Formation Of Benzofurans Research Articles

ChemInform Abstract: Biogenetically Inspired Total Synthesis of (+)‐Liphagal: A Potent and Selective Phosphoinositide 3‐Kinase α (PI3Kα) Inhibitor from the Marine Sponge Aka coralliphaga.

A biologically attractive and structurally unique marine natural product, (+)-liphagal, was biomimetically synthesized in 29 % overall yield in a longest linear sequence of 13 steps from commercially available (+)-sclareolide. This synthesis involved the following crucial steps: (i) stereocontrolled hydrogenation of an endo-olefinic decalin to install the C8 stereogenic centre present in the requisite decalin segment; (ii) coupling of the decalin segment with an aromatic moiety to assemble the desired carbon skeleton; (iii) ring expansion of a proposed biogenetic intermediate followed by benzofuran formation to establish the requisite tetracyclic core structure. A few new aspects of the proposed biosynthetic pathway to this class of natural products were revealed.

Synthesis of indoles, benzofurans, and related heterocycles via an acetylene-activated SNAr/intramolecular cyclization cascade sequence in water or DMSO.

The synthesis of 2-substituted indoles and benzofurans was achieved by nucleophilic aromatic substitution, followed by subsequent 5-endo-dig cyclization between the nucleophile and an ortho acetylene. The acetylene serves the dual role of the electron withdrawing group to activate the substrate for SNAr, and the C1-C2 carbon scaffold for the newly formed 5-membered heteroaromatic ring. This method allows for the bond forming sequence of Ar-X-N/O-C1 to proceed in a single synthetic step, furnishing indoles and benzofurans in moderate to high yields. Since the method is not transition metal mediated, brominated and chlorinated substrates are tolerated, and benzofuran formation can be conducted using water or water-DMSO mixtures as solvent.

Biogenetically Inspired Total Synthesis of (+)‐Liphagal: A Potent and Selective Phosphoinositide 3‐Kinase α (PI3Kα) Inhibitor from the Marine Sponge Aka coralliphaga

AbstractA biologically attractive and structurally unique marine natural product, (+)‐liphagal, was biomimetically synthesized in 29 % overall yield in a longest linear sequence of 13 steps from commercially available (+)‐sclareolide. This synthesis involved the following crucial steps: (i) stereocontrolled hydrogenation of an endo‐olefinic decalin to install the C8 stereogenic centre present in the requisite decalin segment; (ii) coupling of the decalin segment with an aromatic moiety to assemble the desired carbon skeleton; (iii) ring expansion of a proposed biogenetic intermediate followed by benzofuran formation to establish the requisite tetracyclic core structure. A few new aspects of the proposed biosynthetic pathway to this class of natural products were revealed.

Alternative spiroketalization methods toward purpuromycin: a hemiketal conjugate addition strategy and use of an electron-rich isocoumarin precursor.

Two methods are presented that were designed to circumvent the persistent problem of benzofuran formation and instead yield a spiroketal of the rubromycin family type. First, using an alternative disconnection, a hemiketal conjugate addition to a naphthaquinone electrophile was investigated. Synthesis of the requisite electrophile provided insight into the selective oxidation and functionalization of the naphthalene portion. Second, the electronic features of the isocoumarin ring system were adjusted, and the corresponding reactivity further supports the hypothesis that electron-rich isocoumarins are capable of spiroketalization. Robust, flexible syntheses from simple precursors were developed that allowed multiple reduced isocoumarins to be generated. Combined, the data presented herein give insight into the sensitivities of this family and illuminate other potential methods of spiroketalization. In addition, the convergent assembly of substrates containing different naphthaquinone and isocoumarin subunits highlights the utility of our 1,3-dipolar cycloaddition approach to generate analogs of these structures for SAR, as well as chemical reactivity studies.

Alternative Spiroketalization Methods toward Purpuromycin: A Diketone Approach To Prevent Benzofuran Formation

The central portion of purpuromycin has been assembled via a classical spiroketalization reaction. Key to promoting this reaction mode versus benzofuran formation was the oxidation state of the spiroketal core. With a higher oxidation state, even the electron-deficient isocoumarin found in purpuromycin could be employed directly in the spiroketalization. The two halves of the spiroketalization precursor were joined via a nitrile oxide/styrene 1,3-dipolar cycloaddition. A very mild selenium dioxide oxidation was used to introduce the required oxidation state of the spiroketal core.

ChemInform Abstract: Platinum(II)‐Catalyzed Generation and [3 + 2] Cycloaddition Reaction of α,β‐Unsaturated Carbene Complex Intermediates for the Preparation of Polycyclic Compounds.

Pt(II)-catalyzed generation of unsaturated carbene complex intermediates from various propargyl ether derivatives based on electrophilic activation of alkynes was realized. These in situ generated unsaturated carbene complexes undergo [3+2] cycloaddition reaction with various vinyl ethers, leading to efficient formation of indoles, naphthols, and benzofuran fused with a five-membered ring in high yields.

Platinum(II)-Catalyzed Generation and [3+2] Cycloaddition Reaction of α,β-Unsaturated Carbene Complex Intermediates for the Preparation of Polycyclic Compounds

Pt(II)-catalyzed generation of unsaturated carbene complex intermediates from various propargyl ether derivatives based on electrophilic activation of alkynes was realized. These in situ generated unsaturated carbene complexes undergo [3+2] cycloaddition reaction with various vinyl ethers, leading to efficient formation of indoles, naphthols, and benzofuran fused with a five-membered ring in high yields.

Synthesis, Spectroscopy, Crystal Structure Determination, and Quantum Chemical Calculations of BODIPY Dyes with Increasing Conformational Restriction and Concomitant Red‐Shifted Visible Absorption and Fluorescence Spectra

Starting from the conformationally unconstrained compound 3,5-di-(2-bromophenoxy)-4,4-difluoro-8-(4-methylphenyl)-4-bora-3a,4a-diaza-s-indacene (1), two BODIPY dyes (2 and 3) with increasingly rigid conformations were synthesized in outstanding total yields through palladium catalyzed intramolecular benzofuran formation. Restricted bond rotation of the phenoxy fragments leads to dyes 2 and 3, which absorb and fluoresce more intensely at longer wavelengths relative to the unconstrained dye 1. Reduction of the conformational flexibility in 2 and 3 leads to significantly higher fluorescence quantum yields compared to those of 1. X-ray diffraction analysis shows the progressively more extended planarity of the chromophore in line with the increasing conformational restriction in the series 1-->2-->3, which explains the larger red shifts of the absorption and emission spectra. These conclusions are confirmed by quantum chemical calculations of the lowest electronic excitations in 1-3 and dyes of related chemical structures. The effect of the molecular structure on the visible absorption and fluorescence emission properties of 1-3 has been examined as a function of solvent by means of the new, generalized treatment of the solvent effect (J. Phys. Chem. B 2009, 113, 5951-5960). Solvent polarizability is the primary factor responsible for the small solvent-dependent shifts of the visible absorption and fluorescence emission bands of these dyes.

Single Bifunctional Ruthenium Catalyst for One‐Pot Cyclization and Hydration giving Functionalized Indoles and Benzofurans

DOI: 10.1002/chem.201001075 Single Bifunctional Ruthenium Catalyst for One-Pot Cyclization and Hydration giving Functionalized Indoles and Benzofurans Reji N. Nair, [a] Paul J. Lee, [a] Arnold L. Rheingold, [b] and Douglas B. Grotjahn* [a] Indole [1] and benzofuran [1d, 2] heterocycles are key structur- al units in a variety of biologically active natural products and unnatural synthetic materials. Over the last few years, transition-metal catalysts have been extensively used in the cyclization of o-alkynylarylamines [3a–l] and phenols [3m–p] to construct benzoheterocycles through intramolecular [3] and intermolecular reactions. [4] Many of these reactions required the use of a nitrogen protecting group in the case of indo- les [3g,i,k] or stoichiometric amounts of the metal. [3l] McLory and Trost [3d] synthesized both unprotected indoles or N- benzyl analogues by using rhodium–phosphine complexes, but to optimize the benzofuran synthesis, large amounts of phosphine (0.6 equiv) were needed. Saa and co-workers [3q] recently reported the use of 10 mol % catalyst and amine solvents in benzofuran synthesis at 90 8C. Herein, we report that the bifunctional ruthenium catalyst 1 which has been used for anti-Markovnikov alkyne hydration [5] emerges as a versatile choice for both indole and benzofuran formation, with a number of unique advantages, including the use of only 2 mol % catalyst in most cases and the unprecedented ability of a cycloisomerization catalyst to perform hydration or deuteration in the same reaction. We envisioned that the use of alkyne hydration catalyst 1 on substrates, such as 2, (Scheme 1) would generate the al- dehyde 3, on which cyclization and dehydration would then enable facile synthesis of heterocycles. Indeed, 2 a cyclized to hemiaminal 4 a, [5a] with some equilibrium amount of 3 a, [a] R. N. Nair, P. J. Lee, Prof. D. B. Grotjahn Department of Chemistry and Biochemistry San Diego State University 5500 Campanile Drive, San Diego, CA 92182-1030 (USA) Fax: (+ 1) 619-594-4634 E-mail: grotjahn@chemistry.sdsu.edu [b] Prof. A. L. Rheingold Department of Chemistry and Biochemistry University of California–San Diego La Jolla, CA 92093-0358 (USA) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201001075. Scheme 1. The use of bifunctional catalyst 1 for hydration and cycliza- tion; Cp = cyclopentadienyl. but elimination of water from 4 a required heating in second step, forming 5 a in 46 % overall yield. The same two-step process could be used on the homologous substrate 2 b, to form 5 b in 56 % overall yield. Encouraged by these results, and because of the impor- tance of indoles, we shifted our attention to substrates de- rived from o-ethynylaniline. The first four entries of Table 1 demonstrate that 1 cyclizes a wide range of aniline deriva- tives; most significantly, the simplest, unprotected parent compound 6 cyclized to indole 17 in 99 % yield (Table 1, entry 1). Sulfonamide 7 (Table 1, entry 2) was cyclized to give the N-tosyl (Ts) protected indole in just 2 h. Entries 3 and 4 in Table 1 show the ability of the catalyst to form ni- trogen analogues with different alkyl substituents. Especially notable is the selectivity of 1: the N-allyl group (Table 1, entry 3) is fully tolerated without the decomposition by iso- merization seen when using a Rh-based catalyst. [3d] The fact that a wide variety of nucleophilic nitrogen cen- ters could be used in indole formation encouraged us to ex- plore the scope of 1 not only in making more complex indole derivatives, but also in cyclizing phenol derivatives to benzofurans. Gratifyingly, 1 forms both 7-aza- and 6-nitroin- doles (Table 1, entries 5 and 6), showing tolerance of various ring substituents, including those that might coordinate to the catalyst. Furthermore, entry 9 (Table 1) shows the ability of 1 to form the benzofuran nucleus in essentially quantita- 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2010, 16, 7992 – 7995

ChemInform Abstract: The Reactions of Diazo Compounds with Lactones. Part 2. The Reaction of Cyclic 2-Diazo-1,3-dicarbonyl Compounds with Diketene: Benzofuran Formation.

Cyclic 2-diazo-1,3-dicarbonyl compounds react with diketene in the presence of rhodium(II) salts to give benzofurans as the major isolated products. The formation of intermediate products with exocyclic double bonds which isomerise to benzofurans provides support for the proposed mechanism which involves initial formation of a dioxaspirooctenone by a formal dipolar cycloaddition reaction of a carbenoid to the exocyclic double bond of diketene followed by the loss of carbon dioxide. Acyclic 2-diazo-1,3-dicarbonyl compounds give furans in poor yield.

Pd‐Catalyzed Reactions of Allenylphosphonates and Related Allenes with Functionalized 2‐Iodophenols, 2‐Iodobenzoic Acid, and 2‐Iodobenzyl Alcohol Leading to Functionalized Benzofurans, Isocoumarins, and Benzopyrans

AbstractRegioselective, palladium‐catalyzed coupling reactions of allenylphosphonates (OCH2CMe2CH2O)P(O)CH=C=CRR′ [R, R′ = H (1a), R = H, R′ = Me (1b), R = R′ = Me (1c)] and phenyl allenes PhCH=C=CR2 [R = H (2a), Me (2b)] with functionalized iodophenols (in PEG‐400), 2‐iodobenzoic acid, and 2‐iodobenzyl alcohol are investigated. Benzofurans with free aldehyde functionalities are formed in high yields (1H/31P NMR) in reactions by using functionalized iodophenols, essentially as single isomers. The synthetic potential of these products possessing an aldehyde functionality is demonstrated by isolating a compound with the skeleton of Obovaten and many other 2,3,5,7‐tetrasubstituted benzofurans. From the reaction of 2‐iodophenol and PdII(OAc)2/PAr3, isolation and structural characterization of the (hydroxy)aryl phosphane oxides (Ar)2P(O)(C6H4‐2‐OH) (Ar = Ph, 4‐MeOC6H4) that suggests the P–aryl to Pd–aryl bond exchange,is described. An interesting structural problem related to the formation/crystallization of benzofurans is also highlighted. The reaction of allenes with iodobenzyl alcohol or iodobenzoic acid led to benzopyrans or isocoumarins (isochromanones), respectively, as single isomers in good to excellent yields. The reaction of 3‐methylbuta‐1,2‐dienyl acetate with 2‐iodobenzoic acid led to a novel acetic acid elimination product along with the expected isocoumarin. The structures of key compounds are confirmed by X‐ray crystallography. These results establish that in the formation of benzofurans or benzopyrans, [β,γ] attack on the allene is preferred except in the case of PhC=C=CH2, where [β,α] attack is observed. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Iron-Catalyzed Tandem Oxidative Coupling and Annulation: An Efficient Approach to Construct Polysubstituted Benzofurans

The combination of FeCl(3) x 6 H(2)O and di-tert-butyl peroxide offers a novel and efficient method for the construction of polysubstituted benzofurans 3 from the reaction of simple phenols 1 and beta-keto esters 2, which are expected to give coumarins in the well-known Pechmann condensation. A variety of phenols reacted with beta-keto esters to provide a range of benzofuran products in moderate to excellent yields. The regio-specific annulation was proven by the X-ray molecular structure of the product 3k. Hydrate of FeCl(3) is essential for an achievement of the present transformation. The kinetic isotopic effect (KIE) experiments were carried out by competition experiments and displayed a k(H)/k(D) = 1.0 +/- 0.1. The kinetic isotopic effect indicated that aromatic C-H bond cleavage is not involved in the rate-determining steps of the present transformation. Moreover, the results clearly demonstrate that the dichotomous catalytic behavior of the iron catalyst, which is transition-metal catalyst in the oxidative coupling step and Lewis acid in the condensation step. The possible intermediate 5 was synthesized and converted into the desired benzofuran 3a under the reaction conditions. A tentative mechanism of the formation of benzofurans 3 was proposed.

Gold catalysis: benzanellation versus alkylidenecyclopentenone synthesis

A series of different furan-yn-ols were prepared by a three-step sequence. Their reaction with Gagosz's catalyst Ph 3PAuNTf 2 depends strongly on the substitution pattern of the substrate and the quality of the leaving group. Benzofurans, alkylidenecyclopentenones or Meyer–Schuster type products can be obtained. Improving the leaving group quality leads to the preferred formation of benzofurans.

Total Synthesis of (+)‐Machaeriols B and C and of Their Enantiomers with a Cannabinoid Structure

AbstractAn efficient and concise synthesis of the biologically interesting (+)‐machaeriol B (2) and its enantiomer 5 was accomplished from O‐phenylhydroxylamine (7) in four steps (Scheme 2). In addition, the first total synthesis of natural (+)‐machaeriol C (3) and its enantiomer 6 was achieved from the readily available ester 15 in eight steps (Scheme 4). The key strategies in the syntheses of 2 and 5 involved benzofuran formation through a [3,3]‐sigmatropic rearrangement and trans‐hexahydrodibenzopyran formation by a domino aldol‐type/hetero‐Diels–Alder reaction. In the case of 3 and 6, the key steps were stilbene formation by a Horner–Wadsworth–Emmons reaction and trans‐hexahydrodibenzopyran formation by domino reactions.

Formation of benzofurans in a stoichiometric annulation reaction between stable Pallada (II) Cycles hypervalent vinyl- and alkynyl(phenyl)iodonium salts

Stable pallada(II)cycles featuring Csp 2–Pd and Csp 3–Pd bonds reacted with vinyl- and alkynyl(phenyl)iodonium salts to generate two new geminal carbon–carbon bonds to the terminal carbon of the vinyl and alkynyl substituents providing benzofuran and dihydrobenzofuran heterocycles. The new annulation process was rationalized by the involvement of Pd(IV) intermediates arising via an initial oxidative addition of hypervalent iodonium electrophiles to the Pd(II) center. Reaction monitoring via low temperature 1H NMR spectroscopy was performed, and organopalladium(II) intermediates featuring a new Csp 2–Csp 2 or Csp 2–Csp bond were isolated and characterized, providing insights into the regiochemical course of the proposed mechanistic pathway.

Rhodium‐Catalyzed Cycloisomerization: Formation of Indoles, Benzofurans, and Enol Lactones.

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Rhodium‐Catalyzed Cycloisomerization: Formation of Indoles, Benzofurans, and Enol Lactones

Innere Angelegenheit: Indole, Benzofurane und Enollactone entstehen chemoselektiv in der rhodiumkatalysierten Cycloisomerisierung einfach herzustellender Alkinylanilin-Substrate (siehe Schema, cod=Cycloocta-1,5-dien, DMF=N,N-Dimethylformamid). Die Reaktion könnte über das nucleophile Abfangen eines Vinyliden-Intermediats verlaufen. Indole werden unter milden Bedingungen mit niedriger Katalysatorbeladung gebildet.

Rhodium‐Catalyzed Cycloisomerization: Formation of Indoles, Benzofurans, and Enol Lactones

Internal affairs: Indoles, benzofurans, and enol lactones are formed chemoselectively from the rhodium-catalyzed cycloisomerization reaction of easily prepared alkynyl aniline substrates (see scheme, cod=cycloocta-1,5-diene, DMF=N,N-dimethylformamide). The reaction may proceed by nucleophilic capture of a vinylidene intermediate. Indoles are formed under mild conditions using low catalyst loadings.

Mechanistic Studies on the Photochemical Deprotection of 3′,5′‐Dimethoxybenzoin Esters

Several mechanistic alternatives proposed for the photochemical deprotection of dimethoxybenzoin esters are presented. Both experimental and theoretical evidence suggest the mechanism is heterolysis of the singlet excited state to form a carboxylate and the alpha-ketocation. The alpha-ketocation has been observed by transient spectroscopy. We propose the alpha-ketocation undergoes electrocyclization to an intermediate with extended conjugation, whose deprotonation gives the observed benzofuran product. A Brønsted study of the rates of benzofuran formation with dimethoxybenzoin esters derived from acids of varying pKa shows the rate is independent of the basicity of the leaving group. In this multistep reaction, benzofuran formation by a final deprotonation is slower than alpha-ketocation generation.

A First Regioselective Synthesis of 3‐Fluoroalkylated Benzofurans via Palladium‐Catalyzed Annulation of Fluorine‐Containing Internal Alkynes with Variously Substituted 2‐Iodophenol.

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