Competitive Cyclization Research Articles

On the Role of the Solvent in the Synthesis of Spirocycles from Alkyne Cations Catalyzed by Triflic Acid: A DFT Study

The role of discrete solvent molecules in the reactivity of alkyne cations has been analyzed computationally. Analysis of the possible reaction mechanisms towards competitive cyclization and elimination processes including a molecule of solvent show the crucial role of dichloromethane (DCM) and tetrahydrofuran (THF). In the presence of DCM, a strong intramolecular p‐cation interaction between the electrophilic center and the triple bond favors the [5‐exo‐dig] cyclization route, with no direct participation of the solvent in the reaction path. On the contrary, in the presence of a discrete molecule of THF, a strong solvent–cation interaction via formation of a dative C(+)–O(THF) bond drastically modifies the energy profile, thus promoting the elimination pathway.

Trifunctionalized Allenes. Part IV. Cyclization Reactions of 4-Phosphorylated 5-Hydroxyhexa-2,3-dienoates

This manuscript focuses on the reactions of 4-phosphorylated 5-hydroxyhexa-2,3-dienoates with protected or unprotected hydroxy groups involving 5-endo-trig cyclizations. Reactions with electrophiles result in mixtures of the 2,5-dihydro-1,2-oxaphosphole-5-carboxylates and the 5-phosphorylfuran- 2(5H)-ones by competitive electrophilic cyclization due to the neighboring phosphonate (phosphine oxide) and the carboxylate groups participation. 4-Phosphorylated 5-hydroxyhexa-2,3-dienoates were smoothly transformed into the corresponding 4-phosphoryl-2,5-dihydrofuran-2-carboxylates by using 5 mol % of a silver salt as a catalyst in the 5-endo-trig cycloisomerization reaction.

Competitive cascade cyclization of 2′-tosyloxychalcones: An easy access to thioflavones and thioaurones

A new and efficient approach for the synthesis of thioflavones and thioaurones by competitive cascade cyclization of 2′-tosyloxychalcones has been developed. 2′-Tosyloxychalcones were smoothly converted into thioflavones and thioaurones by incorporation of sulfur atom using elemental sulfur and triethylamine in DMSO with good yields. The advantages of the methodology are the formation of both thioflavones and thioaurones in a single step. Easily accessible substrates, mild reaction conditions and compatibility with a broad range of functional groups make this protocol clean and inexpensive.

Bifunctionalized allenes. Part XXIV. Competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates leading to 2,5-dihydro-1, 2-oxaphospholes and 5,6-dihydro-2H-pyranes

We report herein a study on the competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates involving 5-endo-trig and 6-endo-trig mode cyclizations. Reaction with electrophiles produces mixtures of the 2-(2-oxo-2,5-dihydro-1,2-oxaphosphol-5-yl)-alkanoates and (6-oxo-5,6-dihydro-2H-pyran-2-yl)-phosphonates by competitive electrophilic cyclization due to the participation of the neighboring phosphonate and carboxylate groups.

Trifunctionalized allenes. Part III. Electrophilic cyclization and cycloisomerization of 4-phosphorylated 5-hydroxypenta-2,3-dienoates: An expedient synthetic method to construct 2,5-dihydro-1,2-oxaphospholes, furan-2(5H)-ones and 2,5-dihydrofurans

This chapter discusses the reactions of 4-phosphorylated 5-hydroxypenta-2,3-dienoates with protected or unprotected hydroxy group involving 5-endo-trig cyclizations. Reactions with electrophiles produce mixtures of the 2,5-dihydro-1,2-oxaphosphole-5-carboxylates and the 5-phosphoryl-furan-2(5H)-ones by competitive electrophilic cyclization due to the neighboring phosphonate (phosphine oxide) and the carboxylate groups participation. 4-Phosphorylated 5-hydroxypenta-2,3-dienoates were smoothly converted into the corresponding 4-phosphoryl-2,5-dihydrofuran-2-carboxylates by using 5 mol% of a silver salt as a catalyst in the 5-endo-trig cycloisomerization reaction.

Rh-Catalyzed Hydrogenation of Amino Acids to Biobased Amino Alcohols: Tackling Challenging Substrates and Application to Protein Hydrolysates

While protein-rich biomass waste is nowadays mainly used for animal feed, conversion of its amino acid constituents to nitrogenous chemicals is a potential higher value route. To that end, the hydrogenation of amino acids to amino alcohols was studied in this work. Using a bimetallic Rh–MoOx/SiO2 catalyst, glutamic acid was for the first time hydrogenated to the aminodiol in high yield. By minimizing partial reduction and consecutive hydrogenolysis and by suppressing the competitive cyclization to pyroglutamic acid (and derivatives thereof), glutamidiol was obtained in 77% yield at 70 bar H2 and 80 °C. High yields (typically >80%) and selectivities were also achieved for most other natural amino acids, except for the S-containing amino acids cysteine and methionine, which act as catalyst poisons. This limitation was overcome by applying a simple oxidation step with performic acid prior to the hydrogenation. The system was applied successfully to a mixture of amino acids obtained by hydrolysis of preoxidiz...

Intramolecular cyclization of polyfluoroalkyl-containing 2-(arylhydrazinylidene)-1,3-diketones

Refluxing of polyfluoroalkyl-containing 2-(arylhydrazinylidene)-1,3-diketones in dichloroalkanes in the presence of TiCl4 gives 3-acyl-4-polyfluoroalkylcinnolines as a result of Friedel-Crafts intramolecular cyclization with the participation of polyfluoroacyl and arylhydrazone moieties. 2-(Arylhydrazinylidene)-3-phenyl-1-polyfluoroalkylpropan-1,3-diones in the presence of CF3SO3H in dichloromethane at −20…−30 °C undergo the competitive cyclization with the participation of polyfluoroacyl and benzoyl groups to form 3-hydroxy-2-(arylhydrazinylidene)-3-polyfluoroalkylindan-1-ones. The heating of 2-(arylhydrazinylidene)-1,3-diketones in polyphosphoric acid at 115…120 °C resulted in 2-polyfluoroalkyl-1-(2-arylhydrazinylidene)ethan-2-ones. The tuberculostatic activity of the obtained cinnolines and indanone was found to be at the level of pyrazinamide or higher. It was established that these compounds do not inhibit cholinesterases and have rather weak inhibitory activity against carboxylesterase. A high antiradical activity was shown for indanone.

Trading N and O. Part 3: Synthesis of 1,2,3,4-tetrahydroisoquinolines from α-hydroxy-β-amino esters

A range of enantiopure 1,2,3,4-tetrahydroisoquinolines have been prepared directly from α-hydroxy-β-amino esters. Activation of the α-hydroxy group upon treatment with Tf2O and 2,6-di-tert-butyl-4-methylpyridine promotes aziridinium formation, which is then followed by rupture of the C(3)–N bond and Friedel–Crafts alkylation-type cyclisation of an N-benzyl moiety onto the resultant benzylic carbenium ion. The nature of the N-protecting group was varied and it was found that superior yields were obtained for reactions employing two benzylic groups. In the cases where two different N-benzyl groups were used, the regioselectivity resulting from competitive cyclisation of either N-benzyl group was addressed by the introduction of a p-trifluoromethyl group on one of the N-benzyl moieties, which retarded the rate of cyclisation via this electron poor aryl ring. This methodology was employed in the asymmetric synthesis of a range of enantiopure 1,2,3,4-tetrahydroisoquinolines, which were isolated in good yields as single diastereoisomers.

Synthesis of substituted imidazolines by an Ugi/Staudinger/aza-Wittig sequence

A series of 2-(acetamide-2-yl)-imidazolines (II) with 5 points of diversity were prepared by an Ugi-4CR–Staudinger–aza-Wittig-sequence starting from simple azidoalkylamines. The intramolecular aza-Wittig cyclization between the iminophosphane and the tertiary amide of the Ugi product (I) was effected by short microwave irradiation. Competitive cyclization to the secondary amide was not relevant, however, in some cases subsequent formation of the bicyclic ortho-amidines (III) was observed.

Synthesis and Characterization of Complex Mixtures Consisting of Cyclic and Linear Polyamides from Ethyl Bis-Ketal Galactarates

Bis-ketal-protected diethyl galactarate was condensed with different diamines to prepare sugar-based polyamides. Ketal-protected polyamides, which are soluble in organic solvents, were deprotected with 90% trifluoroacetic acid to yield water insoluble materials. FTIR, NMR, GPC, MALDI-TOF, ESI and TGA techniques were used to characterize the structure and the properties of these biodegradable materials. D-galactaric acid-based polyamides are complex mixtures of cyclic and linear structures. High molecular weight linear polymer formation was limited by competitive cyclization reactions. The percentage of cyclization was highly dependent on the nature of the diamine used. Polycondensation with linear aliphatic diamines favored the formation of macrocycles, identified by MALDI-TOF and ESI.

Competitive Condensation and Tandem Cyclization Reactions of 2-Cyano-3-ferrocenylacrylonitrile with Amidines in an Aqueous Medium

Competitive Condensation and Tandem Cyclization Reactions of 2-Cyano-3-ferrocenylacrylonitrile with Amidines in an Aqueous Medium

A cascade reaction of azolopyrimidines. Synthesis of unusual indole and azaindole derivatives

The reaction of bromo substituted pyrido[3',2':4,5]pyrrolo-[1,2-c]pyrimidine and pyrimido[1,6-a]indole methyl carboxylates with primary amines is described. The expected amide formation occurs but it is followed by an unexpected cascade process involving attack of the amine to the pyrimidine ring, opening of the pyrimidine ring, loss of the bromine substituent and competitive cyclizations to afford unusual imidazolidene substituted indoles and azaindoles.

Competitive photocyclization/rearrangement of 4-aryl-1,1-dicyanobutenes controlled by intramolecular charge-transfer interaction. Effect of medium polarity, temperature, pressure, excitation wavelength, and confinement

A series of 4-aryl-1,1-dicyanobutenes (1a-1f) with different substituents were synthesized to control the intramolecular donor-acceptor or charge-transfer (C-T) interactions in the ground state. Photoexcitation of these C-T substrates led to competitive cyclization and rearrangement, the ratio being critically controlled by various environmental factors, such as solvent polarity, temperature and static pressure, and also by excitation wavelength and supramolecular confinement (polyethylene voids). In non-polar solvents, the rearrangement was dominant (>10 : 1) for all examined substrates, while the cyclization was favoured in polar solvents, in particular at low temperatures. Selective excitation at the C-T band further enhanced the cyclization up to >50 : 1 ratios. More importantly, the cyclization/rearrangement ratio was revealed to be a linear function of the C-T transition energy. However, the substrates with a sterically demanding or highly electron-donating substituent failed to give the cyclization product.

ChemInform Abstract: Cyclization of Selected Benzyl Sulfone Derivatives Under Phase- Transfer Catalytic Conditions.

Abstract Seven selected benzyl chloroalkyl sulfones(1a-c) and benzyl carboethoxyalkyl sulfones (1d-q) has been subjected to treatment with aqueous NaOH (50%) under PTC conditions. Analysis of the product mixtures revealed competitive cyclization, elimination and hydrolysis reactions. Correlation of the reaction products and the starting sulfone has been discussed.

Cycle formation from acetylene addition on C4H3 radicals

Various reactions following acetylene addition on i- and n-C(4)H(3) radicals are studied using a modified G3B3 method. For the addition of C(2)H(2) on n-C(4)H(3), the commonly admitted phenyl radical decomposition path of Madden and coworkers has been considered. In addition, several energetically competitive cyclisation steps are described for the first time. Data concerning addition to form non-cyclisable compounds are also provided. Addition on i-C(4)H(3) is extensively described including new cyclisation steps and hydrogen elimination reactions. The lowest energy path from n- or i-C(4)H(3) to a cyclic system goes through dehydro-fulvene radicals formation, which in the case of n-C(4)H(3) + C(2)H(2) is energetically competitive to the formation of the phenyl radical. Considering the degradation of the latter, the formation of 6-dehydrofulvene is energetically competitive as compared to the decomposition to ortho-benzyne + H, which is the assumed main degradation channel of the phenyl radical. Rate constants for all the steps considered in this work are obtained through the conventional transition state theory and provided at the end of the paper.

An Efficient Synthesis of 2-Phenyl-4H-1-benzothiopyran-4-ones from Thiosalicylic Acid

2 such as antimalarial, antimicrobial, and antifungal activity and are useful as potent inhibitors of steroid sulfatase. 3 In general, 2-phenyl-4H-1-benzothiopyran-4-ones are synthesized by the condensation of thiophenols with ethyl benzoylacetates in polyphosphoric acid at 90 o C, but the yields are low to mode- rate. 4 The cyclization of ethyl β-(arylthio)cinnamates, derived from Michael addition of thiophenols to ethyl phenylpro- piolates, with stannic chloride or phosphorus pentoxide/met- hanesulfonic acid gives 2-phenyl-4H-1-benzothiopyran-4-ones. 5 However, this method could not be applied for the synthesis of methoxy substituted thioflavones because competitive cyclization into the cinnamyl aromatic ring, rather than the sulfur-bearing ring, occurs when cinnamyl ring is activated by methoxy substituents. The reaction of S-aroyl derivatives of thiosalicylic acid with N-phenyl(triphenylphosphoranylidene) ethemine 6 or (trimethylsilyl)methylenetriphenylphosphorane 7

Competition Studies in Alkyne Electrophilic Cyclization Reactions

The relative reactivity of various functional groups toward alkyne electrophilic cyclization reactions has been studied. The required diarylalkynes have been prepared by consecutive Sonogashira reactions of appropriately substituted aryl halides and competitive cyclizations have been performed using I(2), ICl, NBS and PhSeCl as electrophiles. The results indicate that the nucleophilicity of the competing functional groups, polarization of the alkyne triple bond, and the cationic nature of the intermediate are the most important factors in determining the outcome of these reactions.

Peptide-Heterocycle Hybrid Molecules: Solid-Phase-Supported Synthesis of SubstitutedN-Terminal 5-Aminotetrazole Peptides via Electrocyclization of Peptidic Imidoylazides

A method for the synthesis of polypeptides modified with a tetrazole ring at the N-terminus is described. Reaction of the N-terminal amino group of solid-supported peptides with arylisothiocyanates generates thiourea intermediates, which upon treatment with Mukaiyama's reagent (2-chloro-1-methylpyridinium iodide) generate electrophilic carbodiimide functionality. Trapping by the azide anion and electrocyclization of the intermediate imidoylazide generates an aryl-substituted 5-aminotetrazole at the N-terminus of the peptide. To prevent competitive cyclization of a neighboring amide N-H into the carbodiimide, there should not be a free N-H at the [X-1] position relative to the activated carbodiimide. Protection of the N-H group at this position or incorporation of a secondary amino acid is thus required for optimal tetrazole formation. Cleavage from the resin releases the hybrid molecules incorporating a 5-aminotetrazole ring conjugated onto a peptidic fragment.

Stereoselective iodocyclisation of 3-acylamino-2-methylene alkanoates: a computational insight

In order to explain the high stereocontrol occurring in the iodocyclisation of 3-acylamino-2-methylenealkanoates, either the conformational space of the starting products or the cyclisation reaction potential energy surface (PES) was explored at DFT level of theory, the polarised continuum formalism (PCM) for chloroform being used in order to consider the solvent effect. The observed stereoselection was ascribed to both the near attack conformations (NACs) distribution and the energy differences between the two possible and competitive cyclisation pathways leading to cis- and trans-diastereomers.

Cationic Palladium Complex-catalyzed Cyclization–Hydrosilylation of Alkadiynes and Enynes

Abstract A cationic π-allylpalladium complex, [(η3-C3H5)Pd (cod)]+[PF6]−, catalyzes hydrosilylation of 1,6-heptadiyne derivatives to form 1-methylene-2-(silylmethylene) cyclopentanes, HSiMenCl3−n (n = 0–2) being equally applicable to this cyclization–hydrosilylation. Certain 1,6-enynes react faster than 1,6-diynes under same reaction conditions, and 9-oxa-1-dodecene-6,11-diyne undergoes competitive cyclization–hydrosilylation at either diyne or enyne moiety, indicative of an unexpectedly high-reactive ene counterpart.