of the chloromethylene group (i.e., 4.45 ppm) displays coupling constants of J_ax-ax = 10.9 Hz and J_ax-eq = 5.2 Hz that support an axial-axial and axial-equatorial coupling, respectively. Analysis of the ¹H–¹H 2D NOESY and ¹H–¹⁹F 2D HOESY NMR data also support this assignment.²⁴ In an analogous fashion, the fluorinated gem-diol 20¹⁷ was reacted with α-bromocyclohexanone, and the syn-product 23 was isolated. Analysis of the NMR data for 23 supported the similar stereochemical assignment.

Scheme 3.

Examples of reactions of α-haloketones that produce epoxides and generate multiple stereogenic centers.

Halohydrins are valuable synthetic intermediates, especially in the construction of heterocycles.²⁵ The assembly of heterocycles is imperative in the pharmaceutical industry, particularly for fluorinated targets.^10,26 Toste and coworkers have recently disclosed a procedure to produce oxazolines displaying an adjacent difluoromethyl group,¹⁰ and we envisioned that a difluorinated bromohydrin could also be used to make these useful products. Accordingly, the treatment of the bromohydrin 1 with cesium fluoride and boron trifluoroetherate in acetonitrile gave the difluorinated oxazoline 24. Halohydrins are also precursors on tertiary alcohols, and we have observed that the bromohydrin 5 transformed into the alcohol 25 by radical-mediated dehalogenation. These experiments demonstrate some of the potential uses of difluorinated halohydrins.

These studies validate the use of difluoroenolates to create difluorinated bromohydrins and chlorohydrins. The difluoroenolates are generated in situ from the release of trifluoroacetate from fluorinated gem-diols and react chemoselectively with the carbonyl group of α-haloketones without further cyclization or rearrangement. This method is compatible with aromatic, heteroaromatic, and aliphatic pentafluoro-gem-diols as well as aromatic and aliphatic α-haloketones. The difluorinated halohydrins can be transformed into a tertiary alcohol or an oxazoline. This work provides an entrance into fluorinated derivatives of halohydrins, which are valuable intermediates in the synthesis of many fine chemicals and naturally occurring compounds.

Scheme 4.

Synthetic applications of fluorinated halohydrins.

ABBREVIATIONS

NMR

nuclear magnetic resonance