Direct transfer of tri- and di-fluoroethanol units enabled by radical activation of organosilicon reagents

Trifluoroethanol and difluoroethanol units are important motifs in bioactive molecules, but the methods to direct incorporate these units are limited. Herein, we report two organosilicon reagents for the transfer of trifluoroethanol and difluoroethanol units into molecules. Through intramolecular C-Si bond activation by alkoxyl radicals, these reagents were applied in allylation, alkylation and alkenylation reactions, enabling efficient synthesis of various tri(di)fluoromethyl group substituted alcohols. The broad applicability and general utility of the approach are highlighted by late-stage introduction of these fluoroalkyl groups to complex molecules, and the synthesis of antitumor agent Z and its difluoromethyl analog Z′. Methods for direct incorporation of tri- and di-fluoroethanol units in molecules are relatively limited. Here, the authors report two organosilicon reagents which are applied to allylation, alkylation and alkenylation reactions as tri- and di-fluoroethanol transfer reagents.

F luorine incorporation has been a routine strategy for the design of new drugs and materials, because it can often improve the chemical, physical, and/or biological properties of organic molecules 1,2 . Fluoroalkylsilicon reagents, such as TMSCF 3 (Rupert-Prakash reagent), TMSCF 2 H, and others are widely used reagents in the synthesis of organofluorine compounds 3 . Among various fluorine-containing molecules, the secondary fluoroalkyl alcohols are of particular importance; monoamine oxidase A inhibitor Befloxatone 4 and antitumor agent Z 5 are examples of bioactive molecules containing trifluoroethanol motif (Fig. 1a). Anionic activation of C-Si bond of fluoroalkylsilicon reagents by Lewis bases is a powerful method to transfer α-fluoro carbanions into aldehydes, affording fluoroalkyl alcohol products (Fig. 1b) [6][7][8] . However, we enviosioned that the development of organosilicon reagents such as 1a and 2a which allows direct transfer of trifluoroethanol and difluoroethanol into organic molecules would represent a conceptually different means to construct fluoroalkyl alcohols (Fig. 1c). Actually, the synthetic chemistry based on carbonyl group (Fig. 1b) possesses some limitations: (1) many aldehydes are not stable and/or need multistep synthesis 9,10 ; (2) it is hard to control the regioselectivity when there are more than one aldehyde sites in the same molecule. Moreover, the design and synthesis of pharmacuticals call for strategies to incorporate important structural motifs at latestage, because this will aviod de novo synthesis 11,12 .
Herein, we report two fluoroalkylsilicon reagents 1a and 2a. Through intramolecular C-Si bond activation by alkoxyl radicals [13][14][15][16][17][18][19] , these developed β-fluorinated organosilicon reagents were successfully applied in radical allylation, alkylation, and alkenylation reactions, enabling efficient synthesis of a variety of fluoroalkyl group substituted alcohols (Fig. 1c). The broad applicability and general utility of the approach are highlighted by late-stage introduction of fluoroalkyl groups to complex molecules, such as the derivatives from biologically active naturally occuring epiandrosterone, cholesterol, testosterone, diosgenin, vitamin E, estrone, and (8α)-estradiol, and the synthesis of antitumor agent Z and its difluoromethyl analog Z′. Moreover, our radical reactions show conjunctive group tolerance to that of the traditional nucleophilic fluoroalkylation reactions with α-fluoro carbanions 3,20,21 (Radical reactions often show different reactivity to the anionic reactions, see refs. 20,21 ).

Results
Preparation of reagents 1a and 2a. The fluoroalkyl group transfer reagents 1a and 2a were easily synthesized in three steps (Fig. 2). Following the reported procedure 22 , with commercially available inexpensive trifluoroethanol 3 as starting material, we prepared difluorinated enol silyl ether 4 in 84% yield.
Electrophilic fluorination of compound 4 with Selectfluor afforded trifluoroacetylsilane 5 in 82% yield. Reagent 1a was then synthesized in 86% yield through reduction of acylsilane 5 with NaBH 4 . We also prepared different silyl group-substituted compounds 1b-1d through similar procedures as 1a in good yield (for details, see Supplementary Figs. [2][3][4]. It is worthy to note that trifluoroacetyltriphenylsilane (precursor to 1d) can be synthesized directly from the reaction of Ph 3 SiLi and (CF 3 CO) 2 O in one step 23 . The difluoroacetylsilane 6 was easily prepared in 79% yield through the hydrolysis of enol silyl ether 4 under acidic conditions. Reduction of compound 6 delivered difluoromethyl containing reagent 2a in 88% yield.
Attempts for anionic activation and design of radical activation. With reagent 1a in hand, we investigated the substitution reaction with allylic sulfone 7a as model substrate. Firstly, we tried anionic activation strategy which has been widely used in the C-Si bond cleavage for the fluoroalkyl transfer reactions [6][7][8] . Common activators such as TBAF, CsF, KF, t-BuOK were tried, but no substitution product 8a or 9a was observed, albeit full conversion of compound 1a was observed (Fig. 3a). The decomposition of compound 1a could be explained by the facile fluoride elimination of β-fluoro carbanions (Fig. 3b) [23][24][25] . For example, Xu and coworkers reported the reaction of trifluoroacetyltriphenylsilane with Grignard reagents, but no desired trifluoromethylated alcohols were obtained. Instead, 2,2-difluoro enol silyl ethers were formed through nucleophilic addition, anion Brook rearrangment, and fluoride elimination processes 23 . It is known that fluorine radical possesses much higher energy than fluorine anion does (Fluorine possesses high electron affinity (3.448 eV), extreme ionization energy (17.418 eV), see ref 1a, pp [5][6][7][8]. Therefore, we envisioned that in-situ generated carbon radical from alkoxyl radicals should not prefer β-F elimination. Consequently, they could be trapped by radical acceptors to generate trifluoroethanol transfer products (Fig. 3b).
Identification of conditions for radical C-Si activation. With this idea in mind, we investigated a variety of conditions which could generate alkoxyl radicals (for details, see Supplementary  Tables 1-3). After extensive screening, we found that employing 2 equivalent of Mn(OAc) 3 ·2H 2 O as oxidant, DCM as solvent led to allylation product in 68% yield (  [27][28][29] ). The attempt to use Smith's condition 19 to achieve the reaction between 1a and 7a failed to afford any amount of product 8a or 9a, highlighting the influence of CF 3 group on the reactivity of reagent 1a.
Synthesis of α-trifluoromethylated alkyl alcohols. After achieving the radical C-Si bond activation to access αtrifluoromethylated homoallylic alcohols, we wondered whether the same strategy can be applied in double functionalization of alkenes to prepare α-trifluoromethylated alkyl alcohols. Acryl amides 10 were chosen to test the possibility [35][36][37][38] . To our delight, under Mn(II)/TBPB conditions, various acryl amides can be converted to corresponding trifluoromethylated alcohols 11 in 63-91% yield (Fig. 5). Me, Ph, and Bn groups on the N of amides do not affect the reaction. The reaction tolerates halides, such as F and Cl. Both electron-donating OMe and electron-withdrawing CO 2 Me on the arenes were maintained after the reaction. It is worthy to note that compounds 11 are difficult to be synthesized through the nucleophilic trifluoromethylation reaction of aldehydes with TMSCF 3 , because the aldehydes themselves need multistep synthesis 10 .
Synthesis of α-trifluoromethylated allylic alcohols. Allylic alcohols are important synthetic intermediates for a variety of transformations. Moreover, fluorinated compounds possess unique chemical, physical, and biological properties. Therefore, the development of one step synthesis of α-trifluoromethylated allylic alcohols from readily available starting materials are highly desired. Previous methods to prepare α-trifluoromethylated allylic alcohols mainly rely on nucleophilic trifluoromethylation of α,βunsaturated aldehydes [39][40][41][42][43] . α,β-Unsaturated carboxylic acids are easy to be synthesized and many of them are commercially available. Moreover, they are more stable under atmosphere than corresponding α,β-unsaturated aldehydes. They have been used in the decarboxylative trifluoromethylation reactions for the synthesis of CF 3 -substituted alkenes 44,45 . Encouraged by the success of synthesizing homoallylic and alkyl alcohols with 1a as reagent under the radical C-Si bond activation conditions, we studied the reaction between 1a and acids 12 to prepare αtrifluoromethylated allylic alcohols (Fig. 6). The reaction conditions are slightly different from the above allylation and alkylation reactions: (1) both hexane and DCM could be used as solvent; (2) the desilylation step was performed under lower temperature (−10 vs. 5°C) to avoid side reactions. It can be found from Fig. 7 that various α,β-unsaturated carboxylic acids containing F, Cl, Br, MeO, BnO, and CF 3 substituents were successfully converted to corresponding α-trifluoromethylated allylic alcohols in 51-75% yield. To the best of our knowledge, there has been no report on the synthesis of α-trifluoromethylated allylic alcohols with unsaturated carboxylic acids before this work.
Radical C-Si activation for difluoroethanol unit transfer.  or OH group, and can also behave as a hydrogen donor through hydrogen bonding 46,47 . Therefore, difluoromethylated compounds are strong candidate for drugs. There are examples showing that the CF 2 H-containing compounds exhibit higher bioactivity than their CF 3 -containing counterparts 48,49 . Encouraged by the above success of radical C-Si bond activation to access trifluoromethylated allylic, alkyl, and alkenyl alcohols, we extended the strategy to directly transfer 2,2-difluoroethanol to organic molecules with reagent 2a (Fig. 7). To the best of our knowledge, there has been no report of the synthetic application of carbon radical from 2,2-difuoroethanol. Under the similar reaction conditions as that of 1a, with allylic sulfones as substrates, difluoromethylated homoallylic alcohols 14a-14c were prepared in 66-80% yield. Late-stage functionalization of two complex molecules are also successful; 14d and 14e were isolated in 83% and 67% yield, respectively. The reactions of acryl amides performed well, affording 14f-14i in 76-82% yield. Ph, Bn, and Me groups on the N atom were tolerated; both electronwithdrawing CO 2 Me and electron-donating OMe groups on the aromatic ring were maintained after the reactions. Three Synthesis of antitumor agent Z and its difluoromethyl analog Z′. After achieving the direct transfer of 2,2,2-trifluoroethanol and 2,2-difluoroethanol to simple α,β-unsaturated carboxylic acids, we tested whether our methodology can be applied in the synthesis of antitumor agent Z (Fig. 8) 5 . Starting from known compound 15 5 , the protection of phenol afforded compound 16 in 97% yield. α,β-Unsaturated carboxylic acid 17 was then synthesized in 76% yield after Heck reaction and selective hydrolysis of the ester. The radical reactions performed well under our standard conditions, affording compounds 18 and 19 in 71% yield and 69% yield, respectively. Hydrolysis of the esters afforded the final product Z and Z′ in 94% and 89% yield, respectively.

Difluoromethyl group (CF 2 H) is isopolar and isosteric to an SH
Mechanism of the study. The radical inhibition experiments revealed that addition of 1 equiv. of TEMPO or BHT can completely inhibit the allylation reaction, albeit more than 60% of compound 3a were consumed in both cases (Fig. 9a). In addition, compound 21 was detected by HRMS when TEMPO was added into the reaction (for details, see Supporting Information). Therefore, radical process might be involved in current substitution reaction. Our investigation revealed that Mn (OAc) 3 ·2H 2 O is able to mediate the reaction without external oxidant, but Mn(OAc) 2 ·4H 2 O cannot mediate the reaction without TBPB (Table 1, entries 1 and 8). Based on these results, we propose a possible mechanism as shown in Fig. 9b. Ligand exchange between Mn(III) species and alcohol 1a might generate intermediate I, which undergoes homolysis to produce alkoxyl radical II and Mn(II) intermediate [50][51][52][53] . Carbon radical III would be generated through Brook rearrangement, and then undergo further reaction to generate product IV. Mn(III) catalyst is likely to be regenerated by the oxidation of Mn(II) by TBPB. The alcohol product V would be generated after the desilylation step. It is worthy to note that the reaction pathways in the allylation, alkylation, and alkenylation reactions are probably different (for the proposed possibilities, see Supplementary Figs. [13][14][15]. As for the nature of radical III, we propose that they are nucleophilic radicals. The following facts support this proposal: (1) the reaction partners in the above three kinds of reactions are electrondeficient olefins; (2) more electron-deficient substrate afforded higher yield (for example, Fig. 5, 9ac, 43% yield; 9ae, 70% yield); (3) the carbon radical generated from trifluoroethanol under γray irradiation could add to highly electrophilic hexafluoro-2butyne 27 .

Discussion
In conclusion, we have developed two fluorinated organosilicon reagents, which were used in direct transfer of trifluoroethanol and difluoroethanol units into organic molecules. A radical C-Si bond activation strategy was developed to solve the problem of βfluorine elimination in anionic activation methods. Upon intramolecular activation of C-Si bond by alkoxyl radicals, the βfluoro carbon radicals were generated and participated in efficient allylation, alkylation, and alkenylation reactions, enabling efficient synthesis of numerous fluoroalkyl alcohols. The broad applicability and general utility of the approach are highlighted by late-stage introduction of fluoroalkyl groups to complex molecules and the synthesis of antitumor agent Z and its difluoromethyl analog Z′. Further application of the radical C-Si bond activation of organosilicon reagents are underway in our lab.

Methods
Typical synthesis of compound 9. Under N 2 atmosphere, to a dried 10 mL Schlenk tube equipped with a magnetic stir bar containing Mn(OAc) 2 Fig. 9 Radical inhibition experiments and proposed mechanism. a TEMPO and BHT efficiently inhibited the allylation reaction, supporting radical process might be involved. b A plausible mechanism is proposed.