Intramolecular Heck-type Reaction Research Articles

Recent Developments in Heck-Type Reaction of Unactivated Alkenes and Alkyl Electrophiles

AbstractThe Mizoroki–Heck reaction is considered as one of the most ingenious and widely used methods for constructing C–C bonds. This reaction mainly focuses on activated olefins (styrenes, acrylates, or vinyl ethers) and aryl/vinyl (pseudo) halides. In comparison, the studies on unactivated alkenes and alkyl electrophiles are far less due to the low reactivity, poor selectivity, as well as competitive β-H elimination. In the past years, a growing interest has thus been devoted and significant breakthroughs have been achieved in the employment of unactivated alkenes and alkyl electrophiles as the reaction components, and this type of coupling is called as Heck-type or Heck-like reaction, which distinguishes from the traditional Heck reaction. Herein, we give a brief summary on Heck-type reaction between unactivated alkenes and alkyl electrophlies, covering its initial work, recent advancements, and mechanistic discussions.1 Introduction2 Intramolecular Heck-Type Reaction of Unactivated Alkenes and Alkyl Electrophiles2.1 Cobalt-Catalyzed Intramolecular Heck-Type Reaction2.2 Palladium-Catalyzed Intramolecular Heck-Type Reaction2.3 Nickel-Catalyzed Intramolecular Heck-Type Reaction2.4 Photocatalysis and Multimetallic Protocol for Intramolecular Heck-Type Reaction3 Intermolecular Heck-Type Reaction of Unactivated Alkenes and Alkyl Electrophiles3.1 Electrophilic Trifluoromethylating Reagent as Reaction Partners3.2 Alkyl Electrophiles as Reaction Partners4 Oxidative Heck-Type Reaction of Unactivated Alkenes and Alkyl Radicals5 Conclusions and Outlook

Common Strategy for the Synthesis of Some Strychnos Indole Alkaloids.

Indole alkaloids are important natural compounds with interesting bio-activities that can be found in various species belonging to the Amaryllidaceae, Apocynaceae, or Strychnaceae families. Although these compounds have different connections, substituents, and functionalities, their main core can be produced via the formation of a common functionalized tetracyclic subunit, which is rapidly obtained by an oxidative de-aromatization process mediated by a hypervalent iodine reagent from an inexpensive phenol containing a lactate moiety as the chiral auxiliary. A subsequent stereoselective aza-Michael addition and an intramolecular Heck-type reaction lead to the formation of a common key intermediate. This approach provides a solid foundation for the further elaborations of several natural products. The asymmetric syntheses of (-)-strychnopivotine and the polycyclic main cores of (-)-strychnosplendine, (+)-isosplendine, and (+)-malagashanol, three other indole alkaloids, are reported.

Palladium(0)-Catalyzed Intramolecular Cascade Cyclization of Methylenecyclopropanes.

A Pd(0)-catalyzed cascade cyclization of methylenecyclopropanes (MCPs) involving an intramolecular Heck-type reaction and β-H eliminations has been disclosed in this paper. The reaction proceeds smoothly through an unprecedented ring-opening pattern of MCPs via a cyclopropene intermediate and a vinylpalladium carbene species seemingly, furnishing spirocyclic compounds containing fluorene and 1,2-dihydronaphthalene moieties in moderate to good yields.

ChemInform Abstract: The Barbier‐Type Allylation/Lactamization Cascade Route to Isoindolinones and the Heck‐Type Annulation Route to Isoindolo[2,1‐a]quinolines.

In this paper, we report the construction of pharmacologically relevant isoindolinones and isoindolo[2,1-a]quinolines through the Zn-mediated Barbier-type allylation/lactamization sequential reactions and intramolecular Heck annulation reactions, respectively. The Zn-mediated Barbier-type allylation/lactamization sequential reactions of imine systems derived from alkyl 2-formylbenzoates afforded a library of N-substituted 3-allyl-isoindolinone scaffolds. Then, this route was applied to assemble various N-(2-haloaryl)-3-allyl-isoindolinone derivatives, which were subsequently subjected to the Pd-catalyzed intramolecular Heck-type annulation reaction to afford the corresponding isoindolo[2,1-a]quinoline frameworks. We have shown a formal synthesis of the bio-active isoindolo[2,1-a]quinoline system 1 g by synthesizing the dione system 12, which was an intermediate in the Ishihara's scheme pertaining to the synthesis of the bio-active isoindolo[2,1-a]quinoline system 1 g.

The Barbier-Type Allylation/Lactamization Cascade Route to Isoindolinones and the Heck-Type Annulation Route to Isoindolo[2,1-a]quinolines

In this paper, we report the construction of pharmacologically relevant isoindolinones and isoindolo[2,1-a]quinolines through the Zn-mediated Barbier-type allylation/lactamization sequential reactions and intramolecular Heck annulation reactions, respectively. The Zn-mediated Barbier-type allylation/lactamization sequential reactions of imine systems derived from alkyl 2-formylbenzoates afforded a library of N-substituted 3-allyl-isoindolinone scaffolds. Then, this route was applied to assemble various N-(2-haloaryl)-3-allyl-isoindolinone derivatives, which were subsequently subjected to the Pd-catalyzed intramolecular Heck-type annulation reaction to afford the corresponding isoindolo[2,1-a]quinoline frameworks. We have shown a formal synthesis of the bio-active isoindolo[2,1-a]quinoline system 1 g by synthesizing the dione system 12, which was an intermediate in the Ishihara's scheme pertaining to the synthesis of the bio-active isoindolo[2,1-a]quinoline system 1 g.

ChemInform Abstract: Rhodium(III)‐Catalyzed C—H Activation: An Oxidative Intramolecular Heck‐Type Reaction Directed by a Carboxylate.

ChemInform Abstract: Rhodium(III)‐Catalyzed C—H Activation: An Oxidative Intramolecular Heck‐Type Reaction Directed by a Carboxylate.

Rhodium(III)-Catalyzed C-H Activation: An Oxidative Intramolecular Heck-Type Reaction Directed by a Carboxylic Acid.

Carboxylic acids effectively direct C-H activation for Rhodium(III)-catalyzed intramolecular Heck-type reactions. A catalytic amount of Cu(OAc)2 is used as the external oxidant with oxygen likely acting as the terminal oxidant. Additionally, a novel electron-deficient RhIII catalyst was found to be more effective that [RhCp*Cl2]2 with some substrates. A wide variety of complex dihydrobenzofurans, dihydrobenzopyrans, and other bicycles that can be easily further functionalized are now accessible through relatively mild reaction conditions.

A concise synthesis of indoloquinoline skeletons applying two consecutive Pd-catalyzed reactions

The indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3), and isoneocryptolepine (4) are important tools in traditional medicine. Now, their precursors 1a–4a were synthesized in two steps starting from the corresponding bromo-iodoquinolines. Our strategy is based on palladium-catalyzed reactions, applying regioselective Buchwald–Hartwig amination on 2,3- and 3,4-dihaloquinolines followed by an intramolecular Heck-type reaction. Both steps were carried out under microwave irradiation.

Design and synthesis of pyrido[3,2-α]carbazole derivatives and their analogues as potent antitumour agents

A series of pyrido[3,2-α]carbazole derivatives and their analogues have been prepared and evaluated for their antitumour activity against human lung cancer A549 cells and colon cancer HT29 cells. The intermediates 4a–4k are successfully synthesized from 1a–1k and ethyl 2-(3-bromopyridin-2-yl)acetate by Knoevenagel condensation and intramolecular Heck-type reaction, and this is a novel and efficient synthetic approach to the core scaffold of the target compounds. These target compounds have shown an interesting antitumour profile towards the tested cell lines with IC50 values ranging from 0.07 μM to 4.45 μM. Among all the compounds synthesized, 8 compounds show higher potency than R16, 12 compounds are as potent as R16, and 6 compounds are less potent than R16. The best compound 24 is 7 times and approximately 10 times as potent as R16 against A549 and HT29 cells, respectively.

ChemInform Abstract: Palladium‐Catalyzed Heck‐Type Reaction of Oxime Ether Bearing a Pendant Vinyl Iodide Moiety.

A Pd(0)-catalyzed intramolecular Heck-type reaction of oxime ether has been developed, providing convenient access to heterocyclic oximes.

Palladium-catalyzed Heck-type reaction of oxime ether bearing a pendant vinyl iodide moiety

A Pd(0)-catalyzed intramolecular Heck-type reaction of oxime ether has been developed, providing convenient access to heterocyclic oximes.

ChemInform Abstract: Towards the Total Synthesis of Saponaceolides: Synthesis of cis-2,4-Disubstituted 3,3-Dimethylmethylenecyclohexanes.

Controlling diastereoselectivity by metal coordination: In the case of 3,3-dimethylmethylenecyclohexanes 2—a structural unit present in many interesting natural products—the thermodynamically less stable cis-2,4-disubstituted compounds become available through a cyclization event wherein the configuration is determined by a carbopalladation step. Both the cycloisomerization of 1,7-enynes 1 and the intramolecular Heck-type reaction of compounds of type 3 provide the cis product as the major product.

Toward General Access to the <i>Aspidosperma</i>-Type Terpenoid Indole Alkaloids: Synthesis of the Key 3,3-Disubstituted Piperidones through Enantioselective Intramolecular Heck-Type Reaction of Chloroformamides

An enantioselective intramolecular Heck-type reaction of chloroformamides has been developed for the synthesis of 3,3-disubstituted piperidones. The desired piperidone was formed in the presence of a palladium catalyst, an optically active phosphoramidite ligand, K3PO4 and Ag3PO4. The obtained piperidone was converted to epieburnamonine.

Pd(II)-Catalyzed Enantioselective Intramolecular Heck-Type Reaction to Construct Chiral Sulfonamide Rings

The first example of enantioselective intramolecular Heck-type reaction to construct chiral quaternary carbon centers of sulfonamide rings is reported. The reaction provides the expected Heck products along with the unexpected olefin reduction products. We discovered the catalyst prepared from (S,S)-chiraphos and Pd 2 dba 3 to afford the products in high yields and enantioselectivities up to 86% ee at room temperature. Deuterated solvent and base are also examined to elucidate the mechanism of reduction of olefin. Pd hydride species produced from β-elimination are responsible for olefin reduction.

Synthesis of 7 H-indolo[2,3- c]quinolines: study of the Pd-catalyzed intramolecular arylation of 3-(2-bromophenylamino)quinolines under microwave irradiation

D-ring substituted 5-methyl-5 H-indolo[2,3- c]quinolines ( 4 ) have been synthesized in three steps starting from commercially available 3-bromoquinoline ( 5 ) and 2-bromoanilines ( 6 ). The methodology consists of two consecutive palladium-catalyzed reactions: a selective Buchwald–Hartwig amination followed by a regioselective intramolecular Heck-type reaction. The latter step has been investigated under microwave irradiation. Heating at 180 °C allows to seriously reduce the catalyst loading and get a full conversion to reaction product in 10 min. In addition, the former simplifies the purification.

Amination with Oximes

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of the Benzo‐β‐Carboline Isoneocryptolepine: The Missing Indoloquinoline Isomer in the Alkaloid Series Cryptolepine, Neocryptolepine and Isocryptolepine.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of the benzo-β-carboline isoneocryptolepine: the missing indoloquinoline isomer in the alkaloid series cryptolepine, neocryptolepine and isocryptolepine

7 H-Indolo[2,3- c]quinoline has been synthesized in two steps via a new approach starting from commercially available 3-bromoquinoline and 2-bromoaniline. The new methodology consists of two consecutive palladium-catalyzed reactions: a selective Buchwald/Hartwig amination followed by an intramolecular Heck-type reaction. Alternatively, the same skeleton has also been prepared via the combination of a Suzuki arylation with an intramolecular nitrene insertion starting from 4-chloroquinoline and {2-[(2,2-dimethylpropanoyl)amino]phenyl}boronic acid. Selective methylation of 7 H-indolo[2,3- c]quinoline yielded 5-methyl-5 H-indolo[2,3- c]quinoline (Isoneocryptolepine) which is an interesting new lead compound in the search for new antiplasmodial drugs.

Synthesis of 5 H-pyridazino[4,5- b]indoles and their benzofurane analogues utilizing an intramolecular Heck-type reaction

The title ring systems were prepared from pyridazin-3(2 H)-one precursors in novel, efficient pathways. 2-Methylbenzo[ b]furo[2,3- d]pyridazin-1(2 H)-one was synthesized via a regioselective nucleophilic substitution reaction of a 2-methyl-4,5-dihalopyridazin-3(2 H)-one with phenol followed by an intramolecular Heck-type reaction. The same molecule and its 6-phenyl analogue were also prepared via reaction of 2-methyl-5-iodopyridazin-3(2 H)-one or 2-methyl-5-chloro-6-phenylpyridazin-3(2 H)-one, respectively, with 2-bromophenol or 2-iodophenol followed by Pd-catalyzed cyclodehydrohalogenation. Moreover, a new approach for the synthesis of 2-methyl-2,5-dihydro-1 H-pyridazino[4,5- b]indol-1-ones was also elaborated utilizing a Heck-type ring closure reaction on 5-[(2-bromophenyl)amino]-2-methylpyridazin-3(2 H)-ones which were obtained via Buchwald–Hartwig amination of 2-methyl-5-halopyridazin-3(2 H)-ones with 2-bromoaniline.

Synthesis of aza-heterocycles from oximes by amino-Heck reaction.

Oxidative addition of oximes to palladium(0) complexes generates alkylideneaminopalladium(II) species, which are utilized as key intermediates for carbon-nitrogen bond formation. Various aza-heterocycles, such as pyrrole, pyridine, isoquinoline, spiroimine, and azaazulene, can be synthesized from O-pentafluorobenzoyloximes having an olefinic moiety via an intramolecular Heck-type reaction (amino-Heck reaction) by treatment with a catalytic amount of a Pd(0) complex.