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Wen-Xin Lv Yin Li Yuan-Hong Cai Dong-Hang Tan Zhan Li Ji-Lin Li Qingjiang Li Honggen Wang 《Chemical science》2022,13(10):2981
β-Difluoroalkylborons, featuring functionally important CF2 moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.A hypervalent iodine-mediated gem-difluorination allows the facile synthesis of β-difluoroalkylborons. An unusual 1,2-hydrogen migration, triggered by boron substitution, is involved.Organofluorine compounds have been widely applied in medicinal chemistry and materials science.1a–d In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.2a–c Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,3a,b photoredox difluorination,4 radical difluorination,5 and cross-coupling reactions with suitable CF2 carriers6a–f are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.7a–i Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).7a–f Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.7iOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates8a–c as starting materials.9a–e Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).10 While extending the scope of our previous work,9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.11a–d Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,10 could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.12a–dTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et3N·HF in association with PhI(OAc)2 (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions
Open in a separate windowWith the optimized reaction conditions in hand, we set out to investigate the scope and limitation of this gem-difluorination reaction. The reaction of a series of E-type 1,2-disubstituted alkenyl MIDA boronates were first examined. As shown in Scheme 2, the reaction of substrates with primary alkyl (1b, 1e–g), secondary alkyl (1c, 1d), or benzyl (1h–k) groups proceeded efficiently to give the corresponding gem-difluorinated alkylboronates in moderate to good yields. Halides (1i–k, 1m) and cyano (1l) were well tolerated in this reaction. Of note, cyclic alkene 1n is also a viable substrate, affording an interesting gem-difluorinated cyclohexane product (2n).Open in a separate windowScheme 2Scope of 1,2-H migratory gem-difluorinations. a 4 h. b PIFA was used.To define the scope further, the substrates with Z configuration were also employed under the standard reaction conditions (eqn (1) and (2)). The same type of products were isolated with comparable efficiency, suggesting that the reaction outcome is independent of the substrate configuration and substrates with Z configuration also have a profound aptitude of 1,2-hydrogen migration. Nevertheless, the reaction of t-butyl substituted alkenyl MIDA boronate (1p) delivered a normal 1,2-difluorinated alkylboron product (eqn (3)). The 1,2-hydrogen migration was completely suppressed probably due to unfavorable steric perturbation. With an additional alkyl substituent introduced, a 1,2-alkyl migrated product was formed as expected (eqn (4)).1The gem-difluorination protocol was amenable to gram-scale synthesis of 2a (Scheme 3, 8 mmol scale of 1a, 1.24 g, 50%). To assess the synthetic utility of the resulting β-difluorinated alkylborons, transformations of the C–B bond were carried out (Scheme 3). Ligand exchange of 2a furnished the corresponding pinacol boronic ester 4 without difficulty, which could be ligated with electron-rich aromatics to obtain 5 and 6 in moderate yields. On the other hand, 2a could be oxidized with high efficiency to alcohol 7 using H2O2/NaOH. The hydroxyl group of 7 could then be converted to bromide 8 or triflate 9. Both serve as useful electrophiles that can undergo intermolecular SN2 substitution with diverse nitrogen- (10, 13), oxygen- (14), phosphorus- (11) and sulfur-centered (12) nucleophiles.Open in a separate windowScheme 3Product derivatizations. PMB = p-methoxyphenyl.To gain insight into the reaction mechanism, preliminary mechanistic studies were conducted. The reaction employing deuterated alkenyl MIDA boronate [D]-1a efficiently afforded difluorinated product [D]-2a in 72% isolated yield, clearly demonstrating that 1,2-H migration occurred (Scheme 4a). However, when the MIDA boronate moiety was replaced with a methyl group (15), no difluorinated product (derived from 1,2-migration) was detected at all, suggesting an indispensable role of boron for promoting the 1,2-migration event (Scheme 4b). Also, with a Bpin congener of 1a, the reaction led to large decomposition of the starting material, with no desired product being formed (Scheme 4b).Open in a separate windowScheme 4Mechanistic studies and proposals.Based on the literature precedent and these experiments, a possible reaction mechanism is proposed in Scheme 4c. With linear alkenyl MIDA boronates, the initial coordination of the double bond to an iodium ion triggered a regioselective fluoroiodination to deliver intermediate B. The regioselectivity could arise from an electron-donating inductive effect from boron due to its low electronegativity, consistent with previous observations.13a,b Thereafter, a 1,2-hydrogen shift, rather than the typical direct fluoride substitution of the C–I bond, provides carbon cation C. The formation of a hyperconjugatively stabilized cation is believed to be the driving force for this event.12a–d The trapping of this cation finally forms the product.In conclusion, we demonstrated herein our second generation of β-difluoroalkylboron synthesis via oxidative difluorination of easily accessible linear 1,2-disubstituted alkenyl MIDA boronates. An unexpected 1,2-hydrogen migration was observed, which was found to be triggered by a MIDA boron substitution. Mild reaction conditions, moderate to good yields and excellent regioselectivity were achieved. The applications of these products allowed the facile preparation of a wide range of gem-difluorinated molecules by further transformations of the boryl group. 相似文献
Entry | F− (equiv) | Oxidant | Solvent | Yield (%) |
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1 | CsF (2.0) | PIDA | DCM | 0 |
2 | AgF (2.0) | PIDA | DCM | 0 |
3 | Et3N·HF (40.0) | PIDA | DCM | 0 |
4 | Py·HF (20.0) | PIDA | DCM | 39 |
5 | Py·HF (40.0) | PIDA | DCM | 61 |
6 | Py·HF (100.0) | PIDA | DCM | 55 |
7 | Py·HF (40.0) | PIFA | DCM | 52 |
8 | Py·HF (40.0) | PhIO | DCM | 26 |
9 | Py·HF (40.0) | PIDA | DCE | 49 |
10 | Py·HF (40.0) | PIDA | Toluene | 46 |
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Zhiyang Li Yichen Li Xingguang Li Mandi Wu Ming-Liang He Jianwei Sun 《Chemical science》2021,12(35):11793
A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C–C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.A one-pot oxidation of racemic triarylmethanes to form para-quinone methides followed by enantioselective construction of all-aryl quaternary stereocenters has been developed.Cross dehydrogenative coupling (CDC) is a powerful tool to forge intermolecular C–C bonds from two C–H bonds without prefunctionalization.1 Specifically, the benzylic C–H bond is relatively prone to oxidation and thus it has evolved into a versatile arena for the implementation of this reaction, leading to efficient construction of various benzylic stereogenic centers. As a result, CDC has proved to be useful for the establishment of a wide range of 1,1-diaryl stereocenters (Scheme 1a).2 Recently, Liu and coworkers reported a elegant synthesis of enantioenriched triarylacetonitriles via in situ oxidation of α-diarylacetonitriles to para-quinone methides (p-QMs) followed by asymmetric nucleophilic addition with stereocontrol induced by a chiral phosphoric acid catalyst. This represents a rare example of formal CDC for the synthesis of 1,1,1-triarylalkanes (Scheme 1b).3 However, the establishment of tetraaryl-substituted carbon stereocenters by this approach remains unknown (Scheme 1c).Open in a separate windowScheme 1Catalytic asymmetric synthesis of chiral tetraarylmethanes.Distinct from the asymmetric synthesis of triaryl-substituted stereocenters,4 substantial steric hindrance in establishing tetraaryl-substituted quaternary stereocenters poses significant synthetic challenges.5–8 Indeed, even racemic or achiral syntheses of tetraarylmethanes have been an elusive topic of investigation in organic synthesis.6 In this context and in continuation of our effort in the studies of asymmetric reactions of para-quinone methides (p-QMs)9,10 as well as the synthesis of chiral tetraarylmethanes,8 we envisioned that suitable oxidation of racemic triarylmethane 1 is expected to generate triarylmethyl cation IM1 (Scheme 1c). With one aryl group as para-hydroxyphenyl, this cation could be stabilized in the form of p-QM IM2. Subsequent asymmetric nucleophilic addition by another electron-rich arene to the p-QM intermediate is expected to generate chiral tetraarylmethanes 2. The challenges associated with this one-pot process mainly include the compatibility problem between the oxidative condition and the catalytic asymmetric system in order to achieve both high efficiency and enantioselectivity.We commenced our study with racemic triarylmethane 1a as the model substrate. The initial study was directed to the search for a suitable oxidant to mildly generate the p-QM intermediate (11 At room temperature, the use of superstoichiometric amounts of Ag2O or benzoquinone was completely ineffective (entries 1 and 2). Similarly, the reaction did not proceed using oxygen as the oxidant in combination with catalyst Mn(acac)3 (entry 3). Subsequently, considerable efforts were devoted to screening many other oxidation systems, almost all of which were completely incapable for this oxidation (entries 4–8). However, eventually we were delighted to identify DDQ as the superior oxidant, leading to complete and clean conversion to the desired QM at room temperature (entry 9). In contrast, a combination of catalytic DDQ with 5 equivalents of MnO2 gave only 60% conversion (entry 10).Evaluation of oxidants
Open in a separate windowWe next set out to evaluate the key C–C bond formation step (12,13 After oxidation, the nucleophile and catalyst were added to the reaction mixture. The reaction with catalyst (R)-A1 proceeded smoothly at room temperature to form the desired product 2a in 90% yield, but unfortunately in a racemic form (entry 1). Next, a range of chiral phosphoric acids were screened. To our delight, the BINOL-derived TRIP catalyst, (R)-A4, provided excellent enantioselectivity (93% ee, entry 4). However, those with H8BINOL- and SPINOL-derived catalysts (B and C) bearing the same 2,4,6-triisopropylphenyl substituents proved to be inferior. Finally, a slightly modified acid A5 was found to be the best (95% ee, entry 7). Decreasing the temperature to 0 °C improved the result (97% ee, entry 8). However, no further improvement was observed at a lower temperature. While DCM was comparable to DCE, other solvents (e.g., EtOAc and Et2O) significantly affected the enantioselectivity. Varying the concentration led to no improvement (entries 9–13). Finally, the catalyst loading could be reduced to 7.5 mol% without erosion in yield or enantioselectivity (entry 14). Notably, during the course of our study, the enantioselectivity was found to be sensitive to the amount of DDQ when it was used in excess. For example, with 1.5 equivalents of DDQ (entry 15), the enantioselectivity decreased to 51% ee. However, with 0.8 equivalents, the selectivity remained excellent, albeit with reduced yield. These results suggest that the excessive DDQ might be detrimental to stereocontrol. Unfortunately, this feature also prevented the two-step protocol from merging into one operation. The catalyst has to be added after complete consumption of DDQ to ensure high enantioselectivity (entry 17). Moreover, although the oxidation step was relatively fast (∼30 min) based on TLC analysis, keeping this mixture under stirring for an additional 4 h before adding the acid catalyst was critical to achieve high enantioselectivity, which is likely to ensure complete consumption of DDQ or precipitation of its reduced form DDQH2 from the solution (entry 18).Condition optimizationa
Open in a separate windowaReaction conditions: 1a (0.025 mmol), 3a (0.05 mmol), catalyst (10 mol%), DCE (0.5 mL). Yield is based on analysis of the 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as an internal standard.
Open in a separate windowWith the optimized conditions (entry 14, Scheme 2). A wide range of diversely-substituted triarylmethanes participated in this process with good to excellent efficiency and enantioselectivity. In addition to OMe, other alkoxy groups (e.g., OBn and OAllyl, 2k–l), protected amine groups (e.g., sulfonamides, 2m–o), and even fluorine (2p–q) can serve as an effective directing group when they are present at the ortho position. Moreover, as shown in the case of 2f, the observed good enantioselectivity indicated that the directing ability of alkoxy and fluorine groups is remarkably different. The incorporation of a heterocycle, such as thiophene (2g), did not interfere with the reactivity or enantiocontrol. Some other pyrroles, including 2,4-dimethyl pyrrole (2x), were also good nucleophiles. 4,7-Dihydro-1H-indole also reacted smoothly to form the product 2v. Subsequent oxidation by DDQ could easily afford the indole-substituted tetraarylmethane 2weqn (1). Unfortunately, pyrroles with carbonyl substituents and other electron-rich arenes, such as indole, furan, 2-naphthol, and 1,3,5-trimethoxybenzene, were not reactive under the standard conditions (0 °C). At room temperature, indole could react to form the desired product 2y, but in only 21% ee, while the others remain unreactive.1Open in a separate windowScheme 2Reaction scope. Reaction scale: 1 (0.25 mmol), DDQ (0.25 mmol), DCE (5.0 mL), rt, 5 h; then 3 (0.50 mmol), (R)-A5 (18.8 μmmol), 0 °C, 3 h. Isolated yield is provided. The ee value was determined by chiral HPLC analysis. aRun at −20 °C for 12 h after catalyst addition. bRun at rt for 24 h after catalyst addition.The standard protocol could be scaled to 1.25 mmol without erosion in efficiency or enantiocontrol (Scheme 3). Moreover, the directing groups, such as the para-hydroxy group, could be easily converted or removed. For example, after triflation of the phenol unit in 2d, the triflate 3 could easily participate in coupling reactions to form the arylation, reduction, and allylation products 4–6. The high enantiopurity remained essentially intact.Open in a separate windowScheme 3Product transformations. [a] Tf2O, Et3N, DCM, 0 °C to rt; [b] PhB(OH)2, Pd(OAc)2, BrettPhos, K3PO4, tBuOH, 85 °C; [c] Et3SiH, Pd(OAc)2, dppp, DMF, 60 °C; [d] AllylBpin, Pd(OAc)2, BrettPhos, K3PO4, tBuOH, 85 °C.To understand the reaction mechanism, we carried out some control experiments. First, the intermediate QM, though unstable and easy to undergo addition, was obtained by careful isolation from the oxidation step in the presence of molecular sieves (Scheme 4a). Next, in the absence of DDQ, the standard reaction between QM and 2-methylpyrrole proceeded with high efficiency and excellent enantioselectivity (97% ee, Scheme 4b). However, with DDQ as an additive, the enantioselectivity decreased to 44% ee, which confirmed that it is detrimental to enantiocontrol.14 The methylated substrate 1a-Me was also examined. The desired tetraarylmethane 2a-Me was successfully formed, but in an almost racemic form (Scheme 4c). In this case, the corresponding oxonium cation served as an activated intermediate, rather than p-QM. This result indicated that the free hydroxyl group in the standard substrates is not necessary for DDQ oxidation, but the resulting p-QM intermediate is essential for excellent enantiocontrol.Open in a separate windowScheme 4Mechanistic study.Finally, the substrates bearing other ortho-substituents in place of the ortho-methoxyl group were examined. With ortho-methyl and ethyl groups (1r–s), low enantioselectivies were obtained in spite of excellent yields. In particular, the ethyl group has a similar size to the methoxyl group, but does not provide hydrogen bonding interactions. The dramatically low ee (17% ee) for this case provided strong evidence that steric hindrance is not key to the excellent asymmetric induction for 1a. Furthermore, substrate 1t (with ortho-OiPr) also provided a lower ee (72% ee) than 1a. These results suggested that it is the hydrogen bonding interaction with the ortho-directing group, not the steric or electronic effect, that leads to the excellent enantiocontrol in the standard protocol.8We also randomly selected a few of our products to test their potential antiviral activities in Rhabdomyosarcoma (RD) cells, which are commonly used to investigate enterovirus A71 (EV-A71) infections. Our compounds showed relatively high CC50 measured by MTT assay, indicating low cell toxicity (Fig. 1). Quantitation of viral genome RNA in the secreted virions showed potent inhibition of virus replication with IC50 ranging from 0.20 to 1.24 μM, indicating a high selectivity index (Compound CC50 (μM) IC50 (μM) Selectivity indexb 2k 29.3 0.20 148.5 2u 33.2 0.24 138.3 2r 28.2 1.24 22.7
Entry | [O] | Conv. (%) |
---|---|---|
1 | Ag2O (5.0 equiv.) | 0 |
2 | Benzoquinone (1.5 equiv.) | 0 |
3 | Mn(acac)3 (10 mol%), O2 (1 atm) | 0 |
4 | KBr (1.2 equiv.), Oxone (1.2 equiv.) | 0 |
5 | K3Fe(CN)6 (1.5 equiv.) | 0 |
6 | AIBN (0.5 equiv.), TBHP (3.0 equiv.) | 0 |
7 | FeCl3 (10 mol%), TBHP (3.0 equiv.) | 0 |
8 | TEMPO (3.0 equiv.) | 0 |
9 | DDQ (1.0 equiv.) | 100 |
10 | DDQ (20 mol%), MnO2 (5.0 equiv.) | 60 |
Entry | CPA | Temp. | Yield 2a (%) | ee (%) |
---|---|---|---|---|
1 | (R)-A1 | rt | 90 | 0 |
2 | (R)-A2 | rt | 95 | 47 |
3 | (R)-A3 | rt | 92 | 49 |
4 | (R)-A4 | rt | 96 | 93 |
5 | (R)-B | rt | 93 | 65 |
6 | (R)-C | rt | 91 | 9 |
7 | (R)-A5 | rt | 95 | 95 |
8 | (R)-A5 | 0 °C | 95 | 97 |
Change from the entry 8 | |||
9 | EtOAc as solvent | >95 | 41 |
10 | Et2O as solvent | 88 | 70 |
11 | DCM as solvent | >95 | 93 |
12 | c = 0.1 M | 96 | 95 |
13 | c = 0.025 M | 95 | 93 |
14 | 7.5 mol% of (R)-A5 | 95 | 97 |
15 | 1.5 equiv. of DDQ | 94 | 51 |
16 | 0.8 equiv. of DDQ | 77 | 96 |
17 | Mix all together at the beginning | 47 | 62 |
18 | 1 h (not 5 h) for the first step | 95 | 81 |