Copper-catalyzed multicomponent assembly of γ-butenolides via the interception of carbonyl ylides with iminium ions.

A Cu(I)-catalyzed three-component reaction of cyclopropenes, enamines and aldehydes has been realized. This reaction proceeds via the interception of carbonyl oxonium ylide intermediates with α, ß-unsaturated iminium ions that are in situ generated from enamines and aldehydes under the catalysis of Cu(MeCN)4PF6, leading to the desired γ-butenolide derivatives in good yields and with moderate diastereoselectivities. Access to these derivatives with tethered ketone and alkynal groups will expand the structural diversity of multi-substituted butenolides.

Multicomponent Assembly of Complex Oxindoles by Enantioselective Cooperative Catalysis.

Chiral oxindoles are important chemical scaffolds found in many natural products, and their enantioselective synthesis thus attracts considerable attention. Highly diastereo- and enantioselective synthetic methods for constructing C3 quaternary oxindoles have been well-developed. However, the efficient synthesis of chiral 3-substituted tertiary oxindoles has been rarely reported due to the ease of racemization of the tertiary stereocenter via enolization. Therefore, we herein report on the multicomponent assembly (from N-aryl diazoamides, aldehydes, and enamines/indoles) of complex oxindoles by enantioselective cooperative catalysis. These reactions proceed under mild conditions and show broad substrate scope, affording the desired coupling products (>90 examples) with good to excellent stereocontrol. Additionally, this research also demonstrates the synthetic potential of this annulation by constructing the 6,6,5-tricyclic lactone core structure of Speradine A.

Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds.

One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2═CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

A rhodium-catalysed three-component reaction to access C1-substituted tetrahydroisoquinolines.

A rhodium-catalyzed three-component reaction of diazo compounds, anilines and C,N-cyclic azomethine imines via trapping of transient ammonium ylides was developed. This reaction provided a simple and convenient approach for the synthesis of pharmaceutically intriguing tetrahydroisoquinoline derivatives in moderate to good yields (36-85%) with good diastereoselectivities (up to 95 : 5 dr) under mild reaction conditions.

Diazo Esters as Dienophiles in Intramolecular (4 + 2) Cycloadditions: Computational Explorations of Mechanism.

The first experimental examples of Diels-Alder (DA) reactions of diazo compounds as heterodienophiles with dienes have been studied with density functional theory (DFT) using the M06-2X functional. For comparison, the reactivities of diazo esters as dienophiles or 1,3-dipoles with 1,3-dienes in intermolecular model systems have been analyzed by the distortion/interaction model. The 1,3-dipolar cycloaddition is strongly favored for the intermolecular system. The intramolecular example is unique because the tether strongly favors the (4 + 2) cycloaddition.

Diverse Pathways in Catalytic Reactions of Propargyl Aryldiazoacetates: Selectivity between Three Reaction Sites.

Three catalyst-dependent divergent reaction pathways for reactions of propargyl aryldiazoacetates are disclosed. Transition metal catalysts including those of rhodium(II), palladium(0 and II), silver(I), mercury(II), copper(I and II), platinum(II), and cationic gold(I) are effective for reactions that proceed through dinitrogen extrusion, carbene/alkyne metathesis, and aromatic substitution to form fused indeno-furanones, and use of tetrakis(acetonitrile)copper(I) provides indeno-furanones in the highest product yields. A Lewis acid catalyzed pathway that forms furan-2-ones is uncovered with FeCl3, ZnBr2, and BF3·Et2O as catalysts that proceed through activation of the aryldiazoacetate ester for arylpropargyl cation dissociation followed by recombination through cation addition to the diazo carbon. Neutral gold catalysts selectively activate the triple bond of propargyl aryldiazoacetates, resulting in the formation of allenic aryldiazoesters that further undergo uncatalyzed rearrangement.

Unprecedented Intramolecular [4 + 2]-Cycloaddition between a 1,3-Diene and a Diazo Ester.

Diazo compounds that are well-known to undergo [3 + 2]-cycloaddition provide the first examples of the previously unknown [4 + 2]-cycloaddition with dienes that occur thermally under mild conditions and in high yields. Reactions are initiated from reactants prepared from propargyl aryldiazoacetates that undergo gold(I)-catalyzed rearrangement to activated 1,3-dienyl aryldiazoacetates. These reactions proceed to mixtures of both [4 + 2]-cycloaddition and the 1,3-dienyl aryldiazoacetate after long reaction times. At short reaction times, however, both E- and Z-1,3-dienyl aryldiazoacetates are formed and, after isolation, thermal reactions with the E-isomers form the products from [4 + 2]-cycloaddition with ΔH(‡)298 = 15.6 kcal/mol and ΔS(‡)298 = -27.3 cal/(mol·°C). The Z-isomer is inert to [4 + 2]-cycloaddition under these conditions. The Hammett relationships from aryl-substituted diazo esters (ρ = +0.89) and aryl-substituted dienes (ρ = -1.65) are consistent with the dipolar nature of this transformation.

Catalyst-Free Rearrangement of Allenyl Aryldiazoacetates into 1,5-Dihydro-4H-pyrazol-4-ones.

Phenylpropargyl diazoacetates exist in equilibrium with 1-phenyl-1,2-dien-1-yl diazoacetate - allenes that are rapidly formed at room temperature through 1,3-acyloxy migration catalyzed by gold(I) or gold(III) compounds, and these catalysts react solely with the π-donor rather than with the diazo group. The product allene of the aryldiazoacetates undergoes rearrangement that is not catalyzed by gold in which the terminal nitrogen of the diazo functional group adds to the central carbon of the allene, initiating a sequence of bond-forming reactions, resulting in the production of 1,5-dihydro-4H-pyrazol-4-ones in good yields. These 1,5-dihydro-4H-pyrazol-4-ones undergo intramolecular 1,3-acyl migration to form an equilibrium mixture and can quantitatively transfer the acyl group to an external nucleophile with formation of 4-hydroxypyrazoles. Reactions of phenylpropargyl phenyldiazoacetates catalyzed by cationic gold complexes are initiated at the diazo functional group to form a gold carbene whose subsequent cascade process (intramolecular addition, then aromatic substitution) results in the formation of a product that is uniquely characteristic of this pathway.

Construction of 4-hydroxycoumarin derivatives with adjacent quaternary and tertiary stereocenters via ternary catalysis.

4-Hydroxycoumarin derivatives represent one of the most important scaffolds in biologically active substances, pharmaceuticals and functional materials. Herein, we describe an efficient Pd/amine/Brønsted acid ternary-catalytic multicomponent reaction for the rapid construction of substituted 4-hydroxycoumarin derivatives with adjacent quaternary and tertiary stereocenters via convergent assembly of two in situ generated active intermediates. Furthermore, the late-stage transformations of coumarin derivatives and their in vitro trial of antitumor activity successfully demonstrated the potential utilities of the products as platform molecules.

Photoredox-Catalyzed Carbonyl Alkylative Amination with Diazo Compounds: A Three-Component Reaction for the Construction of γ-Amino Acid Derivatives.

A photoredox-catalyzed reaction of secondary amines, aldehydes, diazo compounds, and Hantzsch ester is reported, affording biologically active γ-amino acid derivatives in high yields. This one-pot process tolerates a broad range of functional groups and various drug molecules and biologically active compounds. Remarkably, a gram-scale reaction and diverse transformations of γ-amino acid derivatives were successfully performed, and the utility of the products is demonstrated in the synthesis of therapeutic agent pregabalin.

Functionalization of DNA-Tagged Alkenes with Diazo Compounds via Photocatalysis.

To explore potential chemical space using DNA-encoded library (DEL) technology, the development of various types of robust DNA-compatible reactions is urgently needed. Diazo compounds, which serve as valuable building blocks and important synthons in synthetic chemistry, have been rarely applied in DEL synthesis, probably because of their potential modifications of the bases and phosphate backbone of DNA. Herein we report two cases of DNA-compatible reactions with alkenes and diazo compounds, providing corresponding hydroalkylation and cyclopropanation products in moderate to excellent yields. Notably, these transformations not only provide new access to C(sp3)-C(sp3) bond formation in DELs with excellent functional group tolerance but also represent practical ligation methods to introduce functionalized molecules into DNA.

An enantioselective four-component reaction via assembling two reaction intermediates.

A reaction intermediate is a key molecular entity that has been used in explaining how starting materials converts into the final products in the reaction, and it is usually unstable, highly reactive, and short-lived. Extensive efforts have been devoted in identifying and characterizing such species via advanced physico-chemical analytical techniques. As an appealing alternative, trapping experiments are powerful tools in this field. This trapping strategy opens an opportunity to discover multicomponent reactions. In this work, we report various highly diastereoselective and enantioselective four-component reactions (containing alcohols, diazoesters, enamines/indoles and aldehydes) which involve the coupling of in situ generated intermediates (iminium and enol). The reaction conditions presented herein to produce over 100 examples of four-component reaction products proceed under mild reaction conditions and show high functional group tolerance to a broad range of substrates. Based on experimental and computational analyses, a plausible mechanism of this multicomponent reaction is proposed.

A gold(i)-catalysed chemoselective three-component reaction between phenols, α-diazocarbonyl compounds and allenamides.

Gold(i) catalysts are considered to be efficient in promoting sp2 C-H bond insertion at the para position of unprotected phenols because of the exceptionally chemical reactivity of gold-stabilized carbophilic carbocations. Herein, we present a gold(i)-catalysed three-component reaction between phenols, diazocarbonyl compounds and allenamides, affording the corresponding three-component reaction products with excellent geometric selectivity (E : Z > 20 : 1) in moderate to high yields (up to 90%) under mild conditions. Additionally, a gram-scale transformation and diverse transformations of the resulting product show the high synthetic utility of the present three-component protocol.

A gold(i)-catalysed three-component reaction via trapping oxonium ylides with allenamides.

A gold(i)-catalysed three-component reaction between alcohols (and water), α-aryl-α-diazoesters and allenamides has been developed, affording three-component products, tert-allylic ethers (and alcohols), in moderate to excellent yields with excellent geometric selectivity (E : Z > 20 : 1). In addition, this transformation proceeds smoothly with high functional group tolerance and a broad substrate scope under exceptionally mild reaction conditions. Remarkably, a gram-scale reaction is also successfully performed, and the corresponding three-component product can readily react with easily obtained reagents, furnishing diverse products in satisfactory yields.

Asymmetric Multicomponent Reactions for Efficient Construction of Homopropargyl Amine Carboxylic Esters.

Developing an efficient and highly enantioselective protocol to access homopropargyl amines is of high interest to the synthetic community and also remains a formidable challenge for organic chemists. Here, we present integrated Rh2(OAc)4- and BINOL-derived chiral phosphoric acid cooperatively catalyzed three-component reactions of alkynyldiazoacetates, imines with various nucleophiles including alcohols, indoles, and N,N-disubstituted anilines, affording the corresponding homopropargyl amines containing two vicinal chiral centers in satisfactory yields with high to excellent diastereo- and enantioselectivities.

Intramolecular cycloaddition/rearrangement cascade from gold(iii)-catalysed reactions of propargyl aryldiazoesters with cinnamyl imines.

Conjugated cycloheptene-1,4-dione-enamines are cycloaddition products from a surprising rearrangement in a Au(iii)-catalysed reaction between propargyl aryldiazoacetates and cinnamyl imines. This complex transformation occurs through an initial rapid Au(iii)-catalysed [4+3]-cycloaddition to form dihydroazepinyl aryldiazoacetates followed by a subsequent uncatalyzed domino transformation that occurs by sequential [3+2]-cycloaddition-/nitrogen extrusion and acyloxy migration/retro-Michael addition/tautomerization.

Efficient synthesis of chiral cyclic acetals by metal and Brønsted acid co-catalyzed enantioselective four-component cascade reactions.

Four-component Mannich reactions subsequently followed by an intramolecular oxo-Michael addition were developed to efficiently produce chiral cyclic acetals with high diastereoselectivity and enantioselectivity.

Highly efficient synthesis of mixed 3,3'-bisindoles via Rh(II)-catalyzed three-component reaction of 3-diazooxindoles with indoles and ethyl glyoxylate.

A series of mixed 3,3'-bisindoles were efficiently synthesized via a Rh2(OAc)4-catalyzed three-component reaction of 3-diazooxindoles with indoles and ethyl glyoxylate in high yields with excellent diastereoselectivities. The product easily underwent further synthetic transformations and could be potentially applied to the total synthesis of (±)-gliocladin C and related natural alkaloids.

Highly enantioselective trapping of zwitterionic intermediates by imines.

Reactions with the unstable and highly reactive zwitterionic intermediates generated in processes catalysed by transition metals are providing new opportunities for molecular constructions. Insertion reactions involve the collapse of zwitterionic intermediates, but trapping them would allow structural elaborations that are not currently available. To synthesize complex molecules in this manner, reactive electrophiles can be used to trap the zwitterionic intermediates. Here, we describe the use of imines, activated by chiral organocatalysts, and a highly efficient integrated rhodium and chiral Brønsted acid co-catalysed process to trap zwitterionic intermediates that have been proposed previously to undergo a formal C-H insertion reaction, allowing us to obtain polyfunctionalized indole and oxindole derivatives in a single step with excellent diastereoselectivity and enantioselectivity.