Palladium-catalyzed ring expansion reaction of (Z)-1-(1,3-butadienyl)cyclobutanols with aryl iodides. stereospecific synthesis of (Z)-2-(3-aryl-1-propenyl)cyclopentanones

[reaction: see text] A novel type of cascade ring expansion process has been developed by the palladium-catalyzed reaction of (Z)-1-(1,3-butadienyl)cyclobutanols with aryl iodides. The reaction proceeds in a stereospecific manner to produce (Z)-2-(3-aryl-1-propenyl)cyclopentanones. It has also been found that regioselective alpha-arylation of alkenyl cyclopentanones proceeds to afford the alpha-arylated cyclopentanones.     

An efficient route to tetrahydroindeno[2,1-b]pyrroles via a base-promoted reaction of (E)-2-alkynylphenylchalcone with 2-isocyanoacetate

A base-promoted cascade reaction of (E)-2-alkynylphenylchalcone with 2-isocyanoacetate provides a novel and efficient route for the synthesis of tetrahydroindeno[2,1-b]pyrroles. The reaction proceeds smoothly in air under mild conditions with high efficiency.     

Silicon-initiated carbonylative carbotricyclization and [2+2+2+1] cycloaddition of enediynes catalyzed by rhodium complexes

The reaction of dodec-11-ene-1,6-diynes or their heteroatom congeners with a hydrosilane catalyzed by Rh(acac)(CO)2 at ambient temperature and pressure of CO gives the corresponding fused 5-7-5 tricyclic products, 5-oxo-1,3a,4,5,7,9-hexahydro-3H-cyclopenta[e]azulenes or their heteroatom congeners, in excellent yields through a unique silicon-initiated cascade carbonylative carbotricyclization (CO-SiCaT) process. It has also been found that the 5-7-5 fused tricyclic products can be obtained from the same type of enediynes and CO through a novel intramolecular [2+2+2+1] cycloaddition process. The characteristics of these two tricyclization processes and the fundamental differences in their reaction mechanisms are discussed. This novel higher-order cycloaddition reaction has also been successfully applied to the tricyclization of undeca-5,10-diyn-1-als, affording the corresponding 5-7-5 fused-ring products bearing a seven-membered lactone moiety. Related [2+2+2] tricyclizations of enediyne and diynal substrates are also discussed. These newly discovered reactions can construct multiple bonds all at once, converting linear starting materials to polycyclic compounds in a single step. Thus, these new processes provide innovative routes to functionalized polycyclic compounds that are useful for the syntheses of natural and unnatural products.     

Additions of allenyl/propargyl organometallic reagents to 4-oxoazetidine-2-carbaldehydes: novel palladium-catalyzed domino reactions in allenynes

Metal-mediated carbonyl allenylation and propargylation of 4-oxoazetidine-2-carbaldehydes were investigated in aqueous environment. Different propargyl bromide and metal promoters showed varied regio- and stereoselectivities on product formation. In addition, an unprecedented one-pot stereoselective synthesis of beta-chlorinated allylic alcohols, which can also be considered as functionalized allylsilanes, has been developed, which involves tin(IV) chloride-mediated reaction of propargyltrimethylsilane and 4-oxoazetidine-2-carbaldehydes. Some of the resulting coupling products were submitted to transition metal catalyzed reactions, such as the allenic Pauson-Khand and palladium-catalyzed reactions, leading to novel fused or bridged tricyclic beta-lactams. Remarkably, a novel domino process, namely the allene cyclization/intramolecular Heck reaction was found. A likely mechanism for the cascade reaction should involve an intramolecular cyclization on a (pi-allyl)palladium complex and a Heck-type reaction.     

Cu(OAc)2/TEMPO Cooperative Promoted Hydroamination Cyclization and Oxidative Dehydrogenation Cascade Reaction of Homopropargylic Amines

A novel and efficient Cu(OAc)₂‐catalyzed hydroamination cyclization and 2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPO)‐mediated oxidative dehydrogenation cascade reaction of homopropargylic amines has been developed. A library of 1,2‐disubstituted pyrrole derivatives were obtained in good‐to‐high yields in one pot with no step‐by‐step feeding process. This reaction involved TEMPO playing dual roles as both an oxidative dehydrogenation reagent and a ligand. An insight into the reaction mechanism was obtained by using several analytical determination methods.     

Cu(II) catalyzed oxidation-[3+2] cycloaddition-aromatization cascade: efficient synthesis of pyrrolo [2, 1-a] isoquinolines

A novel and synthetically efficient Cu(II) catalyzed oxidation-dipolar cycloaddition-aromatization cascade reaction has been developed for a "one-pot" synthesis of biologically important pyrrolo [2, 1-a] isoquinolines.     

alpha-(Arylthio)imidoyl Radicals: [3 + 2] Radical Annulation of Aryl Isothiocyanates with 2-Cyano-Substituted Aryl Radicals

A novel cascade radical reaction is described involving aryl isothiocyanates and 2-cyanoaryl radicals. The mechanism entails the formation of an alpha-(arylthio)imidoyl radical, a 5-exo-dig cyclization onto a cyano group, and a final 6-membered ring closure of an iminyl radical. The competitive 5-membered spiro-cyclization of the iminyl, leading to an isomeric product, was only observed in the case of a disubstituted aryl isothiocyanate. The whole process involves a rare example of [3 + 2] radical annulation and allows the one-pot synthesis of tetracondensed nitrogen heterocycles in good yields.     

A cascade Heck-Aldol-Heck reaction by a combination of transition-metal catalysis and aminocatalysis

An unprecedented cascade Heck-Aldol-Heck reaction was developed to form two C-C single bonds and one C=C double bond in one process by a combination of palladium(0) catalysis and aminocatalysis. Various aryl iodides could perform the cascade reaction with readily available propenol and formaldehyde to afford novel (E)-trisubstituted alkenes in 66-81% yields.     

Mechanistic investigations of the ZnCl2-mediated tandem Mukaiyama aldol lactonization: evidence for asynchronous, concerted transition states and discovery of 2-oxopyridyl ketene acetal variants

The ZnCl(2)-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted β-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl(2)-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama "open" or Zimmerman-Traxler "chair-like" transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl(2) and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated β-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to β-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system.     

BF3 x Et2O-mediated cascade cyclizations: synthesis of schweinfurthins F and G

The total synthesis of the natural stilbene (+)-schweinfurthin G (8) has been accomplished through a sequence based on an efficient cationic cascade cyclization. This cascade process is initiated by Lewis acid promoted ring opening of an epoxide and terminated through a novel reaction with a phenolic oxygen "protected" as its MOM ether. Several Lewis acids have been examined for their ability to induce this new reaction, and BF3 x Et2O was found to be the most effective. The only major byproduct under these conditions was one where the expected secondary alcohol was found as its MOM ether derivative (e.g., 30). While this byproduct could be converted to the original target compound through hydrolysis, it also could be employed as a protected alcohol to allow preparation of a benzylic phosphonate (43) without dehydration of the secondary alcohol. The resulting phosphonate was employed in a Horner-Wadsworth-Emmons condensation with an aldehyde representing the right half of the target compounds, an approach complementary to previous studies based on condensation of a right-half phosphonate and a left-half aldehyde.     

An efficient approach to fused indolines via a copper(I)-catalyzed reaction of sulfonyl azide with 2-ethynylaryl methylenecyclopropane

A cascade reaction of 2-ethynylaryl methylenecyclopropane with sulfonyl azide catalyzed by copper(I) iodide under mild conditions is described, which provides a novel and efficient route for the generation of fused indolines.     

Cascade alkenyl amination/Heck reaction promoted by a bifunctional palladium catalyst: a novel one-pot synthesis of indoles from o-haloanilines and alkenyl halides

A novel approach for the synthesis of the important indole ring is described. Indoles are obtained from o-bromoanilines and alkenyl halides in a Pd-catalyzed cascade process that involves an alkenyl amination followed by an intramolecular Heck reaction. The overall process represents the first example of the participation of alkenyl amination reactions in Pd-catalyzed cascade reactions. Initially, the relative reactivity of aryl and alkenyl bromides and chlorides towards Pd-catalyzed amination was investigated. Competition experiments were carried out in the presence of primary and secondary amines, and these revealed the reactivity order alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides, as well as very high chemoselectivity; the more reactive halide was always favored. Thereafter, optimized reaction conditions for the sequential alkenyl amination/Heck cyclization to give indoles were investigated with the model reaction of o-bromoaniline with alpha-bromostyrene. An extensive screening of ligands, bases, and reaction conditions revealed that the [Pd2(dba)3]/DavePhos, NaOtBu, toluene combination at 100 degrees C were the optimized reaction conditions to carry out the cascade process (dba=dibenzylideneacetone, DavePhos=2-dicyclohexylphosphino-2'-N,N-dimethylaminobiphenyl). The reaction proceeds with aryl, alkyl, and functionalized substitutents in both starting reactants. The cyclization was also studied with N-substituted o-bromoanilines (which would give rise to N-substituted indoles); however, in this case, indole formation occurred only with 1-substituted-2-bromoalkenes. Finally, the application of this methodology to o-chloroanilines required further optimization. Although the catalyst based on DavePhos failed to promote the cascade process, a catalytic combination based on [Pd2(dba)3]/X-Phos promoted the formation of the indole ring also from the less reactive chloroanilines.     

An unexpected palladium-catalyzed reaction of 2-alkynylhalobenzene with 2-alkynylaniline: a novel and efficient route to 11H-indeno[1,2-c]quinolin-11-ols

An unexpected palladium-catalyzed cascade reaction of 2-alkynylhalobenzene with 2-alkynylaniline is reported, which provides a novel and efficient pathway for the synthesis of 11H-indeno[1,2-c]quinolin-11-ols.     

A facile method for synthesis of polysubstituted naphthalene derivatives through pyrrolidine catalyzed domino reaction

A novel synthetic method for polysubstituted naphthalene derivatives via a pyrrolidine-mediated cascade Michael/Henry reaction was developed, in which easily prepared 2-(2-oxoethyl)benzaldehydes and nitroalkenes were employed as the starting materials. The reaction consists of four consecutive reactions that include a cascade Michael/Henry reaction, a dehydration reaction, and an aromatization reaction in one pot to afford synthetically important naphthalene derivatives with moderate yields.     

Facile Synthesis of 2H-Benzo[h]Chromenes via an Arylamine-Catalyzed Mannich Cyclization Cascade Reaction

A simple arylamine-catalyzed Mannich-cyclization cascade reaction was developed for facile synthesis of substituted 2H-benzo[h]chromenes. The notable feature of the process included the efficient generation of ortho-quinone methides (o-QMs) catalyzed by a simple aniline. The mild reaction conditions allowed for a broad spectrum of 1- and 2-naphthols and trans-cinnamaldehydes to engage in the cascade sequence with high efficiency.     

Discovery of a photochemical cascade process by flow-based interception of isomerising alkenes

Herein we report the discovery of a new photochemical cascade process through a flow-based strategy for intercepting diradicals generated from simple alkenes. This continuous process delivers a series of unprecedented polycyclic reaction products. Exploring the scope of this novel process revealed that this approach is general and affords a variety of structurally complex reaction products in high yields (up to 81%), short reaction times (7 min) and high throughputs (up to 5.5 mmol h⁻¹). A mechanistic rationale is presented that is supported by computations as well as isolation of key intermediates whose identity is confirmed by X-ray crystallography. The presented photochemical cascade process demonstrates the discovery of new chemical reactivity and complex chemical scaffolds by continuously generating and intercepting high-energy intermediates in a highly practical manner.

A photochemical cascade process is reported affording complex pentacyclic scaffolds in high yields from readily available substrates. Flow processing provided high reaction control and scalability to generate gram quantities of these intriguing scaffolds for further studies.     

Lewis acid mediated reactions of cyclopropyl aryl ketones with alpha-ketoesters: facile preparation of 5,6-dihydropyran-2-ones

[reaction: see text] A new general method for the synthesis of 5,6-dihydropyran-2-ones from cyclopropyl aryl ketones (monoactivated cyclopropanes) and alpha-ketoesters in good to excellent yields has been developed. The process involves a cascade of reactions, including a nucleophilic ring-opening reaction of monoactivated cyclopropane by H2O, Lewis acid mediated transesterification, and an aldol type reaction.     

Imidazobenzothiazine and primidobenzothiazine derivatives synthesis via an aliphatic SN2 substitution/Cu(I) catalyzed Ullmann coupling cascade process

An efficient method for the preparation of various imidazobenzothiazine and primidobenzothiazine derivatives from readily available 2-mercaptoimidazoles (thiouracils) and bromobenzyl bromides via a copper(I)-catalyzed one-pot cascade process has been developed. The reaction involves a S_N2 process and an intramolecular C–N cross coupling cyclization.     

Synthesis of 1-sulfonyl-2-arylpyrrolidines via intramolecular cyclization/Mannich-type reaction cascade of N-(4,4-diethoxybutyl)sulfonamides

Abstract

Herein, we report the successful application of a novel approach to 2-substituted pyrrolidines based on intramolecular cyclization/intermolecular Mannich-type cascade reaction of N-(4,4-diethoxybutyl)sulfonamides to the synthesis of pyrrolidines possessing heterocyclic and polyaromatic moieties. The proposed approach benefits from mild reaction conditions, moderate to high yields of target compounds and provides a convenient route to the previously unknown 1-sulfonyl-2-arylpyrrolidines.     

Precise 2D-Patterned Incompatible Catalysts for Reactions in One-Pot

Precise and direct two-dimensional (2D) printing of the incompatible polymer acid–base catalysts and their utility in one-pot two-step reactions were shown. Multistep catalytic reactions using incompatible catalysts in a one-pot reaction cascade requires special methods and materials to isolate the catalysts from each other. In general, this is a tedious process requiring special polymer architectures as the carrier for the catalysts to preserve the activity of otherwise incompatible catalysts. We propose the immobilization of incompatible polymer catalysts, such as polymer acid and base catalysts, on a substrate in variable sizes and amounts by precise 2D printing. The terpolymers with basic (4-vinylpyridine) and acidic (styrene sulfonic acid) functionalities and methacryloyl benzophenone as a UV cross-linking unit were used for 2D printing on poly(ethylene terephthalate) (PET). The printed meshes were immersed together in a reaction solution containing (dimethoxymethyl)benzene and ethyl cyanoformate, resulting in a two-step acid–base catalyzed cascade reaction; that is, deacetalization followed by carbon-building reaction. The time-dependent consumption of (dimethoxymethyl)benzene to the intermediate benzaldehyde and the product was monitored, and a kinetic model was developed to investigate the underlying reaction dynamics. The complexity of multistep Wolf–Lamb-type reactions was generally significantly decreased by using our approach because of the easy polymerization and immobilization procedure.