2-Chloro-2,2-difluoroacetophenone:  A Non-ODS-Based Difluorocarbene Precursor and Its Use in the Difluoromethylation of Phenol Derivatives

Abstract

A novel and non-ODS-based (ODS = ozone-depleting substance) preparation of 2-chloro-2,2-difluoroacetophenone (1) was achieved in high yield by using 2,2,2-trifluoroacetophenone as the starting material. Compound 1 was found to act as a good difluorocarbene reagent, which readily reacts with a variety of structurally diverse phenol derivatives 4 in the presence of potassium hydroxide or potassium carbonate to produce aryl difluoromethyl ethers 5 in good yields. This new and easy-to-handle synthetic methodology offers an environmentally friendly alternative to other Freon- or Halon-based difluoromethylating approaches.

Chlorodifluoromethyl aryl ketones and sulfones as difluorocarbene reagents: The substituent effect

“…Therefore, we carried out the O-difluoromethylation reactions by using biphenyl-4-ol (3c) as a model compound. The reaction condition of Odifluoromethylation was similar to our previous report [5]. Potassium hydroxide (25 wt% in H 2 O) was used both as a base to deprotonate phenol (3a) and as an activating agent to react with 1 to generate difluorocarbene species.…”

“…The results are summarized in Table 4. Reagent 2d and 2h were found to be powerful in reacting with a variety of structurally diverse phenol derivatives to give aryl difluoromethyl ethers in good to excellent yields (entries [1][2][3][4][5][6][7][8][9][10][11][12][13]. Naphthols were also successfully difluoromethylated to give the corresponding products in good yields (entries 12 and 13).…”

“…Over the past half century, it has been realized that the reactivity of difluorocarbene is significantly influenced by the way it is generated, and as a result, enormous efforts have been devoted to seek new methods and/or reagents for generation of reactive difluorocarbene species for practical organic synthesis [2,3]. One of the important synthetic applications of difluorocarbene species is the difluoromethylation of O-, N-, S-, C-, and P-nucleophiles, using CHClF 2 , ClCF 2 CO 2 Na, ClCF 2 CO 2 CH 3 , CF 2 Br 2 , CF 3 CO 2 Na, FSO 2 CF 2 CO 2 H, CF 3 ZnBr, and CHF 2 I as difluorocarbene precursors [2][3][4][5]. The difluoromethyl group (CF 2 H) has been proposed both as an isostere of OH (or CH 2 OH) group [6] and as a more lipophilic hydrogen donor (than typical donors such as OH and NH), which makes it an interesting group with respect to the design of bioactive molecules [7].…”

“…The difluoromethyl group (CF 2 H) has been proposed both as an isostere of OH (or CH 2 OH) group [6] and as a more lipophilic hydrogen donor (than typical donors such as OH and NH), which makes it an interesting group with respect to the design of bioactive molecules [7]. In 2006, we reported that 2-chloro-2,2-difluoroacetophenone (PhCOCF 2 Cl, 1a) can be used as a non-ozone-depleting substance-based (non-ODS-based) difluorocarbene precursor for O-difluoromethylation of phenols [5]. Thereafter, we found that chlorodifluoromethyl phenyl sulfone (PhSO 2 CF 2 Cl, 2a) can also serve as a more efficient non-ODS-based difluorocarbene reagent for O-and N-difluoromethylations [8].…”

New trends in the chemistry of α-fluorinated ethers, thioethers, amines and phosphines

“…Zheng and co-workers introduced 2-chloro-2,2-difluoroacetophenone as a non-ODS-based difluorocarbene reagent for O-difluoromethylation of phenol derivatives (Scheme 26, Eq. (1)) [101]. …”