Difluoromethyl 2-Pyridyl Sulfoximine: A Stereoselective Nucleophilic Reagent for Difluoro(aminosulfinyl)methylation and Difluoro(aminosulfonyl)methylation

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE7 Nov 2022Difluoromethyl 2-Pyridyl Sulfoximine: A Stereoselective Nucleophilic Reagent for Difluoro(aminosulfinyl)methylation and Difluoro(aminosulfonyl)methylation Qinghe Liu, Chuanfa Ni, Qian Wang, Depei Meng and Jinbo Hu Qinghe Liu Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Chuanfa Ni Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Qian Wang Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Depei Meng Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 and Jinbo Hu *Corresponding author: E-mail Address: [email protected] Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 https://doi.org/10.31635/ccschem.022.202101634 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail 1,1-Difluorinated sulfonamides are known to have better anti-inflammatory activity and enzyme inhibitory potency than their nonfluorinated counterparts. Two geminal fluorine atoms cause electronic perturbation of the nearby polar groups enhanced the biological activity of the 1,1-difluorinated sulfonamides. However, because methods for their stereoselective synthesis are scarce, such entities remain entirely unexplored. Here, we outline an efficient method for the stereoselective introduction of the difluoro(aminosulfonyl)methyl group (CF2SO2NH2) into carbonyls, imines, and alkyl halides with a new (R)-2-pyridyl difluoromethyl sulfoximine reagent, which provides a unique solution for the synthesis of chiral α,α-difluorinated sulfonamides with a quaternary stereocenter. Its potency is illustrated by the synthesis of fluorinated analogues of bioactive compounds such as 2-OH-SA, an antagonist for the GABAB receptor in guinea pig ileum, and the late-stage modification of complex molecules such as haloperidol, ebastine, cholesterol, and (+)-δ-tocopherol derivatives. Stereoselective difluoro(aminosulfinyl)methylation to yield chiral sulfinylamides is presented, showcasing other uses of this new reagent. Download figure Download PowerPoint Introduction Fluorine, despite its almost complete absence from biological systems in nature, has become one of the most utilized elements for modulating the properties of biologically active molecules.1,2 The sulfonamide moiety, one of most important pharmacophores, is featured in the structure of more than 150 U.S. FDA-approved drugs and a growing number of experimental drugs, and is known to act on a range of targets, including zinc metalloenzyme carbonic anhydrases, dopamine receptors, ion channels, and solute carriers.3–8 1,1-Difluorinated sulfonamides, combining fluorine and sulfonamide moieties, have improved anti-inflammatory activity and enzyme inhibitory potency and can be used as potent pharmacophores,9–12 which is rationalized by two facts: (1) the introduction of two fluorine atoms leads to a linear increase of acidity as well as a significant increase of lipophilicity, both of which are beneficial for improving their binding properties9,10; and (2) replacement of the bridging oxygen with CF2 results in an ∼18 times increase in inhibition of carbonic anhydrase under different pH conditions9,11,12; a demonstration of the beneficial effect of fluorine. Thus 1,1-difluorinated sulfonamides have been used as calcium homeostasis regulators and cryptochrome modulators to treat cryptochrome-dependent diseases (Figure 1a, A–D).13,14 However, previous synthetic efforts were completely confined to simple sulfonamides with the general structure of RCF2SO2NR′2 (R = H, n-alkyl, or aryl), which included stepwise nucleophilic fluorinations, condensations with carboxydifluoromethanesulfonamide, and so on.9–12,15,16 The lack of stereoselective preparation methods largely limits their applications in the field of biological science and pharmaceutical science.17–21 Thus, a promising method is highly desired to directly and stereoselectively introduce the difluoro(aminosulfonyl)methyl group (CF2SO2NH2) into molecules.22,23 Figure 1 | Examples of bioactive sulfonamides and difluorinated sulfonamides, and the first stereoselective difluro(aminosulfonyl)methylation with the sulfoximine reagent. (a) Characteristics of difluorinated sulfonamides as compared to non-fluorinated analogues, and examples of bioactive difluorinated and non-fluorinated sulfonamides. (b) First highly stereoselective difluoro(aminosulfonyl)methylation with difluoromethyl sulfoximine reagent, providing a unique solution for the synthesis of chiral 2-hydroxyl- and 2-amino-1,1-difluorinated sulfonamides. (c) Two modes of sulfinamide formation by carbon-sulfur bond cleavages. BPAO, bovine plasma amine oxidase; Bz, benzoyl; TBS, tert-butyldimethylsilyl. Download figure Download PowerPoint Over the past decades, mild and efficient methods for highly stereoselective fluoroalkylations remain a formidable challenge.24–27 In this context, sulfoximines, because the sulfoximidoyl group has a strong ability to induce stereoselectivity, have attracted much attention in the field of asymmetric synthesis,28–32 and S-fluoroalkyl-S-aryl sulfoximines have emerged as robust fluoroalkylation reagents.31 Based on this background, we envisioned the stereoselectively introduction of the difluoro(arylsulfoximidoyl)methyl group into carbonyl compounds or imines (Figure 1b, step a), followed by aromatic C–S bond cleavage and one-pot oxidation (Figure 1b, step b) to generate difluoro(aminosulfonyl)methylated products with high stereoselectivities. However, the previously known C–S bond cleavage reaction typically proceed via reductive cleavage of the aliphatic C–S bond of sulfoximines to generate thermodynamically favorable arenesulfinamides 1 (Figure 1c, cleavage a).28–42 But if we can switch the cleavage mode from the aliphatic C–S bond to the aromatic C–S bond (via an SNAr ipso-substitution, Figure 1c, cleavage b), the difluoro sulfinamide motif could be released. To realize our hypothesis, a new reagent, (R)-2-pyridyl difluoromethyl sulfoximine, was developed as an equivalent of CF2SO2NH2, which not only can satisfy the requirements of high stereoselectivity but also easy SNAr ipso-substitution (Figure 1b, steps a and b).a Based on this reagent, a stereoselective introduction of CF2SO2NH2 into carbonyls, imines, and alkyl halides was realized to construct enantiomerically enriched 2-hydroxyl- or 2-amino-1,1-difluorinated sulfonamides, whose nonfluorinated counterparts have been widely used as enzyme inhibitors, antibiotics, as well as pharmaceutical drugs for Alzheimer's disease (Figure 1a, E–H).43–47 Experimental Methods General procedure for stereoselective difluoroalkylation Under N2 atmosphere, to a solution of ketone (0.24 mmol, 1.2 equiv) and sulfoximine (R)- 3b (0.2 mmol, 1.0 equiv) in tetrahydrofuran (THF) (4 mL), was added potassium hexamethyldisilazide (KHMDS) (1.0 M in THF, 0.3 mmol, 1.5 equiv) slowly at −94 °C. After 30 min, the reaction was quenched with aqueous saturated ammonium chloride (2 mL), followed by 3M HCl (6 mL). The solution was stirred for 30 min, after which NaOH (20% aq) was added to basify the solution, followed by extraction with ethyl acetate. The organic phase was washed with brine and then dried over anhydrous MgSO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography using petroleum ether/ethyl acetate as eluent to give the major diastereoisomer 5. General procedure for synthesis of chiral difluorosulfonamide Under N2 atmosphere, to a schlenk-type reaction vessel containing a magnetic stirrer and NaH (95% wt, 0.38 mmol, 2.0 equiv), was added dry dimethylformamide (DMF) (1 mL). The solution was cooled to 0 °C and EtSH (2 mL) was added dropwise. After the solution was stirred for 5 min, the mixture of 5 (0.19 mmol, 1.0 equiv) in DMF (1 mL) was added dropwise. The mixture was stirred at 0 °C for 6 h, then at room temperature (rt) for another 6 h. After the solvent was evaporated under vacuum, CH3CN (1 mL), CCl4 (1mL), H2O (2 mL), NaIO4 (0.38 mmol, 2.0 equiv), and ruthenium trichloride hydrate (3 mg) were added to a schlenk-type reaction vessel with the residue. The resulting mixture was stirred at rt overnight. The completion of the reaction was monitored by 19F NMR. After 8 mL of water was added, the resulting black gel was filtered over celite and thoroughly washed with CH2Cl2, followed by extraction with CH2Cl2. The organic phase was washed with brine and then dried over anhydrous MgSO4. After the solution was filtered and the solvent was evaporated under vacuum, the residue was subjected to silica gel column chromatography using petroleum ether/ethyl acetate as eluent to give the desired product. More experimental details are available in the Supporting Information. Results and Discussion Investigation of the reaction conditions To realize this transformation, the reaction between difluoromethyl heteroaryl or electron-deficient aryl sulfoximines and 2-acetonaphthone ( 4l) was examined with extensive screening of the reaction conditions (Table 1). When 3a was used as the reagent, a moderate yield of difluoromethylation products was observed via 19F NMR spectroscopy with a 91/9 diastereomeric ratio (d.r.) (Table 1, entry 1). However, to our delight, when employing 3b as the reagent, the yield and the diastereoselectivity increased to 92% and 92/8, respectively (Table 1, entry 2). For comparison, we conducted reactions between 4l and several other reagents. In the case of 3c, the diastereoselectivity was 92/8 but the yield was significantly lower than the reaction with 3b (Table 1, entry 3); whereas in the case of 3d, the diastereoselectivity was only moderate (Table 1, entry 4). With 3c and 3d, decomposition of the difluoromethyl sulfoximine was observed, and the preliminary results showed that these heteroaryl substituents were less effective at stabilizing α,α-difluorinated carbanions compared with the pyridyl group (the 2-pyridyl group is also more beneficial than the phenyl group to the ipso-substitution via intermolecular Smiles rearrangement, which will be further discussed in the part of difluoro(aminosulfonyl)methylation). Table 1 | Survey of Reaction Conditionsa,b Entry 4l/ 3/Base Base Solvent Yield (%) d.r. 1c 1.2/1.0/1.5 KHMDS THF 57 91/9 2 1.2/1.0/1.5 KHMDS THF 92 92/8 3d 1.2/1.0/1.5 KHMDS THF 14 92/8 4e 1.2/1.0/1.5 KHMDS THF 34 87/13 5 1.2/1.0/1.5 n-BuLi THF 22 83/17 6 1.2/1.0/1.5 LiHMDS THF 42 87/13 7 1.2/1.0/1.5 NaHMDS THF 85 82/18 8f 1.2/1.0/1.5 KHMDS THF/HMPA 52 92/8 9 1.2/1.0/1.5 KHMDS Et2O 88 90/10 10 1.2/1.0/1.5 KHMDS PhMe 87 89/11 11 1.2/1.0/1.5 KHMDS DCM 91 88/12 12g 1.2/1.0/1.5 KHMDS THF 99(91) 94/6(98/2) 13g 1.5/1.0/1.5 KHMDS THF 95 94/6 aTypical procedure: The base was added slowly to a solution of 3 and 4l in THF; 0.5 h later, saturated NH4Cl (aq) was added slowly at −78 °C. Unless otherwise noted, 3b was used. bYields and d.r. values were determined by 19F NMR analysis. The yield in parenthesis is the isolated yield of the major diastereoisomer. The d.r. in parenthesis was determined by 19F NMR analysis of the isolated major diastereoisomer. c 3a was used. d 3c was used. e 3d was used. fv/v = 10/1. gThe temperature was −94 °C. Regarding the availability, stability, and high stereoselectivity, the explicit combination of ketones and 3b is advantageous in terms of the general applicability of the protocol. Thus, based on the combination of 3b and 4l, we further optimized the conditions by screening several reaction parameters, including different bases, solvents, and molar ratios of reactants (Table 1, entries 5–13). When n-butyllithium (n-BuLi) or lithium hexamethyldisilazide (LiHMDS) was used as base, both the yield and the diastereoselectivity decreased significantly (entries 5 and 6). Although the use of sodium hexamethyldisilazide (NaHMDS) gave a yield of 85%, the stereoselectivity was significantly lower than the reaction with KHMDS (entry 7). Interestingly, the addition of hexamethylphosphoramide (HMPA), a strong coordinating solvent, did not affect the diastereoselectivity, although the yield decreased (entry 8). With KHMDS as the base, solvent screening showed that THF was optimal in terms of yield and stereoselectivity (entries 9–11). When the reaction temperature was lowered, both the yield and diastereoselectivity improved slightly (99% yield, 94/6 d.r.; entry 12). Further optimization of the reaction conditions by changing the ratio of 4l, 3b, and KHMDS did not further improve the result (entry 13). Importantly, slow quenching of the reaction at low temperature is essential to prevent the Smiles rearrangement and subsequent elimination that produce 1,1-difluoroalkenes.48 Notably, this is the first reported synthesis of (R)- 3b (Figure 2), and the optically pure product as a stable solid was obtained on 4.3 g scale (please see the Supporting Information for details).b Figure 2 | Synthesis of ( R)-3b. HMDS, hexamethyldisilazide; TBS, tert-butyldimethylsilyl, NFSI, N-fluorobenzenesulfonimide. Download figure Download PowerPoint Substrate scope Having established the reaction conditions, we subsequently examined the substrate scope with (R)- 3b (Table 2), and the N-desilyated products were obtained, which facilitated subsequent derivations of the products. The reaction could tolerate many functional groups, such as chloro, bromo, iodo, methoxy, methylthio, and ethynyl groups (Table 2, entries 1–7). The facial selectivity was insensitive to both the electronic nature and position of substituents (entries 8 and 9). And fused aromatic rings, such as naphthalene and phenathrene, were also compatible with the current reaction (entries 11–13). In addition, the cyclic aromatic ketone, 3,4-dihydronaphthalen-1(2H)-one, was a suitable substrate to afford the corresponding product 5n in 88% yield with 95/5 d.r. (entry 14). The reagent also reacted with an aldehyde in excellent diastereoselectivity (entry 15). Pharmaceutically important heteroaromatics, such as benzopyridine, pyrrole, and thiophene, furnished the corresponding products in excellent yields with high d.r. values (entries 16–19). Remarkably, when imines were investigated as substrates, products 5t– 5v were obtained with high stereoselectivity (entries 20–22). The absolute configuration of 5n was confirmed by X-ray crystal structure analysis and the newly formed quaternary carbon center was found to be in the S configuration. Table 2 | Investigation of the Substrate Scopea Entry 4 5 Yield (%) d.r.b 1 C6H5COCH3 ( 4a) 5a 84 99/1(92/8) 2 4-ClC6H4COCH3 ( 4b) 5b 86 99/1(92/8) 3 4-BrC6H4COCH3 ( 4c) 5c 83 99/1(92/8) 4 4-IC6H4COCH3 ( 4d) 5d 78 99/1(93/7) 5 4-MeOC6H4COCH3 ( 4e) 5e 82 99/1(96/4) 6 4-MeSC6H4COCH3 ( 4f) 5f 90 99/1(94/6) 7 4-Ethynyl-C6H4COCH3 ( 4g) 5g 70 99/1(94/6) 8 3-MeOC6H4COCH3 ( 4h) 5h 85 99/1(91/9) 9 2-ClC6H4COCH3 ( 4i) 5i 52 99/1(95/5) 10 C6H5COCH2CH3 ( 4j) 5j 88 99/1(93/7) 11 1-(Naphthalen-1-yl)ethanone ( 4k) 5k 74 99/1(94/6) 12 1-(Naphthalen-2-yl)ethanone ( 4l) 5l 91 98/2(94/6) 13 1-(Phenanthren-2-yl)ethanone ( 4m) 5m 74 99/1(93/7) 14 3,4-Dihydronaphthalen-1-(2H)-one ( 4n) 5n 88 99/1(95/5) 15 4-MeOC6H4CHO ( 4o) 5o 91 99/1(95/5) 16 6-Acetylquinoline ( 4p) 5p 82 95/5(92/8) 17 2-Acetyl-1-methylpyrrole ( 4q) 5q 71 99/1(94/6) 18 1-(Thiophen-2-yl)ethanone ( 4r) 5r 92 99/1(94/6) 19 1-(Thiophen-3-yl)ethanone ( 4s) 5s 82 99/1(90/10) 20c N-Bus-ketimine ( 4t) 5t 85 95/5(90/10) 21c N-Ts-ketimine ( 4u) 5u 75 96/4(94/6) 22c N-Bus-aldimine ( 4v) 5v 82 95/5(90/10) aYields indicated are isolated yields of the major diastereoisomer. Diastereomeric ratio (d.r.) values are determined by 19F NMR analysis of the isolated major diastereoisomer. Bus, tert-butylsulfonyl; Ts, toluenesulfonyl. bThe d.r. values in parentheses were determined by 19F NMR analysis of the crude products. cDichloromethane (DCM) was used instead of THF. Rationalization of diastereoselectivity Because the addition of HMPA does not influence the diastereoselectivity of the difluoromethylation of 4l with (R)- 3b (Table 1, entry 8), we propose that the cation might not participate in the transition state, which is different from the reactions of lithiated sulfoximine and ketone.49 One can envisage several possible nonchelated transition states, such as TS-1, TS-2, TS-3, and TS-4, as shown in Figure 3. Since the repulsive interactions of CH3⋯S=NTBS and Ph⋯S=NTBS are stronger than that of CH3⋯S=O in TS-3 and TS-4, TS-1 and TS-2 are disfavored (RL = Ph; Rs = CH3). And considering that the steric hindrance of Py⋯Ph is stronger than that of Py⋯CH3, TS-3 is energetically less favorable than TS-4. Thus TS-4 is the most favorable transition state that can give the product of 2S,Rs- 5. Figure 3 | Proposed transition states. Repulsive interactions are indicated by curved arrows. Download figure Download PowerPoint Difluoro(aminosulfonyl)methylation With a series of enantiomerically enriched difluorosulfoximines in hand, we continued our investigation on the removal of the pyridyl group to prepare difluorosulfinamides. With the isolated major diastereomer of 5l as a model compound, the desired (R)-hydroxyl difluorinated sulfinamide was obtained in 85% yield with excellent stereoselectivity when sodium ethanethiolate/ethanethiol was applied in DMF solution (Figure 4a; for details, see Supporting Information Table S1).50–54 It is worth noting that phenyl sulfoximine 7 failed to undergo Ph–S bond cleavage under the same conditions, indicating the necessity of the 2-pyridyl group in this transformation. Figure 4 | (a) Comparison of phenyl sulfoximine and pyridyl sulfoximine. (b) Substrate scope of the stereoselective difluoro(aminosulfonyl)methylation reactions. (c) Highly stereoselective synthesis of difluorinated 2-OH-SA. (d) One-pot and scaled-up reactions. Yields are the isolated yields of the major diastereoisomers. 19F NMR analysis of the isolated product was used to determine d.r. values. The ratios in parentheses were determined by 19F NMR analysis of the crude difluoro sulfinamides. HPLC analysis of the difluoro sulfinamides was used to determine the e.r in parentheses. See the Supporting Information for details. HPLC, high-performance liquid chromatography; Bus, tert-butylsulfonyl; Boc, tert-butoxycarbonyl;. aThe product was obtained from Ph(CH2)3CF2SO(NH)Py. Download figure Download PowerPoint Simple oxidation of unpurified sulfinamides with the neutral aqueous conditions of RuCl3/NaIO4 in one pot provided the desired enantiomerically enriched difluorosulfonamides 8–10 in good to excellent yields. The substrate scope was found to be insensitive to the diversity of functional groups and the effects of steric hindrance and electronic induction, and the α-hydroxyl difluorosulfonamides were efficiently generated ( 8a– 8e, Figure 4b). Additionally, this method is applicable to other types of substrates, such as imines and alkyl halides, and the β-amino difluorosulfonamides and alkyl difluorosulfonamides were obtained ( 9 and 10). To further illustrate the potential value of our present difluoro(aminosulfonyl)methylation reaction in organic synthesis, we applied it to the preparation of a difluorinated analogue of 2-OH-SA, which is one of the antagonism agents for the GABAB receptor in guinea pig ileum47 (Figure 4c). The difluoro sulfoximine 12 was transformed into difluoro sulfonamide 13 in 49% yield with 97/3 enantiomeric ratio (e.r.) without any loss of chirality. Notably, this is the first preparation of enantiomerically enriched fluorinated 2-OH-SA 13 from an easily accessible 11. And, a one-pot procedure can give 8d from the starting ketone with high efficiency and stereoselectivity (Figure 4d). In addition, it can also be readily scaled up. For example, a gram-scale reaction with (+)-δ-tocopherol derivative gave 8f in 74% yield with high stereoselectivity (Figure 4d). Difluoro(aminosulfinyl)methylation Considering chiral sulfinamides have been widely used as chiral auxiliaries, as ligands in transition-metal catalysis, and as organocatalysts,55–58 we were interested in determining whether the corresponding sulfinamide can be obtained. To our delight, with the optimal reaction conditions, various enantiomerically enriched difluorosulfinamides were isolated after SNAr reaction (Figure 5a). Starting materials bearing electron-rich or -deficient substituents were all able to give 6a and 6b in good yields with high d.r. values. When the substituent is an ethyl group, the reaction also proceeded smoothly affording 6d in 75% yield with 99/1 d.r. The reaction was compatible with imines and alkyl halides such as 14 and 15 without erosion of stereoselectivities. Figure 5 | (a) Substrate scope of the stereoselective difluoro(aminosulfinyl)methylation reactions. (b) The transformation from aromatic sulfoximine agent to sulfonimidoyl fluoride and alkyl sulfoximine. (c) procedure with 2-pyridyl difluoromethyl sulfoximine. (d) to the nonfluorinated 2-pyridyl sulfoximine reagent. Yields are the isolated yields of the major diastereoisomers. 19F NMR analysis of the isolated product was used to determine d.r. values. The ratios in parentheses were determined by 19F NMR analysis of the crude product. See the Supporting Information for details. Bus, tert-butylsulfonyl; Boc, Download figure Download PowerPoint The method could be utilized in the late-stage modification of complex molecules in a one-pot directly from carbonyl For the group was into ( and derivative ( efficiently with high stereoselectivities. the agent which and amine was also transformed into an enantiomerically enriched ( To the potential of these 19 Supporting was transformed into the chiral sulfonimidoyl fluoride in 74% yield with 99/1 d.r. by the of oxidation and (Figure also see Supporting Notably, is used in the fluoride in which an easily with and to generate sulfoximines, and an example, with a the sulfoximine without the erosion of the (Figure are known as a in and this is the first of of an aryl sulfoximine to alkyl we realized the addition of 3b to produce a with two carbon and two (Figure In addition, when nonfluorinated sulfoximine reagent reacted with carbonyl under the developed reaction conditions, the corresponding product was obtained in good yield with high d.r. (Figure which not only an efficient method for highly stereoselective but also the scope of this have a new reagent, 2-pyridyl sulfoximine, and an method for synthesis of chiral In to the chiral group 2-pyridyl sulfoximine in this method is a not only as a stereoselective but also as an equivalent to chiral which is new in sulfoximine it and the ability of an of new difluoro sulfonamide analogues as agents in biological and pharmaceutical The of the 2-pyridyl group is for the of this transformation, which both the nucleophilic addition as well as the subsequent ipso-substitution difluoro(aminosulfonyl)methylation was applied to the synthesis of bioactive compounds and the late-stage modification of complex molecules with good of functional is this reagent the synthesis of chiral sulfinylamides and can their applications for the of sulfonimidoyl and only does our an new of sulfoximines, but it also as a for the further of stereoselective or for many potential a not only the high ability of the heteroaryl sulfoximidoyl group, but also uses the group as an equivalent of ( see Supporting Information Figure and ( see Supporting Information Figure and and ( see Supporting Information Figure and the for this The can be obtained of from The via Supporting Information Supporting Information is available including experimental details and of is of to was provided by the Key and of the of the Key of the Key of of and Shanghai and in and and of of the 3. in of as and for and of to for and 5. Liu on

Topics & Concepts