Multifunctional Metal-Organic Frameworks as Catalysts for Tandem Reactions.

Owing to well-defined structure as well as easy synthesis and modification, metal-organic frameworks (MOFs) have emerged as promising catalysts for tandem reactions. In this article, we aim to summarize the development of multifunctional MOFs, including mixed metal MOFs, MOFs that are synergistically catalyzed by metal nodes and organic linkers, MOFs loaded with metal nanoparticles, etc, as heterogenous catalysts for tandem reactions over the past five years. This concept briefly discusses on present challenges, future trends, and prospects of multifunctional MOFs catalysts in tandem reactions.

Skeletal and Mechanistic Diversity in Ir-Catalyzed Cycloisomerizations of Allene-Tethered Pyrroles and Indoles.

Pyrroles and indoles bearing N-allenyl tethers participate in a variety of iridium-catalyzed cycloisomerization processes initiated by a C-H activation step, to deliver a diversity of synthetically relevant azaheterocyclic products. By appropriate selection of the ancillary ligand and the substitution pattern of the allene, the reactions can diverge from simple intramolecular hydrocarbonations to tandem processes involving intriguing mechanistic issues. Accordingly, a wide range of heterocyclic structures ranging from dihydro-indolizines and pyridoindoles to tetrahydroindolizines, as well as cyclopropane-fused tetrahydroindolizines can be obtained. Moreover, by using chiral ligands, these cascade processes can be carried out in an enantioselective manner. DFT studies provide insights into the underlying mechanisms and justify the observed chemo- regio- and stereoselectivities.

Tandem Hock and Friedel-Crafts reactions allowing an expedient synthesis of a cyclolignan-type scaffold.

The Hock cleavage, which is compatible with tandem processes, was applied to the synthesis of 1-aryltetralines through a one-pot transformation from readily available benzyl(prenyl)malonate substrates. After the photooxygenation of the prenyl moiety, the resulting hydroperoxide was directly engaged in a Hock cleavage by adding a Lewis acid. The presence of an aromatic nucleophile in the reaction mixture and that of a benzyl moiety on the substrate resulted in tandem Friedel-Crafts reactions to form the 1-aryltetraline products. These compounds share a close analogy to the cyclolignan natural products. Experimental observations and a DFT study support the involvement of an aldehyde intermediate during the Friedel-Crafts reactions, rather than an oxocarbenium.

Enantioselective Sequential Catalytic Arylation-Fukuyama Cross-coupling of 1,1-Biszincioalkane Linchpins.

1,1-Bis(iodozincio)alkanes are used as dinucleophilic linchpins in an enantioselective double cross-coupling reaction sequence involving aryl iodides and then thioesters. The two catalytic C-C bond-forming reactions are achieved in the same pot through two distinct palladium-based catalytic systems: a first non-enantioselective one delivering configurationally labile secondary benzylzinc species from an achiral precursor, and a second enantioconvergent one that operates a highly efficient dynamic kinetic resolution of the racemic intermediates. This strategy, new in the area of asymmetric synthesis through two consecutive electrophilic substitution reactions of geminated C(sp3 )-organodimetallics, provides useful methodology to access in a modular fashion acyclic α-disubstituted ketone products with very high enantiomeric purity.

Fluorinated Imines in Tandem and Cycloaddition Reactions.

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.

α-(Aminomethyl)acrylates as acceptors in radical-polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping.

We demonstrate that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical-polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen atom to zinc enables this SH2 process which represents a rare example of alkylzinc-group transfer to a tertiary α-carbonyl radical. The zinc enolate thus formed readily undergoes ß-fragmentation unless it is trapped by electrophiles in situ. Enolates of substrates having free N-H bonds undergo protodemetalation to provide ultimately the 1,4-addition adduct. In the presence of carbonyl acceptors, aldol condensation occurs providing overall a tandem 1,4-addition-aldol process. When a tert-butanesulfinyl moiety is present on the nitrogen atom, these electrophilic substitution reactions occur with good levels of chiral induction, paving the way to enantioenriched ß2-amino acids and ß2,2-amino acids.

Tandem Pd-Catalyzed Cyclization/Coupling of Non-Terminal Acetylenic Activated Methylenes with (Hetero)Aryl Bromides.

We report a new method for a tandem Pd-catalyzed intramolecular addition of active methylene compounds to internal alkynes followed by coupling with aryl and heteroaryl bromides. Highly substituted vinylidenecyclopentanes were obtained with good yields, complete selectivity, and excellent functional group tolerance. A plausible mechanism, supported by DFT calculations, involves the oxidative addition of bromoarene to Pd(0), followed by cyclization and reductive elimination. The excellent regio- and stereoselectivity arises from the 5-exo-dig intramolecular addition of the enol form of the substrate to alkyne activated by the π-acidic Pd(II) center, postulated as the rate-determining step.

Tandem Macrolactone Synthesis: Total Synthesis of (-)-Exiguolide by a Macrocyclization/Transannular Pyran Cyclization Strategy.

Tetrahydropyran-containing macrolactones were synthesized by integrating Meyer-Schuster rearrangement, macrocyclic ring-closing metathesis, and transannular oxa-Michael addition under gold and ruthenium catalysis. Single-step access to a variety of 14- to 20-membered macrolactones containing a tetrahydropyran ring was possible from readily available linear precursors in good yields and with moderate to excellent diastereoselectivity. A 13-step synthesis of (-)-exiguolide, an anticancer marine macrolide, showcased the feasibility of our tandem reaction sequence for macrolactone synthesis and also demonstrated the power of transannular reactions for rapid assembly of the tetrahydropyran rings of the target natural product.

Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry.

Iron-based catalysts were applied in cascade-type reactions for the synthesis of different carbonyl compounds. The reactions proceeded by a new iron-catalyzed cascade of alkynylation/hydration by using both the σ- and π-Lewis acid properties of iron salts. The alkynylation reactions of several endo and exocyclic acetoxylactams were achieved with three different catalysts including FeCl3 ⋅ 6H2 O, FeCl3 , and Fe(OTf)3 showing the efficiency of σ-Lewis acidity of iron (III) salts in catalyzing the alkynylation reaction. We also demonstrated that the reaction sequence could be shortened by the direct use of hydroxylactams, leading to an environmentally friendly protocol, avoiding the need to perform unnecessary lengthy steps. A combination of the hard/soft iron Lewis acid properties was then used to implement an unprecedented tandem intermolecular alkynylation/intramolecular hydration sequence allowing expedient access to a new carbonyl structures from trivial materials.

Control of chemoselectivity in asymmetric tandem reactions: Direct synthesis of chiral amines bearing nonadjacent stereocenters.

This paper describes the mechanistic insight-guided development of a catalyst system, employing a phenolic proton donor catalyst in addition to a cinchonium-derived phase-transfer catalyst, to control the chemoselectivity of two distinct intermediates, thereby enabling the desired asymmetric tandem conjugate addition-protonation pathway to dominate over a number of side-reaction pathways to provide a synthetic approach for the direct generation of optically active amines bearing two nonadjacent stereocenters.

Metal-based Heterogeneous Catalysts for One-Pot Synthesis of Secondary Anilines from Nitroarenes and Aldehydes.

Recently, N-substituted anilines have been the object of increasing research interest in the field of organic chemistry due to their role as key intermediates for the synthesis of important compounds such as polymers, dyes, drugs, agrochemicals and pharmaceutical products. Among the various methods reported in literature for the formation of C-N bonds to access secondary anilines, the one-pot reductive amination of aldehydes with nitroarenes is the most interesting procedure, because it allows to obtain diverse N-substituted aryl amines by simple reduction of nitro compounds followed by condensation with aldehydes and subsequent reduction of the imine intermediates. These kinds of tandem reactions are generally catalyzed by transition metal-based catalysts, mainly potentially reusable metal nanoparticles. The rapid growth in the last years in the field of metal-based heterogeneous catalysts for the one-pot reductive amination of aldehydes with nitroarenes demands for a review on the state of the art with a special emphasis on the different kinds of metals used as catalysts and their recyclability features.

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions.

In the presence of a suitable acid or base, α-hydroxyaldehydes, ketones, and imines can undergo isomerization that features the 1,2-shift of an alkyl or aryl group. In the process, the hydroxy group is converted to a carbonyl and the aldehyde/ketone or imine is converted to an alcohol or amine. Such α-ketol/α-iminol rearrangements are used in a wide variety of synthetic applications including asymmetric synthesis, tandem reactions, and the total synthesis and biosynthesis of natural products. This review explores the use of α-ketol rearrangements in these contexts over the past two decades.

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams.

Pyrrolidones are common heterocyclic fragments in various biologically active compounds. Here, a two-step radical-based approach to γ-lactams bearing three to four stereocenters starting from epoxides, N-allylic silylacetamides and TEMPO is reported. The sequence starts with a new tandem nucleophilic substitution/Brook rearrangement/single electron transfer-induced radical oxygenation furnishing orthogonally protected α,γ-dioxygenated N-allylamides with wide scope, mostly good yields, and partly good diastereo- and enantioselectivity for defined combinations of chiral epoxides and chiral amides. This represents a very rare example of an oxidative geminal C-C/C-O difunctionalization next to carbonyl groups. The resulting dioxygenated allylic amides are subsequently subjected to persistent radical effect-based 5-exo-trig radical cyclization reactions providing functionalized pyrrolidones in high yields as diastereomeric mixtures. They converge to 3,4-trans-γ-lactams by base-mediated equilibration, which can be easily further diversified. Stereochemical models for both reaction types were developed.

Tandem Acid/Pd-Catalyzed Reductive Rearrangement of Glycol Derivatives.

Herein, we describe the acid/Pd-tandem-catalyzed transformation of glycol derivatives into terminal formic esters. Mechanistic investigations show that the substrate undergoes rearrangement to an aldehyde under [1,2] hydrogen migration and cleavage of an oxygen-based leaving group. The leaving group is trapped as its formic ester, and the aldehyde is reduced and subsequently esterified to a formate. Whereas the rearrangement to the aldehyde is catalyzed by sulfonic acids, the reduction step requires a unique catalyst system comprising a PdII or Pd0 precursor in loadings as low as 0.75 mol % and α,α'-bis(di-tert-butylphosphino)-o-xylene as ligand. The reduction step makes use of formic acid as an easy-to-handle transfer reductant. The substrate scope of the transformation encompasses both aromatic and aliphatic substrates and a variety of leaving groups.

Immobilization of platinum nanoparticles on the functionalized chitosan particles: an efficient catalyst for reduction of nitro compounds and tandem reductive Ugi reactions.

In this work, we reported a facile synthesis of Pt nanoparticles (NPs) on proline-functionalized cross-linked chitosan particles to catalyze the reduction of R-NO2 to R-NH2 in aqueous medium using sodium borohydride. Chitosan was functionalized with (3-bromopropyl)proline and cross-linked with glutaraldehyde for the synthesis of chitosan NPs. The platinum NPs was prepared on the chitosan NPs. This catalyst showed the good selectivity and activity for reduction of nitro compound as well as for tandem reduction of nitro groups in Ugi reaction.

Enantioselective Catalytic Aldehyde α-Alkylation/Semipinacol Rearrangement: Construction of α-Quaternary-δ-Carbonyl Cycloketones and Total Synthesis of (+)-Cerapicol.

An enantioselective aldehyde α-alkylation/semipinacol rearrangement was achieved through organo-SOMO catalysis. The catalytically generated enamine radical cation serves as a carbon radical electrophile that can stereoselectively add to the alkene of an allylic alcohol and initiate ensuing ring-expansion of cyclopropanol or cyclobutanol. This tandem reaction enables the production of a wide range of nonracemic functionalizable α-quaternary-δ-carbonyl cycloketones in high yields and excellent enantioselectivity from simple aldehydes and allylic alcohols. As a key step, the intramolecular reaction was also successfully applied in the asymmetric total synthesis of (+)-cerapicol.

One-Pot Tandem Michael Addition/Enantioselective Conia-Ene Cyclization Mediated by Chiral Iron(III)/Silver(I) Cooperative Catalysis.

The first one-pot tandem Michael addition/enantioselective Conia-ene cyclization of N-protected prop-2-yn-1-amines with 2-methylene-3-oxoalkanoates promoted by chiral iron(III)/silver(I) cooperative catalysts has been developed. Alkyl 4-methylenepyrrolidine-3-acyl-3-carboxylates, which can be transformed into ß-proline derivatives, are obtained in high yield with high enantioselectivity.

Tandem Photoredox Catalysis: Enabling Carbonylative Amidation of Aryl and Alkylhalides.

We report a new visible-light-mediated carbonylative amidation of aryl, heteroaryl, and alkyl halides. A tandem catalytic cycle of [Ir(ppy)2 (dtb-bpy)]+ generates a potent iridium photoreductant through a second catalytic cycle in the presence of DIPEA, which productively engages aryl bromides, iodides, and even chlorides as well as primary, secondary, and tertiary alkyl iodides. The versatile in situ generated catalyst is compatible with aliphatic and aromatic amines, shows high functional-group tolerance, and enables the late-stage amidation of complex natural products.

Tandem Anionic oxy-Cope Rearrangement/Oxygenation Reactions as a Versatile Method for Approaching Diverse Scaffolds.

Tandem anionic oxy-Cope rearrangement/radical oxygenation reactions provide δ,ϵ-unsaturated α-(aminoxy) carbonyl compounds, which serve as convenient precursors to diverse compound classes. Functionalized carbocycles are accessible by very rare all-carbon 5-endo-trig cyclizations, but also common 5-exo-trig radical cyclizations, based on the persistent radical effect. The tandem reactions can be further extended by highly diastereoselective allylation or reduction steps to give complex scaffolds.

Enantioselective Synthesis of 3-Substituted Cyclobutenes by Catalytic Conjugate Addition/Trapping Strategies.

A copper-catalyzed tandem process to generate chiral cyclobutene derivatives has been developed. It is based on an enantioselective conjugate addition or reduction of a cyclobutenone and sequential trapping with a chlorophosphate in a one-pot process. These phosphates are stable under mildly acidic conditions and serve as good electrophiles in Negishi coupling reactions.