Ligand Relay Catalysis Enables Asymmetric Migratory Hydroarylation for the Concise Synthesis of Chiral α-(Hetero)Aryl-Substituted Amines.

Complementary to the design of a single structurally complex chiral ligand to promote each step in transition-metal catalysis, multiligand relay catalysis through dynamic ligand exchange with each step in the catalytic cycle promoted by its best ligand provides an attractive approach to enhance the whole reaction reactivity and selectivity. Herein, a regio- and enantioselective NiH-catalyzed migratory hydroarylation process with a simple combination of a chain-walking ligand and an asymmetric arylation ligand, producing high-value chiral α-(hetero)aryl-substituted amines and their derivatives under mild conditions, is reported. The potential synthetic applications of this transformation are demonstrated by the concise synthesis of (S)-nicotine and a CDK8 inhibitor.

Nickel-Catalyzed Migratory Cross-Coupling Reactions: New Opportunities for Selective C-H Functionalization.

ConspectusMigratory cross-coupling via metal migration is a process of significant academic and industrial interest. It provides an attractive alternative for the selective installation of a functional group at remote C-H positions from simple precursors, thus enabling the direct synthesis of challenging structures not accessible with traditional cross-coupling. In particular, with the merger of 1,n-Ni/H shift and cross-coupling of nickel, the Ni-catalyzed migratory functionalization of simple precursors has undergone particularly intense development and emerged as a valuable field of research in the past few years. This Account will outline the recent progress made in this arena in terms of migration-functionalization modes, diverse functionalizations, and strategies for regio- and stereocontrol. Mechanistic studies and synthetic applications are also discussed.In detail, we systematically categorize our work into two parts based on the migration modes. In the first part, a platform is created for Ni-catalyzed migratory sp3 C-H functionalization of alkenes or alkyl halides via iterative 1,2-Ni/H shift-selective cross-coupling. The key reactive Ni(II)H species for chain-walking could be generated in situ either in a polarity-reversed fashion relying on stoichiometric reductants (X-Ni(II)-H) or in a redox-neutral fashion with the participation of nucleophilic coupling partners (FG-Ni(II)-H). One significant advantage associated with the polarity-reversed NiH system is the use of relatively stable, abundant, and safe olefin surrogates or alkyl halides instead of the sensitive organometallics required in traditional cross-coupling reactions. Another advantage is that diverse functionalizations, including carbonation and more challenging amination and thiolation could be smoothly achieved with suitable electrophiles or their precursors. Finally, to address the challenging multifaceted selectivity and reactivity issues in asymmetric migratory cross-coupling reactions, we have developed a feasible ligand relay catalytic strategy. In this dynamic ligand exchange process, one ligand promotes rapid migration while the other promotes highly regio- and stereoselective coupling. This innovative strategy overcomes the formidable challenge stemming from the difficulty of designing a single ligand to efficiently promote both steps of chain-walking and asymmetric coupling. In the second part, a new platform for Ni-catalyzed migratory sp2 C-H functionalization via 1,4-Ni/H shift-selective cross-coupling has been reported. Starting from readily available aryl or vinyl coupling partners, the in situ-generated aryl- or vinylnickel(II) species could undergo a rapid and reversible 1,4-Ni/H shift along an sp2 backbone, and subsequent selective coupling with various coupling partners would allow regio- and stereoselective access to diverse 1,4-migratory functionalization products. The key to success was the discovery of an appropriate ligand to efficiently promote both migration and subsequent selective cross-coupling. A vinyl-to-aryl 1,4-Ni/H shift successfully enables the modular ipso/ortho difunctionalization of aryl coupling partners, while an aryl-to-vinyl 1,4-Ni/H shift enables regio- and stereoselective access to functionalized trisubstituted alkenes.We hope that this Account will inspire broad interest and future development of migratory cross-coupling reactions. We strongly believe that continued efforts in this fascinating field will overcome many of the remaining challenges, including cutting-edge ligand/catalyst design to enhance reactivity and selectivity, conceptually new migration modes for additional transformations, and in-depth mechanistic studies for rational reaction design.

Enantio- and Diastereoselective NiH-Catalyzed Hydroalkylation of Enamides or Enecarbamates with Racemic α-Bromoamides.

Catalytic methods which control multiple stereogenic centers simultaneously are highly desirable in modern organic synthesis and chemical manufacturing. Herein, we report a regio-, enantio-, and diastereoselective NiH-catalyzed hydroalkylation process which proceeds with simultaneous control of vicinal stereocenters originating from two readily accessible partners, prochiral internal alkenes (enamides or enecarbamates) and racemic alkyl electrophiles (α-bromoamides or Katritzky salts). This reaction produces high-value ß-aminoamides and their derivatives under mild conditions and with precise selectivity. Preliminary studies of the mechanism indicate that the reaction involves an enantioselective syn-hydronickelation to generate an enantiomerically enriched alkylnickel(II) species. Subsequent enantioconvergent alkylation with a racemic alkyl electrophile generates the desired product as a single stereoisomer.

Synthesis of Enantioenriched 1,2-cis Disubstituted Cycloalkanes by Convergent NiH Catalysis.

Enantioenriched multi-substituted cycloalkanes constitute an essential class of compounds in pharmaceuticals, natural products and agrochemicals. Here we report an NiH-catalyzed asymmetric migratory hydroalkylation process for the efficient and selective construction of such compounds. Through a dynamic kinetic asymmetric transformation (DYKAT), easily accessible racemic and isomeric mixtures of cycloalkenes could be directly utilized as starting materials, convergently producing thermo-dynamically disfavored chiral 1,2-cis disubstituted cycloalkanes bearing vicinal stereocenters with high levels of regio-, diastereo- and enantioselectivity. In addition, prochiral cyclic alkenes can be also employed, and deliver chiral 1,2-cis disubstituted cycloalkanes through desymmetrization process.

Functionalization of Olefinic C-H Bonds by an Aryl-to-Vinyl 1,4-Nickel Migration/Reductive Coupling Sequence.

An attractive approach to selective functionalization of remote C-H bonds is a metal/hydride shift/cross-coupling reaction sequence. Complimentary to the heavily exploited 1,2-nickel/hydride shift along an sp3 chain, a chain-walking process, the 1,4-nickel/hydride shift along an sp2 chain is more complex. Here we report an unprecedented aryl-to-vinyl 1,4-nickel/hydride shift reaction, in which the migratory alkenylnickel species generated in situ is selectively trapped by one of various coupling partners, such as isocyanates, alkyl bromides, aryl chlorides or alkynyl bromides, allowing regio- and stereoselective access to trisubstituted alkenes. In contrast to the well-reported ipso-aryl coupling reactions, this strategy provides remote alkenyl C-H functionalized products with good yield and with excellent chemo-, regio- and E/Z-selectivity.

NiH-Catalyzed Functionalization of Remote and Proximal Olefins: New Reactions and Innovative Strategies.

Transition metal hydride catalyzed functionalization of remote and proximal olefins has many advantages over conventional cross-coupling reactions. It avoids the separate, prior generation of stoichiometric amounts of organometallic reagents and the use of preformed organometallic reagents, which are sometimes hard to access and may compromise functional group compatibility. The migratory insertion of metal hydride complexes generated in situ into readily available alkene starting materials, the hydrometalation process, provides an attractive and straightforward route to alkyl metal intermediates, which can undergo a variety of sequential cross-coupling reactions. In particular, with the synergistic combination of chain-walking and cross-coupling chemistry of nickel, NiH-catalyzed functionalization of remote and proximal olefins has undergone particularly intense development in the past few years. This Account aims to chronicle the progress made in this arena in terms of activation modes, diverse functionalizations, and chemo-, regio-, and enantioselectivity.We first provide a brief introduction to the general reaction mechanisms. Taking remote hydroarylation as an example, the four oxidation states of Ni have allowed us to develop two different reaction strategies to form the final product: a Ni(I)-H/X-Ni(II)-H platform that relies on stoichiometric reductants and a Ni(I/II/III) cycle and a redox-neutral functional group or FG-Ni(II)-H platform that reacts with an alkene substrate and forms the migratory products via a Ni(0/II) pathway. We also demonstrate that diverse functionalization, including general C-C bond-forming reactions and the more challenging C-N/C-S bond-forming reactions could be realized. Moreover, the employment of appropriate chiral ligands has allowed us to successfully realize the corresponding asymmetric hydrofunctionalization reactions of olefins, including hydroalkylation, hydroarylation, hydroalkenylation, hydroalkynylation, and hydroamination. Interestingly, the enantio-determining step could be enantioselective hydronickelation, selective oxidative addition, or selective reductive elimination. To realize more challenging asymmetric migratory hydrofunctionalization, we have developed a general ligand relay catalytic strategy with a combination of two simple ligands, the first for chain-walking and the second for asymmetric coupling. This novel strategy avoids the design of a single, possibly structurally complex chiral ligand to promote both steps of chain-walking and asymmetric coupling. In addition, the success of multicomponent hydrofunctionalization provides a convenient approach to gain simple access to complex molecules. Finally, alkyl halides could be used as olefin precursors to undergo a variety of reductive migratory cross-electrophile coupling reactions. Applications of these remote hydrofunctionalization reactions are also discussed. We hope this Account will inspire future development in the field to overcome key challenges, including conceptually new catalytic strategies, development of high-performance systems with enhanced reactivity and selectivity, cutting-edge catalyst design, and further mechanistic studies.

Ligand Relay Catalysis Enables Asymmetric Migratory Reductive Acylation of Olefins or Alkyl Halides.

Design of ligands in transition-metal catalyzed reactions is challenging, especially in asymmetric transformations. With each step in the catalytic cycle promoted by its privileged ligand and different steps well-connected by dynamic ligand exchange, synergistic combination of multiple ligands could potentially enhance the catalytic efficiency and selectivity. Now, this concept has been applied to the NiH-catalyzed asymmetric remote hydroacylation of olefins and migratory acylation of alkyl halides with excellent regio- and enantioselectivity, utilizing two simple ligands, one for chain-walking and the other for asymmetric acylation. Starting from abundant alkenes/alkyl halides and carboxylic acids, a wide range of enantioenriched chiral α-aryl ketones can be efficiently accessed under mild conditions.

Enantioselective synthesis of α-aminoboronates by NiH-catalysed asymmetric hydroamidation of alkenyl boronates.

Chiral α-aminoboronic acids and their derivatives are generally useful as bioactive compounds and some have been approved as therapeutic agents. Here we report a NiH-catalysed asymmetric hydroamidation process that with a simple amino alcohol ligand can easily produce a wide range of highly enantioenriched α-aminoboronates from alkenyl boronates and dioxazolones under mild conditions. The reaction is proposed to proceed by an enantioselective hydrometallation followed by an inner-sphere nitrenoid transfer and C-N bond forming sequence. The synthetic utility of this transformation was demonstrated by the efficient synthesis of a current pharmaceutical agent, Vaborbactam.

Regio- and enantioselective remote hydroarylation using a ligand-relay strategy.

The design of a single complicated chiral ligand to well-promote each step of an asymmetric cascade reaction is sometimes a formidable challenge in transition metal catalysis. In this work, a highly regio- and enantioselective Ni-catalysed migratory hydroarylation relay process has been achieved with the combination of two simple ligands, one which accomplishes chain-walking and the other causing asymmetric arylation. This formal asymmetric C(sp3)-H arylation provides direct access to a wide range of structurally diverse chiral 1,1-diarylalkanes, a structural unit found in a number of bioactive molecules. The value of this strategy was further demonstrated by the Ni-catalysed migratory asymmetric 1,3-arylboration.

Nickel-Catalyzed Ipso/Ortho Difunctionalization of Aryl Bromides with Alkynes and Alkyl Bromides via a Vinyl-to-Aryl 1,4-Hydride Shift.

Polysubstituted arenes are ubiquitous structures in a myriad of medicinal agents and complex molecules. Herein, we report a new catalytic blueprint that merges the modularity of nickel catalysis for bond formation with the ability to enable a rather elusive 1,4-hydride shift at arene sp2 C-H sites, thus allowing access to ipso/ortho-difunctionalized arenes from readily available aryl halides under mild conditions and exquisite selectivity profile.

Nickel-Catalyzed Multicomponent Coupling: Synthesis of α-Chiral Ketones by Reductive Hydrocarbonylation of Alkenes.

A nickel-catalyzed, multicomponent regio- and enantioselective coupling via sequential hydroformylation and carbonylation from readily available starting materials has been developed. This modular multicomponent hydrofunctionalization strategy enables the straightforward reductive hydrocarbonylation of a broad range of unactivated alkenes to produce a wide variety of unsymmetrical dialkyl ketones bearing a functionalized α-stereocenter, including enantioenriched chiral α-aryl ketones and α-amino ketones. It uses chiral bisoxazoline as a ligand, silane as a reductant, chloroformate as a safe CO source, and a racemic secondary benzyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid as the alkylation reagent. The benign nature of this process renders this method suitable for late-stage functionalization of complex molecules.

Facile Synthesis of Chiral Arylamines, Alkylamines and Amides by Enantioselective NiH-Catalyzed Hydroamination.

Regio- and enantioselective hydroarylamination, hydroalkylamination and hydroamidation of styrenes have been developed by NiH catalysis with a simple bioxazoline ligand under mild conditions. A wide range of enantioenriched benzylic arylamines, alkylamines and amides can be easily accessed by nitroarenes, hydroxylamines and dioxazolones, respectively as amination reagents. The chiral induction in these reactions is proposed to proceed through an enantiodifferentiating syn-hydronickellation step.

Nickel-catalysed migratory hydroalkynylation and enantioselective hydroalkynylation of olefins with bromoalkynes.

α-Chiral alkyne is a key structural element of many bioactive compounds, chemical probes, and functional materials, and is a valuable synthon in organic synthesis. Here we report a NiH-catalysed reductive migratory hydroalkynylation of olefins with bromoalkynes that delivers the corresponding benzylic alkynylation products in high yields with excellent regioselectivities. Catalytic enantioselective hydroalkynylation of styrenes has also been realized using a simple chiral PyrOx ligand. The obtained enantioenriched benzylic alkynes are versatile synthetic intermediates and can be readily transformed into synthetically useful chiral synthons.

Improving Loanword Identification in Low-Resource Language with Data Augmentation and Multiple Feature Fusion.

Loanword identification is studied in recent years to alleviate data sparseness in several natural language processing (NLP) tasks, such as machine translation, cross-lingual information retrieval, and so on. However, recent studies on this topic usually put efforts on high-resource languages (such as Chinese, English, and Russian); for low-resource languages, such as Uyghur and Mongolian, due to the limitation of resources and lack of annotated data, loanword identification on these languages tends to have lower performance. To overcome this problem, we first propose a lexical constraint-based data augmentation method to generate training data for low-resource language loanword identification; then, a loanword identification model based on a log-linear RNN is introduced to improve the performance of low-resource loanword identification by incorporating features such as word-level embeddings, character-level embeddings, pronunciation similarity, and part-of-speech (POS) into one model. Experimental results on loanword identification in Uyghur (in this study, we mainly focus on Arabic, Chinese, Russian, and Turkish loanwords in Uyghur) showed that our proposed method achieves best performance compared with several strong baseline systems.

NiH-catalyzed asymmetric hydroarylation of N-acyl enamines to chiral benzylamines.

Enantiomerically pure chiral amines and related amide derivatives are privilege motifs in many pharmacologically active molecules. In comparison to the well-established hydroamination, the transition metal-catalysed asymmetric hydrofunctionalization of enamines provides a complementary approach for their construction. Here we report a NiH-catalysed enantio- and regioselective reductive hydroarylation of N-acyl enamines, allowing for the practical access to a broad range of structurally diverse, enantioenriched benzylamines under mild, operationally simple reaction conditions.

Nickel-Catalyzed, Regio- and Enantioselective Benzylic Alkenylation of Olefins with Alkenyl Bromide.

A NiH-catalyzed migratory hydroalkenylation reaction of olefins with alkenyl bromides has been developed, affording benzylic alkenylation products with high yields and excellent chemoselectivity. The mild conditions of the reaction preclude olefinic products from undergoing further isomerization or subsequent alkenylation. Catalytic enantioselective hydroalkenylation of styrenes was achieved by using a chiral bisoxazoline ligand.

Extracting Parallel Sentences from Nonparallel Corpora Using Parallel Hierarchical Attention Network.

Collecting parallel sentences from nonparallel data is a long-standing natural language processing research problem. In particular, parallel training sentences are very important for the quality of machine translation systems. While many existing methods have shown encouraging results, they cannot learn various alignment weights in parallel sentences. To address this issue, we propose a novel parallel hierarchical attention neural network which encodes monolingual sentences versus bilingual sentences and construct a classifier to extract parallel sentences. In particular, our attention mechanism structure can learn different alignment weights of words in parallel sentences. Experimental results show that our model can obtain state-of-the-art performance on the English-French, English-German, and English-Chinese dataset of BUCC 2017 shared task about parallel sentences' extraction.

Enantio- and Regioselective NiH-Catalyzed Reductive Hydroarylation of Vinylarenes with Aryl Iodides.

A highly enantio- and regioselective hydroarylation process of vinylarenes with aryl halides has been developed using a NiH catalyst and a new chiral bis imidazoline ligand. A broad range of structurally diverse, enantioenriched 1,1-diarylalkanes, a structure found in a number of biologically active molecules, have been obtained with excellent yields and enantioselectivities under extremely mild conditions.

Ligand-Enabled Nickel-Catalyzed Redox-Relay Migratory Hydroarylation of Alkenes with Arylborons.

A redox-relay migratory hydroarylation of isomeric mixtures of olefins with arylboronic acids catalyzed by nickel complexes bearing diamine ligands is described. A range of structurally diverse 1,1-diarylalkanes, including those containing a 1,1-diarylated quaternary carbon, were obtained in excellent yields and with high regioselectivity. Preliminary experimental evidence supports the proposed non-dissociated chainwalking of aryl-nickel(II)-hydride species along the alkyl chain of alkenes before selective reductive elimination at a benzylic position. A catalyst loading as low as 0.5 mol % proved to be sufficient in large-scale synthesis while retaining high reactivity, highlighting the practical value of this transformation.

NiH-Catalyzed Migratory Defluorinative Olefin Cross-Coupling: Trifluoromethyl-Substituted Alkenes as Acceptor Olefins to Form gem-Difluoroalkenes.

We report a NiH-catalyzed migratory defluorinative coupling between two electronically differentiated olefins. A broad range of unactivated donor olefins can be joined directly to acceptor olefins containing an electron-deficient trifluoromethyl substituent in both intra- and intermolecular fashion to form gem-difluoroalkenes. This migratory coupling shows both site- and chemoselectivity under mild conditions, with the formation of a tertiary or quaternary carbon center.