6-endo Cyclization Research Articles

From Colorless to Near-Infrared S-Heteroarene Isomers: Unexpected Cycloaromatization of Cyclopenta[b]thiopyran Catalyzed by PtCl2

S-heteroarenes containing cyclopenta[ b]thiopyran moieties were synthesized via intramolecular ring-expanding cycloisomerization from 1-acetyl-2-thienyl-substituted precursors catalyzed by PtCl2. In comparison to the other two S-heteroarene isomers experiencing common 6-endo and 5-exo cyclization processes, the aromatic cyclopenta[ b]thiopyran derivative demonstrates intriguing photophysical and electrochemical properties, such as near-infrared absorption, low oxidation potential, and excellent electrochemical stability. Therefore, this work provides an effective pathway to incorporate cyclopenta[ b]thiopyran as building blocks for organic semiconductors with unique properties.

Palladium-Catalyzed One-Pot Highly Regioselective 6- Endo Cyclization and Alkylation of Enynoates: Synthesis of 2-Alkanone Pyrones.

The Pd(II)-catalyzed one-pot tandem cyclization/alkylation reactions of enynoates with allylic alcohols have been demonstrated. In this reaction, an innovative protocol proceeded well through Pd-catalyzed intramolecular selective 6- endo cyclization, insertion of allylic alcohols into the Pd-C bond of vinylpalladium species generated in situ, and β-hydrogen elimination processes. This conversion provides a convenient and efficient methodology for the synthesis of 2-alkanone pyrones in moderate to good yields.

Regioselective Palladium-Catalyzed Heterocyclization–Sonogashira Coupling Cascades from 2-Alkynylbenzamides and Terminal Alkynes: Experimental and DFT Studies

A regioselective heterocyclization–Sonogashira coupling cascade between 2-alkynylbenzamides and terminal alkynes is described. The reaction proceeds under Pd(II) catalysis, with air used as a terminal oxidant to regenerate the catalyst from the Pd(0) produced in the C–C coupling. The cascade process provides alkynyl-substituted isobenzofuranimine products in a single operation. These products are the result of a 5-exo O-cyclization, while products derived from the alternative 6-endo cyclization mode are observed in minor amounts. Two competing mechanisms have been considered to account for the observed results. Both involve heterocyclization, alkyne C–H activation, and reductive elimination steps but differ in the relative order of the first two. Control experiments using a preformed alkynylpalladium complex have shown that a mechanism starting with alkyne C–H activation is viable. On the other hand, DFT calculations indicate that the alternative cyclization-first mechanism is also competitive, particular...

Synthesis of 1-Aminoindenes through Aza-Prins-Type Cyclization.

An acid-catalyzed aza-Prins-type endo cyclization of 2-alkenylbenzaldehydes with BocNH2 or aniline derivatives through in situ generation of iminium intermediates has been developed, and various 1-aminoindene derivatives were readily obtained. The first catalytic asymmetric variant of the present reaction has also been demonstrated.

Divergent synthesis of flavones and aurones via base-controlled regioselective palladium catalyzed carbonylative cyclization

A regioselective approach for construction of 5-membered and 6-membered flavonoid is established by Pd catalyzed carbonylative cyclization of 2-iodophenol with terminal alkynes using different amine bases under mild reaction condition. The catalytic experiments found that piperazine preferentially accelerate 6-endo cyclization, and triethylamine mediated Pd catalyzed 5-exo cyclization. Under optimized reaction condition, Pd catalyzed carbonylative protocol successfully applied for the diverse structures of 39 examples in good to excellent yield and regioselectivity.

Alkyne Origami: Folding Oligoalkynes into Polyaromatics.

Do not bend the triple bonds! This familiar undergraduate mantra must be disobeyed if the alkyne group is used as a building block in molecular construction. This Account will describe our exploits in "alkyne origami", that is, folding oligoalkynes into new shapes via cyclization cascades. This research stems from a set of guidelines for the cyclizations of alkynes that we suggested in 2011 ( Gilmore Chem. Rev. 2011 , 111 , 6513 ; Alabugin J. Am. Chem. Soc. 2011 , 133 , 12608 ). The guidelines blended critical analysis of ∼40 years of experimental research with computations into the comprehensive predictions of the relative favorability of dig-cyclizations of anions and radicals. In this Account, we will show how this new understanding has been instrumental in building polyaromatics. In particular, we illustrate the utility of these stereoelectronic models by developing a toolbox of practical, selective, and efficient synthetic transformations. The high energy and high carbon content render alkynes the perfect precursors for the preparation of polyaromatic ribbons and other carbon-rich materials with precisely controlled structure and reactivity. Still, the paradox of alkyne reactivity (alkynes store a lot of energy but are protected kinetically by their relatively strong π-bonds) requires precise use of stereoelectronic factors for lowering the activation barriers for alkyne cyclizations. These factors are drastically different in the "all-exo" and the "all-endo" cyclization cascades of oligoynes. This Account will highlight the interplay between the stereoelectronics of bond formation and topology of acyclic precursor "folding" into a polycyclic ribbon. The topology of folding is simpler for the endo cascades, which are compatible with initiation either at the edge or at the center. In contrast, the exo cascades require precise folding of an oligoalkyne ribbon by starting the cascade exactly at the center of the chain. These differences define the key challenges in the design of these two types of alkyne cyclization cascades. For the endo processes, the folding is simple, but these processes require a strategy ("LUMO Umpolung") for inverting the usual stereoelectronic requirements of alkyne cyclizations. We also show how alkenes can be used as alkyne equivalents in cyclizations coupled with fragmentations and how one can make endo cyclization products without ever going through an endo cyclization. In contrast, each elementary step of the exo cascades benefits from the inherent exo preference for the radical attack, but these cascades require precise initiation by starting exactly at the central alkyne unit of the oligoyne. This strict selectivity requirement led to the development of traceless directing groups capable of supramolecular assistance to the initiation step and self-terminating departure at the end of the cascade. With attention to electronic effects that can stop radical cascades, oligoalkynes can be selectively converted into precisely shaped and functionalized polyaromatic products. The generality of these concepts is further illustrated by the development of radical "peri annulations" at the zigzag edge of acenes.

Computational insights into the mechanisms of Ru-catalyzed cycloisomerization of 2-ethynylaniline and 2-(2-propynyl)tosylanilide: The role of pyridine in assisting the metal-vinylidene formation

Mechanistic studies of ruthenium-catalyzed cycloisomerization of 2-ethynylaniline and 2-(2-propynyl)tosylanilide were carried out using DFT calculations. A pyridine assisted hydrogen transfer pathway was unveiled for the formation of Ru-vinylidene complex. The proposed pathway was applied to rationalize the origin of the regioselectivity, 5-exo vs 6-endo cyclization, in the ruthenium catalyzed cycloisomerization of 2-(2-propynyl)tosylanilide. The cycloisomerization of 2-(2-propynyl)tosylanilide in the presence of pyridine produced a 6-endo cyclized product via the Ru-vinylidene intermediate assisted by pyridine while its absence afforded a 5-exo cyclized product via a direct nucleophilic addition. This study sheds more light on alternative pathways for reactions involving alkyne-vinylidene species.

Selective oxymetalation of terminal alkynes via 6-endo cyclization: mechanistic investigation and application to the efficient synthesis of 4-substituted isocoumarins.

The cyclization of heteroatom-containing alkynes with π acidic metal salts is an attractive method to prepare heterocycles because the starting materials are readily available and the organometallic compounds are useful synthetic intermediates. A new organometallic species in the heterocyclization provides an opportunity to synthesize heterocycles that are difficult to obtain. Herein, we describe a novel cyclic oxymetalation of 2-alkynylbenzoate with indium or gallium salts that proceeds with an unusual regioselectivity to give isocoumarins bearing a carbon-metal bond at the 4-position. This new type of metalated isocoumarin provided 3-unsubstituted isocoumarins that have seldom been investigated despite their important pharmacological properties. Indium and gallium salts showed high performance in the selective 6-endo cyclization of terminal alkynes while boron or other metals such as Al, Au, and Ag caused 5-exo cyclization or decomposition of terminal alkynes, respectively. The metalated isocoumarin and its reaction intermediate were unambiguously identified by X-ray crystallographic analysis. The theoretical calculation of potential energy profiles showed that oxyindation could proceed via 6-endo cyclization under thermodynamic control while previously reported oxyboration would give a 5-membered ring under kinetic control. The investigation of electrostatic potential maps suggested that the differences in the atomic characters of indium, boron and their ligands would contribute to such a regioselective switch. The metalated isocoumarins were applied to organic synthetic reactions. The halogenation of metalated isocoumarins proceeded to afford 4-halogenated isocoumarins bearing various functional groups. The palladium-catalyzed cross coupling of organometallic species with organic halides gave various 4-substituted isocoumarins. A formal total synthesis of oosponol, which exhibits strong antifungal activity, was accomplished.

Toward a Unified Total Synthesis of the Xiamycin and Oridamycin Families of Indolosesquiterpenes.

A unified synthetic strategy toward the oridamycin and xiamycin families of natural products was designed, aiming to access several natural products from a common synthetic intermediate readily prepared from geranyl acetate. Part of this strategy was successfully realized, culminating in the synthesis of oridamycin A and oridamycin B. Key steps include a Mn(III)-mediated oxidative radical cyclization to construct the trans-decalin ring, and a 6π-electrocyclization/aromatization sequence to produce the 2,3-fused carbazole. Oridamycin B was accessed through a late-stage, C-H oxidation that converted the C16 methyl to a hydroxymethyl. A variety of strategies were explored to form a chelated radical intermediate en route to xiamycin A, including enolate SET oxidation, oxo-vanadium oxidation, and atom-transfer cyclization. Unfortunately, none of these strategies provided the desired C16-epimeric trans-decalin. Exploratory studies on photoredox-catalyzed radical cyclizations yielded interesting results, including the formation of a bicyclic lactone arising from oxidative termination of the photoredox-catalyzed radical cyclization, and a double 6-endo cyclization with catalyst loadings as low as 0.01 mol%.

Iodonium-Induced Cyclization of N-Allenylindoles and N-Allenylpyrroles: An Access to Iododihydropyrido[1,2-a]indoles and Dihydroindolizines

The formation of iodinated dihydropyrido[1,2-a]indoles and dihydroindolizines was achieved by an iodocarbocyclization reaction of N-allenylindoles and N-allenylpyrroles. This transformation proceeded under very mild conditions using N-iodosuccinimide as the electrophilic iodine source to deliver the products via a 6-endo cyclization process. Careful choice of the solvent and concentration were mandatory to obtain the cyclization in good yields.

Regioselective annulation of propargyl alcohols with ambident-enols: A Ca(II)-catalyzed trisubstituted benzochromene synthesis

Highly regioselective, 6-endo cyclization between propargyl alcohols and ambident enols such as naphthols, 4-hydroxy coumarin, cyclohexane-1,3-dione, 5,5-dimethylcyclohexane-1,3-dione is described using Ca(OTf)2 under solvent free conditions. The reaction proceeds through a cascade annulation which involves an etherification, Claisen type rearrangement, allene formation and endocyclization. Further, we extended this method to the synthesis of iodo-derivative and demonstrated the reactivity in cross-coupling reactions.

Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo Cyclization.

Resiniferatoxin (1) belongs to a daphnane diterpenoid family and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from d-ribose derivative 19, was designed to possess the caged orthoester structure with α-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive α-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in the presence of n-Bu3SnH and V-40 by utilizing the xanthate on the C-ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7-endo cyclization but also construction of the C8-stereocenter and the C6-exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis.

Synthesis and preliminary antiproliferative activity of new pteridin-7(8H)-one derivatives

Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8H)-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC50 values of 4.32 and 7.01 μM, respectively. Besides, compound 12 induced morphological changes and apoptosis of MKN-45 cells, increased expression of Bax, down-regulated expression of Bcl-2 and caused cleavage of caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7H-purine-8-carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established.

Accessing pyrrolones and pyridinones: controlling 5-exo and 6-endo ring closures in heterocyclic alkynylamides

Competitive 5-exo and 6-endo anionic intramolecular cyclization reactions in heterocyclic alkynylamides were explored via experimental and computational analysis. The 5-exo-dig cyclization pathway is usually disfavoured in heterocyclic systems, and 6-endo products are often both the kinetic and thermodynamic products. However, we’ve found that it is possible to shift selectivity toward the 5-exo-dig pyrrolone products away from the less strained pyridinone products that are produced via the 6-endo-dig cyclization. Parameters such as identity of heteroatom, heteroatom positioning within the heterocycle, and functionality on the alkyne were investigated and, in many cases, were found to strongly influence product ratios. A series of computational studies was performed to provide further insight into the 5-exo-dig and 6-endo-dig pathways in these heterocyclic systems. Theoretical predictions were found to reproduce experimental results, highlighting the predictive capabilities of the computations in determining preferred products.

Synthesis of the KLMN Fragment of Gymnocin-A from the FGH Fragment.

An improved route for the synthesis of the KLMN fragment of gymnocin-A was developed through the oxiranyl anion coupling of the FGH fragment with a chiral C3 epoxy sulfone, followed by 6-endo cyclization. This straightforward approach reduced the number of synthetic steps by 14 compared with a previous route using alternative building blocks.

Chemical Access to d-Sarmentose Units Enables the Total Synthesis of Cardenolide Monoglycoside N-1 from Nerium oleander.

Herein we present a chemical approach for the ready preparation of d-sarmentosyl donors enabling the first total synthesis and structure validation of cardenolide N-1, a challenging 2,6-dideoxy-3-O-methyl-β-d-xylo-hexopyranoside extracted from Nerium oleander twigs that displays anti-inflammatory properties and cell growth inhibitory activity against tumor cells. The strategy highlights the synthetic value of the sequential methodology developed in our group for the synthesis of 2-deoxyglycosides. Key steps include Wittig-Horner olefination of a d-xylofuranose precursor, [I+]-induced 6-endo cyclization, and 1,2-trans stereoselective glycosylation.

Synthesis of the Tetracyclic ABCD Ring Domain of Calyciphylline A-Type Alkaloids via Reductive Radical Cyclizations.

A tetracyclic compound with the ABCD ring framework of calyciphylline A-type alkaloids was synthesized from a cis-3a-methyloctahydroindole triggered by a 5-endo radical cyclization. The synthesis required two additional ring-forming steps: the construction of a seven-membered ring by aldol cyclization and the azabicyclic fragment by a radical ring closure of a trichloroacetamide-tethered enol acetate followed by a diastereoselective α-methylation of the lactam group.

Formation of Seven-Membered Carbocycles via 7-endo Mode Cyclization of Lithioheptatrienes.

The highly selective synthesis of triene derivatives was achieved by a zirconocene-mediated three-component coupling reaction, and the trienes were efficiently subjected to 7-endo mode cyclization. The reaction of unsymmetrical zirconacyclopentadienes prepared from two different alkynes with N-bromosuccinimide (NBS) followed by treatment with allyl halides in the presence of CuCl afforded the corresponding heptatrienes in good yields. When the trienes reacted with an organolithium reagent, 7-endo mode cyclization occurred smoothly to give the corresponding cycloheptadiene.

Pd catalyzed couplings of “superactive esters” and terminal alkynes: Application to flavones and γ-benzopyranones construction

Lewis base, N-methylmorpholine (NMM) accelerated Pd-catalyzed Sonogashira coupling of steric hindered super active esters, 1a–1e, and terminal alkynes. This approach provided an efficient synthetic protocol for a broad array of acylated o-alkynoylphenols compounds, 3a–3e, under moderate conditions. The mechanistic study clearly demonstrated that NNM stabilized the catalytic palladium species, and accelerated the leaving of triazine moiety during the catalytic cycle of the cross-coupling reactions. In addition, piperazine was found to efficiently catalyze the 6-endo cyclization of acylated o-alkynoylphenols, which achieved the diversity oriented synthesis of γ-benzopyranones, 4aa–4eg, with 93–99% yields.

ChemInform Abstract: Copper(I)‐Catalyzed Sulfonylation of (2‐Alkynylaryl)boronic Acids with DABSO

Abstractaffording benzothiophene 1,1‐dioxides