Regioselective catalytic carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones

A new Pd/Cu-catalyzed carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones with complete regioselectivity has been developed. This transformation shows broad substrate scope and excellent functional-group tolerance. Moreover, the obtained 1,2-carbonylboration products provide substantial opportunities for further transformations which cannot be obtained by known carbonylation procedures. Preliminary mechanistic studies indicate that the three hydrogen atoms of the products originated from ethyl acetate.

A multi-component procedure on the carbonylative and hydroborative synthesis of β-boryl ketones has been developed with alkynes, B₂pin₂ and aryldiazonium salts as the substrates and using ethyl acetate as the reagent and solvent.

Construction of boro-containing organic molecules remains an important and hot research field due to their wide applications in materials science,¹ pharmaceuticals² and organic chemistry.³ A multitude of methods have been developed for the synthesis of organoboron compounds over the past decades.⁴ Among these methods, transition-metal-catalyzed borofunctionalization of alkynes is a powerful synthetic strategy due to its high selectivity and efficiency.⁵ For example, the use of copper as a precatalyst for the borylation of alkynes has generated renewed interest in the area. The β-borylalkenylcopper intermediates obtained via syn addition of borylcopper to alkynes can electrophilically trap various electrophiles to form different alkenylboronates (Scheme 1, 1). The classical approach of this type of transformation is alkyne hydroboration (Scheme 1, 1a).⁶ Subsequently, with vinylcopper species as the proposed key intermediates, their further reactions with halogen substitutes (Scheme 1, 1b),⁷ CO₂ (Scheme 1, 1c),⁸ allyl phosphates (Scheme 1, 1d),⁹ and tin alkoxides (Scheme 1, 1e)¹⁰ to give the corresponding alkenylboronates were reported. More recently, Mankad and Cheng reported their achievements on the direct efficient synthesis of tetrasubstituted β-borylenones using a copper-catalyzed four-component coupling reaction of simple chemical feedstocks: internal alkynes, alkyl halides, bis(pinacolato)diboron (B₂pin₂) and CO (Scheme 1, 1f).¹¹ Inspired by their achievements and considering the advantage of a multicomponent borocarbonylation reaction, we developed a new Pd/Cu-catalyzed multi-component carbonylation and borylation reaction of alkynes, aryldiazonium salts, B₂Pin₂, ethyl acetate and CO to obtain saturated β-boryl ketones (Scheme 1, ​,3).3). In addition, this new catalyst system can catalyze the regioselective functionalization of alkynes to obtain 2,1-carbonylboration products that are different from the 1,2-products by known transition-metal-catalyzed borylacylation (Scheme 1, ​,2a)2a) and borocarbonylation (Scheme 1, ​,2b)2b) of alkenes.¹² Nevertheless, the carbonylative and hydroborative coupling of alkynes with aryldiazonium salts to obtain saturated β-boryl ketones is still a challenge and has never been reported.Open in a separate windowScheme 1Strategies for borofunctionalization.Open in a separate windowScheme 2Scope of alkynes. Reaction conditions: 1 (0.1 mmol, 1 equiv.), B₂pin₂ (0.2 mmol, 2 equiv.), 2a (0.1 mmol, 1 equiv.), Pd(acac)₂ (5 mol%), CuI (10 mol%), PPh₃ (20 mol%), Na₂CO₃ (0.4 mmol, 4 equiv.), CO (20 bar), EA (with molecular sieves, water ≤ 50 ppm, 2 mL), stirred at 110 °C for 12 h, isolated yields.Open in a separate windowScheme 3Scope of aryldiazonium salts. Reaction conditions: 1a (0.1 mmol, 1 equiv.), B₂pin₂ (0.2 mmol, 2 equiv.), 2 (0.1 mmol, 1 equiv.), Pd(acac)₂ (5 mol%), CuI (10 mol%), PPh₃ (20 mol%), Na₂CO₃ (0.4 mmol, 4 equiv.), CO (20 bar), EA (with molecular sieves, water ≤ 50 ppm, 2 mL), stirred at 110 °C for 12 h, isolated yields.Initially, we tested various reaction conditions using phenyl acetylene (1a), 4-methoxybenzenediazonium tetrafluoroborate (2a) and bis(pinacolato)diboron as the reaction partners. To our delight, by using Pd(acac)₂ and CuI as the cooperative precatalyst, PPh₃ as the ligand, Na₂CO₃ as the base and ethyl acetate (EA) as the solvent at 110 °C under a CO atmosphere (20 bar) with 12 h reaction time, the desired borocarbonylative coupling product (3aa) was obtained in a good GC yield of 78% (

Correction: HCOOH disproportionation to MeOH promoted by molybdenum PNP complexes

Correction for ‘HCOOH disproportionation to MeOH promoted by molybdenum PNP complexes’ by Elisabetta Alberico et al., Chem. Sci., 2021, 12, 13101–13119, DOI: 10.1039/D1SC04181A.

The authors regret that in Scheme 2 of the original article, complexes 7 and 8 were drawn incorrectly. The solid-state structure of both complexes, as established by X-ray analysis, had been previously reported (7 (ref. 1) and 8 (ref. 2)). In both complexes, the PNP ligand adopts a facial tridentate coordination to molybdenum and not a meridional one, as erroneously shown in Scheme 2 of the original article. The correct ligand arrangements in the metal coordination sphere for complexes 7 and 8 are reported below in Scheme 1.Open in a separate windowScheme 1Mo–PNP complexes tested in the dehydrogenation of HCOOH.Open in a separate windowScheme 2Proposed mechanisms for HCOOH dehydrogenation (red), disproportionation (blue) and decarbonylation (green) promoted by 5. Evidence for the formation of a Mo(iv) species is based on the detection by NMR of H₂ and HD following addition of DCOOD to Mo(H)_n species (see Fig. SI-31).Please note that complex 8 is also shown in Scheme 4 in the proposed mechanism for HCOOH decarbonylation (green part), and in Fig. 2. In both cases, the correct structure for complex 8 is reported below in Scheme 2 and Fig. 1.Open in a separate windowFig. 1 ¹H and ³¹P{¹H} NMR spectra of a toluene-d₈ solution of {Mo(CH₃CN)(CO)₂(HN[(CH₂CH₂P)(CH(CH₃)₂)₂]₂} 4 in the presence of 100 equivalents of HCOOH ([Mo] 10⁻² M, [HCOOH] 1 M), before (a) and after heating at 90 °C for 1 hour (b). Spectra were recorded at room temperature. Signals related to complex 5 are marked by red dots.Open in a separate windowFig. 2Molecular structure of {Mo(CO)₂(CH₃CN)[CH₃N(CH₂CH₂P(CH(CH₃)₂)₂)₂]} 9. Displacement ellipsoids correspond to 30% probability. Hydrogen atoms are omitted for clarity.Furthermore, a mistake was made in the caption of Fig. 6, showing the solid-state structure of complex 9: the latter has been incorrectly described as a Mo(i)-hydride species {Mo(H)(CO)₂(CH₃CN)[CH₃N(CH₂CH₂P(CH(CH₃)₂)₂)₂]}. The correct formula, in agreement with the X-ray structure, is as follows and is shown above in Fig. 2: {Mo(CO)₂(CH₃CN)[CH₃N(CH₂CH₂P(CH(CH₃)₂)₂)₂]}.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Selective radical cascade (4+2) annulation with olefins towards the synthesis of chroman derivatives via organo-photoredox catalysis

Due to the importance of chroman frameworks in medicinal chemistry, the development of novel synthetic methods for these structures is gaining increasing interest of chemists. Reported here is a new (4 + 2) radical annulation approach for the construction of these functional six-membered frameworks via photocatalysis. Featuring mild reaction conditions, the protocol allows readily available N-hydroxyphthalimide esters and electron-deficient olefins to be converted into a wide range of valuable chromans in a highly selective manner. Moreover, the present strategy can be used in the late-stage functionalization of natural product derivatives and biologically active compounds, which demonstrated the potential application. This method is complementary to the traditional Diels–Alder [4 + 2] cycloaddition reaction of ortho-quinone methides and electron-rich dienophiles, since electron-deficient dienophiles were smoothly transformed into the desired chromans.

We have developed a (4 + 2) radical annulation approach for the synthesis of diverse chromans. This method is complementary to the traditional Diels–Alder [4 + 2] annulation of ortho-quinone methides and electron-rich dienophiles.

Chroman moieties frequently exist as the key subunit in a wide array of natural products, pharmaceuticals, and bioactive molecules.¹ For example, vitamin E,² centchroman,² cromakalim³ and rubioncolin B⁴ are well-known active pharmaceutical ingredients in various therapeutic areas (Scheme 1a). Due to their significant importance in medicinal chemistry, developing new methods towards the synthesis of chromans and the installation of a variety of the functional groups in chroman frameworks are gaining increasing attention of the chemical community.⁵Open in a separate windowScheme 1Selected bioactive molecules and the synthetic methods of chromans.In the past few decades, a great deal of methods have been developed for the assembly of substituted chromans, and among them, the Diels–Alder [4 + 2] cycloaddition reaction provides a highly efficient synthetic platform in the construction of these functional six-membered frameworks.⁶ Extensive work has been done with this strategy, resulting in a lot of significant progress. The ortho-quinone methides (o-QMs) are generally essential dienes for the Diels–Alder reaction towards the synthesis of chromans, as they are highly reactive for rapid rearomatization via Michael addition of nucleophiles, cycloaddition with a dienophile of 2π partners or 6π-electrocyclization (Scheme 1b).⁷ Herein, although various valuable chromans have been successfully synthesized with the Diels–Alder [4 + 2] cycloaddition reaction, the use of o-QMs may lead to several potential limitations in some cases. One of the potential limitations is that o-QMs are used mainly as Michael acceptor and electron-deficient dienes to react only with nucleophiles and electron-rich dienophiles. In these considerations, the evolution of synthetic methods for chromans is very important and highly desirable. In particular, novel (4 + 2) cycloaddition strategies capable of synthesizing chromans with the use of easily available materials and electron-deficient dienophiles are of utmost interest.On the basis of retrosynthetic analysis of chroman shown in Scheme 1c, (4 + 2) radical annulation of the corresponding carbon-centered radical R with olefin would be an alternative route, which is able to overcome the above-mentioned potential limitations. Considering that radical species R is normally nucleophilic, thus, it could react with electron-deficient olefins affording chroman products that generally can''t be synthesized by the traditional Diels–Alder [4 + 2] cycloaddition reaction involving o-QMs. Herein, we reported a highly selective (4 + 2) radical–annulation reaction to construct the chroman framework with the use of easily available NHPI ester as the radical precursor and olefin as the radical acceptor under mild conditions.Compared with other alkyl radical precursors, the redox-active N-(acyloxy)phthalimides (NHPI esters) come to the fore, since they are cheap, stable, readily available, and non-toxic.⁸ Bearing above hypothesis in mind, we commenced to investigate the (4 + 2) annulation reaction by utilizing readily available N-hydroxyphthalimide ester A′ and commercially available ethyl acrylate as model substrates. After a great deal of screening on the reaction parameters, only a trace amount of the target product was detected by GC-MS. In contrast, the main product is anisole, which may result from a rapid hydrogen abstraction reaction of the unstable primary alkyl radical intermediate. To restrain the formation of this by-product, we designed N-hydroxyphthalimide esters A and A′′, which could produce more stable tertiary radicals, for the target (4 + 2) annulation reaction instead of A′ (9 74% yield of ethyl-2,2-dimethylchromane-4-carboxylate upon 1 was selectively obtained after irradiation of the reaction system under blue LEDs at room temperature for 12 h, despite a little by-product ( EntryVariation from standard conditionsYield/%1None742No lightn.d3No EYn.d44-CzIPNn.d5Ru(bpy)₃(PF₆)₂366MeCN347DCEn.d8Air39Open in a separate window^aStandard conditions: A (0.2 mmol), ethyl acrylate (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield; n.d. = not detected.In order to explore the substrate scope of the (4 + 2) annulation reaction, we commenced to scrutinize the generality and selectivity with respect to N-hydroxyphthalimide esters. The functional group applicability of N-hydroxyphthalimide esters was investigated by the examination of various electron donating/withdrawing substituents at the varying positions, as illustrated in Scheme 2. Gratifyingly, we found that substances bearing electron-donating substituents (Me, OMe, ^tBu, SMe, OPh, OBn, and Ph) at the para-position could smoothly be transformed into the corresponding chromans with satisfactory yields (2–8). N-Hydroxyphthalimide esters with halogen substituents, such as fluoride, chloride, bromide and iodide are suitable to produce the corresponding chromans in satisfactory yields, which enable potential application in further functionalization (9–12). Surprisingly, electron-withdrawing substituents, such as MeCO, OCF₃, and CF₃, were also tolerated under standard conditions (13–15). This reaction could proceed effectively with N-hydroxyphthalimide esters containing one group or multiple groups in different positions, which delivered a variety of chroman compounds in moderate to good yields (16–19, 21–23). The annulation reaction is not limited to the construction of benzene compounds, as ethyl-3,3-dimethyl-2,3-dihydro-1H-benzo[f]chromene-1-carboxylate was also obtained in 68% yield (20). After the simple esterification, drug molecules, such as clofibric acid, fenofibric acid and ciprofibrate, could be transformed into the corresponding N-hydroxyphthalimide esters, further engaging with ethyl acrylate (10 and 24–25), which highlighted the synthetic applicability of this protocol.Open in a separate windowScheme 2Reactions of NHPI esters with ethyl acrylate. Standard conditions: NHPI ester (0.2 mmol), ethyl acrylate (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield.Next, we shifted attention to the scope with respect to a wide range of acrylates, as shown in Scheme 3. Methyl acrylate and butyl acrylate were well amenable with N-hydroxyphthalimide esters (26–27). Other acrylates, such as cyclohexyl, tert-butyl and phenyl, were also competent reaction partners with a satisfactory efficiency (28–30). Ethyl (E)-but-2-enoate was tolerant to afford the desired chroman product, albeit in 29% yield (31). It is particularly noteworthy that dimethyl maleate was demonstrated to be a suitable substrate, leading to the formation of sterically hindered product (32). The sensitive benzylic C–H bond and the fragile furan and thiophene moieties could be retained in the radical cascade reaction, providing a series of functionalized chromans (33–35). Alkoxy and aligned alkoxy on substances did not reduce the reaction efficacy (36–37). Chromans possessing various subtle trimethylsilyl, hydroxyl, primary/secondary bromoalkene, cyano and thiomethylene were accessed in reasonable yields, which provided the basis for late-stage derivatization of products (38–41, 43). Owing to the superiority of lipophilicity, permeability and metabolism, we tried to introduce trifluoromethyl into chroman skeletons. To our delight, 2,2,2-trifluoroethyl acrylate gave rise to the corresponding chromans with 52% yield (42). The unactivated alkynyl moiety and alkenyl moiety survived in the photoredox catalysis (44–46).Open in a separate windowScheme 3Reactions of A with various olefins. Standard conditions: A (0.2 mmol), olefin (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield.It is well-known notorious that compounds possessing nitrogen atoms are a very important class of biologically active and functional molecules. Thus, we turned our attention from acrylates to acrylamide derivatives. We were delighted to find that N,N-dimethylacrylamide was a suitable radical receptor to give the target molecule in moderate yield (47). Similarly, a series of chroman products were obtained with cyclic and acyclic acrylamides (48–51). Subsequently, we continued to investigate the reaction of different secondary acrylamides with N-hydroxyphthalimide ester A. These secondary acrylamides bearing NH-isopropyl, -cylopropyl, -benzyl, -phenylethyl and -aryl functionalities, could smoothly be transformed into the desired (4 + 2) annulation products under standard conditions (52–57). Besides acrylates and acrylamides, this method was successfully applied to other Michael acceptors resulting in the synthesis of various functionalized chromans (58–61). In order to demonstrate the potential applicability of this methodology, a variety of natural products, their derivatives and functional molecules, such as isoborneol (62), cedrol (63), citronellol (64), cholesterol (65), and dehydroabietylamine (66), were examined, and all these structures could be embedded into target products in 56–70% yields.The (4 + 2) annulation protocol is not limited to the synthesis of chromans. Under standard conditions, the thiochromane derivative could be formed, although less efficiently (Scheme 4a). With curiosity, we tried to use the commercially available pinacol vinylboronate instead of acrylates for this transformation because of the widespread use of organoboron compounds in organic synthesis. The target compound 2-(2,2-dimethylchroman-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, which is a versatile building block in functionalization of chromans, was obtained in 48% yield under the slightly revised conditions (Scheme 4b). It is noting that the reaction could be conducted smoothly to afford 60% yield under sunlight irradiation, showing the potential of industrial application (Scheme 4c). Furthermore, the versatility of chroman 1 was also explored. The oxidative dehydrogenation process of 1 led to the formation of value-added ethyl 2,2-dimethyl-2H-chromene-4-carboxylate 69 by using DDQ as the oxidant (Scheme 4d). 1 could also be reduced to (2,2-dimethylchroman-4-yl)methanol 70 with lithium aluminum hydride in ethyl ether (Scheme 4d).Open in a separate windowScheme 4The synthetic applications. (a) The synthesis of thiochromane. (b) Pinacol vinylboronate as a substrate. (c) Sunlight condition. (d) The derivatization of products.To further gain mechanistic insights into this process, a series of experiments were conducted. When the model reaction was performed under standard conditions but in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a radical scavenger, the target product was not detected (Scheme 5a). Notably, when butylated hydroxytoluene (BHT) was added to this reaction system, the annulation reaction was significantly suppressed, meanwhile, a coupling product was detected by GC-MS and HRMS (Scheme 5b). These results indicated a radical-involved pathway for this transformation. Subsequently, the carbon radical was captured by an intramolecular aromatic ring, giving the cyclization product 69 in excellent yield (Scheme 5c). Moreover, the intermolecular kinetic isotope effect (KIE) experiment was carried out by using A and A-d5 as competitive substrates. Under standard conditions, a KIE value of 1.05 was observed, indicating that the cleavage of the aromatic C–H bond might not be the rate-determining step in the transformation (Scheme 5d).Open in a separate windowScheme 5The control experiments. (a) The addition of TEMPO. (b) The addition of BHT. (c) Intramolecular reaction. (d) KIE experiment.On the basis of the above experimental results, we proposed a possible mechanism cycle for the reaction, as shown in Scheme 6. Initially, the photocatalyst Eosin Y (EY) was transformed into the excited species EY* (E_1/2[EY˙⁺/EY*] = −1.1 V vs. SCE) under the irradiation with visible light. As a redox-active species, EY* was able to reduce N-hydroxyphthalimide ester (E_1/2[A/I] = −0.8 V, see the CV in the ESI^†) via a single-electron-transfer (SET) process, generating the EY˙⁺ radical cation and the corresponding N-hydroxyphthalimide ester radical anion I. The intermediate I underwent rapid homolytic fragmentation to generate carbon-centered nucleophilic radical II by releasing the phthalimide anion and carbon dioxide. Subsequently, the carbon radical II was captured by ethyl acrylate to form the electrophilic radical III, which underwent rapid intramolecular radical cyclization to afford aryl radical IV. Then, the intermediate IV was converted into cation Vvia a SET oxidation. On the other hand, the EY˙⁺ radical cation was transformed into Eosin Y to accomplish the photocatalytic cycle. The rapid deprotonation of V leads to the formation of the product 1.Open in a separate windowScheme 6Proposed reaction mechanism.     

Hypervalent iodine-mediated β-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution

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 carriers^6a–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) boronates^8a–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

Hydroxy-directed fluorination of remote unactivated C(sp3)–H bonds: a new age of diastereoselective radical fluorination

We report a photochemically induced, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity in this burgeoning field. Numerous simple and complex motifs showcase a spectrum of regio- and stereochemical outcomes based on the configuration of the hydroxy group. Notable examples include a long-sought switch in the selectivity of the refractory sclareolide core, an override of benzylic fluorination, and a rare case of 3,3′-difluorination. Furthermore, calculations illuminate a low barrier transition state for fluorination, supporting our notion that alcohols are engaged in coordinated reagent direction. A hydrogen bonding interaction between the innate hydroxy directing group and fluorine is also highlighted for several substrates with ¹⁹F–¹H HOESY experiments, calculations, and more.

We report a photochemical, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity. Numerous motifs showcase a range of regio- and stereochemical outcomes based on the configuration of the hydroxy group.

The hydroxy (OH) group is treasured and versatile in chemistry and biology.¹ Its ubiquity in nature and broad spectrum of chemical properties make it an attractive source as a potential directing group.² The exploitation of the mild Lewis basicity exhibited by alcohols has afforded several elegant pathways for selective functionalization (e.g., Sharpless epoxidation,³ homogeneous hydrogenation,⁴ cross-coupling reactions,⁵ among others⁶). Recently, we reported a photochemically promoted carbonyl-directed aliphatic fluorination, and most notably, established the key role that C–H⋯O hydrogen bonds play in the success of the reaction.⁷ Our detailed mechanistic investigations prompt us to postulate that other Lewis basic functional groups (such as –OH) can direct fluorination in highly complementary ways.⁸ In this communication, we report a hydroxy-directed aliphatic fluorination method that exhibits unique directing properties and greatly expands the domain of radical fluorination into the less established realm governing high diastereoselectivity.⁹Our first inclination that functional groups other than carbonyls may influence fluorination regiochemical outcomes was obtained while screening substrates for our published ketone-directed radical-based method (Scheme 1).^8a In this example, we surmised that oxidation of the tertiary hydroxy group on substrate 1 cannot occur and would demonstrate functional group tolerance (directing to C11, compound 2). Surprisingly, the two major regioisomers (products 3 and 4) are derivatized by Selectfluor (SF) on C12 and C16 – indicative of the freely rotating hydroxyl directing fluorination. Without an obvious explanation of how these groups could be involved in dictating regiochemistry, we continued the mechanistic study of carbonyl-directed fluorination (Scheme 2A). We established that the regioselective coordinated hydrogen atom abstraction occurs by hydrogen bonding between a strategically placed carbonyl and Selectfluor radical dication (SRD).⁷ However, we noted that the subsequent radical fluorination is not diastereoselective due to the locally planar nature of carbonyl groups. Thus, we posed the question: are there other directing groups that can provide both regio- and diastereoselectivity? Such a group would optimally be attached to a sp³ hybridized carbon; thus the “three dimensional” hydroxy carbon logically comes to mind as an attractive choice, and Scheme 1 illustrates the first positive hint.Open in a separate windowScheme 1Observed products for the fluorination of compound 1.Open in a separate windowScheme 2(A) Proposed mechanism, (B) β-caryophyllene alcohol hypochlorite derivative synthetic probe, (C) isodesmic relation of transition states showing the general importance of the hydroxy group to reactivity (ωB97xd/6-31+G*), and (D) ¹H NMR experiment with Selectfluor and various additives at different concentrations.We began our detailed study with a simple substrate that contains a tertiary hydroxyl group. Alcohol 5 was synthesized stereoselectively by the reaction of 3-methylcyclohexanone, FeCl₃, and 4-chlorophenylmagnesium bromide;¹⁰ the 4-chlorophenyl substituent allows for an uncomplicated product identification and isolation (aromatic chromophore). We sought to determine optimal reaction conditions by examination of numerous photosensitizers, bases, solvents, and light sources (7 Although we utilize cool blue LEDs (sharp cutoff ca. 400 nm), CFLs (small amount of UVB (280–315 nm) and UVA (315–400 nm)) are useable as well.¹¹ A mild base additive was also found to neutralize adventitious HF and improve yields in the substrates indicated ( EntrySensitizer ¹⁹F yield1None0% 2 Benzil 83% 3Benzil, no base63%4Benzil, K₂CO₃68%5Benzil, CFL light source75%65-Dibenzosuberenone15%74,4′-Difluorobenzil63%89,10-Phenantherenequinone71%9Perylene8%10Methyl benzoylformate42%Open in a separate window^aUnless stated otherwise: substrate (0.25 mmol, 1.0 equiv.), Selectfluor (0.50 mmol, 2.0 equiv.), NaHCO₃ (0.25 mmol, 1.0 equiv.), and sensitizer (0.025 mmol, 10 mol%) were dissolved in MeCN (4.0 mL) and irradiated with cool white LEDs for 14 h.Substrate scope^a

Electrification of a Milstein-type catalyst for alcohol reformation

Novel energy and atom efficiency processes will be keys to develop the sustainable chemical industry of the future. Electrification could play an important role, by allowing to fine-tune energy input and using the ideal redox agent: the electron. Here we demonstrate that a commercially available Milstein ruthenium catalyst (1) can be used to promote the electrochemical oxidation of ethanol to ethyl acetate and acetate, thus demonstrating the four electron oxidation under preparative conditions. Cyclic voltammetry and DFT-calculations are used to devise a possible catalytic cycle based on a thermal chemical step generating the key hydride intermediate. Successful electrification of Milstein-type catalysts opens a pathway to use alcohols as a renewable feedstock for the generation of esters and other key building blocks in organic chemistry, thus contributing to increase energy efficiency in organic redox chemistry.

Electrification of the Milstein catalyst enabled successful molecular electrocatalytic oxidation of ethanol to the four-electron products acetate and ethyl acetate.

In order to achieve the goals of the Sustainable Development Scenario (SDS) of the International Energy Agency, the chemical industry''s emission should decline by around 10% before 2030.^1,2 This could be achieved by increasing energy efficiency and the usage of renewable feedstocks. In this respect, molecular electrocatalytic alcohol oxidation could be powerful tool by potentially providing energy and atom efficiency for organic synthesis and energy applications.^2–7 Besides the use of aminoxyl-derivatives,^8–13 especially the seminal work of Vizza, Bianchini and Grützmacher demonstrated that (transfer)-hydrogenation (TH) catalysts could be activated electrochemically and used in a so-called “organometallic fuel cell”.¹⁴ Other TH systems are however mostly limited to two electron oxidations of secondary or benzylic alcohols (Scheme 1A).^15–21Open in a separate windowScheme 1(A) Advantages/limitation of electrochemical homogeneous alcohol oxidation using well-defined catalysts. (B) Current efforts to electrify acceptor-less alcohol dehydrogenation (AAD) systems due to their large range of application in thermal catalysis.As an exception, Waymouth et al. recently reported an example of the intramolecular coupling of vicinal benzylic alcohols to the corresponding esters.^19,22 In order to extend the range of possible catalysts candidates, the Waymouth group recently also explored the possibility to use an iron-based acceptor-less alcohol dehydrogenation (AAD) catalysts²³ for electrocatalytic alcohol oxidation (Scheme 1B).²⁴ The stability under electrochemical conditions in this case is limited to <2 turnovers, but it opens the door to explore a wide range of AAD reactions under electrochemical conditions. Here, we demonstrate that a commercially available Milstein-type AAD catalyst (1)²⁵ is competent for the electrocatalytic alcohol oxidation of ethanol to ethyl acetate and acetate (Scheme 1B).The cyclic voltammogram (CV) of complex 1 (Fig. 1) shows a quasi-reversible diffusive one electron oxidation wave at 0.2 V (all potentials are referenced vs. Fc⁺/Fc⁰) in 0.2 M NaPF₆ THF/DFB (2 : 1) (DFB = 1,2 difluoro benzene) assigned to the Ru(ii)–Ru(iii) couple (see ESI, section 2.2^†). The addition of 1 to a 10 mM sodium ethoxide (NaOEt) solution in 200 mM ethanol (EtOH) in 0.1 M NaPF₆ (2 : 1 THF/DFB) gives rise to several waves at ca. −0.5, 0.0 and 0.2 V with currents significantly higher than in the absence of catalysts or substrate, indicative of possible catalytic turnover (Fig. 2). Gradual increase of the EtOH concentration from 200 mM to 1 M is accompanied by the disappearance of the first wave at −0.5 V, while a new oxidation wave appears at ca. −0.25 V (Fig. 2, light to dark green traces).Open in a separate windowFig. 1Scan rate dependence of a 1 mM solution of 1 in in 2 : 1 THF/DFB + 0.2 M NaPF6 (from light to dark green: 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5 V s⁻¹, 3 mm GC electrode). Inset: evolution of the peak current as a function of the square root of the scan rate.Open in a separate windowFig. 2CVs of 10 mM NaOEt (grey) and of 5 mM 1 + 5 mM NaOEt with increasing concentrations of EtOH (from light to dark green: 200, 400, 600, 800 and 1000 mM) in 2 : 1 THF/DFB + 0.2 M NaPF₆. Scan rate 0.1 V s⁻¹, electrode: 3 mm diameter GC electrode.Increasing the base loading gradually from 5 to 20 mM yields a stark increase of current at this new wave at ca. −0.25 V (Fig. 3). Using (TBA)PF₆ instead of NaPF₆ (used to avoid Hofmann-elimination²⁶) gave similar results (see ESI, section 2.2–2.5 and section 4^†). In order to assess catalytic turnover under preparative conditions, controlled potential electrolysis (CPE) was performed. CPE experiments were run in pure ethanol (to reduce cell resistance) in the presence of 0.1 M electrolyte of well soluble bases (e.g. NaOEt, LiOH, see ESI section 4^†). CPE in 0.1 M LiOH with 1 mM 1 at E = 0 V vs. Fc^0/+ delivered ca. 15 mM of acetate and 6 mM of ethyl acetate, corresponding to 21 turnovers (per 4 electrons, or 42 turnovers per two electrons) and a faradaic efficiency (FE) of ca. 62% (see ESI section 4.3^†). In the absence of applied potential (OCP, open circuit potential), no ethyl acetate was formed (see ESI, section 4.4^†). Likewise, in the absence of catalyst, the passed charge was significantly lower (7C vs. 40C) with no detected formation of ethyl acetate. The low FE could be due to catalyst degradation, as Ru-nanoparticle formation is observed on the electrode post CPE (confirmed by SEM/Elemental mapping, see ESI section 5^†). Noteworthy, rinse-test CPE and a CPE using a simple Ru-precursor, RuCl₃, did not show any ethyl acetate formation and gave similar results to blank experiments, indicating that Ru-nanoparticles are probably not the active catalyst species and that catalyst instability could be responsible for low FE. Further studies are underway to fully understand catalyst speciation under preparative conditions (see ESI section 4.7^†) the observed catalytic activity of 1 compares well in terms of TON and product selectivity with other molecular homogeneous TH systems, with most systems being limited to the two-electron oxidation of secondary or benzylic alcohols. The Waymouth group reported a NNC ruthenium pincer for the oxidation of isopropanol to acetone with a TON of 4.¹⁸ The same group reported on the usage of phenoxy mediators with an iridium pincer complex, reaching a TON of 8 for the same reaction.²² Bonitatibus and co-workers demonstrated the activity of an iridium-based systems with a TON of 32 for the formation of p-benzaldehyde.¹⁷ Appel and co-workers reported on a nickel (TON = 3.1)¹⁵ and a cobalt triphos systems (TON = 19.9)¹⁶ for benzaldehyde formation from benzyl alcohol. To the best of our knowledge, there is only one acceptor-less alcohol dehydrogenation (AAD) catalyst that has been activated electrochemically so-far,²⁴ generating acetone with a TON <2. Only a handful of molecular systems are known to catalyze the electrochemical four electron alcohol reformation to esters, however at significantly higher potentials (1.15 V vs. Fc⁺/Fc⁰).^2,27,28 Thus, although not designed for electrochemical applications, 1 shows high activity for the challenging 4 electron oxidation of aliphatic substrates.Open in a separate windowFig. 3CV of 5 mM NaOEt (grey), 5 mM of 1 + 1 M EtOH with varying concentrations of base (5, 10, 15, and 20 mM NaOEt, light to dark green) in 2 : 1 THF/DFB + 0.2 M NaPF₆. Scan rate 0.1 V s⁻¹, electrode: 3 mm diameter GC electrode.To achieve the transposition from thermal to electrochemical TH, both Grützmacher et al. and Waymouth took advantage of a fast equilibrium between the alcohol substrate and a metal hydride intermediate that could be readily oxidized. The chemistry of ruthenium pincer AAD systems is well studied (Scheme 2)^25,29–33 and allows for a putative assignment of the observed CV-behavior. In the presence of excess base and alcohol (Fig. 2 and ​and3),3), 1 is expected to yield dearomatized complex 2,²⁵ as well as the alkoxide species 3.^25,32 We might therefore assign the first wave at −0.5 V to the oxidation of dearomatized complex 2 and the wave around 0 V to the oxidation of the alkoxide complex 3. Indeed, independently synthesized samples of 2 and 3 (in the presence of excess ethanol) give rise to oxidation half-waves at −0.45 V and −0.1 V respectively (see ESI, section 3 and 5.2^†). This is also in agreement with the observed behavior upon increasing the alcohol concentration with the expected consumption of dearomatized species 2 and concomitant disappearance of the first oxidation wave at −0.5 V. The equilibrium between 2, 3 and 4 has been reported³² and addition of excess ethanol to 2 is thus not only generating 3, but also is expected to deliver 4 (Scheme 2). The appearance of a new anodic wave at ca. −0.25 V (Fig. 2) is thus attributed to the increasing formation of 4 upon addition of larger amounts of EtOH. Complex 4 is relatively unstable in solution,^25,32,33 and decomposes in the presence of electrolyte (see ESI section 3.1^†). DFT calculations were thus used to predict its oxidation potential (see ESI, section 6^†), which was in reasonable agreement with the observed wave (−0.19 V). The DFT calculations also confirmed the assignment of the other waves related to the dearomatized complex 2 (−0.33 V) and the ethoxide species 3 (−0.1 V). A more detailed mechanistic analysis remains currently hampered by the chemical instability of 4 under the employed reaction conditions, as well as difficulties to isolate 3 in the solid state (limiting kinetic measurements). DFT calculations were thus used to get a better view on possible reaction pathways (Schemes 2, ​,33 and ESI section 6.3^†). The oxidation of 4 at −0.19 V (DFT) yields the radical cation 5, with a calculated pK_a in THF of 8.2. In the presence of NaOEt, 5 should thus deprotonate readily to give radical 6, which has an extremely negative oxidation potential of −2.1 V. At the potential it is generated, 6 should thus directly be oxidized to cationic complex 7. This cationic species 7 has a calculated pK_a of 22.7 in THF, which is in good agreement with experimental data from the Saouma group on a similar system.²⁶ The high pK_a of 7 in THF also validates the need for a strong base (e.g. NaOEt) to reform dearomatized 2. Both Grützmacher and co-workers,¹⁴ as well as Waymouth²⁴ have noted that the accelerating effect during electrocatalysis stems from the oxidation of a metal hydride intermediate that is generated by fast chemical steps. In order to verify this hypothesis and to exclude an electrochemical activation of this hydride formation step, transition state barriers were computed (Scheme 3). Taking the dearomatized complex 2 as a reference point, a first step will form the alkoxide species 3 (TS₀ = 21.2 kcal mol⁻¹). Oxidizing 2 to 8 slows down the formation of the alkoxide species (T_S0^ox = 27.5 kcal mol⁻¹), most-likely due to decreased basicity of the ligand. From the alkoxide species 3 dihydride 4 is formed via a linear, charge-separated transition state TS₁ (15.7 kcal mol⁻¹). The role of such linear transition states was highlighted recently in the case of ruthenium pincer catalysis for alcohol oxidation.^34–37 In principle, it might be envisioned that the oxidation of the metal center could be an additional driving force for this hydride abstraction step. However, after oxidation, the energy span^38,39 rises by about 11 kcal mol⁻¹ (TS₁^ox = 24.7 kcal mol⁻¹). Likewise, a beta-hydride elimination via side-arm opening is not accelerated either by oxidation (TS₂^ox = 37.5 kcal mol⁻¹, see ESI section 6.4^†). It thus seems that the generation of 4 is not accelerated by electron transfer steps and relies on a thermally activated chemical step. Importantly, alkoxide solutions were shown to be excellent hydride donors electrochemically, further corroborating that under the employed basic conditions, generation of 4 from 3 should be fast.⁴⁰ Oxidation of 4 to 5 also doesn''t accelerate thermal intramolecular release of H₂ (TS_3B^ox = 37.5 kcal mol⁻¹), which is significantly higher than neutral thermal H₂-releasing states (TS_3A and TS_3B). The experimentally observed acceleration via electron-transfer is thus proposed to follow a classical ECEC mechanism initiated by the oxidation of 4 to 5 (at roughly −0.19 V (DFT)), followed by deprotonation and re-oxidation as described above, finally delivering 2 at the electrode surface. Importantly, at the electrode surface 2 and 3 should be oxidized at the employed potentials, but based on DFT-calculations, these pathways are thought to be non-productive (Scheme 3) and could explain the low catalyst life-time and degradation under electrochemical conditions.Open in a separate windowScheme 2Reactivity of pyridine-based ruthenium complexes via dearomatization/aromatization, as well as DFT-based.Open in a separate windowScheme 3DFT-calculated energy landscape for the neutral (black dotted lines and bars) and cationic surface (blue dotted lines and bars) of ethanol dehydrogenation starting from 2 or its cationic analogue 8.     

Ruthenium pincer complex-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides: substrate keeps the catalyst active

The electron pair of the heteroatom in heterocycles will coordinate with metal catalysts and decrease or even inhibit their catalytic activity consequently. In this work, a pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed. Benefitting from the pincer ligand, a variety of heterocycles, such as thiophenes, morpholine, unprotected indoles, pyrrole, pyridine, pyrimidine, furan, thiazole, pyrazole, benzothiadiazole, and triazole, are compatible here.

A pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed.

Since the pioneering work on the catalytic alkoxycarbonylation of unactivated alkyl halides reported by Heck and Breslow in 1963,¹ this transformation has attracted a great deal of interest due to its modularity and the direct employment of CO as a cheap and abundant C1 feedstock.² However, compared with aryl halides, the development of alkoxycarbonylation of alkyl halides has been much more gradual.^2,3 This situation is due to both the slow oxidative addition of C(sp³)–X bonds to the metal center and the easy β-hydride elimination of the alkyl-metal intermediate, particularly in the presence of carbon monoxide.⁴ Several catalytic systems for this process have been successfully developed in recent years (Scheme 1A), such as pure radical-based systems,⁵ palladium-based systems,⁶hν/palladium-based systems,⁷ rhodium-based systems,⁸ copper-based systems,⁹ and other metal carbonyl complex-based systems.¹⁰ Very recently, Neumann, Skrydstrup, and co-workers reported a nickel pincer-mediated alkoxycarbonylation for complete carbon isotope replacement, and this approach provided a procedure for generating carbon-labeled versions of potential simple carboxylate prodrug derivatives (Scheme 1B).¹¹ Besides their advantages, in these cases the heterocycles, particularly those containing multiple N atoms or NH groups, are hardly compatible, which is considered as a remaining challenge. We attribute this to the Lewis-basic atoms in heterocyclic motifs being particularly detrimental to catalyst activity and potentially quenching the radical intermediates.¹² Indeed, the development of heterocycle compatible catalytic systems remains an exciting task in the field of alkoxycarbonylation.Open in a separate windowScheme 1Approaches to alkoxycarbonylation of alkyl halides.On the other hand, heterocycles constitute important structural components of biologically active compounds and are ubiquitous in agrochemical and pharmaceutical industries.¹³ In a recent survey, 88% of small molecule drugs approved by the FDA between 2015 and June 2020 were found to contain at least one N-heterocycle.¹⁴ Specifically, heterocyclic subunits can modify the solubility, lipophilicity, polarity and hydrogen bonding ability of biologically active agents, thereby optimizing the corresponding ADME/Tox (absorption, distribution, metabolism, excretion, and toxicity) properties of drugs or drug candidates.¹⁵ Under this premise, the pursuit of new synthetic methods with good heterocycle compatibility is a worthwhile endeavor.Herein we report a heterocycle compatible catalytic system for alkoxycarbonylation of alkyl iodides. With a ruthenium pincer complex as the catalyst, the tight coordination of the pincer ligand can effectively prevent the ruthenium from deactivation by heterocycle coordination (Scheme 1C). To the best of our knowledge, this is the first example of a ruthenium pincer complex-catalyzed carbonylation reaction.¹⁶ This new catalytic system might lead to novel synthetic routes toward heterocyclic carbonyl-containing compounds.Pincer complexes of ruthenium are among the most effective catalysts for hydrogen transfer reactions between alcohols and unsaturated compounds.¹⁷ We initially used it to attempt the carbonylative coupling of acetophenone with iodobutane, as shown in eqn (1). Although we did not get the desired product I, the ester II could be obtained in 22% yield. By literature survey, we found there was no example showing that alkyl halides could be activated by ruthenium in previous reports on carbonylation reactions.^3,16,18 We thus envisioned that the ruthenium pincer complex played a key role in this transformation.^11,191With this discovery in mind, we started the investigation of this ruthenium-catalyzed alkoxycarbonylation of alkyl halides by examining the reaction of (3-iodopropyl)benzene (1) with isopropanol (2) at 100 °C under a CO atmosphere (10 bar) in the presence of a catalytic amount of various readily available ruthenium pincer complexes (†). The improved yield of the desired product 3 was obtained when utilizing Milstein''s catalyst Ru-2²⁰ (21 were applied in the reaction; however, the selectivity obtained was unsatisfactory (eqn (2), when we removed isopropanol from the reaction, byproduct 2 which was produced by carbonylative homocoupling of the alkyl halide could be obtained in 71% yield.²² However, the reduced conversion and the absence of byproduct 3 implied that the alcohol plays more than a nucleophile role in this reaction. It is important to mention that the addition of water had no effect on the yield of byproduct 2. Concerning the effects from bases, organic bases, such as NEt₃ and DBU, were tested, but no desired ester could be detected. Inorganic bases, including K₂CO₃ and K₃PO₄, were also tested, but very low yield of the ester was obtained. Notably, comparable yield of ester 3 can be obtained when LiO^tBu was used as the base.2Optimization of the alkoxycarbonylation of 1^a

Oxindole synthesis via polar–radical crossover of ketene-derived amide enolates in a formal [3 + 2] cycloaddition

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates. Various easily accessible N-alkyl and N-arylanilines are added to disubstituted ketenes and the resulting amide enolates undergo upon single electron transfer oxidation a homolytic aromatic substitution (HAS) to provide 3,3-disubstituted oxindoles in good to excellent yields. A variety of substituted anilines and a 3-amino pyridine engage in this oxidative formal [3 + 2] cycloaddition and cyclic ketenes provide spirooxindoles. Both substrates and reagents are readily available and tolerance to functional groups is broad.

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates.

Oxindoles, in particular the 3,3-disubstituted congeners, are highly valuable substructures in medicinal chemistry. The oxindole core can be found in various biologically active compounds, that are for example used in the treatment of cancer or as antibacterial agents.¹ In addition, the oxindole moiety also occurs in several complex natural products.² The first oxindole synthesis was reported by Baeyer and Knop in 1866.³ That time, isatin was converted by sodium amalgam reduction to the corresponding oxindole. Since then, many methods for the preparation of 3,3-disubstituted oxindoles have been developed that proceed via functionalization of a pre-existing oxindole core.⁴ In addition, methods for the construction of 3,3-disubstituted oxindoles starting from acyclic precursors have also been introduced.^5,6 Along these lines, transition metal-mediated reactions^5,7 or homolytic aromatic substitutions (HAS)^8–14 have found to be highly efficient for the construction of the oxindole core. Focusing on the latter approach, the intramolecular HAS proceeds via α-carbonyl radicals derived from radical addition to N-arylacrylamides,⁸ reduction of α-haloarylamides⁹ or oxidation of the corresponding enolates^10–14 (Scheme 1a).Open in a separate windowScheme 1Selected strategies for the synthesis of oxindoles.In 2017, the group of Taylor developed a transition metal-free enolate oxidation-HAS-approach towards oxindoles at low temperature using elemental iodine as the oxidant and malonic acid derived N-aryl amides as substrates which are readily deprotonated.¹⁴The unique reactivity of ketenes¹⁵ has been explored extensively,¹⁶ especially in [2 + 2]-cycloadditions.¹⁷ Moreover, Staudinger,¹⁸ Lippman¹⁹ and Taylor²⁰ showed that ketenes react with aryl nitrones in a tandem [3 + 2]-cycloaddition-[3,3]-sigmatropic-rearrangement cascade²¹ followed by hydrolysis to provide oxindoles (Scheme 1b). The use of chiral nitrones leads to chirality transfer and enantiomerically enriched oxindoles can be obtained via this approach.^21,22 In contrast to the examples discussed in Scheme 1a, two σ-bonds are formed and the overall sequence can be regarded as a formal [3 + 2] cycloaddition. Despite good yields and high enantiomeric excess, nitrones have to be used as precursors and an aldehyde is formed as the byproduct diminishing reaction economy of these elegant cascades.To address these drawbacks, we decided to use the nucleophilic addition^23–26 of deprotonated anilines to ketenes for the generation of the corresponding amide enolates that should then be oxidized in a single electron transfer process to α-amide radicals which can undergo a homolytic aromatic substitution providing direct access to sterically challenging 3,3-disubstituted oxindoles in a straightforward one-pot sequence (Scheme 1c). This polar–radical crossover reaction shows high atom economy and as the reaction with the nitrones can also be regarded as a formal [3 + 2] cycloaddition.We initiated the optimization study with N-methylaniline 1a and ethyl phenyl ketene 2a, which was prepared in an easy and scalable one-pot protocol starting from the corresponding carboxylic acid, as model substrates. Deprotonation of 1a with n-BuLi in THF and subsequent addition to the ketene 2a led to desired Li-enolate which was confirmed by protonation with water and isolation of the amide 4aa (56%). Pleasingly, addition of ferrocenium hexafluorophosphate (FcPF₆, 2.2 equiv.) at room temperature to the Li-enolate afforded the desired oxindole 3aa in 29% yield (14 Light does not appear to play a crucial role in this transformation, as performing the reaction in the dark does not have a significant effect on the reaction outcome ( EntryBaseConc. (M)Oxidant (equiv.)Yield 3aa (%)^b1 n-BuLi0.1FcPF₆ (2.2)29 (18)^c2^d n-BuLi0.1CuCl₂ (2.2)34^c3 n-BuLi0.1I₂ (2.2)41^c4EtMgBr0.1I₂ (2.2)44^c5EtMgBr0.02I₂ (2.2)78 6 EtMgBr 0.01 I ₂ (2.2) 90 (82) ^c 7EtMgBr0.01I₂ (1.2)258EtMgBr0.01NIS^e (2.2)399EtMgBr0.01I₂ (1.2)^f8010EtMgBr0.01I₂ (2.2)^g8211EtMgBr0.01I₂ (2.2)^h7412EtMgBr0.01I₂ (2.2)ⁱ93Open in a separate window^aReactions (0.20 mmol) were conducted under argon atmosphere.^{b 1}H NMR yield using 1,3,5-trimethoxybenzene as internal standard.^cIsolated yield.^dStep 1 and 2 were conducted at 0 °C.^e N-Iodosuccinimide.^fIodine addition at −78 °C, then slowly allowed to warm to room temperature.^14gIn the dark.^hIrradiation with blue LED (40 W, 467 nm, rt, 8 h).ⁱRefluxing THF for step 3, reaction completed within 2 h.With the optimized reaction conditions in hand, we investigated the scope by first varying the R¹-substituent at the N-atom using the ketene 2a as the reaction partner (Scheme 2). In general, increasing the steric bulk at the nitrogen leads to diminished yields of the targeted oxindoles. The lower yields go along with the formation of a larger amount of the corresponding α,β-unsaturated amide side product 5. Thus, as compared to the parent N-methyl derivative, all other N-alkyl derivatives were formed in lower yields (49%, 3ab; 35%, 3ac; 49%, 3ad). The N-benzyl protected oxindole 3af and the N-phenyl oxindole 3ae were isolated in 54% and 56% yield, respectively. Next, a diastereoselective oxindole synthesis was attempted using chiral anilines 1g and 1h. Surprisingly, despite the bulkiness of these nucleophiles containing styryl-type N-substituents, good yields were obtained for the oxindoles 3ag and 3ah (73–79%). Unfortunately, diastereocontrol was low in both cases (1.9 : 1 d.r. and 1.5 : 1 d.r.). Of note, addition of Mg-1g and Mg-1h to ketene 2a was rather slow under the standard reaction condition and a significant amount of unreacted aniline was recovered. That problem could be solved by prolonging the reaction time of both step 1 (deprotonation) and also step 2 (Mg-enolate formation).Open in a separate windowScheme 2Substrate scope – variation of substituents at the nitrogen. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a For step 1 and 2 reaction time was 1 h.Next, the substrate scope was investigated by using different anilines in combination with the ketene 2a (Scheme 3). N-Methyl-p-toluidine 1i and N-methyl-p-haloanilines 1j–m could be successfully transformed to the corresponding oxindoles 3al–am in moderate to good yields (53–87%). Electron-withdrawing and also electron-donating substituents are tolerated and oxindoles derived from p-cyano- (3an, 92%), p-acetyl- (3ao, 30%), p-methoxycarbonyl- (3ap, 82%) and p-methoxy- (3aq, 71%) anilines were isolated in moderate to excellent yields documenting a high functional group tolerance of this reaction. The meta-methyl aniline afforded oxindole 3ar in 76% yield as a 1.8 : 1 mixture of the two regioisomers (only the major isomer drawn). For the pyridyl derivative 3as, a lower yield was obtained (39%), but reaction occurred with complete regiocontrol. Of note, ortho-methyl N-methylaniline provided the corresponding oxindole only in trace amounts (not shown).Open in a separate windowScheme 3Substrate Scope – variation of anilines and ketenes. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a Isolated as an inseparable mixture (1 : 1.4) with the protonated enolate 4fa (56% combined yield).The ketene component was also varied using N-methylaniline 1a as the reaction partner. The transformation of methyl phenyl ketene 2b provided the oxindole 3ba in 58% yield. p-Bromophenyl ethyl ketene 2c and p-iodophenyl ethyl ketene 2d afforded the oxindoles 3ca and 3da in good yields (70% and 76%). For the ibuprofene-derived ketene 2e a lower yield was obtained (3ea, 40%) and the bulkier phenyl isopropyl congener 3fa was isolated in 27% yield as an inseparable mixture with the protonated enolate 4fa (56% combined yield). In the latter case, increasing the reaction time did neither lead to a higher yield of 3fa nor to a suppression of the formation of 4fa. The lower yield is likely caused by steric effects. Surprisingly, diphenyl ketene 2g delivered the targeted oxindole 3ga in acceptable 55% yield despite the steric demand of the two phenyl groups and the high stability of the corresponding α-amide radical. Spirocyclic oxindoles are of great interest due to their high pharmaceutical potential.²⁷ We were pleased to find that our method also works for the preparation of such spiro compounds as documented by the successful synthesis of 3ha (26%).Mechanistically, we propose initial formation of the enolate A by nucleophilic attack of the deprotonated aniline to the ketene 2, which is then oxidized by elemental iodine to the α-amide radical B (pathway b). The radical nature of the transformation is supported by the fact that electronic effects on the arene show no influence on the efficiency of the cyclization, as would be shown by a conceivable polar aromatic substitution. Radical B readily cyclizes onto the aniline ring to generate the cyclohexadienyl radical D which is oxidatively rearomatized via cationic intermediate E to finally give the oxindole 3 (Scheme 4).^10–14 Alternatively, enolate A can be iodinated with I₂ to give the unstable iodide C which then undergoes C–I bond homolysis to generate the radical B (pathway a). Indeed, Taylor and coworkers¹⁴ observed under similar reaction conditions the decay of α-iodinated compounds of type Cvia C–I homolysis^14,28 to give radicals of type B. Usually, we observed α,β-unsaturated amides analogous to 5aa as by-products. However, the corresponding protonated enolates were detected only in tiny amounts in most of these cases. This strongly suggests that those amides are not formed via disproportionation of radical B. HI-elimination seems more likely, pointing towards the presence of the iodinated species C and thus the contribution of pathway b to product formation. In addition, dimerization of radical B was also not observed.Open in a separate windowScheme 4Suggested mechanism.To further support pathway b, isolation of the iodinated intermediate C was attempted at low temperature. Upon addition of iodine (1.2 equiv.) to the preformed Mg-enolate A derived from aniline 1a and ketene 2a at −78 °C,¹⁴ TLC analysis showed a clean conversion to a single new compound, which was analyzed by rapid ESI-MS analysis and provided evidence for the formation of the iodinated intermediate C (Scheme 5). However, isolation of this highly unstable compound was not possible due to rapid HI-elimination to the amide 5aa. Note that oxindole formation worked well upon I₂-addition at −78 °C and subsequent warming to room temperature (see Scheme 5). This is consistent with the observation from our optimization studies that irradiation with blue light does not contribute to the yield of oxindole 3aa (Open in a separate windowScheme 5Mechanistic experiments. (a) (1) EtMgBr (1.1 equiv.), rt, 30 min, (2) 2a (1.5 equiv.), −78 °C, 30 min, (3) I₂ (1.2 equiv.), −78 °C, 15 min in THF (0.01 M). (b) Warm to room temperature in THF (0.01 M), 18 h. (c) NaI (1.2 equiv.) in acetone (0.77 M), rt, 18 h. (d) Irradiation with blue LED (40 W, 467 nm) in THF (0.01 M), rt, 8 h.     

Three-component 1,2-carboamination of vinyl boronic esters via amidyl radical induced 1,2-migration

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented. Vinylboron ate complexes generated in situ from the boronic ester and an organo lithium reagent are shown to react with readily available N-chloro-carbamates/carboxamides to give valuable 1,2-aminoboronic esters. These cascades proceed in the absence of any catalyst upon simple visible light irradiation. Amidyl radicals add to the vinylboron ate complexes followed by oxidation and 1,2-alkyl/aryl migration from boron to carbon to give the corresponding carboamination products. These practical cascades show high functional group tolerance and accordingly exhibit broad substrate scope. Gram-scale reaction and diverse follow-up transformations convincingly demonstrate the synthetic potential of this method.

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented.

Alkenes are important and versatile building blocks in organic synthesis. 1,2-Difunctionalization of alkenes offers a highly valuable synthetic strategy to access 1,2-difunctionalized alkanes by sequentially forming two vicinal σ-bonds.^1a–h Among these vicinal difunctionalizations, the 1,2-carboamination of alkenes, in which a C–N and a C–C bond are formed, provides an attractive route for the straightforward preparation of structurally diverse amine derivatives (Scheme 1a).^2a–c Along these lines, transition-metal-catalyzed or radical 1,2-carboaminations of activated and unactivated alkenes have been reported.^3a–p However, the 1,2-carboamination of vinylboron reagents, a privileged class of olefins,^4a–h to form valuable 1,2-aminoboron compounds which can be readily used in diverse downstream functionalizations,^{5a–c,6a–d} has been rarely investigated. To the best of our knowledge, there are only two reported examples, as shown in Schemes 1b and c. In 2013, Molander disclosed a Rh-catalyzed 1,2-aminoarylation of potassium vinyltrifluoroborate with benzhydroxamates via C–H activation (Scheme 1b).⁷ Thus, the 1,2-carboamination of vinylboron reagents is still underexplored but highly desirable.Open in a separate windowScheme 1Intermolecular 1,2-carboamination of alkenes.1,2-Alkyl/aryl migrations induced by β-addition to vinylboron ate complexes have been shown to be highly reliable for 1,2-difunctionalization of vinylboron reagents (Scheme 1c).^4d–h In 1967, Zweifel''s group developed 1,2-alkyl/aryl migrations of vinylboron ate complexes induced by an electrophilic halogenation.⁸ In 2016, the Morken group reported the electrophilic palladation-induced 1,2-alkyl/aryl migration of vinylboron ate complexes.^9a–k Shortly thereafter, we,^10a–c Aggarwal,^11a–c and Renaud¹² developed alkyl radical induced 1,2-alkyl/aryl migrations of vinylboron ate complexes. In these recent examples, the migration is induced by a C-based radical/electrophile, halogen and chalcogen electrophiles.^13a,bIn contrast, N-reagent-induced migration of vinylboron ate complexes proceeding via β-amination is not well investigated. To our knowledge, as the only example the Aggarwal laboratory described the reaction of a vinylboron ate complex with an aryldiazonium salt as the electrophile, but the desired β-aminated rearrangement product was formed in only 9% NMR yield (Scheme 1c).^13a No doubt, β-amino alkylboronic esters would be valuable intermediates in organic synthesis. Encouraged by our continuous work on amidyl radicals^14a–i and 1,2-migrations of boron ate complexes,^{10a–c,15a–f} we therefore decided to study the amidyl radical-induced carboamination of vinyl boronic esters for the preparation of 1,2-aminoboronic esters. N-chloroamides were chosen as N-radical precursors,^16a–c as these N-chloro compounds can be easily prepared from the corresponding N–H analogues.¹⁷ Herein, we present a catalyst-free three-component 1,2-carboamination of vinyl boronic esters with N-chloroamides and readily available alkyl/aryl lithium reagents (Scheme 1d).We commenced our study by exploring the reaction of the vinylboron ate complex 2a with tert-butyl chloro(methyl)carbamate 3a applying photoredox catalysis. Complex 2a was generated in situ by addition of n-butyllithium to the boronic ester 1a in diethyl ether at 0 °C. After solvent removal, the photocatalyst fac-Ir(ppy)₃ (1 mol%) and THF were added followed by the addition of 3a. Upon blue LED light irradiation, the mixture was stirred at room temperature for 16 hours. To our delight, the desired 1,2-aminoboronic ester 4a was obtained, albeit with low yield (26%, EntryPhotocatalystSolventT (°C)Yield^b (%)1 fac-Ir(ppy)₃THFrt262 fac-Ir(ppy)₃DMSOrt23 fac-Ir(ppy)₃MeCNrt564Ru(bpy)₃Cl₂·6H₂OMeCNrt695Na₂Eosin YMeCNrt696^cNa₂Eosin YMeCNrt707^cNoneMeCNrt458^cNoneMeCN0789^cNoneMeCN−2088 (85)10^c,dNoneMeCN−202Open in a separate window^aReaction conditions: 1a (0.20 mmol), ⁿBuLi (0.22 mmol), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar. After vinylboron ate complex formation, solvent exchange to the selected solvent (2 mL) was performed.^bGC yield using n-C₁₄H₃₀ as an internal standard; yield of isolated product is given in parentheses.^c4 mL MeCN was used.^dReaction carried out in the dark.With optimal conditions in hand, we then investigated the scope of this new 1,2-carboamination protocol keeping 2a as the N-radical acceptor (Scheme 2). This transformation turned out to be compatible with various primary amine reaction partners bearing carbamate (4a, 4b and 4d–4g) or acyl protecting groups (4c) (20–85%). Notably, N-chlorolactams can be used as N-radical precursors, as shown by the successful preparation of 4h (71%). Moreover, Boc-protected ammonia was also tolerated, delivering 4i in an acceptable yield (55%).Open in a separate windowScheme 21,2-Carboamination of 1a with various amidyl radical precursors. Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), ⁿBuLi (0.22 mmol, 1.1 equiv.), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar; then [N]-Cl (0.24 mmol, 1.2 equiv.), −20 °C, 16 h, in MeCN (4 mL). Yields given correspond to yields of isolated products. ^aA solution of [N]-Cl (0.30 mmol, 1.5 equiv.) in MeCN (1 mL) was used. See the ESI^† for experimental details.We continued the studies by testing a range of vinylboron ate complexes (Scheme 3). To this end, various vinylboron ate complexes were generated by reacting the vinyl boronic ester 1a with methyllithium, n-hexyllithium, isopropyllithium and tert-butyllithium. For the n-alkyl-substituted vinylboron ate complexes, the 1,2-carboamination worked smoothly to afford 4j and 4k in good yields. However, the vinylboron ate complex derived from isopropyllithium addition provided the desired products in much lower yield (4l, 18% yield). When tert-butyllithium was employed, only a trace of the targeted product was detected (see ESI^†). As expected, cascades comprising a 1,2-aryl migration from boron to carbon worked well. Thus, by using PhLi for vinylboron ate complex formation, the 1,2-aminoboronic esters 4m–4o were obtained in 69–73% yields with the Boc (t-BuOCONClMe), ethoxycarbonyl-(EtOCONClMe) and methoxycarbonyl (Moc)-(MeOCONClMe) protected N-chloromethylamines (for the structures of 3, see ESI^†) as radical amination reagents. Keeping 3b as the N-donor, other aryllithiums bearing various functional groups at the para position of the aryl moiety, such as methoxy (4p), trimethylsilyl (4q), methyl (4r), phenyl (4s), trifluoromethoxy (4t), trifluoromethyl (4u), and halides (4v–4x) all reacted well in this transformation. Aryl groups bearing meta substituents are also tolerated, as documented by the preparation of 4y (81%). To our delight, a boron ate complex generated with a 3-pyridyl lithium reagent engaged in the cascade and the carboamination product 4z was isolated in high yield (82%).Open in a separate windowScheme 3Scope of vinylboron ate complexes. Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), R_MLi (0.22 mmol, 1.1 or 1.3 equiv.), Et₂O or THF, under Ar; then [N]-Cl (0.30 mmol, 1.5 equiv.), −20 °C, 16 h, in MeCN. Yields given correspond to yields for isolated products. See the ESI^† for experimental details.The reason for the dramatic reduction in yield when α-branched alkyllithium or electron-rich aryllithium reagents were used might be that the corresponding vinylboron ate complexes could be oxidized by N-chloroamides via a single-electron oxidation process.^18a–e Furthermore, the α-unsubstituted vinyl boronic ester and vinyl boronic ester bearing various α-substituents are suitable N-radical acceptors and the corresponding products 4aa–4ac were obtained in 48–70% yield.To gain insights into the mechanism of this 1,2-carboamination, a control experiment was conducted. The reaction could be nearly fully suppressed when the reaction was carried out in the presence of a typical radical scavenger (2,2-6,6-tetramethyl piperidine-N-oxyl, TEMPO), indicating a radical mechanism (Scheme 4a). Further, considering an ionic process, the N-chloroamides would react as Cl⁺-donors that would lead to Zweifel-type products, which were not observed under the applied conditions. The proposed mechanism is shown in Scheme 4b. As chloroamides have been recently proposed to undergo homolysis under visible light irradiation,^19a,b we propose that initiation proceeds via homolytic N–Cl cleavage generating the electrophilic amidyl radical A, which then adds to the electron-rich vinylboron ate complex 2a to give the adduct boronate radical B. The radical anion B then undergoes single electron transfer (SET) oxidation with 3a in an electron-catalyzed process^20a,b or chloride atom transfer with 3a to provide C or D along with the amidyl radical A, thereby sustaining the radical chain. Intermediates C or D can then react via a boronate 1,2-migration^10c,11c,21 to eventually give the isolated product 4a.Open in a separate windowScheme 4Control experiment and proposed mechanism.To document the synthetic utility of the method, a larger-scale reaction and various follow-up transformations were conducted. Gram-scale reaction of 2a with 3a afforded the desired product 4a in good yield, demonstrating the practicality of this transformation (Scheme 5a). Oxidation of 4a with NaBO₃ provided the β-amino alcohol 5 in 89% yield (Scheme 5b). The N-Boc homoallylic amine 6 was obtained by Zweifel-olefination with a commercially available vinyl Grignard reagent and elemental iodine in good yield (79%).²² Heteroarylation of the C–B bond in 4a was realized by oxidative coupling of 4a with 2-thienyl lithium to provide 7.²³Open in a separate windowScheme 5Gram-scale reaction and follow-up chemistry.In summary, we have described an efficient method for the preparation of 1,2-aminoboronic esters from vinyl boronic esters via catalyst-free three-component radical 1,2-carboamination. Readily available N-chloro-carbamates/carboxamides, which are used as the N-radical precursors, react efficiently with in situ generated vinylboron ate complexes to afford the corresponding valuable 1,2-aminoboronic esters in good yields. The reaction features broad substrate scope and high functional group tolerance. The value of the introduced method was documented by Gram-scale reaction and successful follow-up transformations.     

Correction: Suppressing carboxylate nucleophilicity with inorganic salts enables selective electrocarboxylation without sacrificial anodes

Correction for ‘Suppressing carboxylate nucleophilicity with inorganic salts enables selective electrocarboxylation without sacrificial anodes’ by Nathan Corbin et al., Chem. Sci., 2021, DOI: 10.1039/D1SC02413B.

We regret that there was a minor error in the structure of the benzyl chloride in Scheme 2, Fig. 2 and the ESI. The structure of the benzyl chloride should be 4-methyl benzyl chloride but was instead given as 3-methyl benzyl. The correct figure and scheme are shown below, and the ESI has been updated.Open in a separate windowFig. 2(A) Comparison of acid yields for non-sacrificial-anode and sacrificial-anode carboxylation of various substrates. (B) Ratio of carboxylic acid to nucleophilic side products (ester + carbonate + alcohol) for various systems and substrates. Effect of adding MgBr₂ to the sacrificial-anode system on the (C) acid yield and (D) ratio of acid to S_N2 side products for benzyl bromide. Acid yields are tabulated in Table S6.† ND: acid not detected (acid-to-S_N2 ratio <0.1).Open in a separate windowScheme 2Substrate scope for the sacrificial-anode-free electrochemical carboxylation of organic halides. ^aStandard reaction conditions: 100 mM electrolyte, 100 mM substrate, 100 mM MgBr₂, silver cathode, platinum anode, 20 sccm CO₂, 2.2 mL DMF, −20 mA cm⁻² for 3.5 h. TBA-Br was used for chlorinated substrates because bromide oxidizes more readily than chloride, and only a small amount of chloride was replaced by bromide (<1% for the alkyl chloride, ∼4% for the benzylic chloride). Yields are referenced to the initial amount of substrate and were calculated from ¹H NMR spectroscopy using either 1,3,5-trimethoxybenzene or ethylene carbonate as internal standards. ^b−15 mA cm⁻² instead of −20 mA cm⁻². ^c150 mM MgBr₂ instead of 100 mM MgBr₂.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Solvent coordination to palladium can invert the selectivity of oxidative addition

Reaction solvent was previously shown to influence the selectivity of Pd/P^tBu₃-catalyzed Suzuki–Miyaura cross-couplings of chloroaryl triflates. The role of solvents has been hypothesized to relate to their polarity, whereby polar solvents stabilize anionic transition states involving [Pd(P^tBu₃)(X)]⁻ (X = anionic ligand) and nonpolar solvents do not. However, here we report detailed studies that reveal a more complicated mechanistic picture. In particular, these results suggest that the selectivity change observed in certain solvents is primarily due to solvent coordination to palladium. Polar coordinating and polar noncoordinating solvents lead to dramatically different selectivity. In coordinating solvents, preferential reaction at triflate is likely catalyzed by Pd(P^tBu₃)(solv), whereas noncoordinating solvents lead to reaction at chloride through monoligated Pd(P^tBu₃). The role of solvent coordination is supported by stoichiometric oxidative addition experiments, density functional theory (DFT) calculations, and catalytic cross-coupling studies. Additional results suggest that anionic [Pd(P^tBu₃)(X)]⁻ is also relevant to triflate selectivity in certain scenarios, particularly when halide anions are available in high concentrations.

In the presence of the bulky monophosphine P^tBu₃, palladium usually prefers to react with Ar–Cl over Ar–OTf bonds. However, strongly coordinating solvents can bind to palladium, inducing a reversal of selectivity.

Oxidative addition is a key elementary step in diverse transformations catalyzed by transition metals.¹ For instance, this step is common to traditional cross-coupling reactions, which are among the most widely used methods for small molecule synthesis. During the oxidative addition step of cross-coupling reactions, a low valent metal [usually Pd(0)] inserts into a C–X bond with concomitant oxidation of the metal by two electrons. The “X” group of the C–X bond is commonly a halogen or triflate. Despite a wealth of research into this step,^2–5 uncertainties remain about its mechanistic nuances. The mechanistic details are especially pertinent to issues of selectivity that arise when substrates contain more than one potentially reactive C–X bond.⁶One of the best-studied examples of divergent selectivity at the oxidative addition step is the case of Pd-catalyzed Suzuki couplings of chloroaryl triflates. In 2000, Fu reported that a combination of Pd(0) and P^tBu₃ in tetrahydrofuran (THF) effects selective coupling of 1 with o-tolylB(OH)₂via C–Cl cleavage, resulting in retention of the triflate substituent in the final product 2a (Scheme 1A).⁷ In contrast, the use of PCy₃ (ref. 7) or most other phosphines⁸ provides complementary selectivity (product 2b) under similar conditions. The unique selectivity imparted by P^tBu₃ was later attributed to this ligand''s ability to promote a monoligated oxidative addition transition state on account of its bulkiness.^5,8 Smaller ligands, on the other hand, favor bisligated palladium, which prefers to react at triflate. The relationship between palladium''s ligation state and chemoselectivity has been rationalized by Schoenebeck and Houk through a distortion/interaction analysis.⁵ In brief, the selectivity preference of PdL₂ is dominated by a strong interaction between the electron-rich Pd and the more electrophilic site (C–OTf). On the other hand, PdL is less electron-rich and its selectivity preference mainly relates to minimizing unfavorable distortion energy by reacting at the more easily-distorted C–Cl bond.Open in a separate windowScheme 1Seminal reports on the effects of (A) ligands and (B) solvents on the selectivity of cross-coupling of a chloroaryl triflate.^5,7,9Proutiere and Schoenebeck later discovered that replacing THF with dimethylformamide (DMF, Scheme 1B, entry 1) or acetonitrile caused a change in selectivity for the Pd/P^tBu₃ system.^9,10 In these two polar solvents, preferential reaction at triflate was observed, and P^tBu₃ no longer displayed its unique chloride selectivity. The possibility of solvent coordination to Pd was considered, as bisligated Pd(P^tBu₃)(solv) would be expected to favor reaction at triflate. However, solvent coordination was ruled out on the basis of two intriguing studies. First, DFT calculations using the functional B3LYP suggested that solvent-coordinated transition states are prohibitively high in free energy (about 16 kcal mol⁻¹ higher than the lowest-energy monoligated transition structure). Second, the same solvent effect was not observed in a Pd/P^tBu₃-catalyzed base-free Stille coupling in DMF (Scheme 1B, entry 2). Instead, the Stille coupling was reported to favor reaction at chloride despite the use of a polar solvent. This result appears inconsistent with the possibility that solvent coordination induces triflate-selectivity, as coordination of DMF to Pd should be possible in both the Stille and Suzuki conditions, if it happens at all. Instead, it was proposed that the key difference between the Suzuki and Stille conditions was the absence of coordinating anions in the latter (unlike traditional Suzuki couplings, Stille couplings do not necessarily require basic additives such as KF to promote transmetalation). Indeed, when KF or CsF was added to the Stille reaction in DMF, selectivity shifted to favor reaction at triflate (Scheme 1B, entry 3), thereby displaying the same behavior as the Suzuki coupling in this solvent. On the basis of this and the DFT studies, it was proposed that polar solvents induce a switch in chemoselectivity if coordinating anions like fluoride are available by stabilizing anionic bisligated transition structures (Scheme 1B, right).However, our recent extended solvent effect studies produced confounding results.¹¹ In a Pd/P^tBu₃-catalyzed Suzuki cross-coupling of chloroaryl triflate 1, we observed no correlation between solvent polarity and chemoselectivity (Scheme 2). Although some polar solvents such as MeCN, DMF, and dimethylsulfoxide (DMSO) favor reaction at triflate, a number of other polar solvents provide the same results as nonpolar solvents by favoring reaction at chloride. For example, cross-coupling primarily takes place through C–Cl cleavage when the reaction is conducted in highly polar solvents like methanol, water, acetone, and propylene carbonate. In fact, the only solvents that promote reaction at triflate are ones that are commonly thought of as “coordinating” in the context of late transition metal chemistry.¹² These are solvents containing nitrogen, sulfur, or electron-rich oxygen lone pairs (nitriles, DMSO, and amides). The observed solvent effects were upheld for a variety of chloroaryl triflates and aryl boronic acids.¹¹Open in a separate windowScheme 2Expanded solvent effect studies in the Pd/P^tBu₃-catalyzed Suzuki coupling.¹¹We have sought to reconcile these observations with the earlier evidence⁹ against solvent coordination. Herein we report detailed mechanistic studies indicating that coordinating solvents alone are sufficient to induce the observed selectivity switch. In solvents like DMF and MeCN, stoichiometric oxidative addition is favored at C–OTf even in the absence of anionic additives. The apparent contradiction between our observations and the previously-reported DFT calculations and base-free Stille couplings is reconciled by a reevaluation of those studies. In particular, when dispersion is considered in DFT calculations, neutral solvent-coordinated transition structures involving Pd(P^tBu₃)(solv) become energetically feasible. Furthermore, we find that the selectivity analysis in the Stille couplings is convoluted by low yields, the formation of side products, and temperature effects. When these factors are disentangled, the Stille coupling in DMF displays selectivity similar to the Suzuki coupling in the same coordinating solvent. In light of these new results, anionic bisligated [Pd(P^tBu₃)(X)]⁻ does not appear to be the dominant active catalyst in nonpolar or polar solvents unless special measures are taken to increase the concentration of free halide, such as adding tetraalkylammonium halide salts or crown ethers.     

Non-directed Pd-catalysed electrooxidative olefination of arenes

The Fujiwara–Moritani reaction is a powerful tool for the olefination of arenes by Pd-catalysed C–H activation. However, the need for superstoichiometric amounts of toxic chemical oxidants makes the reaction unattractive from an environmental and atom-economical view. Herein, we report the first non-directed and regioselective olefination of simple arenes via an electrooxidative Fujiwara–Moritani reaction. The versatility of this operator-friendly approach was demonstrated by a broad substrate scope which includes arenes, heteroarenes and a variety of olefins. Electroanalytical studies suggest the involvement of a Pd(ii)/Pd(iv) catalytic cycle via a Pd(iii) intermediate.

The Fujiwara–Moritani reaction using electric current is a powerful tool for the olefination of arenes by Pd-catalysed C–H activation.

Transition metal-catalysed C–H functionalisation reactions have increasingly gained importance over the last few decades since they allow direct and rapid installation of functionality. Regardless of the undeniable synthetic value of such transformations, the need for superstoichiometric quantities of expensive and hazardous oxidants (e.g., silver and copper salts) remains a major drawback from a sustainable chemistry perspective.^1,2 Additionally, chemical oxidants often lead to the formation of by-products, hindering purification and decreasing atom economy. Nevertheless, very few reports were also reported in the literature wherein mild oxidant such as molecular oxygen can also serve as the oxidising agent.^2j To make chemical processes and transformations intrinsically sustainable, organic chemists re-discovered synthetic electrochemistry as an environmentally friendly approach.^3–6 In the domain of synthetic electrochemistry, the Lei group achieved a significant milestone and installed C–C bonds through a different cross-coupling strategy.^1k,2f–h Electroorganic synthesis utilizes electric current to realize redox processes and thereby avoids the use of dangerous, expensive, and polluting chemical oxidising or reducing agents. Precise control of electrochemical reaction parameters often leads to commendable reactivity and chemoselectivity and hence to an improved atom economy. In addition, electrochemical processes fulfil the expectations of sustainability since electricity can be generated from renewable energy sources, such as wind, sunlight or biomass. Recent efforts in the field of electrochemical C–H activation resulted in significant progress towards efficient C–C and C–heteroatom bond formations.^7–10 Hence, the utilization of electric current as an alternative oxidant in Pd-catalysed C–H functionalisations is emerging as an attractive alternative to stoichiometric reagents.^11–13The Fujiwara–Moritani reaction is one of the earliest known examples of Pd-catalysed oxidative C–H functionalisations for C–C bond formation.¹⁴ This extraordinary C(sp²)-H alkenylation reaction avoids the use of prefunctionalised starting materials; however, it suffers from the drawbacks of regioselectivity, reactivity and use of excess arenes.¹⁵ Since its development, a number of modified strategies have been reported by different research groups to address the issue of reactivity and selectivity.^16–21 In recent times, the ligand assisted oxidative C–H alkenylation of arenes without directing substituents has been established as one of the major strategies to overcome the reactivity issue and to elaborate the substrate scope.However, regioselectivity for most of the sterically and electronically unbiased arenes is still not up to the mark. The most recent studies on the non-directed oxidative C–H olefination of arenes were reported independently by Yu and van Gemmeren (Scheme 1). The Yu group employed electron-deficient 2-pyridone as an X-type ligand for the olefination of both electron-rich and electron-poor arenes including heteroarenes as the limiting reagent (Scheme 1a).¹⁸ The pyridone ligand improves the selectivity in a non-directed approach as compared to the directed C–H olefination reaction by enhancing the influence of steric effects. On the other hand, the van Gemmeren group utilizes two complementary ligands N-Ac–Gly–OH and a 6-methylpyridine derivative in a 1 : 1 ratio to accomplish the non-directed olefination reaction of arenes (Scheme 1b).²⁰ Despite the indisputable advances made by these research groups in the area of non-directed oxidative C–H olefination of arenes, the use of superstoichiometric amounts of toxic and waste-generating oxidants (Ag salts) deciphers into a strong call for an environmentally responsive and atom-economic protocol. To address these shortcomings, we recently introduced Pd-photoredox catalysed olefination of non-directed arenes with excellent site selectivity under oxidant free conditions.²¹Open in a separate windowScheme 1Recent approaches to sustainable C–H alkenylation reactions.In 2007, Jutand reported the directing group assisted Pd-electracatalysed ortho-olefination of acetyl protected aniline in a divided cell by utilizing catalytic amounts of benzoquinone as a redox mediator (Scheme 1c).^22a A Rh-catalysed ortho-C–H olefination of benzamide was developed through an electrooxidative pathway by the Ackermann group (Scheme 1d).^22b Simple arenes that bear no directing groups are cheap, easily available and very desirable starting materials. However, the use of such arenes is significantly more challenging for selective functionalisation as transformations often result in the formation of complex product mixtures. With no report of an electrooxidative Pd-catalysed C(sp²)-H alkenylation of simple arenes present, we wish to present such a variant of the Fujiwara–Moritani reaction (Scheme 1e). The developed method proceeds through a non-directed pathway and is controlled by stereoelectronic factors. This protocol does not require additional chemical oxidizing agents and is executed using an operator-friendly undivided cell setup.To start our study, naphthalene was chosen as a challenging substrate because of its ability to form α- and β-products. We examined various reaction conditions for the desired Pd-catalysed electrooxidative C–H alkenylation in a simple undivided cell setup (†) with n-butyl acrylate as the coupling partner. After rigorous optimisation, we found that naphthalene reacts with n-butyl acrylate in dichloroethane (DCE) in the presence of Pd(OAc)₂ (10 mol%), ligand L1 (20 mol%), and the electrolyte tetra-n-butylammonium hexafluorophosphate (TBAPF₆, 0.5 equiv.) while employing a graphite felt anode and a platinum cathode maintaining constant current electrolytic conditions (j = 2.5 mA cm⁻², EntryAlteration from standard conditionsYield of 1^b (%)Selectivity (β : α)1None70>25 : 12Co(OAc)₂·4H₂O instead of Pd(OAc)₂91 : 13[Ru(p-cymene)Cl₂]₂ instead of Pd(OAc)₂NR4Pd(OAc)₂·(5 mol%)51>25 : 15Pd(OAc)₂·(20 mol%)71>25 : 16L2 instead of L1458 : 17L3 instead of L15920 : 18L4 instead of L1195 : 19L5 instead of L181 : 110Benzoquinone (10 mol%)68>25 : 111PivOH (1.0 equiv.)6120 : 112Ni foam instead of Pt64>25 : 113GF instead of Pt4915 : 114Steel instead of Pt3113 : 1156 mA cm⁻² instead of 2.5 mA cm⁻²2711 : 11624 h reaction time4720 : 11712 h reaction time5621 : 118No electricityNR—19No Pd(OAc)₂NR— Open in a separate window^aStandard reaction conditions: undivided cell, GF anode, Pt cathode, j = 2.5 mA cm⁻², naphthalene (0.2 mmol), n-butyl acrylate (0.5 mmol), Pd(OAc)₂ (10 mol%), L1 (20 mol%), TBAPF₆ (0.5 equiv.), DCE (3 mL), 15 h, under air.^bYield determined by ¹H-NMR of crude reaction mixture. NR = no reaction; TBAPF₆ = tetra-n-butylammonium hexafluorophosphate. GF = graphite felt. Surface area of electrodes dipped in solution = 0.7 cm × 0.7 cm, current = 1.225 mA and current density = 2.5 mA cm⁻² (electrochemical surface area = 1.23 cm²).Notably, in the present transformation the ligand has a major influence on the reactivity and selectivity aspects (see the ESI, Table S4^†). After studying a series of 2-pyridone, pyridine and amino acid-based ligands L2–L5 it was found that L1 is the optimal ligand since it provided superior yield and selectivity (entries 6–9). Addition of catalytic amounts of p-benzoquinone as a redox mediator (entry 10) or pivalic acid as an additive (entry 11, Scheme 2). Following the olefination of naphthalene (68%, >25 : 1 β : α selectivity), 1,2,3,4-tetrahydronaphthalene was successfully reacted (52%, 11 : 1 β : α-selectivity). Next, we applied our standard reaction conditions to benzene and found them not to be equally effective as only 25% of the olefinated product 3 was obtained. As a result, further optimizations of electric current density and solvent were carried out to enhance the yield (see the ESI, Table S9^†). To our satisfaction, the yield of product 3 increased to 63% when the electrolysis was carried out with an electric current density of j = 1.5 mA cm⁻² and in a solvent mixture of DCE/HFIP (5 : 1). These modified reaction conditions were applied to the electrosynthesis of all other olefinated products 4–26 (Scheme 2). The olefination of 1,3,5-trimethoxybenzene and mesitylene with n-butyl acrylate proceeded smoothly under the revised reaction conditions to afford products 4–5 in up to 65% yield. The regioselectivity issue was more prominent for arenes bearing two or more electronically similar C–H bonds (e.g., electron-rich arenes: ortho vs. para). Dimethoxy benzene gives β-selective olefinated product 6 (β : α; 7 : 1). While toluene was converted with para-selectivity (7 : 1) to 7, phenol afforded olefinated product 8 with ortho-selectivity (o : others; 9 : 1, Scheme 2). On the other hand, subjecting TBDMS (tert-butyldimethylsilyl) protected phenol to the established protocol furnished 9 with 8 : 1 para-selectivity (Scheme 2). The TBDPS (tert-butyldiphenylsilyl) protected phenol afforded exclusively the para-olefinated product 10 which might be due to the steric repulsion caused by the bulky protecting group. Conversion of 2,6-diiso-propylphenol provided olefinated product 11 as a single para-olefinated isomer with 67% yield. Anisole and ethoxybenzene both reacted smoothly to produce 12 (72%, 15 : 1) and 13 (70%, 10 : 1) with ortho-selectivity (Scheme 2). The compatibility of the present transformation was further showcased by the olefination of N,N-dimethyl aniline in 70% yield (14) and 8 : 1 ortho-selectivity. Similarly, methyl ferrocene carboxylate and biologically active caffeine reacted smoothly with n-butyl acrylate to produce olefinated products 15 and 16 in good yields (Scheme 2). Moderately electron-withdrawing arenes such as a phenyl acetic acid derivative (17, 51%, o : others = 7 : 1), a homoveratric acid derivative (18, 48%, o : others = 15 : 1) or 4-methoxy acetophenone (19, 59%, m : others = 7 : 1) gave the corresponding products in satisfactory yields. The coupling of unsubstituted thiophene and furan with n-butyl acrylate afforded the olefinated products 20 and 21 (64% and 68%) with synthetically useful C2-selectivity, respectively (C2 : others; 18 : 1 and C2 : others; 19 : 1, Scheme 2). In contrast, thiophenes bearing a substituent at the C2 position such as 2-phenylthiophene and 1-(4-(thien-2-yl)phenyl)ethan-1-one reacted with high C5-selectivity (>20 : 1) to afford the arylated α,β-unsaturated esters 22 and 23 (76% and 73% yield). Conversion of 2-(2-nitrophenyl)thiophene delivered the desired product 24 in 64% yield with exclusive C5-selectivity. A C3-substituted thiophene also reacted with the acrylate to afford 25 in 72% yield (C5 : others; 6 : 1 selectivity). Heteroarenes bearing electron-withdrawing substituents such as 2-acetyl thiophene (26) afforded the C5-olefinated product in moderate yield and selectivity (60%, C5 : others = 8 : 1). However, aromatic rings bearing strong electron-withdrawing groups (–NO₂, –CHO, –CF₃, –F etc.) are not compatible under our present reaction conditions (see details in the ESI, Section 4.3^†).Open in a separate windowScheme 2Evaluation of simple arenes and heteroarenes in the electrochemical olefination.^a Reaction conditions: undivided cell, GF anode, Pt cathode, j = 2.5 mA cm⁻² or j = 1.5 mA cm⁻², corresponding arenes or heteroarenes (0.2 mmol), n-butyl acrylate (0.5 mmol), Pd(OAc)₂ (10 mol%), L1 (20 mol%), TBAPF₆ (0.5 equiv.), DCE (3 mL) or 5 : 1 ration of dichloroethane (DCE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 15 h, under air. ^bYields of isolated products are reported.Next, we investigated the applicability of other olefins by reacting them with simple arenes (Scheme 3). In addition to other acrylates (methyl 27, ethyl 28 and tert-butyl 29), acrylic acid was successfully converted with naphthalene to its arylated product 30. Moderate yields (54–60%) and moderate to high β : α selectivities (up to >25 : 1) were obtained for all reactions. Coupling of methyl acrylate with benzene under adjusted electrochemical conditions (j = 1.5 mA cm²; DCE/HFIP mixtures) gave 62% of olefinated product 31. Other activated olefins such as methyl vinyl sulfone, and acrylonitrile were also amenable to the present olefination protocol. Subjecting these substrates in combination with different arenes to our protocol led to a variety of arylated products 32–35 in good yields and regioselectivities. α,β-Unsaturated ester derivatives of bioactive molecules such as δ-tocopherol and cholesterol were efficiently reacted with naphthalene to the olefinated products 36–37 in moderate yields. To further elaborate the scope of present protocol, un-activated olefins such as aliphatic olefins and styrene derivatives were tested. However, none of them afford olefinated products under our reaction conditions (see details in the ESI, Section 4.3^†). To monitor the scalability of the present transformation, two reactions were performed with the model reaction at scales of 0.504 g (46%, β : α = 7 : 1) and 1.08 g (41%, β : α = 7 : 1; see ESISection 4.2^†).Open in a separate windowScheme 3Evaluation of other α,β-unsaturated systems in the electrochemical olefination of arenes. ^aReaction conditions: undivided cell, GF anode, Pt cathode, j = 2.5 mA cm⁻² or j = 1.5 mA cm⁻², corresponding arenes or heteroarenes (0.2 mmol), activated olefins (0.5 mmol), Pd(OAc)₂ (10 mol%), L1 (20 mol%), TBAPF₆ (0.5 equiv.), DCE (3 mL) or 5 : 1 ratio of dichloroethane (DCE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), 15 h, under air. ^bYields of isolated products are reported.To gain insights into the catalytic mode of action, electrochemical and spectroelectrochemical experiments were performed. Cyclic voltammetry (CV) of Pd(OAc)₂ in DCE revealed two oxidation waves at +1.42 V vs. NHE (Normal Hydrogen Electrode) and at +2.47 V vs. NHE (Fig. 1a) which might refer to the redox conversion of Pd(ii/iii) and Pd(iii/iv).²³Fig. 1b shows the CVs of naphthalene (substrate), ligand L1, n-butyl acrylate, and Pd(OAc)₂. In comparison to the Pd(ii/iii) redox pair, a significantly higher oxidation potential (+2.16 V vs. NHE) was observed for naphthalene, which suggests that substrate activation is potentially induced by a Pd species with an oxidation state greater than +II (Fig. 1b). The CVs of other substrates followed the same pattern (see the ESI, Fig. S2^†). According to an electrochemical study on approximate ranges of standard redox potentials for Pd intermediates in catalytic reactions, the oxidation of Pd(ii) to Pd(iv) is usually observed in the range of +1.00–2.00 V (vs. Fc/Fc⁺ = ferrocene) or 1.63–2.63 V (vs. NHE).²³ The CV profile of Pd(OAc)₂ in the negative scan revealed two reduction waves at −0.23 V and at −1.06 V vs. NHE (Fig. S6^†) which might refer to the redox conversion of Pd(ii/i) and Pd(i/0). Taking these results into account, involvement of a Pd(ii/iv) catalytic cycle during the present transformation appears to be likely as the negative scan rules out a Pd(ii/0) cycle.^23d,eOpen in a separate windowFig. 1(a) Cyclic voltammograms of Pd(OAc)₂ and L1-Pd(OAc)₂ (1 mM, 100 mV s⁻¹ scan rate, glassy carbon, potential vs. NHE, 0.1 M TBAPF₆ in DCE); (b) cyclic voltammogram of reactants (1 mM, 100 mV s⁻¹ scan rate, glassy carbon, potential vs. NHE, 0.1 M TBAPF₆ in DCE); (c) in situ UV-Vis spectroelectrochemical spectra of the reaction mixture during bulk electrolysis at +2.61 V vs. NHE; (d) in situ UV-Vis spectroelectrochemical spectra of the Pd-ligand complex during bulk electrolysis at +2.61 V vs. NHE.In order to obtain further evidence for this hypothesis, we examined the reaction mixture at a constant potential of +2.61 V (vs. NHE) spectroelectrochemically (SEC) to check any changes in optical features during the reaction. This in situ UV-visible analysis of the reaction mixture revealed the gradual decrease of an absorption band at 379 nm and a new peak (∼350 nm) appeared over time (Fig. 1c). Similar behaviour was observed for the Pd-ligand complex as a blue shift of optical bands was found from 368 nm to 352 nm at the same potential of +2.61 V (vs. NHE, Fig. 1d). The differences in the observed UV-Vis peak positions are presumably due to a change in the geometry of the Pd-complex upon oxidation in the analysed reaction mixtures.To further consolidate this hypothesis, the same SEC experiment was repeated with only Pd(OAc)₂ which showed an absorption peak at 404 nm (Fig. S3^†). Electrolysis of Pd(OAc)₂ at +2.61 V (vs. NHE) also resulted in a blue shift with a new peak appearing at almost the same wavelength of 349 nm (Fig. S4^†). All these results led us to postulate that the new peak was associated with a change in the oxidation state of the Pd(ii) center. Moreover understand the nature of intermediates involved in the catalytic cycle, a series of electron paramagnetic resonance (EPR) experiments of the reaction mixture were conducted at different time intervals employing optimised reaction conditions. The EPR spectra (273 K) after 1 h showed a strong peak at g = 2.005 which was presumably due to the formation of an organic radical (Fig. 2a), however no naphthalene homo-coupled product was detected after different time intervals or under different conditions. At longer time intervals (4 h and 7 h), weak peaks at g_x = 2.139, g_y = 2.081 and g_z = 2.055 arose due to the asymmetry of the electronic distribution. The appearance of rhombic signals suggested the formation of a Pd(iii) intermediate having a d⁷ center (Fig. 2a).²⁴ An enlarged version of the spectra for Pd(iii) after 7 h is shown with simulated data in Fig. 2b. Time-dependent EPR spectra highlight that the build-up of Pd(iii) was concomitant with the decreased formation of an organic radical (Pd^III–R to Pd^IIR^.) as the corresponding peak diminished. This implied that the catalytically active Pd(iii) species got accumulated as the reaction approached towards completion. Furthermore, the EPR data in the absence of n-butyl acrylate (after 2 h) also revealed a very strong peak at g = 2.005; hence the formation of a radical species from the olefin was ruled out (Fig. S5^†).Open in a separate windowFig. 2(a) EPR spectrum of the reaction mixture under the standard reaction conditions at different time intervals (273 K); (b) enlarged EPR spectra of Pd(iii) after 7 h of experiment at 273 K (experimental vs. simulated).Additionally, radical quenching experiments with TEMPO did not show any effects under the standard reaction conditions. Furthermore, electrochemical arene oxidation to generate organic radicals has been well reported in the literature.^5f All these control experiments suggest that a phenoxy radical from L1 (C′) might be formed from intermediate C (Scheme 4).Open in a separate windowScheme 4Proposed catalytic cycle for the electrooxidative olefination of arenes.All of the performed experiments give a strong indication that a Pd(ii)/Pd(iv) cycle is involved in this electrochemical variant of the Fujiwara–Moritani reaction. Also, a palladium complex Pd^II(L1)₄ was synthesised and characterised by X-ray crystallography (Fig. 3). This Pd^II(L1)₄ complex was found to be a competent intermediate for the Pd-catalysed electrooxidative olefination of arenes.Open in a separate windowFig. 3Single X-ray crystal structure of Pd-complex [Pd(L1)₄].²⁵Based on these results and literature precedence,²³ a plausible Pd(ii/iv)-catalytic cycle is proposed for the electro-oxidative olefination of simple arenes (Scheme 4). The catalytic cycle starts with the anodic oxidation of the Pd(ii) catalyst A to form a Pd(iii) intermediate B. Arene C (sp²)–H bond activation delivers the organopalladium complex C which is converted to the Pd(iv) species D by anodic oxidation. Next, olefin coordination to form E followed by migratory insertion results in the formation of another organopalladium intermediate F. Finally, β-hydride elimination followed by reduction of Pd furnishes the olefinated product 1 and the Pd(ii) catalyst A is regenerated.     

Modular allylation of C(sp3)–H bonds by combining decatungstate photocatalysis and HWE olefination in flow

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, furnishing a rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp³)–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner–Wadsworth–Emmons (HWE) reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and has been applied to structurally complex molecules.

We report a flow platform for the modular allylation of strong aliphatic C(sp³)–H bonds based on the merger of photocatalytic HAT and a HWE reaction. This approach enables both early- and late-stage diversification of various hydroalkanes.

Modern drug discovery programs capitalize increasingly on the application of late-stage functionalization methodologies to accelerate the lead optimization phase.^1,2 Such strategies allow for the rapid and cost-efficient^3,4 diversification of the parent molecule by exploiting native functionalities (e.g., C–H bonds), thus effectively avoiding the need to redesign its entire synthetic route to access new leads.^5–7 More specifically, the late-stage decoration of organic molecules with multipurpose functional groups would provide new points of entry for subsequent diversification.⁸ Such a strategy could be particularly convenient when it is realized via a chemo- and regioselective functionalization of C–H bonds in the absence of any proximal directing or activating groups.⁷ However, while C(sp²)–H activation has been extensively investigated, the direct functionalization of C(sp³)–H bonds remains challenging and is often narrow in scope.⁹ Recently, photocatalytic Hydrogen Atom Transfer (HAT) has been exploited to enable the late-stage functionalization of C(sp³)–H bonds, showing remarkable levels of regioselectivity even in complex molecules (Scheme 1A).¹⁰ In HAT photocatalysis, a catalyst converts light energy into chemical energy for the homolytic cleavage of strong aliphatic C–H bonds.Open in a separate windowScheme 1Allylation of C(sp³)–H bonds. (A) Photocatalytic HAT enables late-stage functionalization of structurally complex molecules. (B) Reported approaches for the photocatalyzed radical allylation of organic molecules. (C) A telescoped approach for the modular allylation of C(sp³)–H bonds (this work).Especially, the decatungstate anion ([W₁₀O₃₂]⁴⁻) has shown remarkable selectivity for specific C(sp³)–H bonds, governed by an intricate balance between steric and electronic interactions.^9,11,12We envisioned that the regioselective introduction of an allyl moiety onto hydrocarbon frameworks would be particularly useful as it provides a convenient branching point for further late-stage synthetic exploitation.¹³ To install such moieties, radical allylation has manifested itself as a valuable strategy. One approach relies on the use of transition metal complexes to activate a substrate containing an allylic leaving group to afford a π-allyl complex, which is then suited to trap a C-centered radical (Scheme 1B).¹⁴ This strategy can engage a diverse set of allyl coupling partners but typically requires purposely designed radical precursors, which prevents the direct allylation of unactivated C(sp³)–H bonds.Another tactic exploits radicofugal groups X (e.g., X = halide, SO₂R, SnR₃, etc) in the allylic position to afford the desired product via a radical addition–fragmentation process (Scheme 1B).^15–28 However, while synthetically useful, this transformation is not suitable for the synthesis of densely functionalized allylic functionalities.Seeking to address these challenges, we sought to develop a robust and versatile synthetic platform for the allylation of strong aliphatic C(sp³)–H bonds. Hereto, a modular synthetic sequence is preferred in which the allylic moiety is assembled in a stepwise fashion, enabling the rapid generation of structurally diverse analogues. Specifically, our sequence features the merger of two distinct synthetic steps to accomplish this goal (Scheme 1C). First, we planned to activate C(sp³)–H bonds via decatungstate-catalyzed Hydrogen Atom Transfer^29,30 and subsequently trap the resulting C-centered radical with a vinyl phosphonate.^31,32 The ensuing radical addition product serves as a suitable linchpin for the second step, in which a classical Horner–Wadsworth–Emmons (HWE) olefination^33,34 is able to deliver the targeted allylated compounds. In order to streamline these two steps, we reasoned that a telescoped flow protocol where the reactions are performed in tandem without the need for tedious purification of intermediates would be indispensable not only to accelerate access to these valuable building blocks but also to ensure facile scalability.^35–37 Herein, we report the successful realization of a flow platform enabling the allylation of a wide range of unactivated hydrocarbons.Our investigations commenced with the decatungstate-enabled hydroalkylation of ethyl 2-(diethoxyphosphoryl)acrylate (2) using cyclohexane as the H-donor (see ESI, Table S1^†). Following a careful optimization of different reaction parameters, we found that the photocatalytic radical addition performed optimal in continuous-flow using a commercially available Vapourtec UV-150 photochemical reactor (PFA (perfluoroalkoxy) capillary, ID: 0.75 mm; V = 3.06 mL, flow rate = 0.612 mL min⁻¹, t_r = 5 min) equipped with a 60 W UV-A LED light source (λ = 365 nm), which matches the measured absorption spectrum of decatungstate. A 65% NMR yield (64% after isolation) was obtained for the targeted hydroalkylated compound when a CH₃CN solution of the acrylate (0.1 M), cyclohexane (20 equivalents) and tetrabutylammonium decatungstate (TBADT, (Bu₄N)₄[W₁₀O₃₂]) as the photocatalyst (1 mol%)^38–46 was irradiated for 5 minutes (see ESI, Table S1, Entry 9^†). Other HAT photocatalysts, such as Eosin Y,⁴⁷ anthraquinone,⁴⁸ 5,7,12,14-pentacenetetrone²⁸ and 9-fluorenone⁴⁹ were also evaluated, but failed to deliver the targeted product. Interestingly, benzophenone^50,51 showed a comparable activity to the decatungstate anion, although only when used at high catalyst loading (20 mol%, 68% NMR yield). Due to the lower extinction coefficient of benzophenone compared to TBADT (<200 vs. 13 500 M⁻¹ cm⁻¹),^52,53 and its known tendency to dimerize to form benzopinacol upon UV-A irradiation, we selected TBADT as the best photocatalyst for the targeted hydroalkylation reaction. Notably, this transformation is quite general and a diverse set of alkylphosphonates (3) could be readily isolated and characterized (see ESI, Section 7). A mechanistic study confirmed the radical nature of the process (see ESI, Section 5), where HAT is likely to occur during the rate-determining step (KIE = 1.9).Next, the obtained alkylphosphonates were subjected to the successive HWE olefination (Scheme 2). A telescoped flow approach was developed in which the two individual steps were connected in a single streamlined flow process without intermediate purification. We selected 1,3-benzodioxole (1a), a common moiety in many medicinally-relevant molecules, as the H-donor and exposed it to the photocatalytic reaction conditions. Upon exiting the photochemical reactor, the reaction mixture containing the alkylphosphonate is merged with a stream containing paraformaldehyde (3 equiv.) and lithium tert-butoxide (1.1 equiv.) in tetrahydrofuran. The combined reaction mixture is subsequently introduced into a second capillary microreactor (PFA, ID: 0.75 mm; V = 7.1 mL; t_r = 5 min; T = 40 °C) and, after only 5 minutes of residence time, the targeted C(sp³)–H allylated product 4 could be obtained in 80% overall NMR yield (70% after isolation). Interestingly, the reaction performed decently also with 1 equivalent of 1a (65% NMR yield). Notably, the tactical combination of these two steps in flow results in a very efficient and operationally simple protocol, delivering these coveted scaffolds in only 10 minutes overall reaction time. As another benefit, the flow process could be readily scaled to produce 10 mmol of the desired compound 4 (1.52 g, 65% isolated yield, Scheme 2) without the need for tedious reoptimization of the reaction conditions, which is typically associated with batch-type scale up procedures.Open in a separate windowScheme 2Scope of the modular allylation of strong aliphatic C–H bonds with (deuterated) paraformaldehyde. Yields are given over two steps. For further experimental details see the SI. ^a For (CH₂O)_n: 0.23 M aldehyde and 0.084 M LiOtBu solution in tetrahydrofuran; flow rate = 0.802 mL min⁻¹; t_R = 5 min. For (CD₂O)_n: 0.11 M aldehyde and 0.084 M LiOtBu solution in tetrahydrofuran; flow rate = 0.802 mL min⁻¹; t_R = 8 min. ^b TBADT was used 5 mol%.This telescoped strategy could be subsequently applied to a wide variety of hydrogen atom donors 1 (Scheme 2). Activated substrates, such as hydrocarbon scaffolds with α-to-O C(sp³)–H bonds (5–7), were regioselectively allylated in yields ranging from 49–66% over two steps. Similarly, substrates containing α-to-S (8 and 9) and α-to-N (10–13) C(sp³)–H bonds were functionalized without difficulty (52–70% overall yield). Allylic functional groups could also be appended to activated benzylic positions (14, 32% overall yield).Finally, even strong, non-activated aliphatic C–H bonds could be readily allylated using our approach (15–19, 44–53% overall yield).To further demonstrate the potential of this operationally facile approach to introduce allylic functional groups, we wondered whether paraformaldehyde-d₂ could be used in the HWE step. Such a straightforward, regioselective introduction of deuterium atoms in organic molecules would be of tremendous importance for mechanistic,^54,55 spectroscopic and tracer studies.⁵⁶ Using our two-step flow protocol, the analogous deutero-allylated compound 4-d₂ was isolated in 68% yield, perfectly matching the result obtained for the non-deuterated version 4. Similarly, N-Boc piperidinone and N-methyl-2-pyrrolidone were competent substrates for this protocol affording the deuterated products 20 and 21 in 44% and 52% yield, respectively. Finally, in an effort to demonstrate the applicability of this method to the late-stage functionalization of medicinally relevant molecules, we subjected biologically active molecules to our two-step flow protocol: the terpenoid ambroxide (22, 40% yield) and the nootropic drug aniracetam (23, 21% yield) could be decorated with a deuterated allylic moiety.In a similar vein, we turned our attention to introduce aromatic and aliphatic aldehydes in the second step, yielding trisubstituted allylic moieties, which are particularly challenging to synthesize via traditional photocatalyzed radical allylation approaches (Scheme 1B). By exploiting our modular protocol, a virtually limitless array of substituents can be systematically introduced (Scheme 3). In most cases, prolonged reaction times were required to obtain full conversion. In particular, electron-deficient aldehydes were convenient substrates for a fully telescoped manifold, where the flow exiting the photoreactor was directly merged with a stream containing the aldehyde and the base (see e.g., 26–30, 35–40). The HWE step required 30 minutes residence time and the temperature was kept at 40 °C. We found that a range of pyridine-derived nicotinaldehydes and heteroaromatic aldehydes (35–41) were ideal substrates for this approach as well. As for electron-neutral and -rich carbonyl compounds, the HWE step required considerably longer reaction times and thus a fed-batch approach was found to be more practical (e.g., 25, 31). Here, the reaction stream exiting the photoreactor was directly dosed into a stirring solution of aldehyde and base. It is important to stress that a fully telescoped approach was still possible in these cases, however higher reaction temperature (60 °C) and a back-pressure regulator (BPR, 2.8 bar) were needed to obtain full conversion within 1 hour (e.g., 24, 33, 45). Another general observation that could be made is that the presence of ortho-substituents resulted in higher E : Z ratios (e.g., 28–31, 33 and 40).Open in a separate windowScheme 3Scope of the modular allylation of strong aliphatic C–H bonds with aromatic and aliphatic aldehydes. Yields are given over two steps. For the experimental details of the fed-batch procedure see GP4 in the ESI,^† while for fully telescoped approach see GP5. ^a Reactions were carried out on a 0.5 mmol scale and yields refer to isolated products, E : Z ratios were measured by ¹H-NMR. ^b Reaction performed according to GP5, but the HWE step required 60 °C, a BPR (2.8 bar) and 1 hour residence time. ^c Reaction time: 16 h. ^d Reaction performed via general procedure GP6 in the ESI.^†Next, we turned to investigate different classes of hydrogen donors, such as hydrocarbons (43, 43%), (thio)ethers (44–45, 47–68%), protected amines (46, 51%) and amides (47, 55%): all proved to be competent reaction partners. In all cases, the reaction performed well, delivering densely functionalized alkenes in good yields and stereoselectivity.It is important to note that it would be extremely challenging to access either of these motifs with the current radical allylation methodologies (Scheme 1B). Unfortunately, all attempts to engage ketones in the HWE step did not afford the desired fully-substituted olefins.Interestingly, our protocol was also amenable to aliphatic aldehydes containing enolizable positions (48–52, 57–71% yield). The use of protected piperidine-4-carboxaldehydes allowed to obtain the corresponding allylated products 51 and 52 in excellent yields (60–68%) and with good diastereomeric ratios. In addition, medicinal agents and natural products containing carbonyls, such as acetyl-protected helicin, citronellal and indomethacin aldehyde derivatives, were also reactive delivering the targeted olefins in synthetically useful yields (53–55, 20–63%). This proves the potential of this strategy to rapidly diversify double bonds.Next, the importance of the ester moiety as electron-withdrawing group (EWG) in the substrates to enable the targeted transformations was evaluated (Scheme 4A). Thus, we synthesized different vinyl phosphonates (2′–2′′′) and found that all of them performed well (40–68% ¹H-NMR yield) in the photocatalytic radical hydroalkylation. We then tested our streamlined process with benzaldehyde (GP4) to study the effect of the EWG on the diastereomeric ratio in the final allylated compound. The cyano group-bearing substrate furnished the targeted compound 56 with an excellent diasteroselectivity; however, a poor mass balance was observed (22% yield despite full conversion of 3′). In contrast, products 57 and 58 (EWG : COR) were not formed, with a complete recovery of 3′′ and 3′′′. Interestingly, we found that compound 2′′′′ could serve as a suitable radical trap as well (Scheme 4B). Using 1a as coupling partner, the targeted hydroalkylation product was obtained in excellent yield (3′′′′, 90% by ¹H-NMR). A solvent switch and a stronger base (nBuLi, n-butyl lithium) were however required to induce the subsequent HWE step yielding styrenes 59–61 in good yields after isolation (see GP7 in the ESI^†).^57,58Open in a separate windowScheme 4(A) Effect of the EWG on the diasteroselectivity in the final allylated product; (B) synthesis of densely functionalized styrenes by exploiting phenyl-substituted vinyl phosphonate 2′′′′; (C) examples of further diversification of compound 4, including olefin reduction, ester reduction, Giese-type radical addition and Mizoroki–Heck coupling. ^a Full conversion of 3′ was observed. ^b Full recovery of the alkyl phosphonates.The regioselective and late-stage installation of allylic groups opens up innumerable possibilities for further diversification.¹³ As an illustration of this synthetic potential, we explored diverse conditions for the conversion of 4 into functionalized derivatives (Scheme 4C). The olefin and the ester functionalities could be orthogonally reduced by exploiting different reduction conditions, yielding compounds 62 (70%) and 63 (62%), respectively.^59,60 Moreover, compound 4 was an ideal substrate for another Giese-type radical addition using decatungstate-photocatalyzed HAT (64, 62%). Finally, product 65 could be obtained via a classical Mizoroki–Heck-type coupling (60%).⁶¹     

Correction: Biofunctional Janus particles promote phagocytosis of tumor cells by macrophages

Correction for ‘Biofunctional Janus particles promote phagocytosis of tumor cells by macrophages’ by Ya-Ru Zhang et al., Chem. Sci., 2020, 11, 5323–5327, https://doi.org/10.1039/D0SC01146K.

The authors regret an error in Fig. 4a, where two of the panels contain partial overlap.Open in a separate windowFig. 1Tf–SPA3–aSIRPα JMPs promote the interaction and subsequent phagocytosis of B16F10 cells by BMDMs. (A) Representative confocal images of phagocytosis assays treated with different formulations for 2 or 4 h, respectively. (B) Time-dependent of phagocytosis treated with Tf–SPA3–aSirpα JMPs. In (A) and (B), B16F10 cells were labelled with CFSE (green), BMDMs were labelled with eFluor 670 (red) and particles were labelled with RB (blue). Scale bar: 20 μm.The panels for 2 h SPA3 and 2 h Tf + aSIRPα + SPA3 contain overlap, as the wrong data was initially used for 2 h SPA3. An independent expert has viewed the new data and has concluded that it is consistent with the discussions and conclusions presented.The correct Fig. 4 is shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Palladium/GF-Phos-catalyzed asymmetric carbenylative amination to access chiral pyrrolidines and piperidines

The cross-coupling of N-tosylhydrazones has emerged as a powerful method for the construction of structurally diverse molecules, but the development of catalytic enantioselective versions still poses considerable challenges and only very limited examples have been reported. We herein report an asymmetric palladium/GF-Phos-catalyzed carbenylative amination reaction of N-tosylhydrazones and (E)-vinyl iodides pendent with amine, which allows facile access to a range of chiral pyrrolidines and piperidines in good yields (45–93%) with up to 96.5 : 3.5 er. Moreover, mild conditions, general substrate scope, scaled-up preparation, as well as the efficient synthesis of natural product (−)-norruspoline are practical features of this method.

An efficient asymmetric palladium/GF-Phos-catalyzed carbenylative amination reaction to access structurally diverse chiral pyrrolidines and piperidines in good yields with high chemo-, regio- and enantioselectivities has been developed.

N-tosylhydrazones, readily prepared from aldehydes or ketones, served as a safe source of carbene precursors and have attracted much attention of chemists.¹N-tosylhydrazone-mediated applications have been continuously developed, such as cyclopropanation or cyclopropenation, X–H insertion, ylide formation, cycloaddition, aza-Wacker-type cyclization, asymmetric allylic substitution, etc.² Among them, transition-metal-catalyzed cross-coupling is one of the powerful protocols for C–X or C C bond formation in organic synthesis involving versatile intermediates, of which in situ generation of diazo compounds and carbene migratory insertion are considered key steps.^3–5 Over the past decades, considerable progress has been made in the asymmetric cross-coupling reactions of N-tosylhydrazones with various coupling partners, including cyclobutanols, terminal alkynes, silacyclobutanes and so on.⁴ Relatively, only a few examples focus on the cross-coupling reactions of aryl halides with N-tosylhydrazones involving benzyl metal intermediates [Scheme 1A, eqn. (a)].⁶ For example, Gu,^6a Wu,^6b Lassaletta^6c and coworkers have developed a palladium-catalyzed asymmetric synthesis of axial chiral compounds from aryl bromides and N-tosylhydrazones, ending with β-H elimination. Very recently, we realized palladium/GF-Phos catalyzed asymmetric three component cross-coupling reactions of aryl halides, N-tosylhydrazones, with terminal alkynes.^6f In contrast, much less progress has been made in N-tosylhydrazone-based carbenylative insertions from vinyl halides, which would generate a π-allylic metal intermediate followed by nucleophile attack, providing a unique approach for building C–X bonds, especially for N-heterocyclic compounds [Scheme 1A, eqn. (b)].⁷N-heterocycles are important structural motifs for the development of various types of valuable chemicals and materials.⁸ Importantly, optically active 2-substituted pyrrolidine and piperidine derivatives are privileged scaffolds in many natural products and pharmaceuticals with a wide range of biological activities,⁹ as well as the backbone of organocatalysts in asymmetric catalysis (Fig. 1).¹⁰Open in a separate windowScheme 1Asymmetric transition-metal-catalyzed carbenylative cross-coupling reactions.Open in a separate windowFig. 1Selected natural products and pharmaceuticals containing chiral 2-substituted pyrrolidine and piperidine units.Notably, Van Vranken and coworkers reported an elegant palladium-catalyzed carbenylative amination reaction of N-tosylhydrazones and (E)-vinyl iodides pendent with amine, providing facile access to pyrrolidine and piperidine ring systems that are common to alkaloid natural products (Scheme 1B).¹¹ Unfortunately, only up to 58.5 : 41.5 er was obtained after they made a lot of efforts to screen a series of chiral phosphine ligands, indicating that this asymmetric reaction indeed poses considerable challenges in addition to competitive side reactions such as the dimerization of vinyl iodides,¹² the formation of diene via the palladatropic rearrangement/β-H elimination or allene via β-H elimination from C_sp²,¹³ and the π-allylpalladium intermediate trapped by the byproduct sulfinic acid salt.¹⁴ Given the significance of chiral pyrrolidines and piperidines as core structures in alkaloid natural products, the development of an asymmetric version of this elegant carbenylative amination reaction is highly desirable. In recent years, our group has developed a series of chiral sulfinamide phosphine ligands (so-called Sadphos), which showed unique potential in asymmetric transition-metal catalysis,^6f,15 so we wondered whether Sadphos could address this challenging asymmetric carbenylative amination reaction (Scheme 1C).Initially, our study began with (E)-vinyl iodide 1a and N-tosylhydrazone 2a in the presence of Pd₂(dba)₃, t-BuOLi, Et₃N, and triethylbenzylammonium chloride (TEBAC) in THF at 30 °C. A series of commercially available chiral ligands were first screened (Fig. 2). Only (R, R)-DIOP (L1), (R)-DTBM-SegPhos (L3) and (R)-MOP (L4) provided the desired product 3aa with poor enantioselectivity and other ligands such as (R, R)-Ph-BPE (L2), (R, S)-Josiphos (L5) and (S, S)-ⁱPr-FOXAP (L6) showed low reactivity. We next turned to systematically investigate Sadphos, such as Wei-Phos,¹⁶ Xiao-Phos,^15d,17 Ming-Phos,^15a,18 Xu-Phos,^15b,19 Xiang-Phos²⁰ and PC-Phos^15c,21 (Fig. 2). To our delight, PC1 delivered 3aa in 32% yield and 85.5 : 14.5 er. Inspired by this result, we further screened PC2–PC5 which vary in the substituent of phenyl, but unfortunately none of them showed better results. Surprisingly, the reactivity of this reaction could be greatly improved with our recently developed GF-Phos GF1, delivering 71% yield. When steric hindered tert-butyl groups were introduced on the phenyl group (GF2), the product 3aa was obtained in 77% yield with 91.5 : 8.5 er. After screening different palladium catalysts and solvents (Open in a separate windowFig. 2Screened chiral ligands.Optimization of reaction conditions^a

Cu-catalyzed carboboration of acetylene with Michael acceptors

A copper-catalyzed three-component carboboration of acetylene with B₂Pin₂ and Michael acceptors is reported. In this reaction, a cheap and abundant C2 chemical feedstock, acetylene, was used as a starting material to afford cis-alkenyl boronates bearing a homoallylic carbonyl group. The reaction was robust and could be reliably performed on the molar scale. Furthermore, the resulting cis-alkenyl boronates could be converted to diverse functionalized molecules with ease.

A copper-catalyzed three-component carboboration of acetylene with B₂Pin₂ and Michael acceptors was achieved. The small acetylene molecule enabled faster rate of borylcupration and easier C–C bond formation compared with substituted alkynes.

Copper-catalyzed syn-1,2-borofunctionalization of alkynes has become a powerful and practical strategy for the installation of both boron and other functional groups across the C C bond in excellent regio- and stereoselectivity.¹ The general mechanism is that the borofunctionalization is initiated by the syn-addition of nucleophilic Cu-Bpin across the C C bond to generate the key intermediate species borylated alkenyl copper, followed by the interception of electrophiles to produce multi-substituted alkenyl boronates (Scheme 1a). So far, different electrophiles, such as H⁺, halides (including alkyl, allyl, aryl and alkynyl halides) and CO₂, have been successfully and efficiently employed to intercept the putative borylated alkenyl copper.^2–4 In sharp contrast, as excellent electrophiles, Michael acceptors (acrylate, vinyl ketone, acrylonitrile etc.) have rarely been employed to capture the in situ generated borylated alkenyl copper intermediate. This is not because Michael acceptors are not capable of reacting with the nucleophilic alkenyl copper, but because the electron-deficient Michael acceptors are typically more reactive than the electron-rich alkynes toward the borylcupration of Cu-Bpin species⁵ (Scheme 1b). To circumvent this challenge, Lin and Tian reported a Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes through an intramolecular Michael addition.⁶ In this reaction, the authors smartly leveraged the steric hindrance from the quaternary carbon of C1 to suppress the undesired borylcupration of cyclohexadienone (Scheme 1c). Recently, by using the same strategy, Carretero and Mauleón also reported an intramolecular borylative cyclization of 1,6-enynes with a β,β-disubstituted acrylate fragment to provide densely functionalized pyrrolidines.⁷ Despite these elegant studies, due to the competition between two different borylcupration pathways, copper-catalyzed carboboration of alkynes through intermolecular Michael addition is still challenging and remains unknown.Open in a separate windowScheme 1Cu-catalyzed borofunctionalization of alkynes.Acetylene, with the molecular formula C₂H₂, is the simplest and smallest alkyne.⁸ Due to its structural simplicity and high reactivity, acetylene represents a unique C2 alkenyl building block for organic synthesis through addition of its triple bond.⁹ Highly industrially important vinyl-containing monomers, such as vinyl ether,¹⁰ vinyl amine,¹¹ vinyl chloride,¹² acrylic acid and its derivatives,¹³ are being synthesized in millions of tons per year globally. However, in fine chemistry, catalytic protocols directly incorporating acetylene into high value-added chemicals are limited. In fact, while phenylacetylene acts as a model substrate in many state-of-the-art catalytic systems concerning alkyne transformations, acetylene is usually neglected in the substrate scope studies due to its gaseous nature and explosive hazard.^9i,h This obscures the true reactivity of acetylene and makes the acetylene chemistry lag behind in the progress of modern catalytic alkyne chemistry.Inspired by the elegant studies of Lin, Tian, Carretero and Mauleón, in which a steric hindered Michael acceptor was used to suppress the undesired conjugate borylation of Cu-Bpin, we envisioned that the small size of acetylene might also enable the borylcupration of the C C bond to outcompete the borylcupration of the Michael acceptor, thus allowing the Cu-catalyzed carboboration of acetylene through the challenging intermolecular Michael addition (Scheme 1d). However, the application of acetylene in the copper-catalyzed carboboration reaction through intermolecular Michael addition might encounter the following potential challenges: (1) competition between two different borylcupration processes; (2) suppression of the undesired hydroborylation side reaction; (3) safety issues related to the manipulation of acetylene gas and formation of the potentially explosive copper acetylide.With this above design in mind, we initially investigated the competition of the borylcupration reaction among different types of alkynes. As shown in Scheme 2, when equal amounts of acetylene, phenylacetylene and 1-pentyne were subjected to the typical borylcupration catalytic system with 1.0 equivalent of B₂pin₂ as the limiting reagent and IMesCuCl as the catalyst, an unexpected reaction selectivity was observed. The hydroborylation product of acetylene (A1) was observed in 62% yield, which is about 8 times higher than that of phenylacetylene (A2). In addition, no corresponding hydroborylation product of 1-pentyne (A3) was detected by NMR. The competition results obviously indicated that the borylcupration of acetylene is much faster than that of both aryl alkynes and alkyl alkynes. More importantly, by comparison of the hydroborylation of acetylene and 1-pentyne, we can draw the conclusion that the steric hindrance of the substituent does have a significant impact on the borylcupration of the C C bond by taking into account that both of them are unactivated alkynes.Open in a separate windowScheme 2The competition of borylcupration among different alkynes.Encouraged by the above results, we further investigated Cu-catalyzed three-component carboboration of different alkynes in the presence of B₂pin₂ and butyl acrylate 1a with IMesCuCl as the catalyst and NaO^tBu as the base. As shown in Scheme 1b). In sharp contrast, the desired three-component carboboration product 2a could be successfully generated when acetylene was applied as the alkyne component (entries 5 and 6). The carboboration product 2a could be produced in 38% yield even with 1.0 equivalent of acetylene, which is equal to the yield of hydroborylation product B (entry 5). When the amount of acetylene was further increased up to 12.5 equivalents (the gaseous acetylene was supplied with a balloon), the hydroborylation of butyl acrylate was completely suppressed with no byproduct B detected, furnishing the desired carboboration product 2a in 62% yield (entry 6). Taken together, the application of acetylene, due to its small size, could enable the realization of the syn-1,2-carboboration of the C C bond through an intermolecular Michael addition, producing the highly useful alkenyl boronates.Cu-catalyzed carboboration of different alkynes

Correction: Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling

Correction for ‘Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling’ by Arndt Robert Finkelmann et al., Chem. Sci., 2014, 5, 4474–4482, DOI: 10.1039/C4SC01605J.

The authors regret that there were minor typographical errors in two figures. In Fig. 9 and ​and11,11, the internuclear distances were swapped. The Fe-bound hydrogen atoms are affected, where H_p is the hydrogen atom proximal to the oxypyridine ligand and H_d is the hydrogen atom distal to the oxypyridine ligand. In Fig. 9, left panel, the distance between H_p and the oxypyridine O atom was given as 1.82 Å and the distance between H_p and the Fe atom was given as 1.7 Å. However, it should read 1.82 Å between H_p and Fe and 1.70 Å between H_p and the oxypyridine O atom. In Fig. 11, top left panel, the distance between H_p and Fe was shown to be 1.70 Å and the distance between H_d and Fe was given as 1.73 Å. However, it should read 1.73 Å between H_p and Fe and 1.70 Å between H_d and Fe. The correct versions of these figures are given below. The results and conclusions are not affected by these typographical errors.Open in a separate windowFig. 9QM/MM-optimized reactant (left) and product (right) structures of the H₂ cleavage reaction for the scenario with oxypyridine ligand. Distances are given in Å.Open in a separate windowFig. 11Top row: structures of the H₂ adduct for the second scenario with neutral pyridinol; the pyridinol OH can be oriented away from Fe (top left) or towards Fe (top right). Bottom row: products of H₂ cleavage, with the proton transferred to the thiolate; with the hydroxyl oriented away from Fe (bottom left) and towards Fe (bottom right). Distances are given in Å; relative energies with respect to the favoured adduct are indicated in red in kcal mol⁻¹.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Correction: In situ monitoring of functional activity of extracellular matrix stiffness-dependent multidrug resistance protein 1 using scanning electrochemical microscopy

Correction for ‘In situ monitoring of functional activity of extracellular matrix stiffness-dependent multidrug resistance protein 1 using scanning electrochemical microscopy’ by Shuake Kuermanbayi et al., Chem. Sci., 2022, https://doi.org/10.1039/d2sc02708a.

The authors regret that an incorrect version of Fig. 5f was included in the original article. This error does not affect the conclusions of the original article as the correct Fig. 5f also proves that there is no significant difference in the mRNA levels of MRP1 in the MCF-7 cells on the PA gels with three stiffness. The correct version of Fig. 5 is presented below.Open in a separate windowFig. 1(a and b) Immunofluorescence images and (c and d) the normalized total MRP1 intensities of (a and c) MCF cells and (b and d) MDA-MB-231 cells on the PA gels with stiffness of 2.5, 17.1 and 26.2 kPa, respectively (scale bar: 40 μm). (e) Western blot analysis of the MRP1 expressions of the MCF-7 and MDA-MB-231 cells on the PA gels with stiffness of 2.5, 17.1 and 26.2 kPa, respectively. (f and g) The relative MRP1 mRNA expressions in (f) the MCF-7 cells and (g) the MDA-MB-231 cells on the PA gels with stiffness of 2.5, 17.1 and 26.2 kPa, respectively.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Ligand-dependent,palladium-catalyzed stereodivergent synthesis of chiral tetrahydroquinolines

The most fundamental tasks in asymmetric synthesis are the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. Although great progress has been made in the past few decades, developing general and practical strategies that allow selective generation of any diastereomer of a reaction product bearing multiple stereocentres through switching distinct chiral catalysts is a significant challenge. Here, attaining precise switching of the product stereochemistry, we develop a novel P-chirogenic ligand, i.e.YuePhos, which can be easily derived from inexpensive and commercially available starting materials in four chemical operations. Through switching of three chiral ligands, an unprecedented ligand-dependent diastereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-arylidene succinimides was developed. This novel method provides an efficient route for the stereodivergent synthesis of six stereoisomers of pyrrolidines bearing up to three adjacent stereocenters (one quaternary center). Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to 98% ee. In addition, the synthetic utilities of optically active hexahydrocarbazoles are also shown.

An unprecedented ligand-dependent stereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-aryliene succinimides was developed.

The chirality of a biologically active molecule can alter its physiological properties. Therefore, highly efficient access to and fully characterizing all possible stereoisomers of a chiral molecule is one of the fundamental challenges in organic synthesis, drug discovery and development processes. However, most asymmetric catalytic transformations afford products enantioselectively and diastereoselectively and only form one of the stereoisomers containing multiple stereocenters. Stereodivergent access to all possible stereoisomers of the products is incredibly difficult because diastereochemical preference is largely dominated by the inherent structural and stereoelectronic characteristics of substrates, while absolute conformation can be dictated by the choice of the chiral catalyst.¹ In 2013, Carreira and co-workers addressed this limitation by introducing the concept of stereodivergent dual-catalytic synthesis, reporting the allylation of aldehydes in a diastereodivergent fashion by the synergistic reactivity of iridium and amine catalysts under acidic conditions.² Soon after, Carreira,³ Zhang,⁴ Hartwig,⁵ Dong,⁶ Wang,⁷ Zi,⁸ Lee,⁹ and other groups¹⁰ reported using an appropriate combination of dual chiral catalysts in a series of elegant studies (Scheme 1A). Recently, chemists found, in some cases, that tuning non-chiral parameters, including solvents or additives, also controlled the stereochemical outcomes through subtle perturbation of the key diastereomeric transition states.¹¹ In 2018, You and co-workers reported a solvent-controlled palladium-catalyzed enantioselective dearomative formal [3 + 2] cycloaddition, affording stereodivergent synthesis of two diastereomeric tetrahydrofuroindoles.¹² However, a rapid and predictable way to access complete stereoisomers of products bearing multiple stereocentres (for example, three contiguous stereocentres) remains an unsolved challenge through switching of ligands. To the best of our knowledge, only two successful examples were reported by Buchwald and Zhang, in which eight stereoisomers were obtained through tuning catalysts and reactive substrates (Scheme 1B).^4a,13Open in a separate windowScheme 1Strategy for stereodivergent synthesis of different stereoisomers.In metal-catalyzed reactions, ligands can manipulate the reactivity and selectivity by affecting the steric and electronic properties of metal catalysts. Therefore, the design and development of new ligands to improve the utility, activity and selectivity of their related metal catalysts are greatly desired by organic chemists. Recently, our groups have synthesized a new and promising class of P-chiral ligands ZD-Phos (including Ganphos and Jiaphos), and their conformational rigidity and chemical robustness have endowed the structure and its variants with outstanding activity and selectivity as well as excellent stereocontrol features essential to asymmetric cycloaddition reactions.¹⁴ Inspired by these advances, we are interested in continuing the development of P-chiral ligands with new structural motifs in the search for new reactivity and selectivity to tackle current synthetic challenges. More recently, Sadphos has emerged as another superior chiral skeleton, owing to the pioneering contributions by Zhang.¹⁵ Thus its aminophosphine scaffold is envisaged to be introduced into our 1-phosphanorbornene framework (ZD-Phos).¹⁶ We aim to combine the advantages of the aforementioned two types of chiral motifs, thus developing a novel P,P-bidentate ligand. Thus the novel P-chiral ligands, called Yuephos, may show unique stereoselectivity in a metal-catalyzed asymmetric cycloaddition reaction (Fig. 1).Open in a separate windowFig. 1Design of the Yuephos framework.Tetrahydroquinolines are important molecular skeletons that widely occur in natural molecules, pharmaceuticals, and functional materials. For this reason, realizing stereodivergent synthesis of all stereoisomers of fully substituted tetrahydroquinolines has been an important and challenging task in organic synthesis. However, to date, full control of absolute and relative stereochemical configuration of these molecules has remained an unmet synthetic challenge. Considering the potentiality of fully substituted chiral tetrahydroquinolines in drug discovery and stereodivergent synthesis,¹⁷ we envisioned that using our new palladium/ZD-Phos catalytic system may offer an efficient strategy for overcoming the challenges related to regio-, enantio-, and diastereo-selectivity. Herein, we report our studies on the unexplored stereodivergent synthesis of fully substituted tetrahydroquinolines through ligand-controlled, metal-catalyzed asymmetric annulation. Six possible stereoisomers bearing two tertiary and one quaternary stereocenters were easily synthesized in good yields with high enantio- and diastereo-selectivities from the same starting materials (Scheme 1C).The new bisphosphorus ligands we report herein can be easily synthesized by a two-pot method with good yields (Scheme 2). Starting from the corresponding aldehyde¹⁸ and commercially available chiral amine, one-pot sequential reaction gave diastereomers Y1 and Y1′ with 1 : 1 dr, which could be straightforwardly separated by column chromatography. The subsequent reduction using Raney Ni produced the final Yuephos in good yields. The absolute configuration of Yue-1′ was established by single crystal X-ray diffraction.¹⁹ Importantly, the ligands Yuephos can remain stable in air and moisture for more than one year.Open in a separate windowScheme 2Synthesis of Yuephos ligands.With new Yuephos ligands in hand, we began our study by choosing vinyl benzoxazinanone 1a with α-phenylidene succinimide 2a as the model substrate, combined with the Pd₂dba₃·CHCl₃/L complex as the catalyst. Details of [Pd] source and solvent screening can be found in the ESI (Table S1 and S2^†). Notably, using Pd₂dba₃·CHCl₃/Yuephos as the catalyst in ethyl acetate, the reaction proceeded smoothly, affording the desired product 3a in 69% yield with 96% ee and >20 : 1 dr (entry 1). It should be noted that Yuephos ligands were found to be efficient for this reaction, and the product 3a was obtained in good enantioselectivity with seemingly irregular yields and diastereoselectivities (entries 2–6). Trost''s ligand (L1) and chiral diphosphine ligand (L2) promoted the reaction with good diastereoselectivity but in a low yield and poor enantioselectivity (entries 7–8). However, (R)-SegPhos (L3) failed to afford the desired product (entry 9). To our surprise, when the phosphoramidite ligand (L4) was used, the diastereoselectivity was reversed compared to that in Yuephos (entry 10). Thus, a diastereodivergent phenomenon induced by the chiral ligand was discovered. To further improve the yield and selectivity, various solvents and [Pd] sources were screened (Table S3 and S4 in the ESI^†), and an obvious improvement in the enantioselectivity and diastereoselectivity was observed when using DCM as the solvent (entries 10 vs. 11). The reaction enantioselectivity was further increased to 92% with good yield (85%) when the reaction temperature was reduced to −20 °C (entries 12–14).With the optimal conditions established for (S, R, S)-3a (20Optimization of reaction conditions^a