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1.
Ryan P. Sweeney Phillip M. Danby Andreas Geissner Ryan Karimi Jesper Brask Stephen G. Withers 《Chemical science》2021,12(2):683
α-Amylases are among the most widely used classes of enzymes in industry and considerable effort has gone into optimising their activities. Efforts to find better amylase mutants, such as through high-throughput screening, would be greatly aided by access to precise and robust active site titrating agents for quantitation of active mutants in crude cell lysates. While active site titration reagents designed for retaining β-glycosidases quantify these enzymes down to nanomolar levels, convenient titrants for α-glycosidases are not available. We designed such a reagent by incorporating a highly reactive fluorogenic leaving group onto unsaturated cyclitol ethers, which have been recently shown to act as slow substrates for retaining glycosidases that operate via a covalent ‘glycosyl’-enzyme intermediate. By appending this warhead onto the appropriate oligosaccharide, we developed efficient active site titration reagents for α-amylases that effect quantitation down to low nanomolar levels.α-Amylases are among the most widely used classes of enzymes in industry and considerable effort has gone into optimising their activities.Amylases are among the most common classes of enzymes employed in industrial settings, being used in detergents, bread, beer, biofuel, and many other sectors. Accordingly, α-amylases account for 25% of the world''s multi-billion dollar enzyme market.1,2 α-Amylases are endo-acting enzymes that cleave starch into malto-oligosaccharides, which are further degraded by exo-acting α-glucosidases, glucoamylases, β-amylases and α-glucan phosphorylases and lyases. They are found in CAZy GH families 13, 57, 119 and 126, with the vast majority in the large GH13 family.3 GH13 enzymes adopt a (β/α)8 fold with three highly conserved active site carboxylic acids.4–6 They employ a classical double-displacement mechanism7 in which one of the glutamic acids provides acid catalytic assistance to the leaving group departure while an aspartate attacks the anomeric centre, forming a covalent glycosyl enzyme intermediate. In a second step, water attacks the anomeric centre with base assistance from the glutamate residue (Fig. 1A and B).Open in a separate windowFig. 1Koshland mechanism of retaining β- and α-glycosidases (A & B). The same mechanism has been observed for the hydrolysis of “β”-valienols (C), and for “α”-valienols (D).Given their industrial importance, a huge amount of attention has been given to the discovery and improvement of α-amylases to attain optimal performance for particular applications. These approaches typically require high-throughput analysis of large numbers of gene products or mutants thereof.8–10 Identification of the best candidates then ideally requires high-throughput assay coupled with a method for determining the enzyme concentration in each sample. This can be a challenging task in the absence of purification, as would be the case for truly high-throughput approaches. The “gold standard” method to quantify active enzyme concentration is active site titration.11 Active site titrants react stoichiometrically with their target enzymes and release one equivalent of a quantifiable agent, which is typically either a chromophore or fluorophore. For enzymes that operate via a covalent intermediate, such as retaining glycosidases, the active site titrants are usually chromogenic or fluorogenic substrates that form this intermediate with a rate constant (kon) that is much greater than that for its hydrolysis (koff) – ideally with koff approaching zero.Our lab has previously developed active site titration reagents for several retaining β-glycosidases12,13 and neuraminidases.14,15 By replacing the substituent on the position adjacent to the anomeric centre of the sugar (the hydroxyl at C-2 for many monosaccharides) with a fluorine atom, both the formation and the hydrolysis of the glycosyl-enzyme intermediate are slowed, largely through inductive destabilisation of the transition state. Further incorporation of a reactive fluorogenic leaving group generates a reagent that, upon covalently inactivating the glycosidase, releases a stoichiometric and quantifiable amount of fluorophore. The fluorogenic response is then measured to determine the amount of active glycosidase that is present in solution.Unfortunately, this same strategy does not work for retaining α-glycosidases. In those cases, koff remains greater than kon, likely due to the inherently greater reactivity of the β-glycosyl-enzyme intermediate,16,17 and the compounds are simply substrates with low turnover numbers. By use of 2,2-dihalosugars with yet more reactive leaving groups, this problem could be solved in some cases, but their synthesis is challenging, and inactivation rates were low, or non-existent in some cases.18,19 Alternative approaches were called for.Recently, a new class of glycosidase substrates was reported in which the sugar moiety is replaced by an equivalently hydroxylated cyclohexene.20–23 Hydrolysis of these enol ethers likely occurs via an allylic cation of almost identical reactivity to that of the equivalent oxocarbenium ion. Glycosidases cleave these substrates via the classical Koshland mechanism7 (Fig. 1C and D), but considerably more slowly than their natural substrates. However, incorporation of a good leaving group will accelerate, relatively, the first step such that, in some cases, they act as mechanism-based inactivators making them candidates for development of an active site titrant for α-amylases.Since α-amylases are endo-acting enzymes that do not usually cleave monosaccharide glycosides, an ‘extended” oligosaccharide version containing a total of 2 or 3 sugar/pseudosugar moieties would be needed. Substrates longer than this would be prone to internal glycoside cleavage. Since 2-chloro-4-nitrophenyl maltotrioside (CNP-G3) functions as a substrate for most amylases, we focused on addition of a maltosyl unit to a valienol moiety containing a 6,8-difluorocoumarin (F2MU) leaving group at its “anomeric centre”. The low pKa of this coumarin, 4.7,14 results in a greater reactivity of the reagent and also ensures the coumarin will be deprotonated and thus fluorescent, upon release at neutral pH.Synthesis of partially protected alcohol 2 from gluconolactone 1via literature methods24 was followed by attachment of F2MU via a Mitsunobu reaction and subsequent removal of the protecting groups under acidic conditions, generating known pseudo-glycoside 3.23 To check this concept before we synthesized the longer version, we tested compound 3 as a titrant of a simple α-glucosidase and found that it did indeed titrate the enzyme (Fig. S5†). Since elongation of this pseudosugar via classical organic synthesis would require substantial protecting group chemistry, we elected instead to employ an enzymatic coupling strategy using the GH13 cyclodextrin transglycosidase, CGTase. This enzyme can use glycosyl fluorides, such as α-maltosyl fluoride, to effect glycosyl transfer onto suitable acceptors. However, a significant competing reaction would involve self-condensation of glycosyl fluorides ultimately forming cyclodextrins. To avoid this problem, we employed a maltosyl fluoride donor (4), in which the 4′-hydroxyl had been capped with a methyl group.25,26 Incorporation of 4′-methoxy groups does not alter the reaction with α-amylases, as this site in the normal substrate is occupied by additional sugar residues. Thus CGTase-catalysed glycosylation between known glycosyl fluoride 4 and pseudo-glycoside 3, gave the pseudo-trisaccharide 5 in 64% isolated yield (Scheme 1).Open in a separate windowScheme 1Synthesis of titration reagent 5.With this reagent in hand, we proceeded to screen its ability to inactivate a small panel of α-amylases. As shown in Fig. 2, time-dependent inactivation was observed for all enzymes tested, with the most industrially relevant enzymes, Effusibacillus pohliae amylase (EPA) and Aspergillus oryzae amylase (AOA), being inactivated the fastest.Open in a separate windowFig. 2Time-dependent inactivation of a small panel of amylases, showing remaining % activity versus time. Red box with X: AOA (91 nM); blue square: EPA (66.7 nM); purple cross: PPA (500 nM); green triangle: HPA (125 nM). AOA = A. oryzae amylase; EPA = E. pohliae amylase; HPA = human pancreatic amylase; PPA = porcine pancreatic amylase.Kinetic parameters for inactivation were then determined by directly monitoring the release of F2MU by UV-Vis (Table 1). To determine kon and koff (Scheme 2), we monitored chromophore (F2MU) release by absorbance at 370 or 380 nm (dependent on the concentration of 5 in the measurements of each enzyme). After mixing 5 with each enzyme individually, a burst phase followed by a steady-state phase was observed. For each enzyme, this was then repeated with varying concentrations of 5. Initial rates of F2MU release versus concentration of 5 were fit to a Michaelis–Menten equation to provide kon. The rate constant of cyclitol release, koff, was determined by measuring rates of the steady-state region at a saturating concentration (5× Ki). We found that several amylases: Effusibacillus pohliae amylase (EPA), Aspergillus oryzae amylase (AOA), Rhizomucor pusillus amylase (RPA) and porcine pancreatic amylase (PPA), inactivated quickly (highest kon, lowest koff, and greatest kon/Ki), and are therefore ideal candidates for titration with compound 5. Human pancreatic amylase (HPA), on the other hand, while inactivating rapidly, binds the reagent relatively poorly.Open in a separate windowScheme 2Kinetic parameters for the hydrolysis of 5 by several amylases (at 25 °C for EPA, AOA, and RPA and 30 °C for human pancreatic amylase [HPA] and porcine pancreatic amylase [PPA])
Open in a separate windowConfirmation that the inactivation observed was a result of stoichiometric covalent derivatisation of the enzyme was obtained for three representative enzymes by monitoring the enzyme molecular weights before and after inactivation, by electrospray ionisation mass spectrometry. As shown in Table 2, Fig. 3 and in ESI Fig. S1,† the mass of each enzyme after the reaction was increased by the expected 496 mass units relative to that of the unlabelled enzyme. Complete reaction is evident by the absence of any unlabelled enzyme peak after addition of 5 (Fig. 3 and S1†). It should also be noted, that all glycoforms of AOA underwent complete reaction (Fig. 3).Open in a separate windowFig. 3MS-plot of AOA before (left side, blue) and after (right side, green) addition of 5 showing the expected increase of 496 mass units.Intact-MS results confirming the stoichiometric addition of pseudo-trisaccharide (+496 m/z) to each amylase
Open in a separate windowHaving demonstrated that these reagents function as effective time-dependent inactivators, we then evaluated their utility as active site titration agents. Initially, we tested the ability of compound 5 to titrate ∼100 nM EPA (Fig. 4A) and observed a classical burst of fluorescence followed by a steady-state turnover phase. The active enzyme concentration can be quantified from such plots by extrapolating the steady-state portion back to the y-intercept (t = 0) and fitting the burst to eqn (1), as described previously.11Burst = [E]0 × (kon/kon + koff)21Open in a separate windowFig. 4(A) Titration of EPA with 100 μM of 5. The release of F2MU was monitored fluorimetrically (λEx = 353 nm, λEm = 451 nm). The steady-state signal was extrapolated back to the y-axis to get the corresponding burst amplitude and fit to eqn (1) to give enzyme concentration. (B) Titration of a set of serial dilutions of EPA. Red small box with X: 100 nM; yellow triangle: 50 nM; green (small) square: 25 nM; blue-green cross: 12.5 nM; blue (large) square: 6.3 nM; pink star: 3.1 nM. Burst responses show a detectable response down to 3 nM. (C) Plot of dilution factor versus the calculated [Novamyl], based on the burst response in Fig. 4B with the colours corresponding to the concentrations indicated in Fig. 4B.The values we obtained in this way are shown in Table 3 and compared with the concentrations claimed by the manufacturers: agreement was excellent for EPA and AOA. To explore a case in which total protein concentration was likely to be different from active concentration, we titrated a commercial porcine pancreatic amylase (PPA) that was purchased from Sigma-Aldrich several years prior to this set of experiments. The concentration of the active enzyme was found to be almost 4-fold lower than the original stated value. This discrepancy is likely due to the degradation of the enzyme over the long storage period. Indeed, such discrepancies in active enzyme concentration and total protein concentration are exactly what the titration agent is designed to detect.Concentrations of several amylases determined by titration with reagent 5, compared with manufacturers'' listed concentrationa
Open in a separate windowaDetermined by declared activity measurements.bSubstrate 3 was used for titration of this enzyme. The manufacturer''s concentration was determined by measuring the enzyme activity with PNP-Glc (Vmax) and using their reported units of activity vs. PNP-Glc.Finally, the sensitivity and linearity of the response of our titration reagent 5 were tested using a crude, commercial batch of EPA (5 mg mL−1; 66.7 μM). After initial dilution of this batch of EPA to 100 nM, a series of 2× dilutions gave a reliable and detectable fluorogenic response down to enzyme concentrations as low as 3 nM (Fig. 4B and C). 相似文献
Enzyme: | K i (μM) | k on (min−1) | k on/Ki (min−1 nM−1) | k off (min−1) |
---|---|---|---|---|
HPA | 3040 | 0.20 | 0.07 | n.d. |
PPA | 228 | 0.48 | 2.1 | 0.024 |
EPA | 45.0 | 1.70 | 28.9 | 0.002 |
AOA | 73.0 | 0.34 | 4.6 | 0.001 |
RPA | 160 | 0.25 | 1.6 | 0.004 |
Enzyme: | Enzyme (M + H+) | Enzyme + 5 (M + H+) |
---|---|---|
HPA | 56 066.7 | 56 563.0 |
EPA | 75 190.6 | 75 686.0 |
AOA | 53 863.3 | 54 358.6 |
Enzyme: | [Manufacturers] (nM) | [Titration] (nM) |
---|---|---|
AOA | 91 | 93 |
EPA | 100 | 116 |
PPA | 610 | 164 |
Yeast α-glucosidaseb | 8800 | 7500 |
2.
Joel Hfliger Keith Livingstone Constantin G. Daniliuc Ryan Gilmour 《Chemical science》2021,12(17):6148
Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis. This inexpensive main group catalysis strategy employs p-TolI as an effective organocatalyst when combined with Selectfluor® and simple amine·HF complexes. Modulating Brønsted acidity enables simultaneous geminal and vicinal difluorination to occur, thereby providing a platform to generate multiply fluorinated scaffolds for further downstream derivatization. The method facilitates access to a tetrafluorinated API candidate for the treatment of amyotrophic lateral sclerosis. Preliminary validation of an enantioselective process is disclosed to access α-phenyl-β-difluoro-γ-bromo/chloro esters.Simple α-(bromomethyl)styrenes can be processed to a variety of 1,1-difluorinated electrophilic building blocks via I(I)/I(III) catalysis.Structural editing with fluorine enables geometric and electronic variation to be explored in functional small molecules whilst mitigating steric drawbacks.1 This expansive approach to manipulate structure–function interplay continues to manifest itself in bio-organic and medicinal chemistry.2 Of the plenum of fluorinated motifs commonly employed, the geminal difluoromethylene group3 has a venerable history.4 This is grounded in the structural as well as electronic ramifications of CH2 → CF2 substitution, as is evident from a comparison of propane and 2,2-difluoropropane (Fig. 1, upper). Salient features include localized charge inversion (C–Hδ+ to C–Fδ−) and a widening of the internal angle from 112° to 115.4°.5 Consequently, geminal difluoromethylene groups feature prominently in the drug discovery repertoire6 to mitigate oxidation and modulate physicochemical parameters. Catalysis-based routes to generate electrophilic linchpins that contain the geminal difluoromethylene unit have thus been intensively pursued, particularly in the realm of main group catalysis.7–9 Motivated by the potential of this motif in contemporary medicinal chemistry, it was envisaged that an I(I)/I(III) catalysis platform could be leveraged to convert simple α-(bromomethyl)styrenes to gem-difluorinated linchpins: the primary C(sp3)–Br motif would facilitate downstream synthetic manipulations (Fig. 1, lower). To that end, p-TolI would function as a catalyst to generate p-TolIF2in situ in the presence of an external oxidant10 and an amine·HF complex. Alkene activation (I) with subsequent bromonium ion formation (II)11 would provide a pre-text for the first C–F bond forming process (III) with regeneration of the catalyst. A subsequent phenonium ion rearrangement12/fluorination sequence (III and IV) would furnish the geminal difluoromethylene group and liberate the desired electrophilic building block.Open in a separate windowFig. 1The geminal difluoromethylene group: bioisosterism, and catalysis-based access from α-(bromomethyl)styrenes via I(I)/I(III) catalysis.To validate this conceptual framework, a short process of reaction optimization (1a → 2a) was conducted to assess the influence of solvent, amine·HF ratio (Brønsted acidity)13 and catalyst loading (Table 1). Initial reactions were performed with p-TolI (20 mol%), Selectfluor® (1.5 equiv.) as an oxidant, and CHCl3 as the reaction medium. Variation of the amine : HF ratio was conducted to explore the influence of Brønsted acidity on catalysis efficiency (entries 1–4). An optimal ratio of 1 : 6 was observed enabling the product 2a to be generated in >95% NMR-yield. Although reducing the catalyst loading to 10 and 5 mol% (entries 5 and 6, respectively) led to high levels of efficiency (79% yield with 5 mol%), the remainder of the study was performed with 20 mol% p-TolI. Notably, catalytic vicinal difluorination was not observed at any point during this optimization, in contrast with previous studies from our laboratory.9d,i A solvent screen revealed the importance of chlorinated solvents (entries 7 and 8): in contrast, performing the reaction in ethyl trifluoroacetate (ETFA) and acetonitrile resulted in a reduction in yield (9 and 10). Finally, a control reaction in the absence of p-TolI confirmed that an I(I)/I(III) manifold was operational (entry 11). An expanded optimization table is provided in the ESI.†Reaction optimizationa
Open in a separate windowaStandard reaction conditions: 1a (0.2 mmol), Selectfluor® (1.5 equiv.), amine : HF source (0.5 mL), solvent (0.5 mL), p-TolI, 24 h, rt.bDetermined by 19F NMR using α,α,α-trifluorotoluene as internal standard.To explore the scope of this geminal difluorination, a series of α-(bromomethyl)styrenes were exposed to the standard reaction conditions (Fig. 2). Gratifyingly, product 2a could be isolated in 80% yield after column chromatography on silica gel. The parent α-(bromomethyl)styrene was smoothly converted to species 2b, as were the p-halogenated systems that furnished 2c and 2d (71 and 79%, respectively). The regioisomeric bromides 2e and 2f (70 and 62%, respectively) were also prepared for completeness to furnish a series of linchpins that can be functionalized at both termini by displacement and cross-coupling protocols (2a, 2e and 2f). Modifying the amine : HF ratio to 1 : 4.5 provided conditions to generate the tBu derivative 2g in 68% yield.14 Electron deficient aryl derivatives were well tolerated as is demonstrated by the formation of compounds 2h–2k (up to 91%). Disubstitution patterns (2l, 81%), sulfonamides (2m, 75%) and phthalimides (2n, 80%) were also compatible with the standard catalysis conditions. Gratifyingly, compound 2n was crystalline and it was possible to unequivocally establish the structure by X-ray crystallography (Fig. 2, lower).15 The C9–C8–C7 angle was measured to be 112.6° (cf. 115.4° for 2,2-difluoropropane).5 Intriguingly, the C(sp3)–Br bond eclipses the two C–F bonds rather than adopting a conformation in which dipole minimization is satisfied (F1–C8–C9–Br dihedral angle is 56.3°).Open in a separate windowFig. 2Exploring the scope of the geminal difluorinative rearrangement of α-(bromomethyl)styrenes via I(I)/I(III) catalysis. Isolated yields after column chromatography on silica gel are reported. X-ray crystal structure of compound 2n (CCDC 2055892†). Thermal ellipsoids shown at 50% probability.Cognizant of the influence of Brønsted acidity on the regioselectivity of I(I)/I(III) catalyzed alkene difluorination,9d the influence of the amine : HF ratio on the fluorination of electronically non-equivalent divinylbenzene derivatives was explored (Fig. 3, top). Initially, compound 3 bearing an α-(trifluoromethyl)styrene motif was exposed to the standard catalysis conditions with a 1 : 4.5 amine : HF ratio. Exclusive, chemoselective formation of 4 was observed in 79% yield. Simple alteration of the amine : HF ratio to 1 : 7.5 furnished the tetrafluorinated product 5 bearing both the geminal and vicinal difluoromethylene16 groups (55% yield. 20% of the geminal–geminal product was also isolated. See ESI†). Relocating the electron-withdrawing group (α-CF3 → β-CO2Me) and repeating the reaction with 1 : 4.5 amine : HF generated the geminal CF2 species 7 in analogy to compound 4. However, increasing the amine : HF ratio to 1 : 6.0 led exclusively to double geminal difluorination (8, 55%).Open in a separate windowFig. 3Exploring the synthetic versatility of this platform. (Top) Leveraging Brønsted acidity to achieve chemoselective fluorination. (Centre) Bidirectional functionalization. (Bottom) Preliminary validation of an enantioselective variant.Similarly, bidirectional geminal difluorination of the divinylbenzene derivatives 9 and 11 was efficient, enabling the synthesis of 10 (46%) and 12 (70%), respectively. This enables facile access to bis-electrophilic fluorinated linchpins for application in materials chemistry.Preliminary validation of an enantioselective variant8d was achieved using the trisubstituted alkene 13. To that end, a series of C2-symmetric resorcinol-based catalysts were explored (see Fig. 3, inset). This enabled the generation of product 15 in up to 18 : 82 e.r. and 71% isolated yield. It is interesting to note that this catalysis system was also compatible with the chlorinated substrate E-14. A comparison of geometric isomers revealed a matched-mismatched scenario: whilst E-14 was efficiently converted to 16 (75%, 14 : 86 e.r.), Z-14 was recalcitrant to rearrangement (<20%).To demonstrate the synthetic utility of the products, chemoselective functionalization of linchpin 2a was performed to generate 17 (57%) and 18 (87%), respectively (Fig. 4). Finally, this method was leveraged to generate an API for amyotrophic lateral sclerosis. Whereas the reported synthesis17 requires the exposure of α-bromoketone 19 to neat DAST over 7 days,18 compound 2h can be generated using this protocol over a more practical timeframe (24 h) on a 4 mmol scale. This key building block was then processed, via the amine hydrochloride salt 20, to API 21.Open in a separate windowFig. 4Selected modification of building blocks 2a and 2h. Conditions: (a) NaN3, DMF, 110 °C, 16 h. (b) Pd(OH)2/C (10 mol%), EtOH, 1 M HCl, rt, 24 h; (c) CDI, Et3N, THF, 60 °C, 16 h; (d) malonyl chloride, DCM, 0 °C, 2 h. 相似文献
Entry | Solvent | Amine/HF | Catalyst loading [mol%] | Yieldb [%] |
---|---|---|---|---|
1 | CHCl3 | 1 : 4.5 | 20 | 72 |
2 | CHCl 3 | 1 : 6.0 | 20 | >95 |
3 | CHCl3 | 1 : 7.5 | 20 | 94 |
4 | CHCl3 | 1 : 9.23 | 20 | 87 |
5 | CHCl3 | 1 : 6.0 | 10 | 87 |
6 | CHCl3 | 1 : 6.0 | 5 | 79 |
7 | DCM | 1 : 6.0 | 20 | >95 |
8 | DCE | 1 : 6.0 | 20 | 93 |
9 | ETFA | 1 : 6.0 | 20 | 84 |
10 | MeCN | 1 : 6.0 | 20 | 50 |
11 | CHCl3 | 1 : 6.0 | 0 | <5 |
3.
4.
The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative. The [6,6]-bicyclic decalin B–C ring and the all-carbon quaternary stereocenter at C-6 were prepared via a desymmetric intramolecular Michael reaction with up to 97% ee. The naphthalene diol D–E ring was constructed through a sequence of Ti(Oi-Pr)4-promoted photoenolization/Diels–Alder, dehydration, and aromatization reactions. This asymmetric strategy provides a scalable route to prepare target molecules and their derivatives for further biological studies.The asymmetric total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B was achieved in 6–7 steps using an easily accessible meso-cyclohexadienone derivative.Various halenaquinone-type natural products with promising biological activity have been isolated from marine sponges of the genus Xestospongia1 from the Pacific Ocean. (+)-Halenaquinone (1),2,3 (+)-xestoquinone (2), and (+)-adociaquinones A (3) and B (4)4,5 bearing a naphtha[1,8-bc]furan core (Fig. 1) are the most typical representatives of this family. Naturally occurring (−)-xestosaprol N (5) and O (6)6,7 have the same structure as 3 and 4 except for a furan ring, while a naphtha[1,8-bc]furan core can also be found in fungus-isolated furanosteroids (−)-viridin (7) and (+)-nodulisporiviridin E (8)8,9 (Fig. 1). Halenaquinone (1) was first isolated from the tropical marine sponge Xestospongia exigua2 and it shows antibiotic activity against Staphylococcus aureus and Bacillus subtilis. Xestoquinone (2) and adociaquinones A (3) and B (4) were firstly isolated, respectively, from the Okinawan marine sponge Xestospongia sp.4a and the Truk Lagoon sponge Adocia sp.,4b and they show cardiotonic,4a,c cytotoxic,4b,i antifungal,4i antimalarial,4j and antitumor4l activities. These compounds inhibit the activity of pp60v-src protein tyrosine kinase,4d topoisomerases I4e and II,4f myosin Ca2+ ATPase,4c,g and phosphatases Cdc25B, MKP-1, and MKP-3.4h,kOpen in a separate windowFig. 1Structure of halenaquinone-type natural products and viridin-type furanosteroids.Owing to their diverse bioactivities, the synthesis of this family of natural compounds has been extensively studied, with published pathways making use of Diels–Alder,3a,d,e,5a–c,e,g furan ring transfer,5b Heck,3b,c,5f,7,9b,d palladium-catalyzed polyene cyclization,5d Pd-catalyzed oxidative cyclization,3f and hydrogen atom transfer (HAT) radical cyclization9c reactions. In this study, we report the asymmetric total synthesis of (+)-xestoquinone (2), (−)-xestoquinone (2′), and (+)-adociaquinones A (3) and B (4) (Fig. 1).The construction of the fused tetracyclic B–C–D–E skeleton and the all carbon quaternary stereocenter at C-6 is a major challenge towards the total synthesis of xestoquinone (2) and adociaquinones A (3) and B (4). Based on our retrosynthetic analysis (Scheme 1), the all-carbon quaternary carbon center at C-6 of cis-decalin 12 could first be prepared stereoselectively from the achiral aldehyde 13via an organocatalytic desymmetric intramolecular Michael reaction.10,11 The tetracyclic framework 10 could then be formed via a Ti(Oi-Pr)4-promoted photoenolization/Diels–Alder (PEDA) reaction12–16 of 11 and enone 12. Acid-mediated cyclization of 10 followed by oxidation state adjustment could be subsequently applied to form the furan ring A of xestoquinone (2). Finally, based on the biosynthetic pathway of (+)-xestoquinone (2)4b,5c and our previous studies,7 the heterocyclic ring F of adociaquinones A (3) and B (4) could be prepared from 2via a late-stage cyclization with hypotaurine (9).Open in a separate windowScheme 1Retrosynthetic analysis of (+)-xestoquinone and (+)-adociaquinones A and B.The catalytic enantioselective desymmetrization of meso compounds has been used as a powerful strategy to generate enantioenriched molecules bearing all-carbon quaternary stereocenters.10,11 For instance, two types of asymmetric intramolecular Michael reactions were developed using a cysteine-derived chiral amine as an organocatalyst by Hayashi and co-workers,11a,b while a desymmetrizing secondary amine-catalyzed asymmetric intramolecular Michael addition was later reported by Gaunt and co-workers to produce enantioenriched decalin structures.11c Prompted by these pioneering studies and following the suggested retrosynthetic pathway (Scheme 1), we first screened conditions for organocatalytic desymmetric intramolecular Michael addition of meso-cyclohexadienone 13 (Table 1) in order to form the desired quaternary stereocenter at C-6. Compound 13 was easily prepared on a gram scale via a four-step process (see details in the ESI†).Attempts of organocatalytic desymmetric intramolecular Michael additiona
Open in a separate windowaAll reactions were performed using 13 (5.8 mg, 0.03 mmol, 1.0 equiv., and 0.1 M) and a catalyst at room temperature in analytical-grade solvents, unless otherwise noted.bThe yields and diastereoisomeric ratios (d.r.) were determined from the crude 1H NMR spectrum of 14 using CH2Br2 as an internal standard, unless otherwise noted.cThe enantiomeric excess (e.e.) values were determined by chiral high-performance liquid chromatography (Chiralpak IG-H).dCompound 13: 9.6 mg, 0.05 mmol, and 0.1 M.eIsolated combined yield of 14a + 14b.fCompound 13: 192 mg, 1.0 mmol, and 0.1 M.gThe d.r. values decreased to 1 : 1 after purification by silica gel column chromatography.hCompound 13: 1.31 g, 6.82 mmol, and 0.1 M.iIsolated combined yield of 12a + 12b.jThe d.r. values were determined from the crude 1H NMR spectrum of 12 obtained from the one-pot process.We initially investigated the desymmetric intramolecular Michael addition of 13 using (S)-Hayashi–Jørgensen catalysts,17 and found that the absolute configuration of the obtained cis-decalin was opposite to the required stereochemistry of the natural products (see Table S1 in the ESI†). In order to achieve the desired absolute configuration of the angular methyl group at C-6, (R)-cat.I was used for further screening. In the presence of this catalyst, the intramolecular Michael addition afforded 14a (96% e.e.) and 14b (75% e.e.) in a ratio of 10.3 : 1 and 52% combined yield (entry 1, Table 1). We assumed that the enantioselectivity of the reaction was controlled by the more sterically hindered aromatic group of (R)-cat.I, which protected the upper enamine face and allowed an endo-like attack by the si-face of cyclohexadienone, as shown in the transition state TS-A (Table 1). In order to increase the yield of this reaction and improve the enantioselectivity of 14b, we further screened solvents and additives. Increasing the catalyst loading from 0.5 to 1.0 equivalents and screening various reaction solvents did not improve the enantiomeric excess of 14b (entries 2–7, Table 1). Therefore, based on previous studies,11d,e we added 5.0 equivalents of acetic acid (AcOH) to a solution of compound 13 and (R)-cat.I in toluene, which improved the enantiomeric excess of 14b to 95% with a 60% combined yield (entry 8, Table 1). And, the stability of (R)-cat.I has also been verified in the presence of AcOH (see Table S2 in the ESI†). Further adjustment of the (R)-cat.I and AcOH amount and ratio (entries 9–12, Table 1) indicated that 0.2 equivalents each of (R)-cat.I and AcOH were the best conditions to achieve high enantioselectivity for both 14a and 14b, and it also increased the reaction yield (entry 12, Table 1). The enantioselectivity was not affected when the optimized reaction was performed on a gram scale: 14a (97% e.e.) and 14b (91% e.e.) were obtained in 80% isolated yield (entry 12, Table 1). We also found that the gram-scale experiments needed a longer reaction time which led a slight decrease of the diastereoselectivity. The purification of the cyclized products by silica gel flash column chromatography indicated that the major product 14a was epimerized and slowly converted to the minor product 14b (entry 11, Table 1). Both 14a and 14b are useful in the syntheses because the stereogenic center at C-2 will be converted to sp2 hybridized carbon in the following transformations. Therefore, the aldehyde group of analogues 14a and 14b was directly protected with 1,3-propanediol to give the respective enones 12a and 12b for use in the subsequent PEDA reaction.Afterward, we selected the major cyclized cis-decalins 12a and 12a′ (obtained by using (S)-cat.I in desymmetric intramolecular Michael addition, see Table S1 in the ESI†) as the dienophiles to prepare the tetracyclic naphthalene framework 10 through a sequence of Ti(Oi-Pr)4-promoted PEDA, dehydration, and aromatization reactions (Scheme 2). When using 3,6-dimethoxy-2-methylbenzaldehyde (11) as the precursor of diene, no reaction occurred between 12a/12a′ and 11 under UV irradiation at 366 nm in the absence of Ti(Oi-Pr)4 (Scheme 2A). In contrast, the 1,2-dihydronaphthalene compounds 16a and 16a′ were successfully synthesized when 3.0 equivalents of Ti(Oi-Pr)4 were used. Based on our previous studies,13a,e the desired hydroanthracenol 15a was probably generated through the chelated intermediate TS-B and the cycloaddition occurred through an endo direction (Scheme 2B).18 The newly formed β-hydroxyl ketone groups in 15a and 15a′ could then be dehydrated with excess Ti(Oi-Pr)4 to form enones 16a and 16a′. These results confirmed the pivotal role of Ti(Oi-Pr)4 in this PEDA reaction: it stabilized the photoenolized hydroxy-o-quinodimethanes and controlled the diastereoselectivity of the reaction.Open in a separate windowScheme 2PEDA reaction of 11 and enone 12.Subsequent aromatization of compounds 16a and 16a′ with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) at 80 °C afforded compounds 10a and 10a′ bearing a fused tetracyclic B–C–D–E skeleton. The stereochemistry and absolute configuration of 10a were confirmed by X-ray diffraction analysis of single crystals (Scheme 3). The synthesis of (+)-xestoquinone (2) and (+)-adociaquinones A (3) and B (4) was completed by forming the furan A ring. Compound 10 was oxidized using bubbling oxygen gas in the presence of t-BuOK to give the unstable diosphenol 17a, which was used without purification in the next step. The subsequent acid-promoted deprotection of the acetal group led to the formation of an aldehyde group, which reacted in situ with enol to furnish the pentacyclic compound 18 bearing the furan A ring. The stereochemistry and absolute configuration of 18 were confirmed by X-ray diffraction analysis of single crystals (Scheme 3). Further oxidation of 18 with ceric ammonium nitrate afforded (+)-xestoquinone (2) in 82% yield. Following the same reaction process, (−)-xestoquinone (2′) was also synthesized from 10a′ in order to determine in the future whether xestoquinone enantiomers differ in biological activity. Further heating of a solution of (+)-xestoquinone (2) with hypotaurine (9) at 50 °C afforded a mixture of (+)-adociaquinones A (3) (21% yield) and B (4) (63% yield). We also tried to optimize the selectivity of this condensation by tuning the reaction temperature and pH of reaction mixtures (see Table S3 in the ESI†). The 1H and 13C NMR spectra, high-resolution mass spectrum, and optical rotation of synthetic (+)-xestoquinone (2), (+)-adociaquinones A (3) and B (4) were consistent with those data reported by Nakamura,4a,g Laurent,4j Schmitz,4b Harada5a,c and Keay.5dOpen in a separate windowScheme 3Total synthesis of (+)-xestoquinone and (+)-adociaquinones A and B. 相似文献
Entry | Cat. (equiv.) | Additive (equiv.) | Solvent | Time | Yield/d.r. at C2b | e.e.c |
---|---|---|---|---|---|---|
1 | (R)-cat.I (0.5) | — | Toluene | 10.0 h | 52%/10.3 : 1 | 14a: 96%; 14b: 75% |
2 | (R)-cat.I (1.0) | — | Toluene | 4.0 h | 60%/10.0 : 1 | 14a: 93%; 14b: 75% |
3 | (R)-cat.I (1.0) | — | MeOH | 4.0 h | 47%/5.5 : 1 | 14a: 86%; 14b: −3% |
4 | (R)-cat.I (1.0) | — | DCM | 10.0 h | 28%/24.0 : 1 | 14a: 91%; 14b: 7% |
5 | (R)-cat.I (1.0) | — | Et2O | 10.0 h | 22%/22.0 : 1 | 14a: 91%; 14b: 65% |
6 | (R)-cat.I (1.0) | — | MeCN | 10.0 h | 12%/2.6 : 1 | 14a: 90%; 14b: 62% |
7 | (R)-cat.I (1.0) | — | Toluene/MeOH (2 : 1) | 4.0 h | 47%/10.0 : 1 | 14a: 87%; 14b: −38% |
8d | (R)-cat.I (1.0) | AcOH (5.0) | Toluene | 4.0 h | 60%e/2.1 : 1 | 14a: 96%; 14b: 95% |
9d | (R)-cat.I (0.5) | AcOH (2.0) | Toluene | 6.0 h | 75%e/4.0 : 1 | 14a: 97%; 14b: 91% |
10d | (R)-cat.I (0.5) | AcOH (0.2) | Toluene | 6.0 h | 73%e/4.3 : 1 | 14a: 96%; 14b: 92% |
11f | (R)-cat.I (0.5) | AcOH (0.2) | Toluene | 6.0 h | 75%e/8.0 : 1g | 14a: 95%; 14b: 93% |
12h | (R)-cat.I (0.2) | AcOH (0.2) | Toluene | 9.0 h | 80%i/6.0 : 1j | 14a: 97%; 14b: 91% |
5.
Dattatraya H. Dethe Nagabhushana C. Beeralingappa Saikat Das Appasaheb K. Nirpal 《Chemical science》2021,12(12):4367
Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields. Mild reaction conditions, less expensive catalysts, and excellent regio- and diastereoselectivity ensure universality of the reaction. In addition, the unique power of this reaction was illustrated by performing the Diels–Alder reaction, and enantioselective synthesis of highly functionalized cyclohexenone and piperidine and finally synthetic utility was further demonstrated by the efficient synthesis of norpyrenophorin, an antifungal agent.Ru-catalysed oxidative coupling of allylsilanes and allyl esters with activated olefins has been developed via isomerization followed by C(allyl)–H activation providing efficient access to stereodefined 1,3-dienes in excellent yields.1,3-Dienes not only are widespread structural motifs in biologically pertinent molecules but also feature as a foundation for a broad range of chemical transformations.1–14 Indeed, these conjugated dienes serve as substrates in many fundamental synthetic methodologies such as cycloaddition, metathesis, ene reactions, oxidoreduction, or reductive aldolization. It is well-understood that the geometry of olefins often influences the stereochemical outcome and the reactivity of reactions involving 1,3-dienes.15 Hence, a plethora of synthetic methods have been developed for the stereoselective construction of substituted 1,3-dienes.16–24 The past decade has witnessed a huge advancement in the field of metal-catalyzed C–H activation/functionalization.25–27 Although, a significant amount of work in the field of C(alkyl)–H and C(aryl)–H activation has been reported; C(alkenyl)–H activation has not been explored conspicuously, probably due to the complications caused by competitive reactivity of the alkene moiety, which can make chemoselectivity a significant challenge. Over the past few years, several different palladium-based protocols have been developed for C(alkenyl)–H functionalization, but the reactions are generally limited to employing conjugated alkenes, such as styrenes,28–31 acrylates/acrylamides,32–36 enamides,37 and enol esters/ethers.38,39 To date, only a few reports have appeared in the literature for expanding this reactivity towards non-conjugated olefins, which can be exemplified by camphene dimerization,40 and carboxylate-directed C(alkenyl)–H alkenylation of 1,4-cyclohexadienes.41 In 2009, Trost et al. reported a ruthenium-catalyzed stereoselective alkene–alkyne coupling method for the synthesis of 1,3-dienes.42 The same group also reported alkene–alkyne coupling for the stereoselective synthesis of trisubstituted ene carbamates.43 A palladium catalyzed chelation control method for the synthesis of dienes via alkenyl sp2 C–H bond functionalization was described by Loh et al.44 Recently, Engle and coworkers reported an elegant approach for synthesis of highly substituted 1,3-dienes from two different alkenes using an 8-aminoquinoline directed, palladium(ii)-mediated C(alkenyl)–H activation strategy.45 Allyl and vinyl silanes are known as indispensable nucleophiles in synthetic chemistry.46 Alder ene reactions of allyl silanes with alkynes are reported for the synthesis of 1,4-dienes.47 Innumerable methods are known for the preparation of both allyl and vinyl silanes48–52 but limitations are associated with many of the current protocols, which impedes the synthesis of unsaturated organosilanes in an efficient manner. Silicon-functionalized building blocks are used as coupling partners in the Hiyama reaction53 and are easily converted into iodo-functionalized derivatives (precursor for the Suzuki cross-coupling reaction), but there is little attention given for the synthesis of functionalized vinyl silanes. Herein, we report a general approach for the stereoselective synthesis of trisubstituted 1,3-dienes by the Ru-catalyzed C(sp3)–H functionalization reaction of allylsilanes (Scheme 1).Open in a separate windowScheme 1Highly stereoselective construction of 1,3-dienes.In 1993, Trost and coworkers reported an elegant method for highly chemoselective ruthenium-catalyzed redox isomerization of allyl alcohols without affecting the primary and secondary alcohols and isolated double bonds.54,55 Inspired by the potential of ruthenium for such isomerization of double bonds in allyl alcohols, we sought to identify a ruthenium-based catalytic system that can promote isomerization of olefins in allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes. We initiated our studies by choosing trimethylallylsilane 1a and acrylate 2a by using a commercially available [RuCl2(p-cymene)]2 catalyst in the presence of AgSbF6 as an additive and co-oxidant Cu(OAc)2 in 1,2-DCE at 100 °C. Interestingly, it resulted into direct formation of (2E,4Z)-1,3-diene 3aa as a single isomer in 55% yield. It is likely that this reaction occurs by C(allyl)–H activation of the π-allyl ruthenium complex followed by oxidative coupling with the acrylate and leaving the silyl group intact (Table 1). π-Allyl ruthenium complex formation may be highly favorable due to the α-silyl effect which stabilizes the carbanion forming in situ in the reaction.56 Next, the regioselective C–H insertion of vinyl silanes could be controlled by stabilization of the carbon–metal (C–M) bond in the α-position to silicon. This stability arises due to the overlapping of the filled carbon–metal orbital with the d orbitals on silicon or the antibonding orbitals of the methyl–silicon (Me–Si) bond.57 The stereochemistry of the diene was established by 1D and 2D spectroscopic analysis of the compound 3aa. To quantify the C–H activation mediated coupling efficiency, an extensive optimization study was conducted (allylsilanes followed by in situ oxidative coupling with an activated olefin to form substituted 1,3-dienes). The change of solvents from 1,2-DCE to t-AmOH, DMF, dioxane, THF or MeCN did not give any satisfactory result, rather a very sluggish reaction rate or decomposition of starting materials was observed in each case (entry 2–6).Optimization of reaction conditionsa
Open in a separate windowaReaction conditions: 1a (0.24 mmol), 2a (0.2 mmol), [Ru(p-cymene)Cl2]2 (5 mol%), additive (20 mol%) and oxidant (2 equiv.) at 100 °C in a specific solvent (2.0 mL), under argon, for 16 h.bIsolated yields are of product 3aa.cThe reaction was performed at 120 °C.dThe reaction was performed at 80 °C.eThe reaction was performed at 60 °C. t-AmOH – tertiary amyl alcohol, DMF – N,N-dimethylformamide, DCE – 1,2-dichloroethane.The increase of temperature from 100 °C to 120 °C resulted in the formation of diene in lower yield (entry 7). To our delight, it was found that a substantial enhancement in the yield (82%) was observed when the reaction was performed at 80 °C (entry 8). In particular, this was found to be the best reaction condition since further lowering of the temperature led to noteworthy attenuation of the reaction rate and yield (entry 9). Interestingly, the reaction was not efficient, when AgSbF6 was replaced with other additives, such as Ag2CO3 and AgOAc. It was also observed that, co-oxidant Cu(OAc)2 is necessary for the success of this reaction (entry 12).With these optimized conditions in hand, various allyl sources and acrylates have been tested (Table 2). It was found that a variety of acrylates 2 bearing alkyl and sterically crowded cyclic substituents successfully underwent the coupling reaction with allyl silane 1a to afford corresponding silyl substituted (2E,4Z)-1,3-dienes in good yields (3aa–3af). Similarly, dimethyl benzylallylsilane 1b reacted smoothly with acrylates such as methyl, isobutyl and n-butyl to generate desired dienes 3ba, 3bb and 3bc in 83%, 85% and 82% yield respectively. Interestingly, sterically crowded, tert-butyldimethyl allylsilane 1c showed its reactivity towards the coupling reaction with n-butyl acrylate to provide required diene 3cb in 80% yield. It is worth mentioning that allylsilanes 1a and 1b also exhibited their coupling reactivity with phenyl vinyl sulfone and successfully generated corresponding 1,3-dienes 3ag and 3bg in 78% and 76% yield respectively. When tert-butyldiphenylallylsilane 1d was subjected to the coupling reaction with methyl acrylate 2a, end–end coupling product 3da was isolated in 68% yield. This may be attributed to the steric crowding offered by bulky groups on silicon which prevents allyl to vinyl isomerization.Substrate scope for oxidative coupling of allylsilanes with acrylates and vinyl sulfonesa
Open in a separate windowaReaction conditions: 1 (0.24 mmol), 2 (0.2 mmol), [Ru(p-cymene)Cl2]2 (5 mol%), AgSbF6 (20 mol%) and Cu(OAc)2·H2O (2 equiv.) at 80 °C in 1,2-dichloroethane (2.0 mL), under argon, 16 h.bIsolated yields are of product 3. TMS – trimethylsilyl, TBDMS – tertiarybutyldimethyl silyl.To extend the substrate scope of the reaction, we next examined the scope of allylesters by employing 2a as the coupling partner. First, we carried out the coupling reaction between allyl ester derivative 4a and methyl acrylate 2a under standard conditions. To our delight, a single isomer of acetate substituted (2E,4Z)-1,3-diene 5aa was isolated with a good yield (75%) (Table 3). This result may be extremely unusual due to the weak thermodynamic driving force for the double bond migration of allyl esters and tendency of many metal catalysts to insert themselves into the C(allyl)–O bond to form a stable carboxylate complex.58 Even for unsubstituted allyl esters very few reports of double bond migrations exist.59–62 It is worth mentioning that unlike the Tsuji–Trost reaction,63–65 the C(allyl)–O bond doesn''t break to form the π-allyl palladium complex as an electrophile, instead it forms a nucleophilic π-allylruthenium complex (umpolung reactivity) keeping the acetate group intact, which further reacts with an electrophile. The stereochemistry of the diene was established by 1D and 2D spectroscopic analysis of the compound 5ga and also by comparison of spectroscopic data with those of an authentic compound.66 Next we turned our attention to expand the scope of the coupling reaction between various acrylates and allyl esters. It was found that a variety of allyl esters bearing alkyl substituents on the carbonyl carbon could provide moderate to good yields of the corresponding stereodefined (2E,4Z)-1,3,4-trisubstituted 1,3-dienes successfully. As can be seen from Table 2, alkyl substituents (4b–4d) had little influence on the yields (65–75%). Gratifyingly, we noticed that the presence of a bulky substituent in 4 also showed its viability towards the coupling reaction, albeit with modest yields (5ea & 5fa). Also, various acrylate derivatives reacted smoothly to generate the 1,3-dienes in excellent yield. A simple allyl acetate 4g reacted with a series of different acrylates 2 to afford the desired products in good yields.Substrate scope for oxidative coupling of various allyl esters with different acrylates and vinyl sulfonesa
Open in a separate windowaReaction conditions: 4 (0.24 mmol), 2 (0.2 mmol), [Ru(p-cymene)Cl2]2 (5 mol%), AgSbF6 (20 mol%) and Cu(OAc)2·H2O (2 equiv.) at 80 °C in 1,2-dichloroethane (2.0 mL), under argon, 16 h.bIsolated yields are of product 5.Several acrylates such as methyl-, ethyl-, n-butyl-, isobutyl-, n-heptyl-, cyclohexylmethyl-, benzyl-, etc. were tested and good to very good yields of the products were obtained. Also, gram scale synthesis of 5gh (1.35 g) by the reaction of acetate 4g with 2h gave identical results in terms of yield (69%) and diastereoselectivity, indicating the robustness and practicality of this method. Markedly, a C2-symmetric diacrylate (2e) also reacted with allyl acetate to form a mono-coupled product 5ge, though in a somewhat lower yield. In contrast to the allyl esters, the coupling was not affected by the steric bulk of the acrylate substituents as depicted in Table 3. Even the borneol derivative 2j and menthol derivative 2l, which can offer considerable steric hindrance, were found to be equally effective in the formation of 5gj and 5gl in very good yields. A somewhat reduced yield of the product 5gm was observed while using phenyl acrylate (2m) perhaps due to competitive reactive sites. Interestingly, the versatility of this methodology was not restricted only to acrylates, since phenyl vinyl sulfone was also found to be equally efficient for oxidative C–H functionalization with different allyl esters and a successful C–C coupling reaction was observed in each case with moderate yield and excellent diastereoselectivity.Interestingly treatment of allylsilanes under standard reaction conditions in the absence of an acrylate coupling partner led to isomerization of various allylsilanes to afford corresponding vinylsilanes 6b–6e in excellent yields (Scheme 2a). When allylsilane 1d was subjected to isomerization in the presence of CD3CO2D, a significant amount of deuterium scrambling at the α-position (>20%) as well as at the methyl group (>45%) was observed in corresponding vinylsilane, indicating that the isomerization step is reversible and the rate determining step (Scheme 2b). It is also observed that when vinylsilane 6b was made to react with methyl acrylate 2a under standard conditions, it successfully underwent highly regioselective C–H activation and afforded coupling product 3b′a in 80% yield (Scheme 2c). This result confirms that the coupling reaction proceeds via vinyl silane intermediate 6.Open in a separate windowScheme 2Isomerization of allylsilanes and deuterium study.It is delightful to mention that diene 3aa successfully underwent the Diels–Alder reaction with N-phenyl maleimide 7 in toluene at 80 °C, to afford single isomer 8 in 70% yield which ensures the pragmatism of the method (Scheme 3). The unique power of this ruthenium-catalyzed C–H functionalization strategy is illustrated by the late-stage diversification of the diene 5gh, to a very reactive Michael acceptor 9 (conventional route for preparation of 9 requires in situ oxidation of α-hydroxyketones using 10 equiv. MnO2 followed by the Wittig reaction, which generates a superstoichiometric amount of phosphine waste)67,68via selective hydrolysis of the acetate group, which is useful in the synthesis of ester-thiol 10,69 cyclohexenone 11 and polysubstituted piperidine 12 (ref. 70) (Scheme 4). Thus the Micheal acceptor 9 on reaction with thiophenol generated compound 10 in excellent yield and high regioselectivity. On the other hand compound 9 on reaction with heptanal in the presence of Hayashi–Jørgensen''s catalyst afforded the Michael adduct 13 in 72% yield and excellent diastereoselectivity. Keto-aldehyde 13 was converted to highly substituted cyclohexenone 11 and piperidine 12.Open in a separate windowScheme 3Application to the Diels–Alder reaction.Open in a separate windowScheme 4Application to the organocatalytic Michael addition reaction.The potential of this Ru-catalysed reaction was further demonstrated by norpyrenophorin synthesis.71–74 Norpyrenophorin 14 is a synthetic 16-membered lactone which has essentially the same physiological activity as the natural fungicide pyrenophorin 15 and the antibiotic vermiculin 16.73 A brief retrosynthetic analysis revealed that the dimeric macrocycle 14 could be dissected into monomer 17 which could be easily accessed from oxidative coupling of 2a with 18 using the C–H activation reaction (Scheme 5). Ruthenium catalysed oxidative coupling of symmetric allylester 18 with 2a generated the key intermediate 19 in 32% yield. Selective hydrolysis of acetyl enolate 19 was accomplished by the treatment with K2CO3 in methanol to provide 20 in 70% yield. In accordance with some previously reported studies, the active ketone functionality of 20 was protected as ketal by treatment with ethylene glycol in refluxing benzene to afford substrate 21. Selective hydrolysis of acetate was achieved using Bu2SnO to generate alcohol 22 and finally, aluminium–selenium adduct mediated72 ring closing lactonization followed by deketalization ensured the completion of synthesis of 14 in 23% yield (two steps) (Scheme 6). A similar type of dimerization reaction could be envisioned to synthesize the natural products pyrenophorin 15 and vermiculin 16.Open in a separate windowScheme 5Retrosynthetic analysis of norpyrenophorin.Open in a separate windowScheme 6Synthesis of norpyrenophorin.Based on the above result and previous report, a plausible mechanism for this oxidative coupling reaction is depicted in Scheme 7. The catalytic cycle is initiated by substrate 4g coordination to in situ generated reactive cationic ruthenium complex [Ru(OAc)L]+ A, followed by weakly coordinating ester group directed C–H activation of allyl ester to give a π-allyl ruthenium intermediate C, which again would undergo isomerization to produce intermediate D. In the case of allyl silanes, an α-silyl effect might play an important role for the isomerisation of allylsilanes to vinylsilanes via the silylated allyl anion.56 Regioselective C–H activation of in situ generated vinyl acetate would give intermediate E. Induction of stability to the carbon–metal bond by the silyl group favours regioselective C–H insertion in the case of vinyl silanes.57 Coordination followed by 1,4-addition of vinyl ruthenium species to the activated olefins (acrylate, 2a) would generate intermediate G, which would further undergo β-hydride elimination to provide a single isomer of 1,3-diene H and intermediate I could undergo reductive elimination followed by reoxidation of in situ forming Ru(0) species in the presence of Cu(OAc)2 to regenerate the reactive ruthenium(ii) complex A for the next catalytic cycle.Open in a separate windowScheme 7Plausible reaction mechanism. 相似文献
Entry | Additive (20 mol%) | Oxidant (2 equiv.) | Solvent | Yieldb (%) |
---|---|---|---|---|
1 | AgSbF6 | Cu(OAc)2 | DCE | 55 |
2 | AgSbF6 | Cu(OAc)2 | t-AmOH | 10 |
3 | AgSbF6 | Cu(OAc)2 | DMF | 0 |
4 | AgSbF6 | Cu(OAc)2 | Dioxane | 8 |
5 | AgSbF6 | Cu(OAc)2 | THF | 21 |
6 | AgSbF6 | Cu(OAc)2 | MeCN | 0 |
7c | AgSbF6 | Cu(OAc)2 | DCE | 35 |
8d | AgSbF6 | Cu(OAc)2 | DCE | 82 |
9e | AgSbF6 | Cu(OAc)2 | DCE | 45 |
10d | Ag2CO3 | Cu(OAc)2 | DCE | 0 |
11d | AgOAc | Cu(OAc)2 | DCE | 20 |
12d | AgSbF6 | — | DCE | 0 |
6.
C–O bond cleavage is often a key process in defunctionalization of organic compounds as well as in degradation of natural polymers. However, it seldom occurs regioselectively for different types of C–O bonds under metal-free mild conditions. Here we report a facile chemo-selective cleavage of the α-C–O bonds in α-carboxy ketones by commercially available pinacolborane under the catalysis of diazaphosphinane based on a mechanism switch strategy. This new reaction features high efficiency, low cost and good group-tolerance, and is also amenable to catalytic deprotection of desyl-protected carboxylic acids and amino acids. Mechanistic studies indicated an electron-transfer-initiated radical process, underlining two crucial steps: (1) the initiator azodiisobutyronitrile switches originally hydridic reduction to kinetically more accessible electron reduction; and (2) the catalytic phosphorus species upconverts weakly reducing pinacolborane into strongly reducing diazaphosphinane.Diazaphosphinyl radical-catalyzed chemo-selective deoxygenation of α-carboxy ketones with pinacolborane was achieved through the mechanism switch from direct to stepwise hydride transfer of diazaphosphinane.The importance of reductive deoxygenation can be gauged by the wide use of Barton–McCombie deoxygenation in organic syntheses.1 Such C–O bond cleavage is also a crucial step in the degradation of natural polymers (e.g., sugars and lignins) to recycle sustainable resources.2 Consequently, a great variety of methodologies were explored for activation of these strong C–O bonds.3 Among them, deoxygenation of α-acyloxy ketones3b,c,4 (represented by benzoin derivatives, stemming from simple aldehydes via benzoin condensation5) has attracted considerable attention, because it may provide a facile way for accessing commonly useful building blocks (aryl ketones).6 As known, benzoin derivatives bear two types of C–O bonds—the carbonyl π-C O bond and the benzyl σ-C–O bond (Scheme 1). While reduction of the carbonyl π-C O bonds has been well established through transition metal-7 or Lewis acid-mediated8 hydride transfers, chemo-selective cleavage of the benzyl σ-C–O bonds is challenging and has seldom been achieved.9 The later process is occasionally seen, however, in some radical or electron reductions, but toxic tin hydrides1c or aggressive metal reagents (like Raney nickel,10 zinc dust,11etc.) are inevitably employed.Open in a separate windowScheme 1Possible reactive sites for benzoin reduction.The recent successful development of super electron donors (SEDs),4,12 which are defined as ground-state organic electron-donors capable of reducing aryl halides to aryl radicals or aryl anions,13 and photocatalytic systems3b,c may provide alternative protocols for reductive cleavage of the σ-C–O bonds in O-acetylated benzoin. However, these electron transfer-initiated reductions also suffer from some drawbacks, such as, excessive use of SEDs and their tedious synthetic procedures, expensive photoredox catalysts and ligands, and group-tolerance issues. In fact, there have been few reports to date on metal-free systems for efficiently catalytic deoxygenation with commercially available inexpensive reductants.3h Given the ubiquity of C–O bonds in nature, it is still an unmet need for development of efficient and economical methods for their degradation. N-Heterocyclic phosphines (NHPs)8c,14 have recently found plentiful applications in hydridic reductions8b,15 owing to their outstanding hydricity.16 However, this seems to blind one to search for their other promising reaction patterns, like radical and electron transfer reactivities. Up to now, the catalytic potential of NHPs in radical or electron reductions has never been explored. Given the logical understanding that a deliberately manipulated mechanism variation usually leads to diverse reactivity and selectivity, we anticipate that an intended mechanism switch for NHP-based reactions from the conventional hydride transfer to an alternative electron transfer might provide a chance for originally inaccessible chemo-selectivity in the reduction of the substrates bearing multiple reactive sites. As known from previous studies, NHPs could transfer a hydride ion to carbonyl C O bonds to deliver the corresponding alcohol counterparts (Scheme 2a).8b This is indeed what we have seen. When NHPs are mixed with O-acetylated benzoins, an exclusive hydridic reduction of the carbonyl π-C O bonds is observed, leaving the benzyl σ-C–O bonds intact. How could we make the propensity of NHP reduction to switch from the original hydridic path to a radical one? Inspired by our recent findings that NHPs are also capable of serving as good hydrogen-atom donors (by P–H bond homolysis) and their corresponding phosphinyl radicals are excellent electron donors17 (Scheme 2b, bottom), we envisioned that if phosphinyl radicals can be in situ generated, their super electron-donicity may promote the initial electron transfer to benzoin, and trigger the subsequent benzyl σ-C–O bond scission. If this is realizable, chemo-selective deoxygenation of benzoin derivatives with NHPs may be achieved via such a mechanism switch.Open in a separate windowScheme 2Chemical transformations of N-heterocyclic phosphines NHPs in reduction reactions.It is noted that the phosphorus species NHP-OR′ is produced in either the hydride or electron reduction of benzoin derivatives (Scheme 2c). Based on the previous knowledge that NHP-OR′ can be recycled back to NHP through a σ-bond metathesis between its exocyclic P–O bond and the B–H bond of pinacolborane (HBpin),8b we envisioned that the present deoxygenation may operate in a catalytic fashion with readily available HBpin as the terminal reductant to avoid the use of stoichiometric NHP. To verify this plot, we chose dimethyl 4,4′-(1-acetoxy-2-oxoethane-1,2-diyl)dibenzoate X as the testing substrate, and 1,3-di-tert-butyl-1,3,2-diazaphosphinane 1a as the catalyst based on its compatible reducing capacity (Scheme 3, for structure of 1a, cf.Table 1).17a It is observed that, under the previously established catalytic conditions for carbonyl reduction (20 mol% of 1a and 1.2 equiv. HBpin),8b the product X1 of hydridic reduction was obtained in 86% yield and 1 : 0.69 of diastereomer ratio in 12 h. On the other hand, when 10% azodiisobutyronitrile (AIBN) was added as a radical initiator, the σ-C–O bonds were, indeed, selectively cleaved to give the anticipated product X2 in 87% yield. This distinct chemo-selectivity did echo our proposed mechanism switch from the direct hydridic pathway to an electron reduction. In the following, we report this catalytic transformation in a more inclusive fashion. To our best knowledge, this is the first example of catalytic electron reduction mediated by NHPs.Optimization of reaction conditions for C–O bond cleavage
Open in a separate windowaConditions for C–O bond activation: 2 (0.4 mmol), AIBN (0.04 mmol), 1a (0.08 mmol), HBpin (0.48 mmol) in toluene (1.0 mL).bIsolated yields.cNMR yields using 1,3,5-trimethoxybenzene as the internal standard.Open in a separate windowScheme 3Chemo-selectively reductive cleavage of C–O bonds in O-acetylated benzoin X by diazaphosphinane 1a.To verify the necessity of each component in the above catalytic system, a series of comparative experiments were conducted. We commenced the condition optimization with simple O-acetylated benzoin 2a as the standard substrate – an attractive precursor for accessing α-aryl ketone which is a common pharmacophore and also present in numerous biologically active natural products.18 As shown in Table 1, treatment of 2a with 20 mol% catalyst 1a, 10 mol% initiator AIBN and 1.2 equiv. HBpin in toluene solution harvested the product 1,2-diphenylethanone 3a in 92% isolated yield (entry 1). Decreasing the catalyst loading led to an inferior result (62%, entry 2). Replacement of 1a with structurally similar 1b gave a much lower yield (<10%, entry 3), which is primarily because the weak reducing capacity of 1b-derived phosphinyl radical (Eox = −1.94 V vs. Fc in MeCN)17a prevents its electron transfer to 2a. The same reason can be applied to account for the poor results of 1c and 1d catalysts (<5%, entry 4 and 5). When a stronger hydride donor 1e was employed, a moderate yield (46%, entry 6) was obtained along with 40% byproduct of direct hydride transfer. This may be because enhancing the reducing ability of 1e can simultaneously accelerate its hydride transfer to carbonyl groups, which competes with the electron transfer between its derived phosphinyl radical and benzoin. Commercially available borane ammonia (NH3·BH3) was also examined, furnishing no desired product (<5%, entry 7). In addition, the absence of AIBN, heating or catalyst 1a cannot render efficient C–O bond cleavage (entry 8–10). Therefore, 20 mol% 1a, 10 mol% AIBN and 1.2 equiv. HBpin in toluene solution were eventually used as the standard conditions.Next, we explored the substrate scope starting with different benzoin derivatives 2 (Scheme 4). Besides the acetate, the reaction presented here also worked very well for other leaving groups, such as pivalate 2b, benzoate 2c and 4-cyanophenolate 2d, affording the product 1,2-diphenylethanone 3a in good to excellent yields (72–99%). Then, a series of benzoin derivatives with diverse substituents (2e–i) were synthesized to examine the functional group tolerance. As seen, the substrates with electron-withdrawing F (2e) and Cl (2f) groups gave almost quantitative yields (99%). Noteworthily, in contrast to the previously reported Ru-based photocatalytic deoxygenation,3b the reaction presented here could tolerate the ester group well and gave 3g in 87% yield. As for electron-donating substituents, such as methyl (2h) and methoxy groups (2i), the reaction yields were slightly reduced (72% and 75%), which may be ascribed to their lower reduction potentials. Replacement of the phenyl group with naphthyl (2j) afforded the product 3j in a good yield (80%). Furthermore, some cross-benzoin analogues were also investigated. The unsymmetrical counterpart 2k gave 3k in a moderate yield (62%). Similarly, heteroaromatic substrates (2l and 2m) generated corresponding products in 65% and 55% yields, respectively. Additionally, we examined the acyloin derivative 2n which was previously reported to give a base promoted aldol-type cyclization byproduct in the SED system.4 Notably, our conditions are mild enough for selective cleavage of its C–O bond in a moderate yield (52%), although 1a was necessarily employed as a stoichiometric reductant. However, the analogs 2o and 2p gave poor yields, possibly due to the less stability of their corresponding radical intermediates.Open in a separate windowScheme 4Substrate scope for C–O bond activation. Conditions unless otherwise specified: 2 (0.4 mmol), AIBN (0.04 mmol), 1a (0.08 mmol), HBpin (0.48 mmol) in toluene (1.0 mL). Isolated yields were given. [a] 0.4 mmol of 1a was used. [b] NMR yields using 1,3,5-trimethoxybenzene as the internal standard.Desyl is a classical protection group in organic chemistry and biology.3c,19 We wondered whether the same reaction could serve as a practical strategy to realize catalytic deprotection of various desyl-protected carboxylic acids under metal-free conditions. To assess its feasibility, we tested some carboxylic acids, including aromatic, aliphatic, and amino acids. The results revealed a good tolerance for the present method. As shown in Scheme 5, the substrate 4a gave benzoic acid 5a in a quantitative yield (99%) under the standard conditions. And, the reaction was compatible well with the susceptive acetal moiety and furnished 5b in a good yield (88%). This result indicated the high selectivity of our system to the targeted C–O bond. Substrate 4c with electron-donating groups was also found feasible, and afforded the deprotected product 5c in a slightly lower yield (74%). Interestingly, for the isophthalic acid system whose two carboxylic groups were both protected by desyl groups, the deprotection was proved to be highly reactive, and afforded the fully-deprotected product 5d in an excellent yield (92%). 1-Naphthoic acid 5e could be obtained in a good yield of 85% after deprotection. Furthermore, the deprotection of aliphatic acids 4f furnished 5f in an almost quantitative yield (99%). However, similar 5g with an additional conjugated double bond was obtained in a diminished yield (71%). More importantly, our protocol is also applicable in amino acid systems. As seen, 5h was obtained in 90% yield with conformational retention, and the deprotection of 4i was not affected by other commonly-used protecting group Boc, giving the product 5i in 91% yield.Open in a separate windowScheme 5Substrate scope for catalytic deprotection with desyl as the protecting group. Conditions: 4 (0.4 mmol), AIBN (0.04 mmol), 1a (0.08 mmol), HBpin (0.48 mmol) in toluene (1.0 mL). Isolated yields were given. [a] 0.96 mmol of HBpin was used.Furthermore, we investigated the reaction mechanism by taking substrate 2a as the template compound. As previously established in SED systems, benzoin derivates were deemed to be reduced via a successive double-electron transfer mechanism, affording enolates as the intermediates which eventually captured a proton from the solvent.4 Different from this double-electron transfer pathway, our system would operate in a single-electron reduction mechanism, however. This was deduced from the fact that one equivalent reductant 1a could afford almost quantitative product 3a (eqn (1)). Consequently, the present process clearly displays a superiority in atom economy over the previous SED systems. With respect to the catalyst regeneration, we conducted the reaction of the intermediate 1a-OAc with HBpin in toluene-d8 at room temperature (eqn (2)). Through monitoring the 1H NMR and 31P NMR spectra of the reaction mixture, it is found that as the intermediate 1a-OAc gradually disappeared in about one hour (see ESI† for details), 1a P–H bond was formed synchronously. This confirmed the effective regeneration of 1a from HBpin. Moreover, when 20 mol% 1a-OAc was used as the catalyst, the reduction could also work quite well to furnish the desired product in 63% yield (eqn (3)). Therefore, 1a-OAc can be regarded as an intermediate in the catalytic cycle to regenerate 1a. In addition, to exclude the possibility of a radical chain process, that is, a direct oxygen abstraction from benzoin by the phosphinyl radical, DFT calculations were conducted (see ESI† for details). The results showed that 1a-[P]˙ and 1b-[P]˙ have a comparable ability in abstracting the oxygen atom (with an energy difference of 0.78 kcal mol−1, eqn (4)). This failed to explain the disparate yields for 1a and 1b systems (90% vs. <10%). Besides, the difference in the oxidation potentials of 1a-[P]˙ (Eox = −2.39 V) and of 1b-[P]˙ (Eox = −1.94 V)17a is consistent well with the observed diverse reduction results. All these preferentially support an electron-transfer initiated reduction.1234Based on the above control experiments and the computation, we outlined the catalytic cycle for reductive cleavage of C–O bonds in Scheme 6. The reaction is turned on by the isobutyronitrile radical, which abstracts a hydrogen-atom from diazaphosphinane 1a to produce the actual reductant phosphinyl radical. This potent electron donor (Eox = −2.39 V) then transfers an electron to 2a (Ered = ∼−2.3 V),3c,4 furnishing the ketyl radical anion 6 and the corresponding phosphonium cation. The σ-C–O bond of the intermediate 6 is readily cleaved to afford the ketyl 7 and acetate. The ketyl 7 would not be further reduced into the corresponding enolate, but instead abstracts a hydrogen-atom from 1a and simultaneously triggers the next catalytic cycle. Meanwhile, a combination of the stable phosphonium cation with acetate produces 1a-OAc, which could regenerate the catalyst 1a from the terminal reductant HBpin. Accordingly, the success of the present deoxygenation primarily attributes to two crucial factors: the mechanism switch from the originally hydridic reduction to a kinetically more accessible electron reduction by the initiator azodiisobutyronitrile, and the “upconversion” of weakly reducing HBpin into strongly reducing diazaphosphinane by catalytic phosphorus species.20 Moreover, in our systems, HBpin serves as both the electron and hydrogen-atom sources, namely the apparent hydride donor. This is different from what was known for the previous SED systems, in which the reductants only provide the electron, and hence, extraneous hydrogen sources are necessarily employed.Open in a separate windowScheme 6Proposed mechanism of C–O bond cleavage. 相似文献
Entry | Catalyst | Conditiona | Yieldb |
---|---|---|---|
1 | 1a | Standard condition | 92% |
2 | 1a | 10 mol% 1a | 62% |
3 | 1b | Standard condition | <10%c |
4 | 1c | Standard condition | <5%c |
5 | 1d | Standard condition | <5%c |
6 | 1e | Standard condition | 46% |
7 | 1a | NH3BH3 as reductant | <5%c |
8 | 1a | No AIBN | <5%c |
9 | 1a | No heat | <5%c |
10 | — | Standard condition | <5%c |
7.
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 (%) |
---|---|---|---|---|
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 |
8.
Ke Yang Zhi Li Chong Liu Yunjian Li Qingyue Hu Mazen Elsaid Bijin Li Jayabrata Das Yanfeng Dang Debabrata Maiti Haibo Ge 《Chemical science》2022,13(20):5938
The transient directing group (TDG) strategy allowed long awaited access to the direct β-C(sp3)–H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal methyl functionalization, limiting their structural scopes and applicability. Herein, we report the development of a direct Pd-catalyzed methylene β-C–H arylation of linear unmasked aldehydes by using 3-amino-3-methylbutanoic acid as a TDG and 2-pyridone as an external ligand. Density functional theory calculations provided insights into the reaction mechanism and shed light on the roles of the external and transient directing ligands in the catalytic transformation.Aliphatic aldehydes are among the most common structural units in organic and medicinal chemistry research. Direct C–H functionalization has enabled efficient and site-selective derivatization of aliphatic aldehydes.Simple aliphatic functional groups enrich the skeletal backbones of many natural products, pharmaceuticals, and other industrial materials, influencing the utility and applications of these substances and dictating their reactivity and synthetic modification pathways. Aliphatic aldehydes are some of the most ubiquitous structural units in organic materials.1 Their relevance in nature and industry alike, combined with their reactivity and synthetic versatility, attracted much attention from the synthetic organic and medicinal chemistry communities over the years (Fig. 1).2 Efficient means to the functionalization of these molecules have always been highly sought after.Open in a separate windowFig. 1Select aliphatic aldehyde-containing medicines and biologically active molecules.Traditionally, scientists have utilized the high reactivity of the aldehyde moiety in derivatizing a variety of functional groups by the means of red-ox and nucleophilic addition reactions. The resourceful moiety was also notoriously used to install functional groups at the α-position via condensation and substitution pathways.3 Although β-functionalization is just as robust, it has generally been more restrictive as it often requires the use of α,β-unsaturated aldehydes.4,5 Hence, transition metal catalysis emerged as a powerful tool to access β-functionalization in saturated aldehydes.6 Most original examples of metal-catalyzed β-C–H functionalization of aliphatic aldehydes required the masking of aldehydes into better metal coordinating units since free unmasked aldehydes could not form stable intermediates with metals like palladium on their own.7 Although the masking of the aldehyde moiety into an oxime, for example, enabled the formation of stable 5-membered palladacycles, affording β-functionalized products, this system requires the installation of the directing group prior to the functionalization, as well as the subsequent unmasking upon the reaction completion, compromising the step economy and atom efficiency of the overall process.8 Besides, some masking and unmasking protocols might not be compatible with select substrates, especially ones rich in functional groups. As a result, the development of a one-step direct approach to the β-C–H functionalization of free aliphatic aldehydes was a demanding target for synthetic chemists.α-Amino acids have been demonstrated as effective transient directing groups (TDGs) in the remote functionalization of o-alkyl benzaldehydes and aliphatic ketones by the Yu group in 2016.9 Shortly after, our group disclosed the first report on the direct β-C–H arylation of aliphatic aldehydes using 3-aminopropanoic acid or 3-amino-3-methylbutanoic acid as a TDG.10 The TDG was found to play a similar role to that of the oxime directing group by binding to the substrate via reversible imine formation, upon which, it assists in the assembly of a stable palladacycle, effectively functionalizing the β-position.11 Since the binding of the TDG is reversible and temporary, it is automatically removed upon functionalization, yielding an efficient and step-economic transformation. This work was succeeded by many other reports that expanded the reaction and the TDG scopes.12–14 However, this system suffers from a significant restriction that demanded resolution; only substitution of methyl C–H bonds of linear aldehydes was made possible via this approach (Scheme 1a–e). The steric limitations caused by incorporating additional groups at the β-carbon proved to compromise the formation of the palladacycle intermediate, rendering the subsequent functionalization a difficult task.12Open in a separate windowScheme 1Pd-catalyzed β-C–H bond functionalization of aliphatic aldehydes enabled by transient directing groups.Encouraged by the recent surge in use of 2-pyridone ligands to stabilize palladacycle intermediates,15,16 we have successfully developed the first example of TDG-enabled Pd-catalyzed methylene β-C–H arylation in primary aldehydes via the assistance of 2-pyridones as external ligands (Scheme 1f). The incorporation of 2-pyridones proved to lower the activation energy of the C–H bond cleavage, promoting the formation of the intermediate palladacycles even in the presence of relatively bulky β-substituents.17 This key advancement significantly broadens the structural scopes and applications of this process and promises future asymmetric possibilities, perhaps via the use of a chiral TDG or external ligand or both. Notably, a closely related work from Yu''s group was published at almost the same time.18We commenced our investigation of the reaction parameters by employing n-pentanal (1a) as an unbiased linear aldehyde and 4-iodoanisole (2a) in the presence of catalytic Pd(OAc)2 and stoichiometric AgTFA, alongside 3-amino-3-methylbutanoic acid (TDG1) and 3-(trifluoromethyl)-5-nitropyridin-2-ol (L1) at 100 °C (ii) sources proved Pd(OAc)2 to be the optimal catalyst, while Pd(TFA)2, PdCl2 and PdBr2 provided only moderate yields (entries 10–12). Notably, a significantly lower yield was observed in the absence of the 2-pyridone ligand, and no desired product was isolated altogether in the absence of the TDG (entries 13 and 14). The incorporation of 15 mol% Pd catalyst was deemed necessary after only 55% yield of 3a was obtained when 10 mol% loading of Pd(OAc)2 was instead used (entry 15).Optimization of reaction conditionsa
Open in a separate windowaReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (15 mol%), AgTFA (0.3 mmol), L1, TDG1, solvent (2.0 mL), 100 °C, 12 h. Yields are based on 1a, determined by 1H-NMR using dibromomethane as an internal standard.bIsolated yield.cPd(OAc)2 (10 mol%).To advance our optimization of the reaction conditions, a variety of 2-pyridones and TDGs were tested (Scheme 2). Originally, pyridine-2(1H)-one (L2) was examined as the external ligand, but it only yielded the product (3a) in 7% NMR yield. Similarly, other mono- and di-substituted 2-pyridone ligands (L3–L10) also produced low yields, fixating L1 as the optimal external ligand. Next, various α- and β-amino acids (TDG1–10) were evaluated, yet TDG1 persisted as the optimal transient directing group. These amino acid screening results also suggest that a [5,6]-bicyclic palladium species is likely the key intermediate in this protocol since only β-amino acids were found to provide appreciable yields, whereas α-amino acids failed to yield more than trace amounts of the product. The supremacy of TDG1 when compared to other β-amino acids is presumably due to the Thorpe–Ingold effect that perhaps helps facilitate the C–H bond cleavage and stabilize the [5,6]-bicyclic intermediate further.Open in a separate windowScheme 2Optimization of 2-pyridone ligands and transient directing groups.With the optimized reaction conditions in hand, substrate scope study of primary aliphatic aldehydes was subsequently carried out (Scheme 3). A variety of linear primary aliphatic aldehydes bearing different chain lengths provided the corresponding products 3a–e in good yields. Notably, relatively sterically hindered methylene C–H bonds were also functionalized effectively (3f and 3g). Additionally, 4-phenylbutanal gave rise to the desired product 3h in a highly site-selective manner, suggesting that functionalization of the methylene β-C–H bond is predominantly favored over the more labile benzylic C–H bond. It is noteworthy that the amide group was also well-tolerated and the desired product 3j was isolated in 60% yield. As expected, with n-propanal as the substrate, β-mono- (3k1) and β,β-disubstituted products (3k2) were isolated in 22% and 21% yields respectively. However, in the absence of the key external 2-pyridone ligand, β-monosubstituted product (3k1) was obtained exclusively, albeit with a low yield, indicating preference for functionalizing the β-C(sp3)–H bond of the methyl group over the benzylic methylene group.Open in a separate windowScheme 3Scope of primary aliphatic aldehydes. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)2 (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields. aL1 (60 mol%) was absent and yields are given in parentheses.Next, substrate scope study on aryl iodides was surveyed (Scheme 4). Iodobenzenes bearing either an electron-donating or electron-withdrawing group at the para-, meta-, or ortho-position were all found compatible with our catalytic system (3l–3ah). Surprisingly, ortho-methyl- and fluoro-substituted aryl iodides afforded the products in only trace amounts. However, aryl iodide with ortho-methoxy group provided the desired product 3ac in a moderate yield. Notably, a distinctive electronic effect pattern was not observed in the process. It should be mentioned that arylated products bearing halogen, ester, and cyano groups could be readily converted to other molecules, which significantly improves the synthetic applicability of the process. Delightfully, aryl iodide-containing natural products like ketoprofen, fenchol and menthol were proven compatible, supplying the corresponding products in moderate yields. Unfortunately, (hetero)aryl iodides including 2-iodopyridine, 3-iodopyridine, 4-iodopyridine and 4-iodo-2-chloropyridine failed to produce the corresponding products. Although our protocol provides a novel and direct pathway to construct β-arylated primary aliphatic aldehydes, the yields of most examples are modest. The leading reasons for this compromise are the following: (1) aliphatic aldehydes are easily decomposed or oxidized to acids; (2) some of the prepared β-arylated aldehyde products may be further transformed into the corresponding α,β-unsaturated aldehydes.Open in a separate windowScheme 4Scope of aryl iodides. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields.Density functional theory (DFT) calculations were performed to help investigate the reaction mechanism and to elucidate the role of the ligand in improving the reactivity (Fig. 2). The condensation of the aliphatic aldehyde 1a with the TDG to form imine-1a was found thermodynamically neutral (ΔG° = −0.1 kcal mol−1). As a result, it was permissible to use imine-1a directly in the calculations. According to the calculations results, the precatalyst [Pd(OAc)2]3, a trimeric complex, initially experiences dissociation and ligand metathesis with imine-1a to generate the Pd(ii) intermediate IM1, which is thermodynamically favorable by 21.9 kcal mol−1. Consequently, the deprotonated imine-1a couples to the bidentate ligand to form the stable six-membered chelate complex IM1. Therefore, IM1 is indeed the catalyst resting state and serves as the zero point to the energy profile. We have identified two competitive pathways for the Pd(ii)-catalyzed C–H activation starting from IM1, one of which incorporates L1 and another which does not. On the one hand, an acetate ligand substitutes one imine-1a chelator in IM1 to facilitate the subsequent C–H activation leading to IM2, which undergoes C(sp3)–H activation through concerted metalation-deprotonation (CMD) viaTS1 (ΔG‡ = 37.4 kcal mol−1). However, this kinetic barrier is thought to be too high to account for the catalytic activity at 100 °C. On the other hand, the chelate imine-1a could be replaced by two N-coordinated ligands (L1) leading to the Pd(ii) complex IM3. This process is endergonic by 6.4 kcal mol−1. To allow the ensuing C–H activation, IM3 dissociates one ligand (L1) producing the active species IM4, which undergoes TS2 to cleave the β-C(sp3)–H bond and form the [5,6]-bicyclic Pd(ii) intermediate IM5. Although this step features an energy barrier of 31.2 kcal mol−1, it is thought to be feasible under the experimental conditions (100 °C). Possessing similar coordination ability to that of pyridine, the ligand (L1) effectively stabilizes the Pd(ii) center in the C–H activation process, indicating that this step most likely involves a manageable kinetic barrier. This result explicates the origin of the ligand-enabled reactivity (TS2vs.TS1). Additionally, we considered the γ-C(sp3)–H activation pathway viaTS2′ which was found to have a barrier of 35.5 kcal mol−1. The higher energy barrier of TS2′ compared to that of TS2 is attributed to its larger ring strain in the [6,6]-bicyclic Pd(ii) transition state, which reveals the motive for the site-selectivity. Reverting back to the supposed pathway, upon the formation of the bicyclic intermediate IM5, it undergoes ligand/substrate replacement to afford intermediate IM6, at which the Ar–I coordinates to the Pd(ii) center to enable oxidative addition viaTS3 (ΔG‡ = 27.4 kcal mol−1) leading to the five-coordinate Pd(iv) complex IM7. Undergoing direct C–C reductive elimination in IM7 would entail a barrier of 29.6 kcal mol−1 (TS4). Alternatively, iodine abstraction by the silver(i) salt in IM7 is thermodynamically favorable and irreversible, yielding the Pd(iv) intermediate IM8 coordinated to a TFA ligand. Subsequently, C–C reductive coupling viaTS5 generates the Pd(ii) complex IM9 and concludes the arylation process. This step was found both kinetically facile (6.1 kcal mol−1) and thermodynamically favorable (30.7 kcal mol−1). Finally, IM9 reacts with imine-1avia metathesis to regenerate the palladium catalyst IM1 and release imine-3a in a highly exergonic step (21.0 kcal mol−1). Ultimately, imine-3a undergoes hydrolysis to yield the aldehyde product 3a and to release the TDG.Open in a separate windowFig. 2Free energy profiles for the ligand-promoted Pd(ii)-catalyzed site-selective C–H activation and C–C bond formation, alongside the optimized structures of the C–H activation transition states TS1 and TS2 (selected bond distances are labelled in Å). Energies are relative to the complex IM1 and are mass-balanced. 相似文献
Entry | Pd source | L (mol%) | TDG1 (mol%) | Solvent (v/v, mL) | Yield (%) |
---|---|---|---|---|---|
1 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP | 30 |
2 | Pd(OAc)2 | L1 (30) | TDG1 (40) | AcOH | <5 |
3 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP/AcOH (1 : 1) | 28 |
4 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP/AcOH (9 : 1) | 47 |
5 | Pd(OAc)2 | L1 (30) | TDG1 (40) | HFIP/AcOH (1 : 9) | <5 |
6 | Pd(OAc)2 | L1 (30) | TDG1 (60) | HFIP/AcOH (9 : 1) | 50 |
7 | Pd(OAc)2 | L1 (30) | TDG1 (80) | HFIP/AcOH (9 : 1) | 25 |
8 | Pd(OAc)2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 70(68)b |
9 | Pd(OAc)2 | L1 (75) | TDG1 (60) | HFIP/AcOH (9 : 1) | 51 |
10 | Pd(TFA)2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 60 |
11 | PdCl2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 52 |
12 | PdBr2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 54 |
13 | Pd(OAc)2 | — | TDG1 (60) | HFIP/AcOH (9 : 1) | 9 |
14 | Pd(OAc)2 | L1 (60) | — | HFIP/AcOH (9 : 1) | 0 |
15c | Pd(OAc)2 | L1 (60) | TDG1 (60) | HFIP/AcOH (9 : 1) | 55 |
9.
Yu-Feng Liang Long Yang Becky Bongsuiru Jei Rositha Kuniyil Lutz Ackermann 《Chemical science》2020,11(39):10764
Palladium-catalyzed regioselective di- or mono-arylation of o-carboranes was achieved using weakly coordinating amides at room temperature. Therefore, a series of B(3,4)-diarylated and B(3)-monoarylated o-carboranes anchored with valuable functional groups were accessed for the first time. This strategy provided an efficient approach for the selective activation of B(3,4)–H bonds for regioselective functionalizations of o-carboranes.B–H: site-selective B(3,4)–H arylations were accomplished at room temperature by versatile palladium catalysis enabled by weakly coordinating amides. o-Carboranes, icosahedral carboranes – three-dimensional arene analogues – represent an important class of carbon–boron molecular clusters.1 The regioselective functionalization of o-carboranes has attracted growing interest due to its potential applications in supramolecular design,2 medicine,3 optoelectronics,4 nanomaterials,5 boron neutron capture therapy agents6 and organometallic/coordination chemistry.7 In recent years, transition metal-catalyzed cage B–H activation for the regioselective boron functionalization of o-carboranes has emerged as a powerful tool for molecular syntheses. However, the 10 B–H bonds of o-carboranes are not equal, and the unique structural motif renders their selective functionalization difficult, since the charge differences are very small and the electrophilic reactivity in unfunctionalized o-carboranes reduces in the following order: B(9,12) > B(8,10) > B(4,5,7,11) > B(3,6).8 Therefore, efficient and selective boron substitution of o-carboranes continues to be a major challenge.Recently, transition metal-catalyzed carboxylic acid or formyl-directed B(4,5)–H functionalization of o-carboranes has drawn increasing interest, since it provides an efficient approach for direct regioselective boron–carbon and boron–heteroatom bond formations (Scheme 1a),9 with major contributions by the groups of Xie,10 and Yan,11 among others.12 Likewise, pyridyl-directed B(3,6)–H acyloxylations (Scheme 1b),13 and amide-assisted B(4,7,8)–H arylations14 (Scheme 1c) have been enabled by rhodium or palladium catalysis, respectively.15,16 Despite indisputable progress, efficient approaches for complementary site-selective functionalizations of o-carboranes are hence in high demand.17 Hence, metal-catalyzed position-selective B(3,4)–H functionalizations of o-carboranes have thus far not been reported.Open in a separate windowScheme 1Chelation-assisted transition metal-catalyzed cage B–H activation of o-carboranes.Arylated compounds represent key structural motifs in inter alia functional materials, biologically active compounds, and natural products.18 In recent years, transition metal-catalyzed chelation-assisted arylations have received significant attention as environmentally benign and economically superior alternatives to traditional cross-coupling reactions.19 Within our program on sustainable C–H activation,20 we have now devised a protocol for unprecedented cage B–H arylations of o-carboranes with weak amide assistance, on which we report herein. Notable features of our findings include (a) transition metal-catalyzed room temperature B–H functionalization, (b) high levels of positional control, delivering B(3,4)-diarylated and B(3)-monoarylated o-carboranes, and (c) mechanistic insights from DFT computation providing strong support for selective B–H arylation (Scheme 1d).We initiated our studies by probing various reaction conditions for the envisioned palladium-catalyzed B–H arylation of o-carborane amide 1a with 1-iodo-4-methylbenzene (2a) at room temperature (Tables 1 and S1†). We were delighted to observe that the unexpected B(3,4)-di-arylated product 3aa was obtained in 59% yield in the presence of 10 mol% Pd(OAc)2 and 2 equiv. of AgTFA, when HFIP was employed as the solvent, which proved to be the optimal choice (entries 1–5).21 Control experiments confirmed the essential role of the palladium catalyst and silver additive (entries 6–7). Further optimization revealed that AgOAc, Ag2O, K2HPO4, and Na2CO3 failed to show any beneficial effect (entries 8–11). Increasing the reaction temperature fell short in improving the performance (entries 12 and 13). The replacement of the amide group in substrate 1a with a carboxylic acid, aldehyde, ketone, or ester group failed to afford the desired arylation product (see the ESI†). We were pleased to find that the use of 1.0 equiv. of trifluoroacetic acid (TFA) as an additive improved the yield to 71% (entry 14). To our delight, replacing the silver additive with Ag2CO3 resulted in the formation of B(3)–H mono-arylation product 4aa as the major product (entries 15–16).Optimization of reaction conditionsa
Open in a separate windowaReaction conditions: 1a (0.20 mmol), 2 (0.48 mmol), Pd(OAc)2 (10 mol%), additive (0.48 mmol), solvent (0.50 mL), 25 °C, 16 h, and isolated yield.bWithout Pd(OAc)2.cAt 40 °C.dAt 60 °C.eTFA (0.2 mmol) was added.f 1a (0.20 mmol), 2a (0.24 mmol), Pd(OAc)2 (5.0 mol%), and Ag2CO3 (0.24 mmol).g 2a was added in three portions every 4 h. DCE = dichloroethane, TFE = 2,2,2-trifluoroethanol, HFIP = hexafluoroisopropanol, and TFA = trifluoroacetic acid.With the optimized reaction conditions in hand, we probed the scope of the B–H di-arylation of o-carboranes 1a with different aryl iodides 2 (Scheme 2). The versatility of the room temperature B(3,4)–H di-arylation was reflected by tolerating valuable functional groups, including bromo, chloro, and enolizable ketone substituents. The connectivity of the products 3aa and 3ab was unambiguously verified by X-ray single crystal diffraction analysis.22Open in a separate windowScheme 2Cage B(3,4)–H di-arylation of o-carboranes.Next, we explored the effect exerted by the N-substituent at the amide moiety (Scheme 3). Tertiary amides 1b–1f proved to be suitable substrates with optimal results being accomplished with substrate 1a. The effect of varying the cage carbon substituents R1 on the reaction''s outcome was also probed, and both aryl and alkyl substituents gave the B–H arylation products and the molecular structures of the products 3dd, 3ea and 3fa were fully established by single-crystal X-ray diffraction.Open in a separate windowScheme 3Effect of substituents on B–H diarylation. aAt 50 °C.The robustness of the palladium-catalyzed B–H functionalization was subsequently investigated for the challenging catalytic B–H monoarylation of o-carboranes (Scheme 4). The B(3)–H monoarylation, as confirmed by single-crystal X-ray diffraction analysis of products 4aa and 4ai, proceeded smoothly with valuable functional groups, featuring aldehyde and nitro substituents, which should prove invaluable for further late-stage manipulation.Open in a separate windowScheme 4Cage B(3)–H mono-arylation of o-carboranes.To elucidate the palladium catalysts'' working mode, a series of experiments was performed. The reactions in the presence of TEMPO or 1,4-cyclohexadiene produced the desired product 3aa, which indicates that the present B–H arylation is less likely to operate via radical intermediates (Scheme 5a). The palladium catalysis carried out in the dark performed efficiently (Scheme 5b). Compound 4aa could be converted to di-arylation product 3aa with high efficiency, indicating that 4aa is an intermediate for the formation of the diarylated cage 3aa (Scheme 5c).Open in a separate windowScheme 5Control experiments.To further understand the catalyst mode of action, we studied the site-selectivity of the o-carborane B–H activation for the first B–H activation at the B3 versus B4 position and for the second B–H activation at the B4 versus B6 position using density functional theory (DFT) at the PBE0-D3(BJ)/def2-TZVP+SMD(HFIP)//TPSS-D3(BJ)/def2-SVP level of theory (Fig. 1). Our computational studies show that the B3 position is 5.8 kcal mol−1 more favorable than the B4 position for the first B–H activation, while the B4 position is 3.4 kcal mol−1 more favorable than the B6 position for the second B–H activation. It is noteworthy that here the interaction between AgTFA and a cationic palladium(ii) complex was the key to success, being in good agreement with our experimental results (for more details, see the ESI†).Open in a separate windowFig. 1Computed relative Gibbs free energies in kcal mol−1 and the optimized geometries of the transition states involved in the B–H activation at the PBE0-D3(BJ)/def2-TZVP+SMD(HFIP)//TPSS-D3(BJ)/def2-SVP level of theory. (a) First B–H activation transition states at the B3 and B4 positions. (b) Second B–H activation transition states at the B4 and B6 positions. Irrelevant hydrogen atoms in the transition states are omitted for clarity and the bond lengths are given in Å.A plausible reaction mechanism is proposed which commences with an organometallic B(3)–H activation of 1a with weak assistance of the amide group and assistance by AgTFA to form the cationic intermediate I (Scheme 6). Oxidative addition with the aryl iodide 2 affords the proposed cationic palladium(iv) intermediate II, followed by reductive elimination to give the B(3)-mono-arylation product 4aa. Subsequent B(4)-arylation occurs assisted by the weakly coordinating amide to generate the B(3,4)-di-arylation product 3aa. Due to the innate higher reactivity of the B(4)–H bond in intermediate 4aa – which is inherently higher than that of the B(6)–H bond – the B(3,6)-di-arylation product is not formed.Open in a separate windowScheme 6Proposed reaction mechanism.In summary, room temperature palladium-catalyzed direct arylations at cage B(3,4) positions in o-carboranes have been achieved with the aid of weakly coordinating, synthetically useful amides. Thus, palladium-catalyzed B–H activations enable the assembly of a wealth of arylated o-carboranes. This method features high site-selectivity, high tolerance for functional groups, and mild reaction conditions, thereby offering a platform for the design and synthesis of boron-substituted o-carboranes. Our findings offer a facile strategy for selective activations of B(3,4)–H bonds, which will be instrumental for future design of optoelectronics, nanomaterials, and boron neutron capture therapy agents. 相似文献
Entry | Additive | Solvent | Yield of 3aa/% | Yield of 4aa/% |
---|---|---|---|---|
1 | AgTFA | PhMe | 0 | 0 |
2 | AgTFA | DCE | 0 | 0 |
3 | AgTFA | 1,4-Dioxane | 0 | 0 |
4 | AgTFA | TFE | 21 | 3 |
5 | AgTFA | HFIP | 59 | 4 |
6 | AgTFA | HFIP | 0 | 0b |
7 | — | HFIP | 0 | 0 |
8 | AgOAc | HFIP | 5 | <3 |
9 | Ag2O | HFIP | <3 | <3 |
10 | K2HPO4 | HFIP | 0 | 0 |
11 | Na2CO3 | HFIP | 0 | 0 |
12 | AgTFA | HFIP | 53 | 4c |
13 | AgTFA | HFIP | 42 | 3d |
14 | AgTFA | HFIP | 71 | <3 e |
15 | Ag2CO3 | HFIP | 9 | 34f |
16 | Ag 2 CO 3 | HFIP | 5 | 55 f , g |
10.
Nicholas G. W. Cowper Matthew J. Hesse Katie M. Chan Sarah E. Reisman 《Chemical science》2020,11(43):11897
The bicyclic tetrahydro-1,2-oxazine subunit of gliovirin is synthesized through a diastereoselective copper-catalyzed cyclization of an N-hydroxyamino ester. Oxidative elaboration to the fully functionalized bicycle was achieved through a series of mild transformations. Central to this approach was the development of the first catalytic, enantioselective propargylation of an oxime to furnish a key N-hydroyxamino ester intermediate.The bicyclic tetrahydro-1,2-oxazine subunit of gliovirin is synthesized through a diastereoselective copper-catalyzed cyclization of an N-hydroxyamino ester.The fungal secondary metabolites gliovirin (2)1 and pretrichodermamides A (3)2 and E (4)3 are disulfide antibiotics that possess an unusual tetrahydro-1,2-oxazine (THO) core (Scheme 1). In addition to 2–4, several related oxazine natural products have been isolated, including the monothiolated peniciadametizine B (5);4 however, these oxazine-containing natural products are rare relative to the biosynthetically related diketopiperazine natural products, hundreds of which have been isolated to date.5 In addition to their oxazine cores, 2–4 are unusual in that their disulfide linkages are joined to the carbon framework at C4 and C12, in contrast to the more common epipolythiodiketopiperazines (ETPs) such as gliotoxin (1).6 These fungal metabolites are proposed to be formed through thiolation of simple cyclic dipeptides followed by oxidative elaboration of the peripheral functionality.7 Perhaps because of the synthetic challenge posed by the combined oxazine and disulfide motifs, there have been no syntheses of gliovirin (2) or the related compounds 3 and 4 to date.Open in a separate windowScheme 1PTP isomerism: gliovirin and related natural products.Whereas there are no syntheses of 2, syntheses of related dihydro-1,2-oxazine (DHO) natural products, including trichodermamide A (6), have been reported by the groups of Joullié,8 Zakarian,9 and Larionov.10 These efforts relied upon cycloaddition chemistry or pericyclic rearrangement to install the DHO cores. As part of our larger program targeting the synthesis of polysulfide natural products,11,12 we envisioned a distinct approach to 2 that would involve late-stage diketopiperazine and disulfide formation, thereby reducing the synthetic challenge to that of preparing key THO 7 (Scheme 2). Oxazine 7 was expected to be accessible from 8avia epoxidation, desaturation, and functional group interconversion.Open in a separate windowScheme 2Retrosynthetic analysis of tetrahydro-1,2-oxazine 7.In a key synthetic step, the bicyclic THO 7 would be constructed by an intramolecular oxidative cyclization of N-hydroxydihydrophenylalanine derivative 10. For the preparation of 10, we considered two approaches: (1) N-oxidation of the corresponding dihydrophenylalanine 9, or (2) initial installation of the N–O bond followed by construction of the cyclohexan-1,3-diene from the alkyne of 11a. Given concerns about potential challenges of N-oxidation in the presence of the sensitive 1,3-cyclohexadiene motif, we elected to pursue a route where 10 would be accessed from α-propargyl N-hydroxyamino acid 11a by an enyne metathesis reaction.Having identified 11a as an intermediate on route to 7, a method to prepare this compound in enantioenriched form was desired. The most direct route to 11a was envisioned to be an enantioselective propargylation of N-siloxyglyoxalate 12 (see Table 1). However, no examples of catalytic asymmetric addition of allyl nor propargyl nucleophiles to similar oxime substrates were found in the literature. The most promising lead was from Hanessian and coworkers, in which an excess of a chiral allylzinc reagent was added to an oxime.13 However, this method had not been extended to the corresponding propargylation.Optimization of Cu-catalyzed oxime propargylationa
Open in a separate windowaReactions conducted under inert atmosphere on 0.05 mmol scale for 24 h.bDetermined by 1H NMR versus an internal standard.cDetermined by SFC using chiral stationary phase.dLi(Ot-Bu) (9.5 mol%) was added to the reaction.e2.0 equivalents used in place of 1.4 equivalents.Although there was no direct precedent for the catalytic asymmetric propargylation of oximes, we were inspired to pursue this approach by recent studies describing Cu-catalyzed asymmetric propargylation of imines.14–16 We began by investigating the ability of chiral Cu complexes to catalyze the reaction between glyoxalate-derived oxime 12b and allenyl boronate 13a. Bidentate bisphosphines gave promising levels of enantioinduction, although the reactions produced 11b in very low yield (Table 1, entries 1–2).17 In comparison, monodentate phosphoramidite ligands (e.g.L3) provided 11b in improved yield, but with modest enantioselectivity (entry 3).We hypothesized that the improved yield observed with the use of phosphoramidite ligands resulted from their increased ability to act as π-acceptors.18 It was envisioned that electron-deficient bis-phosphines would combine the benefits of greater π-acceptor ability to increase catalyst turnover while retaining the conformational rigidity of a bidentate ligand to promote asymmetric induction.19 Consistent with this hypothesis, fluorinated, commercially available, bisphosphines including DIFLUORPHOS (L4, entry 4) and BTFM-GARPHOS (L5, entry 5) both gave higher yields of 11b, while also improving the enantioinduction.In contrast to many metal-catalyzed cross-coupling reactions of boronates, a series of control experiments demonstrated that co-catalytic base was not required, and in fact, omitting base from the reaction led to an improvement in yield and ee (entry 6, Table 1). Use of neopentyl boronate 13b further improved the yield. Although ester 12b was used for the optimization process (due to the aryl UV chromophore aiding ee assay development), for the purpose of the synthesis, ethyl ester 11a was accessed in similarly high yield and ee from N-siloxyglyoxalate 12a (Scheme 3).Open in a separate windowScheme 3Realization of proposed oxidative cyclization. aenantiomeric excess determined from 14, following benzoylation, by SFC with a chiral stationary phase.Concomitant to the development of the enantioselective propargylation shown in Table 1, we investigated the elaboration of compound 14, as a racemate, to oxazine 7. Initial attempts to generate the desired 1,3-cyclohexadiene 15a through enyne metathesis proceeded in low yield due to catalyst deactivation and alkyne oligomerization; however, slow addition of 14 to a solution of 1,5-cyclooctadiene and second generation Hoveyda–Grubbs catalyst (Mes-HGII) in benzene produced the desired product, 15, in excellent yield (Scheme 3).20With access to N-hydroxydihydrophenylalanine derivative 15a, we investigated the formation of the THO motif by an oxidative cyclization. The intramolecular oxidative radical addition of hydroxamic acids to generate cyclic hydroxamates was first observed by Perkins21 and later systematically studied by Alexanian.22–24 Furthermore, during the course of our work, the intermolecular addition of phthalimide N-oxyl radical (PINO) to activated alkenes was reported to be initiated by base metal catalysis, visible light, or conventional radical initiators.25–28 While this reactivity encouraged us, there were three issues that remained uncertain: (a) the regioselectivity of cyclization across the diene (i.e. 5-exo vs. 6-endo); (b) the diastereoselectivity of the C–O bond formation with respect the adjacent stereocenter; and (c) whether N-alkylhydroxamic acids would engage in similar reactivity previously observed in N-arylhydroxamic acids. With our cyclization substrate 15a in hand we found that following in situ deprotection, silica-mediated autooxidation provided a mixture of allylic hydroperoxides 16 which could be converted to the corresponding enone 8 through a Kornblum–DeLaMare work-up.29 Under these conditions, the hydroxamic acid exhibits good selectivity for 6-endo-trig cyclization, presumably due to the stability of the intermediate allylic radical.The desired syn-diastereomer 8a was formed as the major product, albeit in modest diastereoselectivity. Eager to improve the dr, we screened a series of copper-diamine catalysts previously studied as copper monooxygenase mimics.30 To our delight, Cu(TMEDA)2(BF4)2 not only improved the diastereoselectivity, but also catalyzed the reaction at lower temperatures in higher combined yield of the 6-endo products.31 When an N-acetylhydroxamic acid (8b) is subjected to the optimal conditions, the dr improves to 13 : 1. The selectivity for the syn diastereomer in these reactions is consistent with related conformationally-controlled selectivity in cyclic amides,32 where the α-substituent adopts a pseudo-axial disposition to alleviate developing A1,3 strain in the chair-like transition state for cyclization.33 Although THO 8b (R = Ac) was formed with higher diastereoselectivity, this compound was unstable to further elaboration. As a result, the more stable N-benzoyl THO 8a was used for further elaboration to fully functionalized 22.With access to the desired bicyclic THO, our efforts turned to parlaying the newly installed enone to the oxidation pattern found in 2. To our dismay, we found that traditional nucleophilic epoxidation conditions (e.g. NaOH, H2O2) led to complete decomposition of enone 8a, while other oxidants, such as DMDO, returned starting material. After an extensive survey of the literature, we found promising reactivity using hydrogen peroxide and sodium bicarbonate, which presumably generates a peroxycarbonate species in situ.34 Further optimization found that use of sodium hypochlorite as the oxidant, in combination with catalytic CrCl3, provided 17 in good yield as a single diastereomer.Initial attempts to desaturate epoxy ketone 17 by using classical Saegusa–Ito conditions or Tsuji-type oxidations of the corresponding silyl enol ethers were unsuccessful. In contrast, ketone 17 underwent smooth desaturation using conditions adapted from a recent report by White and coworkers,35 in which a Lewis acidic palladium catalyst enables in situ enolization and α-palladation. Under these conditions, epoxy enone 18 can be isolated directly in 67% yield.At this stage, elaboration of 18 to 20b was initially envisioned to proceed by diastereoselective ketone reduction followed by 1,3-transposition of the allylic alcohol (Scheme 4).36 Unfortunately, efforts to effect this strategy, or related approaches involving alkene formation and allylic oxidation, proved unsuccessful. As an alternate approach, we envisioned that a bis-epoxyketone (i.e.19), which could potentially undergo chemoselective Wharton rearrangement to the desired allylic alcohol. To this end, treatment of enone 18 with sodium hypochlorite in 1,4-dioxane provided bis-epoxy enone 19 in high yield as a single diastereomer. Addition of 1.0 equiv. anhydrous hydrazine in the presence of catalytic benzoic acid with careful control of the temperature gave a mixture of isomers 20a and 20b in 33% yield. Unfortunately, efforts to further improve the efficiency of this reaction were unfruitful. Nonetheless, when the mixture of isomers was treated with the bulky, Lewis acidic silylating reagent TBSOTf, the corresponding secondary allylic silyl ether was as isolated exclusively.37 When unreacted 20a, recovered from the reaction mixture, was subjected to neutral florisil purification a mixture of 20a and 20b were recovered. Taken together, these data might suggest that 20a and 20b can interconvert through an unusual vinylogous Payne rearrangement under Lewis acidic conditions.38 Finally, chemoselective cleavage of the N-benzoyl protecting group revealed 22,39 our desired substrate for subsequent late stage diketopiperazine formation and thiolation.Open in a separate windowScheme 4Synthesis of oxazine 22. 相似文献
Entry | B(OR2)2 | [Cu], L | Yieldb (%) | eec (%) |
---|---|---|---|---|
1 | Bgly (13a) | Cu(CO2i-Pr)2, L1d | 2 | 63 |
2 | Bgly (13a) | Cu(MeCN)4BF4, L2d | 7 | 72 |
3 | Bgly (13a) | Cu(MeCN)4BF4, L3d | 70 | 30 |
4 | Bgly (13a) | Cu(MeCN)4BF4, L4d | 11 | 80 |
5 | Bgly (13a) | Cu(MeCN)4BF4, L5d | 24 | 82 |
6 | Bgly (13a) | Cu(MeCN)4BF4, L5 | 30 | 95 |
7 | Bgly (13a) | [Cu(L5)(MeCN)2]BF4 | 50 | 92 |
8 | Bneo (13b)e | [Cu(L5)(MeCN)2]BF4 | 87 | 96 |
11.
Described here is a modular strategy for the rapid synthesis of β-functionalized electron-rich naphthalenes, a family of valuable molecules lacking general access previously. Our approach employs an intermolecular benzannulation of in situ generated isobenzopyrylium ions with various electron-rich alkynes, which were not well utilized for this type of reaction before. These reactions not only feature a broad scope, complete regioselectivity, and mild conditions, but also exhibit unusual product divergence depending on the substrate substitution pattern. This divergence allows further expansion of the product diversity. Control experiments provided preliminary insights into the reaction mechanism.A substituent-controlled divergent benzannulation provides rapid access to various β-functionalized naphthalenes from electron-rich alkynes.Functionalized naphthalenes are important structural motifs widely present in bioactive natural products, pharmaceuticals and functional materials.1,2 They also serve as valuable intermediates in organic synthesis.3 Among them, naphthalenes bearing an electron-donating group (EDG) at the β-position (e.g., β-naphthols, β-naphthylamines, and β-naphthyl thioethers) are particularly versatile (Fig. 1).2,3 For example, BINOL, which is derived from β-naphthol, is an extensively utilized synthetic precursor toward a wide range of privileged chiral ligands and catalysts.3 While various approaches have been developed for the synthesis of naphthalenes, efficient and selective de novo strategies toward these β-functionalized ones still remain in high demand. Moreover, to the best of our knowledge, a general and modular approach for rapid access to all these electron-rich β-functionalized naphthalenes remains unknown.4Open in a separate windowFig. 1Useful β-naphthol, β-naphthylamine, and β-naphthyl thioether units.Isobenzopyrylium ions are readily accessible and versatile intermediates in organic synthesis (Scheme 1).5 They are known to participate in cycloaddition reactions with diverse carbon–carbon double bonds or triple bonds for the synthesis of naphthalenes.5,6 While extensive progress has been achieved in this topic, challenges still remain to be addressed. For example, the majority of these benzannulations with alkynes have to be executed at high temperature, except those intramolecular cases or with stoichiometric activators. Moreover, electron-rich alkynes have not been well explored as reaction partners for the benzannulations with isobenzopyrylium ions. Nevertheless, such reactions would provide expedient access to the valuable β-naphthol and β-napthylamine derivatives with diverse substitution patterns (Scheme 1). In this context, here we report our effort in achieving a general and modular strategy toward these electron-rich naphthalenes with high efficiency and regioselectivity under mild conditions. We also observed interesting selectivity divergence controlled by the substituent of the isobenzopyrylium substrates, giving rise to different types of naphthalene products (e.g., 2-hydroxy-1-naphthaldehydes, Scheme 1).Open in a separate windowScheme 1Benzannulation of isobenzopyryliums with electron-rich alkynes.We began our study with isochromene 1a as the isobenzopyrylium precursor. Siloxy alkyne 2a was first employed as the model electron-rich alkyne in view of the extraordinary versatility of this type of alkyne in various cyclization reactions, including benzannulation.7–9 Various Brønsted and Lewis acids were evaluated as catalysts for this reaction. Unfortunately, most of them did not show obvious catalytic activity toward the formation of a naphthalene product (Table 1). These reactions either had little conversion or resulted in a mixture of undesired products. Nevertheless, further screening led to the identification of AgOTf and BF3·OEt2 as capable catalysts (entries 5–6), with the latter being superior, leading to the formation of naphthalene 3a as the major product (75% yield, entry 6). Increasing the catalyst loading to 20 mol% further improved the product yield to 85% (with an isolated yield of 81%, entry 7). Further increasing the catalyst loading proved to be not beneficial (entry 8). Notably, the use of substrate 1a′ bearing an ethoxy leaving group also provided an equally good result. Other solvents, such as toluene and MeCN, were also evaluated, but all gave lower product yields. Finally, it is worth noting that the mild conditions used here are in sharp contrast to the typical high temperature required for the previously known catalytic intermolecular benzannulations involving isobenzopyryliums and alkynes.5dEvaluation of reaction conditions
Open in a separate windowaReaction scale: 1a (0.05 mmol), 2a (0.06 mmol), catalyst (10 mol%), and DCM (0.5 mL). Yield is based on the analysis of the 1H NMR spectrum of the crude product using CH2Br2 as the internal standard.bUnreacted substrates account for the major remainder of the mass balance.cAn unidentifiable mixture accounts for the major remainder of the mass balance.dYield in parentheses is isolated yield.With the optimized conditions, the generality of this process was examined (Scheme 2). A range of isochromenes 1 and siloxy alkynes 2 participated in this benzannulation to form the desired silylated β-naphthols 3 with moderate to good efficiency. Notably, these products were all generated as a single isomer. This is particularly noteworthy when compared with the cases using phthalazines, which gave a mixture of regioisomers if the phthalazine was unsymmetrically substituted.8g The excellent regioselectivity observed in our reaction is likely attributed to the significant polarization of both cycloaddition partners. While alkyl-substituted siloxy alkynes reacted efficiently, unfortunately aryl-substituted ones led to low yield.Open in a separate windowScheme 2Reaction scope. Reaction scale: 1 (0.5 mmol), 2 (0.6 mmol), DCM (5 mL), 12 h, and isolated yield. a Run for 24 h.During the above scope study, we found that the reaction of 3-unsubstituted isochromene 1g and siloxy alkyne 2a did not form the desired product 3a. Instead, 2-hydroxy-1-naphthaldehyde 4a was formed as the major product (64% yield, eqn (1)). Careful analysis of this product structure indicated that the original leaving part in 1a (in the case of 3a) was not completely cleaved from the molecule. Instead, only the C–O bond cleavage took place, which led to a dangling aldehyde group. Another important observation is that the TIPS group was lost in the naphthalene product. It was proposed that the methoxide leaving group in 1a might help remove this silyl group and assist the above C–O bond cleavage. In contrast, in the formation of 3a, this methoxide group was a part of the whole leaving unit during rearomatization and thus unavailable for desilylation (vide infra).In fact, such 2-hydroxy-1-naphthaldehyde products, resembling the highly versatile salicylaldehyde family, are indeed a useful substructure of bioactive molecules, such as gossypol (Fig. 1).2b They can also serve as key intermediates toward functional materials, such as molecular sensors (e.g., AHN, Fig. 1).2e In view of these important applications, considerable efforts were next devoted to further improving the reaction efficiency (see the ESI for details†). Finally, we found that the reaction yield of 4a could be improved to 85% with 2.0 equivalents of BF3·OEt2 and one equivalent of 2,4,6-collidine as the additive. We believe that the role of collidine is to help reversibly stabilize the isobenzopyrylium intermediate and prevent its decomposition during the reaction progress.9b1The above protocol for the synthesis of 2-hydroxy-1-naphthaldehydes is general for a range of 3-substituted isobenzopyryliums (Scheme 3). The reaction efficiency was not affected by electron-donating or electron-withdrawing groups. Various siloxy alkynes were also suitable reaction partners, including aryl- and alkyl-substituted ones. Again, these products were all formed as a single regioisomer. While the majority of these reactions were highly chemoselective toward the formation of aldehydes 4, it is worth noting that tBu- and TBS-substituted alkynes resulted in a mixture of 3 and 4, with the former being major. This is likely due to the substantial steric hindrance in close proximity to the silyl group, whose cleavage was obstructed and thus the driving force for the subsequent C–O bond cleavage was weakened, thereby altering the pathway to preferentially form 3 (vide infra). Finally, the structures of 4a and 4b were unambiguously confirmed by X-ray crystallography.Open in a separate windowScheme 3Scope for the synthesis of 2-hydroxy-1-naphthaldehydes 4. Reaction scale: 1 (0.5 mmol), 2 (0.6 mmol), DCM (5 mL), 12 h, and isolated yield. a Run for 16 h. b Run for 19 h.The divergent reaction patterns observed with siloxy alkynes prompted us to explore other electron-rich alkynes. Thioalkyne 5a was next employed for the reaction with 1a. Indeed, direct extension with BF3·OEt2 as the catalyst successfully resulted in regioselective formation of β-naphthyl thioethers 6a in about 70% yield (Table 2, entries 1 and 2). Further screening of other catalysts was performed to further improve the reaction efficiency (see the ESI for details†). While Brønsted acids led to a significant drop in the yield, we were pleased to find that the Lewis acid AgNTf2 exhibited excellent catalytic activity, furnishing 6a in 89% yield (entry 6).Condition optimizationa
Open in a separate windowaReaction scale: 1a (0.05 mmol), 5a (0.06 mmol), catalyst (10 mol%), and DCM (0.5 mL). The yields are based on NMR analysis of the crude product using CH2Br2 as the internal standard.bIsolated yield.With the above conditions, we carried out a brief examination of the reaction scope (Scheme 4). Interestingly, a similar selectivity divergence was also observed with thioalkynes. Indeed, under identical conditions, the 3-butyl-substituted and 3-unsubstituted isobenzopyryliums all reacted efficiently, with the former leading to only 2-naphthyl thioethers 6, but the latter preferentially to 2-sulfenyl-1-naphthaldehydes 7. It is worth noting that only one regioisomer was observed in all these products.Open in a separate windowScheme 4Scope for the synthesis of 2-naphthyl thioethers. Reaction scale: 1 (0.3 mmol), 5 (0.36 mmol), 12 h, and isolated yield. a Run for 37 h. b Run for 19 h. The unreacted alkyne accounted for the major mass balance.Finally, we were curious about the reactivity of ynamides in such benzannulations.10 To our delight, in the presence of 20 mol% of BF3·OEt2, the reaction between isochromene 1a and different ynamides 8 successfully afforded the desired 2-naphthylamine products 9 with excellent regioselectivity and good efficiency (Scheme 5). Different electron-withdrawing groups on the ynamides were all compatible with this protocol. However, to our surprise, the use of 3-unsubstituted isochromene 1g did not lead to the expected naphthaldehyde 10 at all. Instead, the same product 9a was obtained as the only product, even if two equivalents of BF3·OEt2 were used together with collidine as the additive (conditions in Scheme 3). This result is in dramatic contrast to the cases of siloxy alkynes and thioalkynes.Open in a separate windowScheme 5Scope of ynamides. Reaction scale: 1 (0.5 mmol), 8 (0.6 mmol), DCM (5 mL), 12 h, and isolated yield. a Run for 30 h. b Yield in parentheses is obtained with BF3·OEt2 (2.0 equiv.), 2,4,6-collidine (1.0 equiv.), 0 °C, and DCM.Next, further studies were performed to help understand the unusual selectivity divergence observed with siloxy alkynes and thioalkynes. It is obvious that the substituent at the 3-position of the isochromene substrates has a crucial impact on the product distribution. To further probe the possible steric and electronic effects, we incorporated various other substituents, such as different aryl groups and the bulky tBu group (Table 3). We found that these reactions afforded products 3a and 4′ with variable ratios. With the tBu group, almost the same product distribution as the nBu group was observed, exclusively forming 3a (Table 3, entry 2). However, aryl substitution reversed this ratio, giving product 4′ as the major product (entries 3–5). More importantly, the preference toward 4′ is more pronounced with electron-deficient aryl groups. p-Fluorophenyl substitution led to almost only 4′. These results suggested that the product distribution appeared to be more related to the electronic effect than the steric effect.Influence of the 3-substituents in isochromenesa
Open in a separate windowaReaction scale: 1 (0.05 mmol), 2a (0.06 mmol), and 12 h. Yield is based on the analysis of the NMR yield of the crude mixture using CH2Br2 as an internal standard.bRun with 10 mol% of BF3·OEt2.Possible mechanisms are depicted in Scheme 6 using a siloxy alkyne as an example. The reaction begins with Lewis acid activation on the acetal motif to form the isobenzopyrylium intermediate I. The subsequent cycloaddition with the alkyne triple bond forms the key bicyclic oxonium intermediate II, which has a resonance form II′. This step might also be stepwise by forming one C–C bond first via ketenium III. In either case, the regioselectivity is precisely controlled by matching the polarity of the two partners, which explains the exclusive formation of only one regioisomer in all the cases. Depending on the R substituent, oxonium II can proceed via three possible pathways. In path a (R = alkyl), the methoxide attacks the oxonium carbon to form intermediate IV, which then undergoes retro-[4 + 2] cycloaddition with concomitant rearomatization to form naphthalene 3, together with the release of ester RCO2Me. However, if the oxonium carbon is unsubstituted (R = H), this intermediate is relatively unstable due to less stabilization of the positive charge (also viewed as a secondary cation in II′, versus tertiary carbocation if R ≠ H). Thus, the silyl enol ether motif tends to push the electron toward this unstable oxonium (a “push–pull” scenario) to cleave the bridging C–O bond. This step, likely assisted by the methoxide attack on the silyl unit, leads to 1,3-dicarbonyl intermediate V. The subsequent tautomerization/aromatization leads to the observed 2-hydroxy-1-naphthaldehyde 4.6b As an exception, if the siloxy alkyne is bulky (e.g., R′ = tBu or TBS), the reaction preferentially gives product 3 (Scheme 3, 4l–m). We believe that the increased steric repulsion by bulky R′ significantly disfavors the approach of methoxide to the neighboring silyl group in IIb. Instead, the methoxide prefers to add to the oxonium carbon, which allows path a to operate and forms 3 as the major product. Another exceptional case is the use of ynamides, which exclusively give products 3 even if R = H. Although actual rationalization would require more sophisticated mechanistic study, we currently reason that the enamide unit in the IIb analogue might not be electron-rich enough to exert sufficient driving force to cleave the C–O bond. This can also be viewed from the standpoint of the limited stabilization of the resulting iminium ion next to an electron-withdrawing group if this C–O bond is cleaved. Consequently, the methoxide prefers to attack the oxonium carbon to favor path a. Finally, with 3-aryl-substituted isochromenes (R = Ar), we believe that the oxonium intermediate IIc is well stabilized by aryl resonance. Thus, the effective delocalization of the positive charge makes this oxonium carbon less electrophilic for nucleophilic attack by methoxide. Instead, the methoxide serves as a base to deprotonate the bridgehead hydrogen, which triggers rearomatization and C–O cleavage to form product 4′. The more electron-deficient aryl group makes this bridgehead hydrogen more acidic, thus further favoring this pathway, which explains the trend in entries 3–5, Table 3.Open in a separate windowScheme 6Proposed mechanism.To further substantiate the above rationale, we carried out some control experiments. First of all, to confirm the fate of the leaving part in the isochromene substrates when β-naphthols 3 were formed, we used a large homobenzyl group in isochromene 1p (eqn (2)). After its reaction with 2a, we were able to isolate ester 11, which is consistent with path a of the proposed mechanism. Next, we also suspected that products 3 and 4 might interconvert to each other depending on the reaction conditions. To probe this possibility, a mixture of 3a and methyl formate was treated with BF3·OEt2 and 2,4,6-collidine, the standard conditions toward products 4 (eqn (3)). However, product 4a was not observed at all, indicating that 3 is not an intermediate toward 4. Similarly, subjecting 4a and MeOH (or MeONa) to BF3·OEt2 did not lead to the deformylation product β-naphthol 3a′, suggesting that 4 is unlikely an intermediate in the formation of 3 (eqn (4)). These observations are consistent with the proposed mechanism, in which the product distribution is kinetically controlled by the barrier in each case and these paths are likely irreversible, but not thermodynamically controlled by product stability.234In summary, we have developed a modular strategy for the rapid synthesis of valuable β-functionalized electron-rich naphthalenes, specifically, β-naphthol, β-naphthylamine, and β-naphthyl thioether derivatives. It also represents the first systematic study of the benzannulations of versatile isobenzopyryliums with general electron-rich alkynes. With suitable choice of the isochromene substrates and the Lewis acid catalysts, different types of electron-rich alkynes, such as siloxy alkynes, ynamides, and thioalkynes, participated in the intermolecular cycloaddition reactions under mild conditions with high efficiency and complete regioselectivity. Moreover, depending on the substitution pattern of the isochromene substrates, unusual divergence toward different naphthalene products was observed, thus allowing further diversification of the naphthalene products. Control experiments provided preliminary insights into the intriguing mechanism. Further detailed investigations toward a better understanding are ongoing. 相似文献
Entry | Catalyst | Yielda (%) |
---|---|---|
1 | MeSO3H | <5b |
2 | HNTf2 | <5c |
3 | Sc(OTf)3 | <5c |
4 | TiCl4 | <5b |
5 | AgOTf | 30c |
6 | BF3·OEt2 | 75 |
7 | BF 3 ·OEt 2 (20 mol%) | 85 (81) d |
8 | BF3·OEt2 (1.0 equiv.) | 83 |
9 | BF3·OEt2 (20 mol%), with 1a′ | (75)d |
Entry | Catalyst | Yieldb (%) |
---|---|---|
1 | BF3·OEt2 | 70 |
2 | BF3·OEt2 (20 mol%) | 72 (68)b |
3 | HNTf2 | 20 |
4 | MeSO3H | 7 |
5 | AgOTf | 80 |
6 | AgNTf 2 | 89 (83) b |
12.
Convergent paired electrosynthesis is an energy-efficient approach in organic synthesis; however, it is limited by the difficulty to match the innate redox properties of reaction partners. Here we use nickel catalysis to cross-couple the two intermediates generated at the two opposite electrodes of an electrochemical cell, achieving direct arylation of benzylic C–H bonds. This method yields a diverse set of diarylmethanes, which are important structural motifs in medicinal and materials chemistry. Preliminary mechanistic study suggests oxidation of a benzylic C–H bond, Ni-catalyzed C–C coupling, and reduction of a Ni intermediate as key elements of the catalytic cycle.A direct arylation of benzylic C–H bonds is achieved by integrating Ni-catalyzed benzyl–aryl coupling into convergent paired electrolysis.Electrochemical organic synthesis has drawn much attention in recent years.1 Compared to processes using stoichiometric redox agents, electrosynthesis can potentially be more selective and safe, generate less waste, and operate under milder conditions.1b In the majority of examples, the reaction of interest occurs at one electrode (anode for oxidation or cathode for reduction), while a sacrificial reaction occurs at the counter electrode to fulfil electron neutrality.1a,2 Paired electrolysis uses both anodic and cathodic reactions for the target synthesis, thereby maximizing energy efficiency.1a,3 However, there are comparatively few examples of paired electrolysis for organic synthesis.1a,3,4Paired electrolysis might be classified into three types: parallel, sequential, and convergent (Fig. 1).1a,3a In parallel paired electrolysis (Fig. 1a), the two half reactions are simultaneous but non-interfering. In sequential paired electrolysis (Fig. 1b), a substrate is oxidized and reduced (or vice versa) sequentially. In convergent paired electrolysis (Fig. 1c), intermediates generated by the anodic and cathodic processes react with one another to yield the product.1a,3a,4b,c,5 The activation mode of all three types of paired electrolysis is based on the innate redox reactivity of substrates. As a result, the types of reactions that could be conducted by paired electrolysis remain limited. We proposed a catalytic version of convergent paired electrolysis, where a catalyst is used to cross-couple the two intermediates generated at the two separated electrodes (Fig. 1d). Although mediators have been used in paired electrosynthesis,3a,4c,6 catalytic coupling of anodic and cathodic intermediates remains largely undeveloped. This mode of action will leverage the power of cross-coupling to electrosynthesis, opening up a wide substrate and product space. Here we report the development of such a process, where cooperative nickel catalysis and paired electrolysis enable direct arylation of benzylic C–H bonds (Fig. 1e).Open in a separate windowFig. 1Different types of paired electrolysis: (a) parallel paired electrolysis, (b) sequential paired electrolysis, (c) convergent paired electrolysis, (d) catalytic convergent paired electrolysis and (e) this work.Our method can be used to synthesize diarylmethanes, which are important structural motifs in bioactive compounds,7 natural products8 and materials.9 Direct arylation of benzylic C–H bonds has been recognized as an efficient strategy to synthesize diarylmethanes, and methods using metal catalysis10 and in particular combined photoredox and transition-metal catalysis have been reported.11 Electrosynthesis provides a complementary approach to these methods, with the potential advantages outlined above. The groups of Yoshida12 and Waldvogel13 previously developed synthesis of diarylmethanes via a Friedel–Crafts-type reaction of a benzylic cation and a nucleophile. The benzylic cations were generated by anodic oxidation of benzylic C–H bonds.14 To avoid the overoxidation of products and to stabilize the very reactive benzylic cations, the reactions had to be conducted in two steps, where the benzylic cations generated in the anodic oxidation step had to be trapped by a reagent. We thought a Ni catalyst could be used to trap the benzyl radical to form an organonickel intermediate, which is then prone to a Ni-catalyzed C–C cross-coupling reaction. Although such a coupling scheme was unprecedented, Ni-catalyzed electrochemical reductive coupling of aryl halides was well established.15 We were also encouraged by a few recent reports of combined Ni catalysis and electrosynthesis for C–N,16 C–S,17 and C–P18 coupling reactions.We started our investigations using the reaction between 4-methylanisole 1a and 4-bromoacetophenone 2a as a test reaction (Table 1). Direct arylation of benzylic C–H bonds was challenging and was typically conducted using toluene derivatives in large excess, e.g., as a solvent.11a,b,11d–f To improve the reaction efficiency, we decided to use only 3 equivalents of 4-methylanisole 1a relative to 2a. After some initial trials, we decided to conduct the reaction in an undivided cell using a constant current of 3 mA. These conditions are straightforward from a practical point of view. After screening various reaction parameters, we found that a combination of 4,4′-dimethoxy-2-2′-bipyridine (L1) and (DME)NiBr2 as a catalyst, THF/CH3CN (4 : 1) as a solvent, fluorine-doped tin oxide (FTO) coated glass as an anode and carbon fibre as a cathode gave a 50% GC yield of 1-(4-(4-methoxybenzyl)phenyl)ethanone 3a after 18 h (Table 1, entry 1). Extending the reaction time to 36 h improved the yield to 76% (isolated yield) (entry 2). The target products were formed in a diminished yield with other bipyridine type ligands (entries 3–5). Solvents commonly used in Ni-catalyzed cross-coupling reactions, such as DMA and DMF, were less effective (entries 7–8). Replacing carbon fibre by nickel foam or platinum foil as the cathode was detrimental to the coupling, but substantial yields were still obtained (entries 9–10). On the other hand, FTO could not be replaced as the anode. Using carbon fibre as the anode shut down the reaction (entry 11). Likewise, using Pt foil as the anode gave only a 7% GC yield (entry 12). The sensitivity of the reaction outcomes to the electrodes originates from the electrode-dependent redox properties of reaction components (see below). Additional data showing the influence of other reaction parameters such as nickel sources, current, concentration, and electrolytes are provided in the ESI (Table S1, ESI†).Summary of the influence of key reaction parametersa
Open in a separate windowaReaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), (DME)NiBr2 (6 mol%), ligand (7.2 mol mol%), LutHClO4 (0.1 M), and lutidine (0.8 mmol) in solvent (2 mL) at 40 °C. GC yield.bReaction time: 36 h. Isolated yield.With the optimized reaction conditions in hand, we explored the substrate scope (Table 2). A large number of aryl and heteroaryl bromides could be coupled (3a–3x). These substrates may contain electron-rich, neutral, or poor groups. For aryl bromide bearing electron-donating groups, replacing (DME)NiBr2 by Ni(acac)2 gave higher yields (3k–3o). The method tolerates numerous functional groups in the (hetero)aryl bromides, including for example ketone (3a), nitrile (3b, 3u, and 3v), ester (3c, 3m, 3n, and 3s), amide (3d), aryl-Cl (3q), CF3(3i, 3t, and 3w), OCF3(3e), aryl-F(3x), pyridine (3w and 3x), and arylboronic ester (3g). We then probed the scope of benzylic substrates using 4-bromoacetophenone 2a as the coupling partner (3aa–3ai). Toluene and electron-rich toluene derivatives were readily arylated (3aa–3ac). Toluene derivatives containing an electron-withdrawing group such as fluoride (3ad) and chloride (3ae) could also be arylated, although a higher excess of them (10 equiv.) was necessary. More elaborated toluene derivatives containing an additional ester (3af, 3ai) or ether (3ag, 3ah, and 3ai) were also viable.Substrate scopea
Open in a separate windowaReaction conditions: 1 (0.6 mmol), 2 (0.2 mmol), (DME)NiBr2 (6 mol%), L1 (7.2 mol mol%), LutHClO4 (0.1 M), and lutidine (0.8 mmol) in THF/CH3CN (4 : 1, 2 mL) at 40 °C. Isolated yield.b(DME)NiBr2 (5 mol%) and L1 (6 mol%) were used as the catalysts.cNi(acac)2 was used instead of (DME)NiBr2.dSolvent: THF/CH3CN (3 : 1, 2 mL).e2 mmol toluene or its derivative was used as the substrate.fReaction time: 60 h.Linear sweep voltammetry (LSV) was applied to probe the possible processes at both the anode and cathode. The measurements were made in THF/CN3CN (4 : 1, 2 mL) using [LutH]ClO4 (0.1 M) as the electrolyte and lutidine (0.4 M) as an additional base to mimic the coupling conditions. The LSV curves of individual reaction components indicate that only 4-methylanisole 1a and the Ni catalyst may be oxidized at the anode (Fig. 2a). The current at 3 mA appears to be the sum of the oxidation currents of 1a and the Ni catalyst. Meanwhile, LSV curves indicate that only the Ni catalyst might be reduced at the cathode (Fig. 2b).Open in a separate windowFig. 2The LSV curves of different reaction components at the anode or cathode. The components were dissolved in THF/CN3CN (4 : 1, 2 mL); the solution also contained [LutH]ClO4 (0.1 M) and lutidine (0.4 M). Scan rate: 50 mV s−1. (a) The LSV curves of different reaction components at the FTO anode; (b) the LSV curves of different reaction components at the carbon fibre cathode; (c) the LSV curves of different reaction components at the carbon fibre anode.It was observed that FTO was an essential anode for the reactions. If FTO was replaced by a carbon fibre anode, no coupling product was obtained. LSV was performed to probe the oxidation of 1a and the Ni catalyst on a carbon fibre anode (Fig. 2c). The oxidation of the Ni catalyst was much easier on carbon fibre than on FTO. At 3 mA, the oxidation is exclusively due to the Ni catalyst. This result suggests that the absence of coupling on the carbon fibre anode is due to no oxidation of 1a. The different redox properties of 1a and the Ni catalyst observed on different electrodes might be attributed to the different nature of surface species which influence the electron transfer. Although FTO is rarely used in electrosynthesis, it is widely used in electrocatalysis and photoelectrocatalysis for energy conversion.19 FTO is stable, commercially available and inexpensive. In our reactions, the FTO anode could be reused at least three times.The LSV curves in Fig. 2 revealed the issue of “short-circuit” of catalyzed/mediated paired electrolysis in an undivided cell, as the catalyst or mediator can be reduced and oxidized at both the cathode and anode. When carbon fibre or graphite was used as the anode, the short-circuit problem was very severe so that nearly no current was used for electrosynthesis. However, by using an appropriate anode such as FTO, the short-circuit problem was alleviated and around half of the current was used to oxidize the substrate (1a) while the other half was used to oxidize the nickel complex. The remaining short-circuit is one of the reasons why the current efficiencies of the reactions are low (<10%). Another factor contributing to the low current efficiency is the instability of the benzyl radical, which can abstract hydrogen from the solvent to regenerate the substrate. Nevertheless, useful products could be obtained in synthetically useful yields under conditions advantageous to previous methods.For the test reaction (Table 1), a small amount of homo-coupling product bis(4-methoxyphenyl)methane (<2%) was detected by GC-MS under the optimized conditions. In the absence of ligand L1, the yield of the homo-coupling products increased (∼8%). In the presence of a radical acceptor, the electron-withdrawing alkene vinyl benzoate, the product originating from the addition of a benzyl radical to the olefin was obtained in about 12% GC yield (ESI, Scheme S1†). These data support the formation of a benzyl radical intermediate. As bromide existed in our reaction system, it is possible to be oxidized to form a bromine radical. Previous studies showed that a bromine radical can react with a toluene derivative to give a benzyl radical.11b,g,20 To probe the involvement of the Br radical, we conducted a coupling of 4-methylanisole 1a with 4′-Iodoacetophenone, using Ni(acac)2 instead of (DME)NiBr2 as the Ni source. We obtained a GC yield of 24% for the coupling after 18 h (Scheme S2†). This result suggests that a Br-free path exists for the coupling, although a non-decisive involvement of Br−/Br˙ cannot be ruled out.Based on the data described above, we propose a mechanism for the coupling (Scheme 1). The oxidation of a toluene derivative at the anode gives a benzyl radical. This radical is trapped by a LNi(ii)(Ar)(Br) species (B) in the solution to give a LNi(iii)(Ar)(benzyl)(Br) intermediate (C). The latter undergoes reductive elimination to give a diarylmethane and a LNi(i)(Br) species (A). There are at least two ways A can be convert to B to complete the catalytic cycle: either by oxidative addition of ArBr followed by a 1-e reduction at the cathode or by first 1-e reduction to form a Ni(0) species followed by oxidation addition of ArBr. In addition to a toluene derivative, a Ni species is oxidized at the anode. We propose that this oxidation is an off cycle event, which reduces the faradaic and catalytic efficiency but does not shut down the productive coupling.Open in a separate windowScheme 1Proposed mechanism of the direct arylation of benzylic C–H bonds. 相似文献
Entry | Ligand | Anode | Cathode | Solvent | Yield (%) |
---|---|---|---|---|---|
1 | L1 | FTO | Carbon fibre | THF/CH3CN = 4 : 1 | 56 |
2 | L1 | FTO | Carbon fibre | THF/CH3CN = 4 : 1 | 76b |
3 | L2 | FTO | Carbon fibre | THF/CH3CN = 4 : 1 | 43 |
4 | L3 | FTO | Carbon fibre | THF/CH3CN = 4 : 1 | 46 |
5 | L4 | FTO | Carbon fibre | THF/CH3CN = 4 : 1 | 21 |
6 | L1 | FTO | Carbon fibre | CH3CN | 4 |
7 | L1 | FTO | Carbon fibre | DMA | 15 |
8 | L1 | FTO | Carbon fibre | DMF | 6 |
9 | L1 | FTO | Ni foam | THF/CH3CN = 4 : 1 | 45 |
10 | L1 | FTO | Pt foil | THF/CH3CN = 4 : 1 | 28 |
11 | L1 | Carbon fibre (1 cm2) | Carbon fibre | THF/CH3CN = 4 : 1 | 0 |
12 | L1 | Pt foil (cm2) | Carbon fibre | THF/CH3CN = 4 : 1 | 7 |
13.
Qi Zhang Mong-Feng Chiou Changqing Ye Xiaobin Yuan Yajun Li Hongli Bao 《Chemical science》2022,13(23):6836
Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes. This reaction allows the expansion of the carbon ring by a carbon shift from an all-carbon quaternary center, and enables further C–C bond formation on the tertiary carbon intermediate with the aim of reconstructing a new all-carbon quaternary center. The good functional group compatibility ensures diverse synthetic transformations of this method. Experimental and theoretical studies reveal that the excellent diastereoselectivity should be attributed to the hydrogen bonding between the substrates and solvent.Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes.A leading motive for the impressive achievements in the area of assembling molecular complexity is the transformation of simple feedstock chemicals into complex molecular skeletons with superior bioactive properties. In this respect, the direct functionalization of alkenes has been demonstrated as one of the most effective and simple strategies to meet this criterion at a high level. While the difunctionalization of alkenes in a one-pot process is the major theme of considerable interest in this field,1 the multifunctionalization of alkenes,2 for example, a 1,2,3-trifunctionalization of alkenes, has the power to simultaneously incorporate multifunctional groups. Therefore, this multifunctionalization reaction model can be regarded as an efficient and novel strategy to afford molecules with high structural diversity and complexity. However, such methods are elusive.During the last decades, radical alkene functionalizations have been revealed to be a powerful tool for building complex molecular frameworks by employing a radical initiator, a transition metal catalyst, or a photocatalyst.1f–i However, only several successful methods for the radical multifunctionalization of alkenes have been achieved. For example, the Studer group reported an elegant 1,2-boryl shift-enabled radical 1,2,3-trifunctionalization of allylboronic esters using AIBN as the radical initiator (Fig. 1a).3 Shi et al. disclosed an excellent photocatalytic perfluoroalkylation of a vinyl-substituted all-carbon quaternary center through 1,2-aryl migration (Fig. 1b).4 Herein, we report a new one-pot protocol to realize an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters through a cascade process of deconstruction–reconstruction of the all-carbon quaternary center (Fig. 1c).5Open in a separate windowFig. 1Radical 1,2,3-trifunctionalization of alkenes. (a) Studer''s work; (b) Shi''s work; (c) This work.The direct incorporation of a fluorine atom or fluorinated moieties into organic compounds has been extensively investigated and proved to be an significant synthetic strategy in the field of discovering new pharmaceuticals.6 Recently, we are interested in the radical functionalization of alkenes with fluoroalkyl groups,7 and we envisioned that, different from the typical Dowd–Beckwith8 ring expansion reaction,9 the addition of a fluoroalkyl radical to the C C double bond would generate an adduct radical species I, which will transform into the radical intermediate II upon ring expansion (Fig. 1c). Finally, the cascade C–C coupling affords the product with a reconstructed all-carbon quaternary center. However, there are several challenging issues that need to be addressed: (1) the carbon shift from an all-carbon quaternary center to afford a tertiary carbon center which is bulkier than the tertiary carbon center formed in a typical Dowd–Beckwith ring expansion reaction; (2) the reconstruction of all-carbon quaternary center from tertiary carbon radical II will meet the associated conformational restriction and steric congestion; (3) side reactions, such as 1,2-radical addition to the alkenyl group, homolytic couplings of the carbon radical intermediates I and II, and direct H-atom abstraction;10 (4) how to control the diastereomeric ratio of the products. To meet these challenges, we developed a novel method for the 1,2,3-trifunctionalization of alkenes using alkynyl triflones as both the CF3 (ref. 6) and alkynyl sources, providing the ring-expanded cyclic β-ketoesters with excellent diastereoselectivity and functional group diversity. In addition, good functional group compatibility of this method was observed, which ensures the diverse synthetic transformations. Moreover, hydrogen bonding between the substrates and 2,2,2-trifluoroethanol solvent was revealed to be the key factor for the excellent diastereoselectivity obtained in this reaction, and this result was confirmed by both experimental and theoretical studies.This study began by surveying radical initiators for 1,2,3-tricarbofunctionalizing α-vinyl-β-ketoester 1a with alkynyl triflone 2a11 (12 (13 dramatically increased the diastereoselectivity and (±)-3a could be obtained in an identical yield with an even higher dr value (dr > 20 : 1) (14 Without the addition of a radical initiator, a reaction did not happen ( Entry Solvent Yieldb (%) 1 EA 60 (dr = 13 : 1)c 2 EA 55 (dr = 11 : 1)d 3 EA 63 (dr = 12 : 1) 4 MTBE 45 (dr = 10 : 1) 5 DCE 63 (dr = 15 : 1) 6 Toluene Trace 7 DMF Trace 8 MeOH Trace 9 TFE 63 (dr > 20 : 1) 10e TFE 60 (dr > 20 : 1) 11f TFE 56 (dr > 20 : 1) 12g TFE 70 (dr > 20 : 1) 13h TFE 76 (65)i (dr > 20 : 1) 14j TFE 71 (dr > 20 : 1) 15 TFE Trace