Lithium triethylborohydride-promoted generation of α,α-difluoroenolates from 2-iodo-2,2-difluoroacetophenones: an unprecedented utilization of lithium triethylborohydride

Diuoroenolates are useful uorinated synthons for preparing diuoromethylene compounds, with signicant application in medicinal chemistry. Accordingly, the protocols to generate diuoroenolates have attracted much attention. Colby rstly reported that compounds triuoromethyl-a,a-diuoro-b-keto gem-diols could be used to give diuoroenolates by the release of triuoroacetate. Additionally, more diuorinated compounds have been developed as valuable precursors of diuoroenolates, such as a,a-diuoroketones, a,a-diuoro-a(trimethylsilylacet)amides, a,a-diuoro-b-ketoesters, a,a,atriuoroketones, and 2,2-diuoro-1,3-diketones. Furthermore, diuoroenoxysilanes or diuoroenol O-Boc esters were oen served as diuoroenolates in different diuoromethylenation reactions, as well as transition-metal diuoroenolates. 2-Iodo-2,2-diuoroacetophenones are one of the important building blocks to introduce a,a-diuoromethyl ketone fragment into molecules. Our group has reported several reactions with 2-iodo-2,2-diuoroacetophenones to construct structurally diverse diuoromethylene compounds. As part of our continued research, further structure modication of 2-iodo2,2-diuoroacetophenones was investigated. Lithium triethylborohydride (LiEt3BH, a superhydride, 1 M in THF) is a powerful reducing agent and can efficiently reduce a wide range of functional groups, especially halogen atoms. However, the reaction with 2-iodo-2,2-diuoroacetophenones and LiEt3BH result in the generation of diuoroenolates instead of reduction products. Herein, we disclosed the

Diuoroenolates are useful uorinated synthons for preparing diuoromethylene compounds, 1 with signicant application in medicinal chemistry. 2 Accordingly, the protocols to generate diuoroenolates have attracted much attention. Colby rstly reported that compounds triuoromethyl-a,a-diuoro-b-keto gem-diols could be used to give diuoroenolates by the release of triuoroacetate. 3 Additionally, more diuorinated compounds have been developed as valuable precursors of diuoroenolates, such as a,a-diuoroketones, 4 a,a-diuoro-a-(trimethylsilylacet)amides, 5 a,a-diuoro-b-ketoesters, 6 a,a,a-triuoroketones, 7 and 2,2-diuoro-1,3-diketones. 8 Furthermore, diuoroenoxysilanes or diuoroenol O-Boc esters were oen served as diuoroenolates in different diuoromethylenation reactions, 9 as well as transition-metal diuoroenolates. 10 2-Iodo-2,2-diuoroacetophenones are one of the important building blocks to introduce a,a-diuoromethyl ketone fragment into molecules. 11 Our group has reported several reactions with 2-iodo-2,2-diuoroacetophenones to construct structurally diverse diuoromethylene compounds. 11d-f As part of our continued research, further structure modication of 2-iodo-2,2-diuoroacetophenones was investigated. Lithium triethylborohydride (LiEt 3 BH, a superhydride, 1 M in THF) is a powerful reducing agent and can efficiently reduce a wide range of functional groups, especially halogen atoms. 12 However, the reaction with 2-iodo-2,2-diuoroacetophenones and LiEt 3 BH result in the generation of diuoroenolates instead of reduction products. Herein, we disclosed the LiEt 3 BH-promoted in situ generation of diuoroenolates from 2iodo-2,2-diuoroacetophenones and their application in aldoltype self-condensation and aldol reactions to give various a,a-diuoro-b-hydroxy ketones (Scheme 1).
Initially, we chose LiEt 3 BH as one of the reducing agents to selectively reduce the carbonyl group or iodine atom of 2-iodo-2,2-diuoroacetophenones. Surprisingly, our initial attempt to perform the reaction between 2,2-diuoro-2-iodo-1phenylethanone 1a and LiEt 3 BH at À78 C did not furnish any reduction product, instead leading to a self-adduct a,a,g,g-tetrauoro-b-hydroxy ketone 2a with high yield (Table 1, entry 1). Raising the temperature of LiEt 3 BH only led to a little increasing of the yield of reduction product 3a and 4a (entries 2 and 3). It was speculated that a diuoroenolate 5 was generated from 2,2-diuoro-2-iodo-1-phenylethanone with LiEt 3 BH, then the diuoroenolate 5 went through protonation process to form a,a-diuoroacetophenone 6. The aldol reaction between 5 and 6 gave the a,a,g,g-tetrauoro-b-hydroxy ketone 2a (Scheme 2).
We wonder that whether the uorine atom in 2-iodo-2,2-diuoroacetophenone play an important role in the fortuitous reaction. Therefore, the reaction of 2-halo-acetophenone or 2chloro(bromo, uoro)-2,2-diuoroacetophenone or 2,2-Scheme 1 The novel utilization of LiEt 3 BH for the generation of a,adifluoroenolates from 2-iodo-2,2-difluoroacetophenones. diuoroacetophenone with LiEt 3 BH were also performed in THF at À78 C. The results showed that all these reduction reactions proceeded well leading to the formation of different reduction products (see Scheme 1 in ESI †), which demonstrates the specic characteristic of substrate 2-iodo-2,2-diuoroacetophenone owing to the adjacent uorine atoms of carbonyl group.
The results indicated that 2-iodo-2,2-diuoroacetophenone derivatives bearing different aryl or heterocyclic ring could be served as diuoroenolates precursors through the reaction with LiEt 3 BH, which provided a novel and efficient access to diuoromethylenation reactions.
a,a-Diuoro-b-hydroxy ketones are an important class of substructure in medicinal chemistry, 13 which could be obtained via aldol reaction with diuoroenolates. 14 Accordingly, to further demonstrate the utility of LiEt 3 BH, aldol reaction of 2iodo-2,2-diuoroacetophenones with aldehydes promoted by LiEt 3 BH were conducted. 2-Iodo-2,2-diuoro-1-phenylethanone 1a and benzaldehyde 7 was selected as model reaction substrates to optimize the reaction condition (Table 3). The corresponding aldol produce 8 was produced in the presence of LiEt 3 BH (1.2 equiv. to compound 1a) at À78 C in THF (entry 1). The results showed that raising the temperature led to an increased yield of reduction product 4a (entries 2-4) and the conversation decreased with the decreasing of the amount of LiEt 3 BH (entry 5).
Hence, more aldol reactions were carried out under the optimized condition (Scheme 4). To our delight, the aldol products polyuorinated b-hydroxy ketones were obtained in high yields by employing the uorinated aldehydes such as 2,2- Table 1 The influence of temperature to reaction of 2,2-difluoro-2iodo-1-phenylethanone with LiEt 3 BH a
In summary, we have demonstrated an unprecedented utilization of LiEt 3 BH for the generation of a,a-diuoroenolates from 2-iodo-2,2-diuoroacetophenones in THF. Applications of the protocol led to the synthesis of polyuorinated b-hydroxy ketones via self-condensation reaction and aldol reaction. The effectiveness of LiEt 3 BH was discussed by the variation of ahalogen acetophenones and reducing agents in the reduction reaction. It turned out that LiEt 3 BH was served as a reducing agent with most a-halogen acetophenones, resulting in the formation of different reduction products. The result disclosed the specic property of 2-iodo-2,2-diuoroacetophenones, which might due to that the uorine atoms of 2-iodo-2,2-diuoroacetophenones have signicant impact and change the property of the adjacent C-I bond. Further study to apply the protocol for the preparation of diverse diuoromethylene compounds are in progress in our laboratory.

Conflicts of interest
There are no conicts to declare.