Stereodivergent Synthesis of N‐Heterocycles by Catalyst‐Controlled,Activity‐Directed Tandem Annulation of Diazo Compounds with Amino Alkynes

A stereodivergent synthesis of five‐membered N‐heterocycles, such as 2,3‐dihydropyrroles, and 2‐methylene and 3‐methylene pyrrolidines, has been developed through a tandem annulation of amino alkynes with diazo compounds and involves the trapping of in situ formed intermediates. Mechanistic investigations indicate that the copper‐catalyzed tandem annulations proceed by allenoate formation and subsequent intramolecular hydroamination. In contrast, the rhodium‐catalyzed protocol features a carbenoid insertion into the N H bond and subsequent Conia‐ene cyclization.     

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

An unprecedented tandem N‐alkylation–ionic aza‐Cope (or Claisen) rearrangement–hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N‐alkylation and subsequent microwave‐irradiated ionic aza‐Cope rearrangement–hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2‐reverse quaternary‐centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza‐Cope rearrangement reaction proceeds highly regioselectively to give the quaternary‐centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2‐reverse prenylated indoles, such as indolines, indole‐fused sultams and lactams, and the natural product bruceolline D.     

Palladium‐catalyzed Synthesis of Novel O‐Heterocycles by Domino Suzuki Coupling‐Michael Addition Reaction

Various novel O‐heterocycles were synthesized in a one‐pot operation under relatively mild reaction conditions involving Pd‐catalyzed tandem intermolecular Suzuki crossing coupling and subsequent Michael addition.     

Synthesis of 1,4‐Cyclohexanedimethanol, 1,4‐Cyclohexanedicarboxylic Acid and 1,2‐Cyclohexanedicarboxylates from Formaldehyde,Crotonaldehyde and Acrylate/Fumarate

Valuable polyester monomers and plasticizers—1,4‐cyclohexanedimethanol (CHDM), 1,4‐cyclohexanedicarboxylic acid (CHDA), and 1,2‐cyclohexanedicarboxylates—have been prepared by a new strategy. The synthetic processes involve a proline‐catalyzed formal [3+1+2] cycloaddition of formaldehyde, crotonaldehyde, and acrylate (or fumarate). CHDM is produced after a subsequent hydrogenation step over a commercially available Cu/Zn/Al catalyst and a one‐pot hydrogenation/oxidation/hydrolysis process yields CHDA, whereas 1,2‐cyclohexanedicarboxylate is obtained by a Pd/C‐catalyzed tandem decarbonylation/hydrogenation step.     

Synthesis of 1,4‐Cyclohexanedimethanol, 1,4‐Cyclohexanedicarboxylic Acid and 1,2‐Cyclohexanedicarboxylates from Formaldehyde,Crotonaldehyde and Acrylate/Fumarate

Valuable polyester monomers and plasticizers—1,4‐cyclohexanedimethanol (CHDM), 1,4‐cyclohexanedicarboxylic acid (CHDA), and 1,2‐cyclohexanedicarboxylates—have been prepared by a new strategy. The synthetic processes involve a proline‐catalyzed formal [3+1+2] cycloaddition of formaldehyde, crotonaldehyde, and acrylate (or fumarate). CHDM is produced after a subsequent hydrogenation step over a commercially available Cu/Zn/Al catalyst and a one‐pot hydrogenation/oxidation/hydrolysis process yields CHDA, whereas 1,2‐cyclohexanedicarboxylate is obtained by a Pd/C‐catalyzed tandem decarbonylation/hydrogenation step.     

Copper‐Catalyzed Aminothiolation of 1,3‐Dienes via a Dihydrothiazine Intermediate

Heteroatom‐containing organic molecules are of particular interest to medicinal chemists and materials scientists. A strategy to reach these architectures via direct difunctionalization of abundant 1,3‐dienes is especially attractive. Herein, we describe the development of a regio‐ and diastereoselective 1,4‐aminothiolation of 1,3‐dienes with a sulfur diimide reagent, a copper catalyst, and alkyl Grignard reagents. This unique protocol provides remote nitrogen and sulfur functionalities with high levels of stereocontrol. The reaction proceeds via a tandem hetero‐Diels–Alder cycloaddition of N,N′‐bis(benzenesulfonyl)sulfur diimide with 1,3‐diene followed by copper‐catalyzed Grignard substitution. Mechanistic studies support a copper catalyzed formation of an unprecedented [10‐S‐4] sulfurane that reductively eliminates to afford a 3,6‐dihydrothiazine, which is selectively converted to 1,4‐aminothiols.     

Acid‐Acid‐Catalyzed Tandem Reactions Driven by an Additive‐Like Component

Acid‐catalyzed tandem reactions with auto‐tandem catalysis are effective for simplifying organic synthesis. However, some of the reported reactions were established based on the use of well‐designed substrate with complex structure. In some cases, owing to the existence of a big gap between each catalytic cycle, it is hard to bind all the individual reaction steps to be a peaceful sequence. To enrich the diversity and also to strengthen the practical usefulness of the methodology developed by auto‐tandem catalysis, an additive‐like component was added to induce acid‐acid‐catalyzed tandem reaction. During the reaction, the additive‐like component acted either as an activator to increase the reactivity of the starting material or a hided reagent to enable successful transformation of the intermediate. Many novel tandem reactions were established in a one‐pot manner with the aid of this strategy. Importantly, this strategy not only allows the use of simple and commercially available chemicals as substrates, but also possesses multiple merits, such as simplifying operation, lowering waste generation and enhancing synthetic efficiency and atom‐economy. A summarization of the additive‐like component‐induced auto‐tandem catalysis with an acid catalyst was given in this review, in which many acid‐acid‐catalyzed tandem reactions were discussed. The reported additive‐like components were classified as three types: oxidative type, reductive type and neutral type depending on their mechanisms in assisting the establishment of acid‐acid‐catalyzed tandem reactions. Many examples were collected and analyzed from the viewpoints of simplifying the synthesis and manifesting their superior and distinct functionalities of the additives. A perspective of this concept was also given at the end of this review.     

PdII‐Catalyzed Oxidative Tandem aza‐Wacker/Heck Cyclization for the Construction of Fused 5,6‐Bicyclic N,O‐Heterocycles

A Pd^II‐catalyzed oxidative tandem cyclization was developed for the construction of fused 5,6‐bicyclic N, O‐heterocycles. This reaction was enabled by the combined use of a 3‐methylpyridine ligand and pentafluorobenzoic acid additive. A range of heterocyclic products with different substituents could be prepared in moderate to good yields via this methodology. Several transformations, including a scaled‐up preparation of product 2 a , were also carried out showing the good applicability of our methodology.     

Synthesis of Chiral β‐Lactams by Pd‐Catalyzed Enantioselective Amidation of Methylene C(sp3)–H Bonds

A Pd(II)‐catalyzed enantioselective intramolecular amidation of both benzylic and unbiased methylene C(sp³)?H bonds for the straightforward synthesis of chiral β‐lactams from aliphatic carboxamides is reported. The combination of 2‐pyridinylisopropyl (PIP) auxiliary with 3,3’‐substituted BINOL ligands is crucial for the enhancement of both reactivity and enantiocontrol of differentiating unbiased methylene C(sp³)?H bonds. The desired chemoselective C—N reductive elimination was achieved by employing 2‐fluoro‐1‐iodo‐4‐nitrobenzene as oxidant.     

Palladium‐Catalyzed Multi‐Component Reactions of N‐Tosylhydrazones, 2‐Iodoanilines and CO2 towards 4‐Aryl‐2‐Quinolinones

A palladium‐catalyzed three‐component reaction between N‐tosylhydrazones, 2‐iodoanilines and atmospheric pressure CO₂ was developed whereby a tandem carbene migration insertion/lactamization strategy afforded 4‐aryl‐2‐quinolinones in moderate to good yields. Notably, a wide range of functional groups were tolerated in this procedure. This protocol features the simultaneous formation of four novel bonds; two C?C, one C=C and one C?N (amide), representing an efficient methodology for incorporation of CO₂ into heterocycles.     

One‐Pot Synthesis of Tri‐ and Tetrasubstituted Pyridines by Sequential Ring‐Opening/Cyclization/Oxidation of N‐Arylmethyl 3‐Aziridinylpropiolate Esters

A novel strategy for the one‐pot synthesis of substituted pyridines from N‐arylmethyl 3‐aziridinylpropiolate esters is described. The method employs a three‐step procedure including the formation of allenyl imines, phosphine‐catalyzed cyclization, and subsequent oxidation of the dihydropyridines. Depending on the reaction conditions of the final oxidation step, tri‐ and tetrasubstituted pyridines can be selectively produced.     

Rhodium(II)‐Catalyzed Intramolecular Cycloisomerizations of Methylenecyclopropanes with N‐Sulfonyl 1,2,3‐Triazoles

A novel rhodium(II)‐catalyzed tandem cycloisomerization of methylenecyclopropanes (MCPs) with N‐sulfonyl 1,2,3‐triazoles is disclosed. The reaction produces a series of highly functionalized polycyclic N heterocycles via a rhodium imino carbene intermediate. A distinct feature of this divergent synthesis is that different types of substrates control the reaction pathways. Moreover, several interesting transformations of these products to construct diazabicyclo[3.2.1]octane derivatives are also reported.     

Gold/Acid‐Co‐catalyzed Direct Microwave‐Assisted Synthesis of Fused Azaheterocycles from Propargylic Hydroperoxides

The gold–acid‐co‐catalyzed synthesis of nine series of fused azaheterocycles with structural diversity starting from the same synthons as readily available propargylic hydroperoxides and aromatic amines has been achieved. The overall tandem process consists in a gold‐catalyzed hydroperoxide rearrangement/Michael reaction followed by a final acid‐catalyzed cyclization.     

Divergent Synthesis of Disulfanes and Benzenesulfonothioates Bearing 2‐Aminofurans From N‐Tosylhydrazone‐Bearing Thiocarbamates

An efficient and convenient synthesis of valuable disulfanes and benzenesulfonothioates, having a 2‐aminofuran framework, has been developed by employing a copper‐catalyzed transformation of readily available N‐tosylhydrazone‐bearing thiocarbamates. This method features an inexpensive metal catalyst, mild reaction conditions, good functional‐group tolerance, short reaction times, and delivers valuable and complex products. A copper carbene generated from an N‐tosylhydrazone‐bearing thiocarbamate is proposed as the key intermediate for the transformation and it triggers the subsequent cascade. Remarkably, the Ts anion released from N‐tosylhydrazone further serves as a nucleophile, thus rendering the formation of benzenesulfonothioates under controlled conditions.     

Copper‐Catalyzed Reaction of Trifluoromethylketones with Aldehydes via a Copper Difluoroenolate

A copper‐catalyzed reaction of easily accessible α,α,α‐trifluoromethylketones with various aldehydes affords difluoro‐methylene compounds in the presence of diboron and NaOtBu. The key process of the reaction is the formation of a copper difluoroenolate by 1,2‐addition of a borylcopper intermediate to α,α,α‐trifluoromethylketones and subsequent β‐fluoride elimination. Mechanistic studies including the isolation and characterization of a possible anionic copper alkoxide intermediate are also described.     

Facile Synthesis of Phenanthridinone Alkaloids via Suzuki–Miyaura Cross‐coupling

Phenanthridinone alkaloids crinasiadine 1 and N‐alkylcrinasiadines 6 , 7 , 8 , 9 , 10 have been synthesized based on palladium‐catalyzed tandem C–C and C–N bond formation starting from 2‐aminophenylboronic acid and 2‐bromobenzoate in short steps. Related alkaloids, 5,6‐dihydrobicolorine 2 , trisphaeridine 3 , and bicolorine 12 have also been synthesized.     

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 β‐proline derivatives, are obtained in high yield with high enantioselectivity.     

Gold‐Catalyzed Regiospecific C−H Annulation of o‐Ethynylbiaryls with Anthranils: π‐Extension by Ring‐Expansion En Route to N‐Doped PAHs

We describe a novel, short, and flexible approach to diverse N‐doped polycyclic aromatic hydrocarbons (PAHs) through gold‐catalyzed π‐extension of anthranils with o‐ethynylbiaryls as reagents. This strategy uses easily accessible starting materials, is simple due to high step and atom economy, and shows good functional‐group compatibility as well as scale‐up potential. Mechanistically, the tandem reaction is proposed to involve a nucleophilic addition/ring opening/regiospecific C?H annulation/protodeauration sequence terminated by a Friedel–Crafts‐type cyclization. Photophysical studies of the products indicated violet‐blue fluorescence emission with quantum yields up to 0.45.     

Porphyrinogen fragmentation profiles by ultra‐high‐performance liquid chromatography/electrospray ionisation tandem mass spectrometry

An ultra‐high‐performance liquid chromatography/electrospray ionisation tandem mass spectrometry system is described for the separation and characterisation of uroporphyrinogen, heptacarboxylic acid porphyrinogen, hexacarboxylic acid porphyrinogen, pentacarboxylic acid porphyrinogen and coproporphyrinogen. The separation was carried out on a 100 mm × 2.1 mm Thermo‐Hypersil BDS column (2.4 µm average particle size) by gradient elution with a mixture of acetonitrile, methanol and 1 mol/L aqueous ammonium acetate buffer, pH 5.16, as eluent. The fragmentation pattern of each compound was established by collision‐induced dissociation tandem mass spectrometry. The most characteristic fragmentation was ring opening at one of the four methylene bridges of the protonated porphyrinogen molecule followed by further cleavages of methylene bridges linking the four pyrrole rings at various points to give product ions with methylenepyrrolenine, methylene‐dipyrrolenine and methylene‐tripyrrolenine structures. Copyright © 2011 John Wiley & Sons, Ltd.     

A Facile Access to Polyfunctional Oxygen‐containing Heterocycles via Intramolecularly Formed Protic Oxonium Ylide Trapping Processes

Based on the assumption that intramolecularly formed protic oxonium ylides could be trapped by electrophiles, transition‐metal‐catalyzed reactions of diazoesters bearing a primary hydroxy group with electron‐deficient aldehydes and isatins were examined. Good to high chemo‐ and diastereoselectivities were achieved with reactions catalyzed by Cu(hfacac)₂. The reactions were assumed to occur via tandem intramolecular protic oxonium ylide formation and subsequent aldol‐type addition. They not only provided an efficient entry to 3‐substituted 1,4‐dioxan‐2‐one heterocycles with at least one quaternary carbon center but also provided experimental evidence for a stepwise pathway for the transition‐metal‐catalyzed intramolecular O? H insertion of diazo compounds.