Reactions of 3-vinylindole derivatives with dienophiles

Reactions of 3-(1-cyclohexenyl)-1,2-dimethylindole (1a) and the 1,2-dihydrocarbazole 1b with some carbo- and heterodienophiles are described. Thus, compound 1a reacts to give ene, Michael-type, and Diels-Alder adducts, depending on the dienophile and reaction conditions. The 3-vinylindole 1b reacts with 4-phenyl-1,2,4-triazoline-3,5-dione or N-phenylmaleimide in a dehydrogenative reaction to yield the fully aromatized carbazole 8.

ChemInform Abstract: Palladium-Catalyzed Suzuki Carbonylative Reaction of α-Halomethyl Oxime Ethers: A Regioselective Route to Unsymmetrical 1,3-Oxyiminoketones.

ChemInform Abstract: Switchable Palladium-Catalyst Reaction of Bromomethyl Sulfoxides, CO, and N-Nucleophiles: Aminocarbonylation at Csp3versus Oxidative Carbonylation of Amines.

Pd2(dba)3/ Xantphos-catalyzed coupling of the sulfoxides (I) and (V) with amines and carbon monoxide allows a new and efficient access to amides of type (IV) and (VI).

First synthesis of the chiral mixed O/S ligands, 1,2-sulfinyl thiols: application as chiral proton sources in enantioselective protonations of enolates

Abstract A suitable method for the preparation of the chiral mixed O/S ligands 1,2-sulfinyl thiols is described. These compounds have then been used as a chiral proton source in the enantioselective protonation of 2-methyl tetralone enolate and the results are compared with those obtained from the analogous alcohols. A theoretical model is proposed to explain the different behaviors exhibited in the protonation reaction for each of these proton sources. Configurational assignments for the new chiral thiols have been carried out by means of X-ray analysis.

Cycloaddition Reactions with Vinyl Heterocycles

Publisher Summary The Diels-Alder reaction is one of the most common and elegant methods for the construction of six-membered rings. Although the number of Diels-Alder cycloadditions with open-chain and alicyclic dienes is very large, the number of examples with aromatic heterocyclic compounds is relatively small. The introduction of a vinyl group as a substituent onto a heterocycle increases the number of possible reactions. This new possibility, however attractive for synthetic purposes, is successful only with π-excessive five-membered heterocyclic derivatives with a few exceptions. The chapter discusses the reactions of vinyl heterocycles with carbodienophiles. The endocyclic and exo-en…

Unprecedented Palladium-Catalyzed Cross-Coupling Reaction of α-Bromo Sulfoxides with Boronic Acids

[reaction: see text] A new Suzuki-type palladium-catalyzed reaction of boronic acids with alpha-bromo sulfoxides has been developed using a protocol similar to the well-documented reaction of boronic acids with aryl halides. Both cross-coupling and homocoupling processes were observed. The best yields in cross-coupling products were obtained when the presence of oxygen was carefully excluded using degassed solvents. The oxidative addition palladium complex intermediate could be isolated and characterized by X-ray single-crystal diffraction.

Influence of the Ligand of Palladium(0) Complexes on the Rate of the Oxidative Addition of Aryl and Activated Alkyl Bromides: Csp2 −Br versus Csp3 −Br Reactivity and Selectivity

Kinetic data by means of electrochemical techniques are used to characterize the reactivity of aryl bromides and activated alkyl bromides in oxidative addition to palladium(0) complexes generated from three precursors: Pd0(PPh3)4, {Pd0(dba)2 + 2 PPh3} and {Pd0(dba)2 + 2 P(o Tol)3} in DMF at 25 °C. It is established that, for the investigated substrates 1-6 and 7-11, the oxidative addition at the Csp3 Br bond is much faster than that at the Csp2 Br bond when the palladium(0) is ligated by two PPh3. This explains why the regioselectivity in Suzuki-Miyaura reactions performed from substrates bearing both Csp2 Br and Csp3 Br groups is in favour of the substitution at the Csp3 Br bond. It is in …

ChemInform Abstract: Gold(I)-Catalyzed Reactions of 1-(ortho-Alkynylaryl)ureas: Highly Selective Heterocyclization and Synthesis of Mixed N,O-Acetals.

Treatment of alkynylureas (I) with trifluoroethanol in the presence of a Au/Ag catalytic system provides N-6-exo-dig heterocyclization products (III) and in some cases open chain acetals as side products.

Synthesis of chiral β-disulfoxides and their racemization with strong bases

Abstract β-Disulfoxides can be obtained from different α-sulfunylcarbanions and sulfinates. While α-unsubstituted and monosubstituted β-disulfoxides are configurationally stable in the presence of strong bases, α,α-disubstituted β-disulfoxides epimerize through an intermolecular mechanism.

Enzymatic esterification of bicyclic meso-diols derived from 1,4-bis(hydroxymethyl)furan. An enantioselective Diels–Alder reaction equivalent

Abstract meso -Diols derived from the Diels–Alder adduct 1,4-bis(hydroxymethyl)furan/dimethyl acetylenedicarboxylate can be enantioselectively monoacetylated under CRL or PSL catalysis with very good yields and moderate to excellent ees. (+)-Monoacetates are always preferentially formed in the reactions catalyzed by CRL, and their (−)-enantiomers are the main products in the acetylations under PSL catalysis. Absolute configurations have been determined by X-ray analysis of a single crystal of an ( R )-α-methoxyphenylacetyl derivative.

Frontispiece: Fluorine‐Containing Drugs Approved by the FDA in 2018

The mechanism of formation of 3H,9H-Pyrano[3,4-b]indol-3-ones from 3-indolalkanoic acids

The mechanism of the formation of 1-methyl-3H,9H-pyrano[3,4-b]indol-3-one (4) from the corresponding 3-indolacetic acid 1 is discussed. The suggested mechanism is substantiated by the isolation of a stable intermediate 2 and its transformations in the presence of acetic anhydride and/or Lewis acids.

Synthesis of an enantiopure 2-arylcyclohexanols from prochiral enol acetates by an enantioselective protonation/diastereoselective reduction sequence

Abstract The enantioselective protonation with 2-sulfinyl alcohols of lithium enolates of 2-arylcyclohexanones with different substituents on the phenyl group takes place with excellent enantioselectivities (89–99%). Chiral 2-phenylcyclohexanone and 2-arylcyclohexanones carrying electron donor substituents on the aromatic ring are converted into the corresponding trans -2-arylcyclohexanols by diastereoselective reduction with sodium naphthalenide in the presence of acetamide. The stereochemical integrity of the tertiary stereocenter is fully preserved using this reduction procedure. Interestingly, the chiral proton source is not consumed in the synthesis.

Remarkable effect of lithium bromide in the enantioselective protonation with α-sulfinyl alcohols

Abstract The favourable effect of lithium bromide enhancing the facial enantioselectivity in the protonation of methyl tetralone enolate with α-sulfinyl alcohols is described. Theoretical calculations allow to propose a model to explain the stereochemical course of the protonation reaction.

Gold(I)-catalyzed intermolecular oxyarylation of alkynes: unexpected regiochemistry in the alkylation of arenes.

The reaction between acetylenes and sulfoxides, studied as a test case for gold-catalyzed intermolecular addition, provides the oxyarylation compounds 3 in good yields. Unpredictably, in all cases a single regioisomer arising from the electrophilic aromatic alkylation at the position adjacent to the sulfur atom is obtained instead of the expected Friedel−Crafts regioisomer. A new concerted mechanism based on DFT calculations is proposed to account for the products in this intermolecular gold(I)-catalyzed reaction.

ChemInform Abstract: Cycloaddition Reactions with Vinyl Heterocycles

Publisher Summary The Diels-Alder reaction is one of the most common and elegant methods for the construction of six-membered rings. Although the number of Diels-Alder cycloadditions with open-chain and alicyclic dienes is very large, the number of examples with aromatic heterocyclic compounds is relatively small. The introduction of a vinyl group as a substituent onto a heterocycle increases the number of possible reactions. This new possibility, however attractive for synthetic purposes, is successful only with π-excessive five-membered heterocyclic derivatives with a few exceptions. The chapter discusses the reactions of vinyl heterocycles with carbodienophiles. The endocyclic and exo-en…

ChemInform Abstract: First Synthesis of the Chiral Mixed O/S Ligands, 1,2-Sulfinyl Thiols: Application as Chiral Proton Sources in Enantioselective Protonations of Enolates.

Abstract A suitable method for the preparation of the chiral mixed O/S ligands 1,2-sulfinyl thiols is described. These compounds have then been used as a chiral proton source in the enantioselective protonation of 2-methyl tetralone enolate and the results are compared with those obtained from the analogous alcohols. A theoretical model is proposed to explain the different behaviors exhibited in the protonation reaction for each of these proton sources. Configurational assignments for the new chiral thiols have been carried out by means of X-ray analysis.

Diastereoselectivity of the Addition of Propargylic Magnesium Reagents to Fluorinated Aromatic Sulfinyl Imines.

The addition of propargylmagnesium bromide to fluorinated aromatic sulfinyl imines gave homopropargyl amines with total regio- and diastereoselection. Complete reversal of diastereoselectivity can be achieved in some cases using coordinating (THF) or noncoordinating (DCM) solvents. Substituted propargylic magnesium reagents have been also tested toward fluorinated aryl sulfinyl imines affording chiral homoallenyl amines with good yields and selectivity control. DFT calculations helped to rationalize the origin of the experimental regio- and diastereoselectivities observed in each case.

Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Halomethyl Oxime Ethers and Site-Selective Cross-Coupling of Dihalo Derivatives

The Pd-catalyzed cross-coupling reaction of chloromethyl oxime ethers with a wide range of aryl-, heteroaryl-, and vinylboronic acids proceeds with good yields.

Competitive gold-activation modes in terminal alkynes: an experimental and mechanistic study.

The competition between π- and dual σ,π-gold-activation modes is revealed in the gold(I)-catalyzed heterocyclization of 1-(o-ethynylaryl)urea. A noticeable effect of various ligands in gold complexes on the choice of these activation modes is described. The cationic [Au(IPr)](+) (IPr=2,6-bis(diisopropylphenyl)imidazol-2-ylidene) complex cleanly promotes the π activation of terminal alkynes, whereas [Au(PtBu3 )](+) favors intermediate σ,π species. In this experimental and mechanistic study, which includes kinetic and cross-over experiments, several σ-gold, σ,π-gold, and other gold polynuclear reaction intermediates have been isolated and identified by NMR spectroscopy, X-ray diffraction, or …

First Synthesis of β-Keto Sulfoxides by a Palladium-Catalyzed Carbonylative Suzuki Reaction

[reaction: see text] An unprecedented palladium-catalyzed three-component cross-coupling reaction between alpha-bromo sulfoxide, carbon monoxide, and aromatic boronic acids provides a new and efficient approach to the synthesis of beta-ketosulfoxides. The reaction takes place under mild conditions with a wide range of variously substituted aryl and heteroaryl boronic acids. The carbonylative cross-coupling reaction is strongly favored over competing direct cross-coupling and homocoupling processes, except with boronic acids carrying strong electron-withdrawing substituents.

Switchable palladium-catalyst reaction of bromomethyl sulfoxides, CO, and N-nucleophiles: aminocarbonylation at Csp3 versus oxidative carbonylation of amines.

The palladium-catalyzed reaction of α-bromomethyl sulfoxides, carbon monoxide, and N-nucleophiles follows different reaction pathways according to the catalytic system and the reaction conditions. The Pd-xantphos catalyst affords high yields of α-sulfinyl amides by an aminocarbonylation process and is the first example of this type of transformation for a nonbenzylic sp(3)-hybridized carbon. On the other hand, the oxidative carbonylation of amines occurs with α-bromomethyl sulfoxides, carbon monoxide, and catalytic Pd(PPh(3))(4) under aerobic conditions, yielding ureas and oxalamides from either primary or secondary amines. The reaction with ambident nucleophiles such as amino alcohols was …

Gold(I)-catalysed cascade reactions in the synthesis of 2,3-fused indole derivatives.

A gold(I)-catalysed hydroaminative/arylative cascade for the efficient synthesis of a variety of indole-fused skeletons has been developed. Factors controlling the catalyst loading required in these transformations involving 1,3-unsubstituted indole intermediates have been revealed, allowing isolation of an unprecedented 1,3-dimetallated 3H-indole gold complex characterized by X-ray diffraction.

Palladium-Catalyzed Suzuki Carbonylative Reaction of α-Halomethyl Oxime Ethers: A Regioselective Route to Unsymmetrical 1,3-Oxyiminoketones

Water-Soluble Palladium Nanoparticles: Click Synthesis and Applications as a Recyclable Catalyst in Suzuki Cross-Couplings in Aqueous Media

A new PEG-tagged material, which was prepared by a threefold copper-catalyzed [3+2] cycloaddition (click chemistry), was found to act as an efficient stabilizer for palladium nanoparticles. The newly formed material proved to be active as a recyclable catalyst in Suzuki coupling; the presence of polyether chains allowed for the catalytic runs to be conducted in aqueous media.

Competitive and Selective Csp3Br versus Csp2Br Bond Activation in Palladium-Catalysed Suzuki Cross-Coupling: An Experimental and Theoretical Study of the Role of Phosphine Ligands

Phosphine ligands have been demonstrated to have an effect on reactivity and selectivity in the competitive intramolecular palladium-catalysed Suzuki-Miyaura coupling of dibromo sulfoxide 1a possessing two different hybridised electrophilic carbons. It was found that the bromine bond to the sp(3)-hybridised carbon is selectively replaced in the presence of unhindered phosphines such as PPh(3) or xantphos. The use of hindered phosphine ligands such as P(o-tol)(3) and P(1-naphthyl)(3) reversed the selectivity, conducting the cross-coupling at the Csp(2)-Br. Identical trends were observed in external competition experiments carried out with bromomethyl sulfoxide and different substituted bromo…

Synthesis, Characterisation, and Reactivity of 1-(1-Methylimidazol-2-yl)ethenes

Abstract Thermally labile 1-(1-methylimidazol-2-yl)-ethenes, synthesised using the Wittig reaction, have been characterised as stable picrate or N-phenacyl salts. The free bases can be regenerated from the picrates on treatment with triethylamine and their reactivity with dienophiles is described.

Highly Enantioselective Protonation of the 3,4-Dihydro-2- methylnaphthalen-1(2H)-one Li-Enolate by TADDOLs

A series of nine TADDOLs (=α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols) 1a – 1i, have been tested as proton sources for the enantioselective protonation of the Li-enolate of 2-methyl-1-tetralone (=3,4-dihydro-2-methylnaphthalen-1(2H)-one). The enolate was generated directly from the ketone (with LiN(i-Pr)2 (LDA)/MeLi) or from the enol acetate (with 2 MeLi) or from the silyl enol ether (with MeLi) in CH2Cl2 or Et2O as the solvent (Scheme). The Li-enolate (associated with LiBr/LDA, or LiBr alone) was combined with 1.5 – 3.0 equiv. of the TADDOL at −78° by addition of the latter or by inverse addition. 2-Methyl-1-tetralone of (S)-configuration is formed (≤80% yield) with up to 99.5% sele…

ChemInform Abstract: Efficient Synthesis of Racemic and Chiral Alkenyl Sulfoxides by Palladium-Catalyzed Suzuki Coupling.

Alkenyl sulfoxide derivatives are obtained in high yields through a palladium-catalyzed Suzuki/Miyaura cross-coupling reaction of racemic and chiral 1-halo sulfoxides with aryl and alkenyl boronic acids. Chiral substrates react with no loss of optical purity and high optical yields. The reaction takes place with different palladium catalysts, such as Pd(PPh 3 ) 4 or Pd(OAc) 2 /DABCO. Although nitrogen ligands like DABCO lead to an active palladium catalyst, they are less effective than the phosphine ones.

Anaerobic Palladium-Catalyzed Chemoselective Oxidation of Allylic and Benzylic Alcohols with α-Bromo Sulfoxide as a Co-Oxidant.

A chemoselective palladium-catalyzed anaerobic oxidation of allylic and benzylic alcohols using an α-bromo sulfoxide as a co-oxidant is described for the first time. The catalyst system is simple and has a long life because of the allowance of phosphane ligands under the non-aerobic conditions. The advantages of the described method include no overoxidation of primary alcohols to carboxylic acids because of the mild conditions applied, the tolerance of oxygen-sensitive functionalities such as a carbon-carbon double bond, an organothio group, or a diorganoamino group and the effective preparation of α,β-unsaturated aldehydes and ketones, resulting from the oxidation of primary and secondary …

ChemInform Abstract: FeCl3·6H2O-Catalyzed Mukaiyama-Aldol Type Reactions of Enolizable Aldehydes and Acetals.

A general procedure for the title condensation of dimethylacetals derived from enolizable aldehydes with silyl enol ethers is developed using FeCl3 as the catalyst.

Pauson–Khand reaction of fluorinated compounds

The Pauson–Khand reaction (PKR) is one of the key methods for the construction of cyclopentenone derivatives, which can in turn undergo diverse chemical transformations to yield more complex biologically active molecules. Despite the increasing availability of fluorinated building blocks and methodologies to incorporate fluorine in compounds with biological interest, there have been few significant advances focused on the fluoro-Pauson–Khand reaction, both in the inter- and intramolecular versions. Furthermore, the use of vinyl fluorides as olefinic counterparts had been completely overlooked. In this review, we collect the advances both on the stoichiometric and catalytic intermolecular an…

The Ruthenium‐Catalyzed Domino Cross Enyne Metathesis/Ring‐Closing Metathesis in the Synthesis of Enantioenriched Nitrogen‐Containing Heterocycles

ChemInform Abstract: Gold(I)-Catalyzed Intermolecular Oxyarylation of Alkynes: Unexpected Regiochemistry in the Alkylation of Arenes.

The reaction between acetylenes and sulfoxides, studied as a test case for gold-catalyzed intermolecular addition, provides the oxyarylation compounds 3 in good yields. Unpredictably, in all cases a single regioisomer arising from the electrophilic aromatic alkylation at the position adjacent to the sulfur atom is obtained instead of the expected Friedel−Crafts regioisomer. A new concerted mechanism based on DFT calculations is proposed to account for the products in this intermolecular gold(I)-catalyzed reaction.

ChemInform Abstract: Water-Soluble Palladium Nanoparticles: Click Synthesis and Applications as a Recyclable Catalyst in Suzuki Cross-Couplings in Aqueous Media.

Polyethylene glycol-tagged macrocycle (I) is prepared by a three-fold copper-catalyzed [3 + 2] cycloaddition reaction.

Enantioselective Protonation of the Lithium Transient Enolate of2-Methyltetralone with 2-Sulfinyl Alcohols

A new catalytic cycle for the enantioselective protonation of cyclic ketone enolates with sulfinyl alcohols has been developed. An enol trifluoroacetate that can be easily obtained from the corresponding ketone is used for the first time as an enolate precursor of a cyclic ketone enolate. In this method, the achiral alcohol plays two roles: it is involved, as is usual in catalytic asymmetric protonation reactions, in the turnover of the chiral proton source and also in the generation of a transient enolate through the reaction of its corresponding alkoxide with the enol trifluoroacetate precursor. Stereoselectivity is highly dependent on the structure of the achiral alcohol. High levels of …

Palladium-catalyzed Suzuki-Miyaura reaction involving a secondary sp3 carbon: studies of stereochemistry and scope of the reaction.

Palladium-catalyzed C--C bond formation involving secondary sp3-hybridized carbon is described. These reactions occur with secondary 1-bromoethyl arylsulfoxides and different arylboronic acids, to produce the corresponding arylated sulfoxides in moderate to high yields and with complete stereospecificity. Despite the presence of beta hydrogens in the substrate, the competitive beta-hydride elimination is not a significant side reaction when coordinating solvents are used. The reported cross-coupling involves secondary C(sp3)--C(sp2) bond formation: this is the first time that a mechanistic study has been carried out with such substrates. The reaction proceeds with inversion of configuration…

NHC-Stabilized Gold(I) Complexes: Suitable Catalysts for 6-exo-dig Heterocyclization of 1-(o-Ethynylaryl)ureas

3-Substituted 1-(o-ethynylaryl)ureas 1 selectively undergo either 6-exo-dig or 5-endo-dig cyclization (to give 4-methylene-3,4-quinazolin-2-ones 2 or indoles 3, respectively) depending on the choice of the metal, ligand, and reaction conditions. The best results (up to 96% yield) in the preparation of the hydroamination products 2 are achieved with the highly bulky NHC-stabilized cationic gold(I) complex [Au(IPr)](+). Conversely, ureas bearing an internal alkyne lead to the 5-endo-dig cyclization mode regardless of the gold(I) complex employed. Whereas the nature of the substituent at N-3 does not have any influence on the regiochemistry observed, it does, in some cases, affect the efficien…

Efficient synthesis of racemic and chiral alkenyl sulfoxides by palladium-catalyzed Suzuki coupling

Alkenyl sulfoxide derivatives are obtained in high yields through a palladium-catalyzed Suzuki/Miyaura cross-coupling reaction of racemic and chiral 1-halo sulfoxides with aryl and alkenyl boronic acids. Chiral substrates react with no loss of optical purity and high optical yields. The reaction takes place with different palladium catalysts, such as Pd(PPh 3 ) 4 or Pd(OAc) 2 /DABCO. Although nitrogen ligands like DABCO lead to an active palladium catalyst, they are less effective than the phosphine ones.

ChemInform Abstract: Remarkable Effect of Lithium Bromide in the Enantioselective Protonation with α-Sulfinyl Alcohols.

Abstract The favourable effect of lithium bromide enhancing the facial enantioselectivity in the protonation of methyl tetralone enolate with α-sulfinyl alcohols is described. Theoretical calculations allow to propose a model to explain the stereochemical course of the protonation reaction.

Cycloaddition reactions of 1-tert-butyl-4-vinylpyrazole

1-tert-Butyl-4-vinylpyrazole1 a reacts with dimethyl acetylenedicarboxylate (DMAD), methyl propiolate (MP) and N-phenylmaleimide (NPMI) affording the indazole derivatives2,3, and5 as a result of a Diels-Alder ([4 + 2]) cycloaddition. With diethylazodicarboxylate (DEAZD), tetracyanoethylene (TCNE) and 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) the reaction takes place exclusively through the olefinic substituent and the adducts6,7, and9 were isolated. The alkenylpyrazoles1 b–d reacted withDMAD and N-phenylmaleimide to give polymers.

Vinyl Fluorides: Competent Olefinic Counterparts in the Intramolecular Pauson–Khand Reaction

Despite the great advances achieved in the Pauson-Khand reaction and the ever-increasing demand for fluorinated compounds, the use of vinyl fluorides as olefinic counterparts in the above-mentioned transformation had been completely overlooked. Herein, we describe, for the first time, the intramolecular Pauson-Khand reaction of enynes containing a vinyl fluoride moiety.

ChemInform Abstract: Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Halomethyl Oxime Ethers and Site-Selective Cross-Coupling of Dihalo Derivatives.

The Pd-catalyzed cross-coupling reaction of chloromethyl oxime ethers with a wide range of aryl-, heteroaryl-, and vinylboronic acids proceeds with good yields.

Palladium-Catalyzed Reaction of Boronic Acids with Chiral and Racemic ?-Bromo Sulfoxides.

Palladium-catalyzed cross-coupling reactions of racemic α-bromo sulfoxides with boronic acids are carried out in either aqueous or nonaqueous medium with formation of a new C sp3−C sp2 bond. The arylation of chiral α-bromo sulfoxides occurs without racemization. The cross-coupling reaction is general and gives high yields with arylboronic acids substituted with either donor or acceptor groups but gives poor results with heteroarylboronic acids. The best yields are obtained using degassed solvents and CsF instead of aqueous base. The use of aqueous base and the presence of oxygen favor the homocoupling side reaction.

Asymmetric Synthesis of Fluorinated Monoterpenic Alkaloid Derivatives from Chiral Fluoroalkyl Aldimines via the Pauson‐Khand Reaction

An improved method for the asymmetric protonation of enolates with chiral α-sulfinyl alcohols/trifluoroethanol

Abstract Enantioselective protonation of 2-methyl tetralone enolate using a stoichiometric amount of 2-sulfinyl alcohol ( S , R s )- 1 as a chiral proton donor yields the corresponding chiral ketone with a high level of enantioselectivity, provided that the chiral proton donor (CPD) is regenerated with an achiral proton source (APS). In contrast, stereoselectivity was only moderate if catalytic CPD (0.2 equiv.) and an APS are used.

ChemInform Abstract: The Mechanism of Formation of 3H,9H-Pyrano(3,4-b)indol-3-ones from 3- Indolalkanoic Acids.

The mechanism of the formation of 1-methyl-3H,9H-pyrano[3,4-b]indol-3-one (4) from the corresponding 3-indolacetic acid 1 is discussed. The suggested mechanism is substantiated by the isolation of a stable intermediate 2 and its transformations in the presence of acetic anhydride and/or Lewis acids.

Asymmetric Vinylogous Mukaiyama‐Mannich Reactions of Heterocyclic Siloxy Dienes with Ellman's Fluorinated Aldimines

ChemInform Abstract: NHC-Stabilized Gold(I) Complexes: Suitable Catalysts for 6-exo-dig Heterocyclization of 1-(o-Ethynylaryl)ureas.

Under the optimized gold catalysis, the less favored and more challenging 6-exo-dig cyclized products are formed in yields up to 96% from ureas bearing a terminal alkyne at the ortho-position.

Gold(I)-Catalyzed Reactions of 1-(ortho-Alkynylaryl)ureas: Highly Selective Heterocyclization and Synthesis of MixedN,O-Acetals

Treatment of alkynylureas (I) with trifluoroethanol in the presence of a Au/Ag catalytic system provides N-6-exo-dig heterocyclization products (III) and in some cases open chain acetals as side products.

Osmium(III) Complexes with POP Pincer Ligands: Preparation from Commercially Available OsCl3·3H2O and Their X-ray Structures

Complexes OsCl3{dbf(PiPr2)2} [1; dbf(PiPr2)2 = 4,6-bis(diisopropylphosphino)dibenzofuran], OsCl3{xant(PiPr2)2} [2; xant(PiPr2)2 = 9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene], and OsCl3{xant(PPh2)2} [3; xant(PPh2)2 = 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene] have been obtained in high yield by the reaction of the corresponding diphosphine with OsCl3·3H2O. The ruthenium(III) counterparts RuCl3{dbf(PiPr2)2} (4), RuCl3{xant(PiPr2)2} (5), and RuCl3{xant(PPh2)2} (6) are similarly obtained from RuCl3·3H2O in moderate yields. The X-ray structures of dbf(PiPr2)2 and complexes 1−3 are also reported.

Palladium-Catalyzed C-C Ring Closure in α-Chloromethylimines: Synthesis of 1H -Indoles

Reactions of 3-(tetrahydropyrid-4-yl)-indoles with dienophiles: new heterocyclic functionalized indoles and pyrido[]annellated carbazoles

First reactions of 3-(1,2,3,6-tetrahydropyrid-4-yl)-indoles 1 with a variety of carbo- and heterodienophiles are described. These reactions provide a new access to heterocyclic functionalized indoles and pyrido[c]annellated carbazoles, compounds of interest as potential antidepressive and antitumor active agents.

Palladium-catalyzed reaction of boronic acids with chiral and racemic alpha-bromo sulfoxides.

Palladium-catalyzed cross-coupling reactions of racemic alpha-bromo sulfoxides with boronic acids are carried out in either aqueous or nonaqueous medium with formation of a new C sp(3)-C sp(2) bond. The arylation of chiral alpha-bromo sulfoxides occurs without racemization. The cross-coupling reaction is general and gives high yields with arylboronic acids substituted with either donor or acceptor groups but gives poor results with heteroarylboronic acids. The best yields are obtained using degassed solvents and CsF instead of aqueous base. The use of aqueous base and the presence of oxygen favor the homocoupling side reaction.

ChemInform Abstract: Highly Enantioselective Protonation of the 3,4-Dihydro-2-methylnaphthalen-1(2H)-one Li-Enolate by TADDOLs.

A series of nine TADDOLs (=α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols) 1a – 1i, have been tested as proton sources for the enantioselective protonation of the Li-enolate of 2-methyl-1-tetralone (=3,4-dihydro-2-methylnaphthalen-1(2H)-one). The enolate was generated directly from the ketone (with LiN(i-Pr)2 (LDA)/MeLi) or from the enol acetate (with 2 MeLi) or from the silyl enol ether (with MeLi) in CH2Cl2 or Et2O as the solvent (Scheme). The Li-enolate (associated with LiBr/LDA, or LiBr alone) was combined with 1.5 – 3.0 equiv. of the TADDOL at −78° by addition of the latter or by inverse addition. 2-Methyl-1-tetralone of (S)-configuration is formed (≤80% yield) with up to 99.5% sele…

ChemInform Abstract: Cycloaddition Reactions of 1-tert.-Butyl-4-vinylpyrazole.

1-tert-Butyl-4-vinylpyrazole1 a reacts with dimethyl acetylenedicarboxylate (DMAD), methyl propiolate (MP) and N-phenylmaleimide (NPMI) affording the indazole derivatives2,3, and5 as a result of a Diels-Alder ([4 + 2]) cycloaddition. With diethylazodicarboxylate (DEAZD), tetracyanoethylene (TCNE) and 4-phenyl-1,2,4-triazole-3,5-dione (PTAD) the reaction takes place exclusively through the olefinic substituent and the adducts6,7, and9 were isolated. The alkenylpyrazoles1 b–d reacted withDMAD and N-phenylmaleimide to give polymers.

ChemInform Abstract: Reactions of 3-Vinylindole Derivatives with Dienophiles.

Reactions of 3-(1-cyclohexenyl)-1,2-dimethylindole (1a) and the 1,2-dihydrocarbazole 1b with some carbo- and heterodienophiles are described. Thus, compound 1a reacts to give ene, Michael-type, and Diels-Alder adducts, depending on the dienophile and reaction conditions. The 3-vinylindole 1b reacts with 4-phenyl-1,2,4-triazoline-3,5-dione or N-phenylmaleimide in a dehydrogenative reaction to yield the fully aromatized carbazole 8.

FeCl3·6H2O-catalyzed Mukaiyama-aldol type reactions of enolizable aldehydes and acetals.

Mukaiyama-aldol type reactions of acetals derived from enolizable aldehydes with FeCl3·6H2O, an eco-friendly, low-cost, and stable catalyst, lead to β-methoxycarbonyl compounds with nearly quantitative yields. The methodology is extended to the parent aldehydes as starting materials, leading to the corresponding aldols with lower yields, but efficiently. Different alkyl and aryl substituted acetals and aldehydes have been tested in the reaction with linear and cyclic silyl enol ethers. Reactions are carried out in an open air atmosphere, and additives are not required. Acetals can be considered activating groups of the carbonyl moiety rather than a protecting group in this type of FeCl3·6H2…

The Role of Organic Fluorine in the Supramolecular Assembly of Halogenated β-Hydroxysulphoxides Diastereomers

A series of optically pure γ-halogenated β-hydroxysulphoxides containing two stereogenic centers have been prepared, and the X-ray crystal structures have been determined. The conformational behavior in the solid state and the crystal packing of the different β-hydroxysulphoxide diastereoisomers have been determined. The intermolecular and intramolecular interactions present have been studied in both halogenated and nonhalogenated β-hydroxysulphoxides to establish the influence of the halogen atom in the supramolecular structure. The main intermolecular hydrogen bond OH···OS is always present and produces molecular chains. Self-assembly of these chains includes weak CH···F, C−F···F−C, and C…

Water compatible gold(III)-catalysed synthesis of unsymmetrical ethers from alcohols.

An efficient and broad-scoped method for the preparation of unsymmetrical ethers from alcohols catalysed by the simplest and least expensive gold catalyst, NaAuCl 4 , is described for the first time. The procedure enables the etherification of benzylic and tertiary alcohols with moderate to good yields under mild conditions with low catalyst loading. Symmetrical ethers, the usual side products in the etherification of alcohols, were not detected in this case. The formation of the racemic ether from a chiral benzyl alcohol suggests the intermediacy of a carbocation, which has not previously been postulated for gold-catalysed reactions involving alcohols.

Fluorine-Containing Drugs Approved by the FDA in 2018

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine-containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3 , as well as aliphatic (CF2 ) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

ChemInform Abstract: Palladium-Catalyzed Alkoxy- and Aminocarbonylation of α-Halomethyl Oxime Ethers: Synthesis of 1,3-Alkoxyimino Esters and 1,3-Alkoxyimino Amides.

The three component reactions of α-bromomethyl oxime ethers, carbon monoxide, and alcohols or aromatic amines give imino esters and amides, respectively.

From Overstoichiometric to Substoichiometric Enantioselective Protonation with 2-Sulfinyl Alcohols: A View in Perspective

A general study of the enantioselective protonation of prochiral enolates with 2-sulfinyl alcohols is reported. The modification of reaction conditions to reduce drastically the amount of chiral proton source needed to obtain a good enantiomeric excess is reported. The effects of the different factors controlling the stereoselectivity are clearly established. Different protocols for enolate generation are compared.

Palladium-Catalyzed Alkoxy- and Aminocarbonylation of α-Halomethyl Oxime Ethers: Synthesis of 1,3-Alkoxyimino Esters and 1,3-Alkoxyimino Amides

The three component reactions of α-bromomethyl oxime ethers, carbon monoxide, and alcohols or aromatic amines give imino esters and amides, respectively.

The Fluoro-Pauson-Khand Reaction in the Synthesis of Enantioenriched Nitrogenated Bicycles Bearing a Quaternary C-F Stereogenic Center

The authors are grateful to the Spanish MICINN and the AEI (CTQ2017-84249-P) for financial support, the SCSIE (Universitat de Valencia) for access to instrumental facilities, and M. ̀ R. Pedrosa (Universidad de Burgos) for providing us with MoO2Cl2. The technical and human support provided by SGIker (UPV/EHU, MINECO, GV/DJ, ERDF, and ESF) is also gratefully acknowledged. P.B. thanks the Spanish Ministry of Economy for a Ramon y Cajal contract (RyC-2016-20951). ́ The authors are also grateful to Jose Cabeza for assistance in the synthesis of certain starting materials.

CCDC 965392: Experimental Crystal Structure Determination

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CCDC 1972570: Experimental Crystal Structure Determination

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CCDC 1937096: Experimental Crystal Structure Determination

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CCDC 1061399: Experimental Crystal Structure Determination

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CCDC 965391: Experimental Crystal Structure Determination

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CCDC 953983: Experimental Crystal Structure Determination

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CCDC 953982: Experimental Crystal Structure Determination

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