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′.

Vitamin E for preparation of 7n was purchased from TCI. Other alcohols and ketones were purchased from Bidepharm and Meryer. Cinnamic acids 12a12l were purchased from adamas and used without further purification.
To a solution of Selectfluor (5.4 g, 15 mmol, 1.5 equiv.) in 40 mL of MeCN was added a solution of compound 4b (3.9 g, 10 mmol) in 10 mL of DCM under 0 o C. The resulting mixture was stirred at room temperature for 24 h and quenched by the addition of 20 mL water, then extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. Product 5b was purified by silica gel column chromatography (siliga: 200300 mesh) using PE as eluent (slight yellow oil, 1.0 g, 3.3 mmol, 66% yield).
To a solution of Selectfluor (2.66 g, 7.5 mmol) in 50 mL of MeCN was added a solution of compound 4c (5 mmol) in 12.5 mL of DCM at 0 o C. The resulting mixture was stirred at room temperature for 12 h and quenched by the addition of 20 mL water, then extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. Product 5c was purified by distillation under reduced pressure using cold trap (slight yellow oil, 0.5 g, 2.4 mmol, 48% yield).
To a solution of Selectfluor (5.40 g, 15 mmol, 1.5 equiv.) in 40 mL of MeCN was added a solution of compound 4d (4.5 g, 10 mmol) in 10 mL of DCM at 0 o C. The resulting mixture was stirred at room temperature for 12 h and quenched by the addition of water, then extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated. Product 5d was purified by silica gel column chromatography (siliga: 200300 mesh) using PE as eluent (white solid, 2.0 g, 5.6 mmol, 56% yield).
Then the resulting mixture was stirred at 60 o C. Upon full consumption of S2 (monitored by TLC), the mixture was cooled to ambient temperature and filtered under reduced pressure, the filtrate was extracted with PE (3×50mL), the organic phase was dried over Na2SO4, filtrated and removed the solvent, purification was conducted with column chromatography on silica gel (siliga: 200300 mesh) and PE as eluent to afford the colorless oil S3 (1.57 g, 9.84 mmol, 82% yield).
To a 10 mL tube was added S3 (0.7 g, 4.3 mmol), NBS (0.84 g, 4.73 mmol, 1.1 equiv.) and chloroform (2 M), then the tube was sealed, the resulting mixture was stirred at 100 o C till NBS was completely dissolved, then the mixture was moved to ambient temperature and filtered under reduced pressure, the filtrate was washed with brine, dried over Na2SO4, removed solvent and purified with column chromatography on silica gel (siliga: 200300 mesh) and PE as eluent to afford the slight yellow oil S4 (0.72 g, 3.0 mmol, 70% yield).

synthesis of acrylamides 10
Acrylamides 10a10i was synthesized via condensation of corresponding amine and acyl chloride according to reported reference. [10] Supplementary Figure 8 Synthesis of S6 Under N2 atmosphere, to a stirring mixture of NaH (3.5 g, 87 mmol, 1.1 equiv.) in DMF (30 mL) was added a solution of 4-bromo-2-methylphenol S5 (14.8 g, 79 mmol) in DMF (100 mL) slowly, the resulting mixture was kept stirring for 0.5 h then ethoxymethyl chloride (EOMCl) (9.0 g, 95.7 mmol, 1.1 equiv) was added slowly in 10 min, the reaction medium was stirred for another 5 h and quenched by addition of water, the mixture was extracted with EA (200 mL×3 times), the combined organic phase was washed with water, dried over Na2SO4, concentrated under reduced pressure, the residue was purified through a silica plug, a yellow oil was obtained (15.3 g, 60.0 mmol, 76% yield).
The product (7.4 g, 30.0 mmol) was dissolved in DMF (65 mL), to which was added allyltributyltin (14.3 mL, 45.0 mmol, 1.5 equiv.), then the mixture is degassed, then 900 mg of dichlorobis(triphenylphosphino)palladium was added, the resulting mixture was stirred at 120 o C for 10 h. the reaction was quenched by addition of water, and extracted with EA, the combined organic layer was dried over Na2SO4, and concentrated under reduced pressure, the residue was purified by chromatography on a 10% wt K2CO3-silica column with PE as an eluent. [12] A yellow oil S6 is obtained (5.0 g, 24 mmol, 81% yield).
Supplementary Figure 9 Synthesis of S8 Under N2 atmosphere, to a stirring solution of S7 (8.4 g, 40 mmol), NEt3 (8.4 mL, 62mmol, 1.55 equiv.) and DCM (200 mL) was added Tf2O (11.8 g, 42 mmol, 1.05 equiv.) slowly in 10 min at 0 o C, the resulting mixture was brought to room temperature and stirred for 2 h, and then quenched by addition of water and extracted with DCM (100 mL×3 times), the organic phase was washed with dilute sodium bicarbonate and dried over Na2SO4, and concentrated under reduced pressure, the residue was purified by chromatography on a silica column with PE/EA (8/1, v/v) as an eluent. A yellow oil S8 is obtained (12.3 g, 36.0 mmol, 90% yield).

Supplementary Figure 10 Synthesis of S9
Under N2 atmosphere, 3.5 g (16 mmol) of S6 was dissolved in 40 mL anhydrous THF, the resulting mixture was cooled to 0 o C, 40.8 mL 9-BBN (0.5 M, 1.3 equiv.) was added, and the medium was brought to room temperature and stirred for 12 h. A solution of S8 in 70 mL DMF was added, as well as 4.7 g (34 mmol, 2.1 equiv.) of potassium carbonate and Pd(dppf)Cl2 (652.8 mg, 0.8 mmol, 5 mol%), the reaction mixture was degassed, heated to 50 o C for 3 h and quenched with ammonium chloride solution. The mixture was extracted with EA, the organic phase was washed with dilute sodium bicarbonate and dried over Na2SO4, and concentrated under reduced pressure, the residue was purified by chromatography on a silica column with PE/EA (8/1, v/v) as an eluent. A colorless oil S9 is obtained (4.1 g, 10.2 mmol, 64% yield).

Supplementary Figure 11 Synthesis of 15
Under air atmosphere, to a solution of S5 (2.9 g, 7.3 mmol) in MeOH (30 mL) was added con. HCl (30 mL) slowly at room temperature, the resulting mixture was stirred for 3 h and monitored by TLC, upon completion, extracted with EA, the organic phase was dried over Na2SO4, and concentrated under reduced pressure, the residue was purified by chromatography on a silica column with PE/ EA (4/1, v/v) as an eluent. A colorless oil 15 is obtained (2.3 g, 6.9 mmol, 94% yield).

Investigation of metallic salts
Supplementary Table 1 Investigation of metallic salts

Investigation of oxidant for catalytic reaction conditions
Supplementary Table 3 Investigation

Proposed mechanism for allylation, alkylation and alkenylation via radical C-Si bond activation
Supplementary Figure 13 Proposed Mechanism for allylation via radical C-Si activation The radical inhibitation experiments indicate that a radical process might be involved. We found that Mn(OAc)3•2H2O is able to mediate the reaction without external oxidant, but Mn(OAc)2•4H2O can not mediate the reaction without TBPB (Table 1, entries 1 and 8 in the manuscript). The HRMS analysis of the reaction mixture of 1a and 7a suggests the generation of benzenesulfonyl benzoic anhydride, tert-butyl benzenesulfonate, benzesulfonic acid and benzenesulfinic acid as by-products. Based on these experimental results and literature about allylation from allylic sulfones, [13,14] we propose a possible mechanism (Fig. S2). 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. Carbon radical III would be generated through Brook rearrangement, and then undergo radical addition reaction to generate intermediate

IV.
Compound V would be generated after β-elimination of sulfonyl radical. The alcohol product TM would be generated after the desilylation step. Mn(III) catalyst is likely to be regenerated by the oxidation of Mn(II) by TBPB. The sulfonyl radical is likely to be captured by TBPB, generating the side-product benzenesulfonyl benzoic anhydride. The sulfonyl radical might also be oxidized and captured by PhCO2 − to generate benzenesulfonyl benzoic anhydride.
Benzenesulfonyl benzoic anhydride and tert-butyl benzenesulfonate could be hydrolyzed to generate benzenesulfonic acid. Moreover, the sulfonyl radical could be transformed to sulfinic acid via H atom abstraction reaction under the reaction condition. For the alkylation reaction, we propose that radical III would be generated following similar mechanism as that in the allylation reaction (Fig. S3.). When an acryl amide was used as the radical acceptor instead of an allylic sulfone, we propose that radical III could undergo addition reaction to generate intermediate IV', which undergo intramolecular addition to generate intermediate V'. Aromatization reaction via radical oxidation and deprotonation then would generate compound VI'. The alcohol product TM' would be generated after the desilylation step. Mn(III) catalyst is likely to be regenerated by the oxidation of Mn(II) by TBPB. Similar oxdative aromatization process was also proposed in the Fe and Ag catalyzed radical reactions of acryl amides. [15,16] Supplementary Figure 15 Proposed Mechanism for alkenylation via radical C-Si activation There are reports on radical decarboxylative alkenylation with α,β-unsaturated carboxylic acids. [17,18] Based on our experimental results and literature reports, [17,18] we propose a possible mechanism for our reaction as shown in Fig. S4. dioxide and proton to generate the product VI''. Similar proposal was proposed in Ni-catalyzed radical alkenylation with α,β-unsaturated carboxylic acids. [17] The alcohol product TM'' would be generated after the desilylation step.
Pathway b: compound A could be transformed to compound B via ligand exchange process. Addition of radical III to the α-position of the double bond in compound B would generate intermediate IV''', which then eliminate carbon dioxide and Mn(II) to generate compound VI''. Similar proposal was proposed in Cu-catalyzed alkenylation with α,β-unsaturated carboxylic acids. The alcohol product TM'' would be generated after the desilylation step.
Mn(III) catalyst is likely to be regenerated by the oxidation of Mn(II) by TBPB.