Nickel‐Catalyzed Allylic Alkylation with Diarylmethane Pronucleophiles: Reaction Development and Mechanistic Insights

Palladium‐catalyzed allylic substitution reactions are among the most efficient methods to construct C?C bonds between sp³‐hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a “soft”‐nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with “hard” nucleophiles, which attack the metal before C?C bond formation. Introduced herein is a rare nickel‐based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft‐nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising.     

Allylic Functionalization of Unactivated Olefins with Grignard Reagents

New advances in the functionalization of unactivated olefins with carbon nucleophiles have provided more efficient and practical approaches to convert inexpensive starting materials into valuable products. Recent examples have been reported with stabilized carbon nucleophiles, tethered carbon nucleophiles, diazoesters, and trifluoromethane donors. A general method for functionalizing olefins with aromatic, aliphatic, and vinyl Grignard reagents was developed. In a one‐pot process, olefins are oxidized by a commercially available reagent to allylic electrophiles, which undergo selective copper‐catalyzed allylic alkylation with Grignard reagents. Products are formed in high yield and with high regioselectivity. This was utilized to synthesize a series of skipped dienes, a class of compounds that are prevalent in natural products and are difficult to synthesize by known allylic alkylation methods.     

Chiral Primary Amine/Palladium Dual Catalysis for Asymmetric Allylic Alkylation of β‐Ketocarbonyl Compounds with Allylic Alcohols

An efficient dual catalytic system composed of a chiral primary amine and a palladium complex was developed to promote the direct asymmetric allylic alkylation (AAA) of β‐ketocarbonyl compounds. In particular, the synergistic dual catalytic system enabled the AAA reaction of challenging acyclic aliphatic ketones, such as β‐ketocarbonyl compounds and 1,3‐diketones.     

Byproduct‐Catalyzed Four‐Component Reactions of Aldehydes with Hexamethyldisilazane,Chloroformates, and Nucleophiles in Acetonitrile Leading to Protected Primary Amines, β‐Amino Esters,and β‐Amino Ketones

Multicomponent reactions are a very powerful tool for the construction of complex organic molecules by using readily available starting materials. While most of the multicomponent reactions discovered so far consist of three components, the reactions with four or more components remain sparse. We have successfully developed several four‐component reactions using a catalytic amount of water as a hydrolyzing agent to decompose byproduct chlorotrimethylsilane (TMSCl) to yield secondary byproduct HCl that serves as a catalyst. In the presence of 40 mol % of water, the four‐component reaction of aldehydes with hexamethyldisilazane (HMDS), chloroformates, and silylated nucleophiles proceeds smoothly at room temperature to give a range of protected primary amines in moderate to excellent yields. Importantly, a wide variety of protic carbon nucleophiles, such as β‐keto esters, β‐diketones, and ketones, have further been explored as suitable substrates for the synthesis of protected β‐amino esters and β‐amino ketones that are useful building blocks for various pharmaceuticals and natural products. These four‐component reactions proceed through a pathway of tandem nitrogen protection/imine formation/imine addition, and the decomposition of byproduct TMSCl, generated in the first step of nitrogen protection, with water results in the formation of secondary byproduct HCl, a strong Brønsted acid that catalyzes the following imine formation/imine addition. Taking advantage of the fact that alcohols or phenols are also able to decompose byproduct TMSCl to yield secondary byproduct HCl, no catalyst is needed at all for the four‐component reactions with aldehydes bearing hydroxy groups.     

Silver(I)‐Catalyzed Tandem 1,3‐Acyloxy Migration/Mannich‐type Addition/Elimination of the Sulfonyl Group of N‐Sulfonylhydrazone‐propargylic Esters to 5,6‐Dihydropyridazin‐4‐one Derivatives

The addition of nucleophiles to C?N bonds offers a highly efficient synthetic strategy for accessing nitrogen‐containing molecules. 1 Among the well‐developed addition reactions, such as the highly efficient Mannich reaction, various C? H bond‐activated compounds including carboxylic acid derivatives, nitroalkanes, and terminal alkynes have been applied as nucleophiles to achieve different classes of amines. 2 However, employing new nucleophiles without activated C? H bonds, such as internal alkynes and allenic esters are limited when using metal catalysts. 3 Herein, we wish to report a new addition of allenic esters to C?N bonds initiated by a silver‐catalyzed 1,3‐migration of propargylic esters.     

Nickel‐Catalyzed Site‐Selective Amidation of Unactivated C(sp3)H Bonds

Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp³ carbon atoms by a nickel‐catalyzed C?H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C?H bonds of β‐methyl groups over the γ‐methyl or β‐methylene groups. Additionally, a predominant preference for the β‐methyl C?H bonds over the aromatic sp² C?H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp³ C?H bonds.     

Asymmetric Allylic Alkylation of β‐Ketoesters with Allylic Alcohols by a Nickel/Diphosphine Catalyst

Asymmetric allylic alkylation of β‐ketoesters with allylic alcohols catalyzed by [Ni(cod)₂]/(S)‐H₈‐BINAP was found to be a superior synthetic protocol for constructing quaternary chiral centers at the α‐position of β‐ketoesters. The reaction proceeded in high yield and with high enantioselectivity using various β‐ketoesters and allylic alcohols, without any additional activators. The versatility of this methodology for accessing useful and enantioenriched products was demonstrated.     

Knoevenagel Adducts as Trimethylenemethane Dipole Surrogates

Knoevenagel adducts derived from readily available acetoxyacetone and malonic acid derivatives served as trimethylenemethane surrogates for formal 1,3‐difunctionalization through a sequence of selective γ‐deprotonation/α‐alkylation and palladium(0)‐catalyzed allylic alkylation. Herein, we report the discovery and development of a three‐component 1,3‐difunctionalization of Knoevenagel adducts as well as a unique palladium(0)‐catalyzed branch‐selective allylic alkylation.     

Rhodium‐Catalyzed Regioselective N2‐Alkylation of Benzotriazoles with Diazo Compounds/Enynones via a Nonclassical Pathway

A novel rhodium‐catalyzed highly selective N²‐alkylation of benzotriazoles with diazo compounds/enynones is achieved, providing N²‐alkylated benzotriazoles in good to excellent yields and with excellent N² selectivities. Importantly, different to traditional carbene insertion into X?H (X=N, O etc) bonds, DFT calculations disclose that this selective N²‐alkylation probably proceeds through a formal 1,3‐ rather than 1,2‐H shift to give the final products.     

Practical Synthesis of anti‐β‐Hydroxy‐α‐Amino Acids by PdII‐Catalyzed Sequential C(sp3)H Functionalization

An improved and practical procedure for the stereoselective synthesis of anti‐β‐hydroxy‐α‐amino acids (anti‐βhAAs), by palladium‐catalyzed sequential C(sp³)?H functionalization directed by 8‐aminoquinoline auxiliary, is described. followed by a previously established monoarylation and/or alkylation of the β‐methyl C(sp³)?H of alanine derivative, β‐acetoxylation of both alkylic and benzylic methylene C(sp³)?H bonds affords various anti‐β‐hydroxy‐α‐amino acid derivatives. As an example, the synthesis of β‐mercapto‐α‐amino acids, which are highly important to the extension of native chemical ligation chemistry beyond cysteine, is described. The synthetic potential of this protocol is further demonstrated by the synthesis of diverse β‐branched α‐amino acids. The observed diastereoselectivities are strongly influenced by electronic effects of aromatic AAs and steric effects of the linear side‐chain AAs, which could be explained by the competition of intramolecular C?OAc bond reductive elimination from Pd^IV intermediates vs. intermolecular attack by an external nucleophile (AcO^?) in an S_N2‐type process.     

Enantioselective Synthesis of Vicinal All‐Carbon Quaternary Centers via Iridium‐Catalyzed Allylic Alkylation

The development of the first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers is disclosed. The iridium‐catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo‐ and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all‐carbon quaternary stereocenters.     

First example of a heterobimetallic 'Pd-Sn' catalyst for direct activation of alcohol: efficient allylation, benzylation and propargylation of arenes, heteroarenes, active methylenes and allyl-Si nucleophiles

Arenes, heteroarenes, 1,3-dicarbonyls and organosilicon nucleophiles undergo highly efficient alkylation with allylic, propargylic and benzylic alcohols in the presence of a new 'Pd-Sn' bimetallic catalyst in nitromethane; water being the sole byproduct. The plausible mechanism of alkylation and the intermediacy of ether has been enumerated.     

Enantioselective Alkylation of N‐Arylhydrazones Derived from α‐Keto Esters and Isatin Derivatives through Asymmetric Phase‐Transfer Catalysis

The phase‐transfer‐catalyzed asymmetric alkylation reactions of N‐arylhydrazones derived from α‐keto‐esters and isatin derivatives afford enantioenriched azo compounds that bear a tetra‐substituted carbon stereocenter in good yields with high chemo‐ and enantioselectivity. The alkylation products can be readily converted into chiral amino esters, hydrazine derivatives, and aza‐β‐lactams without loss of enantiopurity.     

Applications of Transition‐Metal‐Catalyzed Asymmetric Allylic Substitution in Total Synthesis of Natural Products: An Update

Metal‐catalyzed asymmetric allylic substitution (AAS) reaction is one of the most synthetically useful reactions catalyzed by metal complexes for the formation of carbon‐carbon and carbon‐heteroatom bonds. It comprises the substitution of allylic substrates with a wide range of nucleophiles or S_N2′‐type allylic substitution, which results in the formation of the above‐mentioned bonds with high levels of enantioselective induction. AAS reaction tolerates a broad range of functional groups, thus has been successfully applied in the asymmetric synthesis of a wide range of optically pure compounds. This reaction has been extensively used in the total synthesis of several complex molecules, especially natural products. In this review, we try to highlight the applications of metal (Pd, Ir, Mo, or Cu)‐catalyzed AAS reaction in the total synthesis of the biologically active natural products, as a key step, updating the subject from 2003 till date.     

Metal-free oxidative C-C bond formation of active methylenic sp C-H bonds with benzylic sp C-H and allylic sp C-H bonds mediated by DDQ

An efficient and simple method for the oxidative coupling of benzylic and allylic sp³ C-H bonds with active methylenic sp³ C-H bonds under metal-free conditions was developed by employing 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) as an oxidant. The reaction was shown to proceed smoothly for various 1,3-dicarbonyl compounds with a range of benzylic and allylic substrates in good to excellent yields.     

Development of Chemo‐ and Enantioselective Palladium‐Catalyzed Decarboxylative Asymmetric Allylic Alkylation of α‐Nitroesters

We describe the development of a Pd‐catalyzed decarboxylative asymmetric allylic alkylation of α‐nitro allyl esters to afford acyclic tetrasubstituted nitroalkanes. Optimization of the reaction parameters revealed unique ligand and solvent combinations crucial for achieving chemo‐ and enantioselective C‐alkylation of electronically challenging benzylic nitronates and sterically encumbered 2‐allyl esters. Substrates were efficiently accessed in a combinatorial fashion by a cross‐Claisen/ α‐arylation sequence. The method provides functional group orthogonality that complements nucleophilic imine allylation strategies for α‐tertiary amine synthesis.     

Anilines as C‐Nucleophiles in Ir‐Catalyzed Intramolecular Asymmetric Allylic Substitution Reactions

Anilines generally act as N‐nucleophiles in transition‐metal‐catalyzed allylic substitution reactions. In this paper, a highly enantioselective intramolecular Friedel–Crafts‐type allylic alkylation of aniline derivatives was realized by using an iridium catalyst derived from [Ir(cod)Cl]₂ and (R _a)‐BHPphos. Various tetrahydroisoquinilin‐5‐amines were obtained in moderate to good yields, excellent enantioselectivity and regioselectivity under mild reaction conditions. BHPphos=N ‐benzhydryl‐N ‐phenyldinaphthophosphoramidite.     

Enantioselective Copper‐Catalyzed Intermolecular Amino‐ and Azidocyanation of Alkenes in a Radical Process

Asymmetric copper‐catalyzed intermolecular amino‐ and azidocyanation reactions of alkenes have been developed that proceed via a radical process in which a key benzylic radical intermediate is enantioselectively trapped by a chiral Box/Cu^II cyanide complex. A variety of enantiomerically enriched β‐amino/azido alkylnitriles were efficiently synthesized. The β‐azido alkylnitriles could be converted into a series of highly valuable optically active amine‐based building blocks and bioactive compounds.     

Brønsted acid-catalyzed benzylation of 1,3-dicarbonyl derivatives

The direct alkylation of 1,3-dicarbonyl compounds with benzylic alcohols is shown to be efficiently catalyzed by simple Br?nsted acids such as triflic acid (TfOH) and p-toluenesulfonic acid (PTS) to give rise to monoalkylated dicarbonyl derivatives in high yields. In the absence of the nucleophile, substituted alkenes, generated through a formal dimerization reaction, are obtained. The reactions are carried out in air using undried solvents, with water being the only side product of the process.     

Direct substitution of the hydroxy group with highly functionalized nitrogen nucleophiles catalyzed by Au(III)

A direct catalytic substitution of various allylic and benzylic alcohols with synthetically useful, but acid-sensitive Boc, Bus, and Dios protected amine nucleophiles, which have not been well utilized for Lewis acid catalysis, with various functionalities (OTBS, OTHP, etc.) was efficiently catalyzed by 1 mol% of Au(III) under mild conditions.