Annulation Products Research Articles

Co(III)‐Catalyzed [4+1] Annulation of Amides with Allenes via C−H Activation

AbstractA Co(III)‐catalyzed [4+1] annulation of amides with allenes to synthesize isoindolone and 1,5‐dihydro‐pyrrol‐2‐one derivatives is reported. A wide range of aromatic and vinylic amides react with allenes to give the corresponding annulation products in good to excellent yields. The mechanistic studies strongly support that the catalytic reaction proceeds through an amide‐directed C−H activation, followed by carbocobaltation of allene, β‐hydride elimination, and an intramolecular 1,2‐hydroamination.magnified image

Formal [3 + 3] Cycloaddition Reactions between Electron-Deficient Cyclopropenes and Hydrazones: A Route to Alkyl 1,4,5,6-Tetrahydropyridazine-3-carboxylates.

A formal [3 + 3] cycloaddition reaction between alkyl 2-aroyl-1-chlorocyclopropanecarboxylates 1 and common hydrazones 2 was developed. This process readily proceeded in diastereo- and regioselective fashion and gave alkyl 1,4,5,6-tetrahydropyridazine-3-carboxylates in high yields under mild basic conditions. Treatment of the annulation products with DDQ leads to the formation of functionalized pyridazine-3-carboxylates, analogues of nicotinic acid ester.

3-Nitro-3,4-dihydrocoumarins: valuable precursors for the synthesis of enantiomerically enriched masked quaternary α-amino acid derivatives with a 3,4-dihydrocoumarin scaffold.

A bifunctional squaramide catalyzed enantioselective formal [2 + 4] annulation reaction with 3-nitro-3,4-dihydrocoumarins and ortho-quinone methide has been developed. Novel chiral masked quaternary α-amino acid derivatives with a 3,4-dihydrocoumarin scaffold are obtained in a highly stereocontrolled manner. Representative transformation of the annulation product to a biologically important quaternary α-amino acid derivative is achieved without any appreciable loss in the diastereo- and enantioselectivity.

Mechanism and stereoselectivity in NHC-catalyzed β-functionalization of saturated carboxylic ester.

To understand the mechanism and origin of the stereoselectivity of the [3 + 2] annulation reaction between a carboxylic ester and an isatin generating spirooxindole lactone catalyzed by N-heterocyclic carbene (NHC), density functional theory (DFT) calculations have been carried out. DFT results indicate that the catalytic cycle begins with the coupling of the catalyst with benzotriazole ester, followed by α-deprotonation to produce the enolate intermediate. The subsequent 1,4-proton transfer affords the homoenolate intermediate. The next crucial step is the stereoselective C–C bond formation. Then proton transfer takes place leading to the formation of the lactone intermediate. Finally, the elimination of the catalyst furnishes the final product. The presence of 1-hydroxybenzotriazole (HOBt) dramatically accelerates the proton transfer step. More importantly, HOBt has a non-negligible impact on stereoselective C–C bond formation, and the SR-configured product is the major stereoisomer of the annulation product, which is in good agreement with the experimental observations. The differential π⋯π stacking, C–H⋯π, lone pair (LP)⋯π and repulsion interactions are found to be responsible for the stereoselectivity. The obtained mechanistic insights should provide valuable information for understanding the important roles of the NHC catalyst and HOBt additive and be helpful for designing better NHC catalysts for this kind of reaction.

Gold‐Catalyzed Enantioselective Intramolecular Annulation of Ene‐Yne‐Carbonyls via Benzopyrylium‐Type Intermediates

It has been established that a cationic gold(I)/(R)‐H8‐binap complex catalyzes the enantioselective intramolecular [4+2] annulation of benzene‐linked ene‐yne‐carbonyls via benzopyrylium‐type intermediates at room temperature to give chiral tricyclic compounds, bearing two stereogenic centers, as single diastereomers with moderate ee values. Interestingly, the reactions of sterically demanding naphthalene‐linked ene‐yne‐carbonyls with the same gold(I) catalyst gave not only [4+2] annulation products but also [3+2] annulation products as minor products with good ee values.

Selective [5 + 1] and [5 + 2] Cycloaddition of Ynamides or Propargyl Esters with Benzo[ d]isoxazoles via Gold Catalysis.

Benzo[ d]isoxazoles are found to act as novel nucleophiles to undergo gold-catalyzed [5 + 1] or [5 + 2] cycloaddition reactions with ynamides. The reaction provides a concise and chemoselective access to polysubstituted 2 H-benzo[ e][1,3]oxazines or benzo[ f][1,4]oxazepines. In addition, benzo[ d]isoxazoles can also react with gold-carbene intermediates derived from propargyl esters to afford [5 + 1] annulation products.

Exceedingly Fast, Direct Access to Dihydroisoquinolino[1,2- b]quinazolinones through a Ruthenium(II)-Catalyzed Redox-Neutral C-H Allylation/Hydroamination Cascade.

A ruthenium(II)-catalyzed redox-neutral synthesis of dihydroisoquinoline-fused quinazolinone derivatives has been accomplished through the merger of C-H activation and alkene difunctionalization using quinazolinone as an inherent directing group. This intermolecular reaction proceeds rapidly and is complete within 10 min, providing the annulation product in high yields without any stoichiometric metal oxidant. Mechanistically, this tandem reaction proceeds through directed ortho C-H allylation followed by hydroamination with the proximal -CONH group, to furnish 6-methyl-5,6-dihydro-8 H-isoquinolino[1,2- b]quinazolin-8-ones in a single operation. The carboxylic acid additive has a dual role in the formation of active catalyst and protodemetalation.

Total synthesis 2-epi-α-cedren-3-one via a cobalt-catalysed Pauson-Khand reaction

Herein we target the total synthesis of 2-epi-α-cedren-3-one, a natural compound isolated from the essential oil of Juniperus thurifera. Overall, our synthetic sequence presents an optimised and robust series of chemical transformations, with prominent features including a low temperature and highly (Z)-selective Wittig olefination reaction, which is vital for the establishment of the relative stereochemistry within the final natural product, and a microwave-assisted, catalytic, intramolecular Pauson-Khand cyclisation reaction, which is used to construct the intriguing tricyclic core of the target molecule. Our optimum cyclisation protocol utilises only 20 mol% of transition metal, and delivers the complex tricyclic structure in just 10 min. Further manipulations of the annulation product culminate in the first total synthesis of the described natural target.

Palladium-Catalyzed [3 + 2]-C-C/N-C Bond-Forming Annulation.

The synthesis of bi- and tricyclic structures incorporating pyrrolidone rings is disclosed, starting from resonance-stabilized acetamides and cyclic α,β-unsaturated-γ-oxycarbonyl derivatives. This process involves an intermolecular Tsuji-Trost allylation/intramolecular nitrogen 1,4-addition sequence. Crucial for the success of this bis-nucleophile/bis-electrophile [3 + 2] annulation is its well-defined step chronology in combination with the total chemoselectivity of the former step. When the newly formed annulation product carries a properly located o-haloaryl moiety at the nitrogen substituent, a further intramolecular keto α-arylation can join the cascade, thereby forming two new cycles and three new bonds in the same synthetic operation.

Metal-free oxidative cyclization of 2-amino-benzamides, 2-aminobenzenesulfonamide or 2-(aminomethyl)anilines with primary alcohols for the synthesis of quinazolinones and their analogues

A general metal-free oxidative cyclization process has been developed for the synthesis of quinazolinones, benzothiadiazines and quinazolines. By this protocol, a range of substituted 2-aminobenzamides, 2-aminobenzenesulfonamide and 2-(aminomethyl)anilines react with various alcohols, leading to the desired annulated products smoothly. This protocol features many advantages as broad substrate scope, mild reaction conditions, low environmental pollution, high atom-economy and good to excellent yields.

Ring-chain isomerism in conjugated guanylhydrazones: Experimental and theoretical study

Treatment of 1,3-diaryl-propene-2-one with aminoguanidine under acidic conditions for a short reaction period (1 h) delivers - in accordance with a literature report - the corresponding guanylhydrazones. However, when the reaction time was increased to 12 h, formation of the ring annulated product 4,5-dihydro-1H-pyrazole-1-carboximidamide was observed. This is the first case of ring-chain isomerism in conjugated guanylhydrazones. The acyclic conjugated guanylhydrazone and the corresponding annulated product (4,5-dihydro-1H-pyrazole-1-carboximidamide) could be clearly distinguished by means of UV and NMR spectroscopy. The formation of the ring isomer was further confirmed by single crystal XRD analysis. The time-dependent 1H NMR study indicated the gradual transformation of the open-chain compound into the cyclic one. The mechanistic insights into the formation of these two products were explored using quantum chemical methods which revealed that the ring isomer is thermodynamically more stable than the open-chain isomer by 6–11 kcal/mol and the barrier for cyclization was found to be 31.37 kcal/mol.

Synthesis and Characterization of (Di)Benzosilaphenalenes

Solid-state fluorescent materials were prepared by the annulation of silylated polycyclic aromatic hydrocarbons (PAHs) with internal alkynes catalyzed by RuH2(CO)(PPh3)3. Single-crystal X-ray analysis revealed that the annulation proceeded through C–H cleavage at the peri-positions and afforded slightly strained six-membered rings containing silicon. In UV-vis absorption and photoluminescence experiments, bathochromic shifts of the annulation product as compared with those of the corresponding substrates were observed.

Photoredox C–F Quaternary Annulation Catalyzed by a Strongly Reducing Iridium Species

We report a fac–Ir(ppy)3*–IrII–IrIII photocatalytic cycle involving t-BuOK as the terminal reductant in a visible-light-induced sp2 C–F quaternary annulation reaction that proceeds in yields up to 98%. Because of the high activity of the IrII(ppy)3 catalyst, even at a loading of 50 ppm, the annulation reaction was able to compete with an uncatalyzed nucleophilic aromatic substitution reaction. The annulation reaction was stereoconvergent, and an annulated product was synthesized with complete retention of enantiomeric excess.

Unusual Ligand‐to‐Metal‐Ratio‐Controlled Bidirectional Enantioselectivity in Pd‐Catalysed [3+3]‐Annulation of Morita–Baylis–Hillman Acetate

An unusual ligand‐to‐palladium‐ratio‐dependent reversal of enantioselectivity was systematically observed in the asymmetric Pd‐catalysed [3+3]‐annulation of Morita–Baylis–Hillman acetate with 4‐hydroxycoumarin or 1,3‐cyclohexanedione. The absolute configurations of the annulation products can be readily inverted by simply modifying the L/Pd ratio from 1:3 to 2:1.

Synthesis of Pyrrole‐Annulated Heterocycles through Copper‐Catalyzed Site‐Selective Dehydrogenative Cross‐Coupling

A method for the Cu‐catalyzed, intramolecular dehydrogenative cross‐coupling of 3‐substituted and 3,4‐disubstituted pyrrole–azole systems was developed. The C–H bond in the C2 position was site‐selectively activated over the C–H bond in the C5 position of unsymmetrically substituted pyrroles, and the six‐ and seven‐membered annulated pyrrole products were directly accessed in moderate to good yields.

Enantioselektive Synthese von Robinson‐Anellierungsprodukten und Michael‐Addukten als Vorstufen

AbstractDie Robinson‐Anellierung hat seit ihrer Entdeckung 1935 in zahlreichen Synthesen Anwendung gefunden, besonders auf dem Gebiet der Steroidsynthese. Die Produkte werden gewöhnlich nach drei aufeinanderfolgenden Stufen erhalten: der Bildung eines Enolats (oder Derivats davon), einer konjugierten Addition und einer Aldolreaktion. Im Laufe der Jahre wurden mehrere methodische Verbesserungen für jede einzelne Stufe vorgenommen oder alternative Synthesewege hin zu Robinson‐Anellierungsprodukten entwickelt. Im ersten Teil dieses Aufsatzes werden die wichtigsten Entwicklungen für die Bildung Monocarbonyl‐abgeleiteter Robinson‐Anellierungsprodukte (MRA‐Produkten, MRAPs) und von einer aktivierten Monocarbonylverbindung abgeleiteter Robinson‐Anellierungsprodukte (AMRA‐Produkten, AMRAPs) erläutert. In den folgenden Abschnitten werden diastereoselektive und enantioselektive Synthesen dieser Produkte beschrieben, und im letzten Abschnitt wird die Racematspaltung von Enantiomerenmischungen dargelegt.

Enantioselective Access to Robinson Annulation Products and Michael Adducts as Precursors.

The Robinson annulation is a reaction that has been useful for numerous syntheses since its discovery in 1935, especially in the field of steroid synthesis. The products are usually obtained after three consecutive steps: the formation of an enolate (or derivative), a conjugate addition, and an aldol reaction. Over the years, several methodological improvements have been made for each individual step or alternative routes have been devised to access the Robinson annulation products. The first part of this Review outlines the most relevant developments towards the formation of monocarbonyl-derived Robinson annulation products (MRA products, MRAPs) and activated monocarbonyl-derived Robinson annulation products (AMRA products, AMRAPs). The following sections are then devoted to the diastereoselective and enantioselective synthesis of these products, while the last section describes the enantiomeric resolution of racemic mixtures.

Detection of Fleeting Amine Radical Cations and Elucidation of Chain Processes in Visible-Light-Mediated [3 + 2] Annulation by Online Mass Spectrometric Techniques.

Visible-light-mediated photoredox reactions have recently emerged as a powerful means for organic synthesis and thus have generated significant interest from the organic chemistry community. Although the mechanisms of these reactions have been probed by a number of techniques such as NMR, fluorescence quenching, and laser flash photolysis and various degrees of success has been achieved, mechanistic ambiguity still exists (for instance, the involvement of the chain mechanism is still under debate) because of the lack of structural information about the proposed and short-lived intermediates. Herein, we present the detection of transient amine radical cations involved in the intermolecular [3 + 2] annulation reaction of N-cyclopropylaniline (CPA, 1) and styrene 2 by electrospray ionization mass spectrometry (ESI-MS) in combination with online laser irradiation of the reaction mixture. In particular, the reactive CPA radical cation 1+•, the reduced photocatalyst Ru(I)(bpz)3+, and the [3 + 2] annulation product radical cation 3+• are all successfully detected and confirmed by high-resolution MS. More importantly, the post-irradiation reaction with an additional substrate, isotope-labeled CPA, following photolysis of 1, 2, and Ru catalyst provides strong evidence to support the chain mechanism in the [3 + 2] annulation reaction. Furthermore, the key step of the proposed chain reaction, the oxidation of CPA 1 to amine radical cation 1+• by product radical cation 3+• (generated using online electrochemical oxidation of 3), is successfully established. Additionally, the coupling of ESI-MS with online laser irradiation has been successfully applied to probe the photostability of photocatalysts.

Assembly of 2-Arylbenzothiazoles through Three-Component Oxidative Annulation under Transition-Metal-Free Conditions.

Highly efficient methods for the synthesis of 2-arylbenzothiazoles and 2-arylnaphtho[2,1-d]thiazoles have been developed. Readily available aromatic amines, benzaldehydes, and elemental sulfur were directly assembled through oxidative annulation and C-H functionalization under transition-metal-free conditions, where DMSO or oxygen served as the oxidant. NH4I or KI as the catalyst was found to be effective to promote the transformations to give the annulation products in good to excellent yields with wide functional group tolerance.

Annulation of five-membered cyclic enols with 3-aryl-2H-azirines: Catalytic versus non-catalytic cycloaddition

A copper(I)-NHC-catalyzed annulation of 5-membered cyclic enols of furan, thiophene and indene family with 3-aryl-2H-azirines has been developed to provide a rapid access to furo[3,4-b]pyrrole, thieno[3,4-b]pyrrole, indeno[1,2-b]pyrrole derivatives. The reaction proceeds via a copper-initiated NC2 azirine bond cleavage with the retention of the CN double bond in the annulation product. The reaction of tetronic acids with 3-aryl-2H-azirines can also proceed under catalyst-free conditions, through a double addition of the enol to the azirine, but this route provides poor yields of the annulation products. This is the first example of the NC2 bond cleavage in 2-unsubstituted 2H-azirines in the absence of a transition metal catalyst.