Regioselective Condensation Research Articles

Regioselective Condensation Polymerization of Propargylic Electrophiles Enabled by Catalytic Element-Cupration.

Here, we report a set of new polymerization reactions enabled by the 1,2-regioselective hydro- and silylcupration of enyne-type propargylic electrophiles. Highly regioregular head-to-tail poly(2-butyne-1,4-diyl)s (HT-PBD), bearing either methyl or silylmethyl side chains, are synthesized for the first time. A rapid entry into carbon-rich copolymers with adjustable silicon content is developed via in situ monomer bifurcation. Furthermore, a one-pot polymerization/semireduction sequence is developed to access a cis-poly(butadiene)-derived backbone by a ligand swap on copper hydride species. Interestingly, borocupration, typically exhibiting identical regioselectivity with its hydro- and silyl analogues, seems to proceed in a 3,4-selective manner. Computational studies suggest the possible role of the propargylic leaving group in this selectivity switch. This work presents a new class of regioregular sp-carbon-rich polymers and meanwhile a novel approach to organosilicon materials.

Phosphazene-Catalyzed Regioselective Condensation of Allyl Thioethers with Aldehydes: A Rapid Approach to 1,3-Dienyl Sulfides, -Sulfoxides and -Sulfones

AbstractThe phosphazene-catalyzed regioselective condensation of allyl thioethers with aldehydes is investigated. Upon treatment of allyl thioethers with P4-t-Bu, allyl thioether anions are generated and rapidly react with aromatic aldehydes, leading to 1,3-dienyl sulfides in good yields with high regioselectivity. This finding provides an alternative approach for the preparation of allyl thioether anions in a regioselective manner. In addition, chemoselective transformations of 1,3-dienyl sulfides to provide the corresponding 1,3-dienyl sulfoxides or 1,3-dienyl sulfones are also demonstrated.

Engineering of two thiamine diphosphate-dependent enzymes for the regioselective condensation of C1-formaldehyde into C4-erythrulose

A number of carboligases, which catalyze condensation of C1- and/or C2-aldehydes into multi-carbon products, have been reported. However, their catalytic activities and/or regioselectivities remained rather low. Thereby, this study has focused on engineering of C1 and C2 carboligases for the regioselective condensation of C1-formaldehyde into C4-erythrulose via C2-glycolaldehyde. The crystal structure of the glyoxylate carboligase from Escherichia coli (EcGCL) was elucidated in complex with glycolaldehyde. A structure-guided rationale generated several mutants, one of whose catalytic activity reached 15.6 M−1·s−1, almost 10 times greater than the wild-type enzyme. Another variant (i.e., EcGCL_R484M/N283Q/L478M/M488L/R284K) has shown significantly increased stability to the glycolaldehyde toxicity, enabling production of glycolaldehyde to 31 mM from 75 mM formaldehyde (conversion: 83 %). Besides, the E1 subunit of α-ketoglutarate dehydrogenase complex from Vibrio vulnificus (VvSucA) was engineered as a regiospecific C2 carboligase for condensation of glycolaldehyde into erythrulose. The combination of EcGCL_R484M/N283Q/L478M/M488L/R284K and VvSucA_K228L led to the cascade production of erythrulose to 8 mM from 90 mM formaldehyde via glycolaldehyde without byproduct formation. This study will contribute to valorization of C1 gases into industrially relevant multi-carbon products in an environment-friendly way.

Synthetic Strategies for Rare Cannabinoids Derived from Cannabis sativa.

Efficient syntheses of eight key cannabinoids were established and optimized. Predominant cannabinoids such as cannabigerol (CBG-C5) and cannabidiol (CBD-C5) were prepared from olivetol via regioselective condensation. Further treatments of CBD led to Δ9-tetrahydrocannabinol (THC-C5), Δ8-iso-tetrahydrocannabinol (iso-THC-C5), and cannabinol (CBN-C5). Alternatively, a [3 + 3] annulation between olivetol and citral yielded the minor cannabinoid cannabichromene (CBC-C5), which was converted into two very rare polycycles, cannabicyclol (CBL-C5) and cannabicitran (CBT-C5), in a one-pot reaction. Finally, all eight syntheses were extended by utilizing resorcinol and two phenolic analogues, achieving a cannabinoid group with more than 30 compounds through a facile synthesis strategy.

Efficient synthesis of some V‐shaped methylene‐bridged compounds via regioselective condensation

AbstractA number of new stable methanobenzo[7,8][1,3] dioxocino[4,5‐d]pyrimidine‐1,3(2H)‐dione derivatives (4a‐l) were synthesized using a simple one‐pot procedure with considerable efficiency. Reaction parameters were further optimized in order to achieve a single‐product procedure. Plausible routes for reaction progress were investigated and it was proved that the reaction goes through regioselective condensation yielding an interesting V‐shaped structure. Spectral data of all products under study were used to elucidate the chemical structure and X‐ray structure analysis was performed to unambiguously prove the proposed structure for 4c.

Understanding the Regioselectivity in the Oxidative Condensation of Catechins Using Pyrogallol-type Model Compounds.

Catechins are found in many foods, including tea. These compounds are bioactive. Previous studies have shown that catechins form dimers on oxidation, and there seem to be distinct regioselective effects. However, the dimerization mechanism and regioselectivity are not well understood. Therefore, we investigated the oxidation of four pyrogallol-type model compounds of epigallocatechin (EGC) having various substituents with 1 equiv of copper chloride and 30% dioxane in water. Compounds having 2C-2C or 2C-4C bonds in the B-ring were obtained in different product ratios. Comparison of the oxidation rates of each compound revealed that the model compounds having an oxygen atom corresponding to the 1-position of the C-ring of EGC underwent slow oxidation. In addition, using density functional theory calculations, we found that the highest occupied molecular orbital energies of these compounds were higher than those of the others. Further, the 2C-2C-bonded oxidation product having an A-ring and an oxygen atom at the C-ring 1-position was confirmed to have the highest thermodynamic stability. From these results, it is suggested that the regioselective condensation reaction of the catechin B-ring is related to interactions between the A-rings, as indicated by earlier studies, and the presence of oxygen at the 1-position of the C-ring in EGC.

Regioselective condensation of hydroxyaromatic compounds with 2,5-dimethoxytetrahydrofuran: facile one-pot synthesis of new substituted diaryl-fused 2,8-dioxabicyclo[3.3.2]nonanes comprising central ketal moieties

Regioselective synthesis of a series of novel diaryl- and naphthyl-fused 2,8-dioxabicyclo[3.3.2]nonanes was accomplished by a one-pot reaction of p-substituted phenols and 2-naphthol with 2,5-dimethoxytetrahydrofuran.

Selective Synthesis of Highly Functionalized Bicyclic Pyridinone and 1,3‐Oxazinane Derivatives

Bicyclic pyridinone and 1,3‐oxazinane derivatives (i.e., 3 and 4) have been synthesized by the regioselective condensation reaction of heterocyclic ketene aminals (HKAs) and either ethyl 2‐cyano‐3,3‐bis(methylthio)acrylate or 2‐[bis(methylthio)methylene]malononitrile in xylene at reflux. Pyridinone compounds 3 were efficiently obtained under catalyst‐free conditions, whereas 1,3‐oxazinane derivatives 4 were obtained by adding Cs2CO3 to the reaction mixture under the same conditions. The reactions afforded the products in excellent yields by using inexpensive starting materials and a convenient workup process.

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Summary 1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C–N bond is a facile condensation between the amine and an ortho -quinone, which triggers redox isomerization to an ortho -iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho -oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

Synthesis and Modular Reactivity of Pyrazole 5-Trifluoroborates: Intermediates for the Preparation of Fully Functionalized Pyrazoles.

The regioselective condensation of hydrazines and ynone trifluoroborates provides access to a range of pyrazole 5-trifluoroborates. The stability of the borate unit allows chemoselective halogenation of the heteroaromatic ring, thereby delivering pyrazole scaffolds that allow orthogonal functionalization at C5 and C4. The modular reactivity of these intermediates is exemplified by cross-coupling reactions, enabling regiocontrolled synthesis of fully functionalized pyrazole derivatives.

Facile and Regioselective Synthesis of Substituted 1H‐Pyrazolo[3,4‐b]quinolines from 2‐Fluorobenzaldehydes and 1H‐Pyrazol‐5‐amines

The present article concerns the scope and limitations of the regioselective condensation of 2‐fluorobenzaldehydes with 1H‐pyrazol‐5‐amines, leading to the synthesis of substituted 1H‐pyrazolo[3,4‐b]quinolines (PQ), in the presence of a base catalyst (DABCO and 2,4,6‐trimethylpyridine). A method to obtain these nitrogen heterocycles with fluorine or trifluoromethyl substituents in different positions in the carbocyclic ring was developed as a part of a systematic research on the influence of fluorine‐containing substituents on the parameters of PQ. Those compounds, characterized by high‐fluorescence intensity, have been tested as emitters for the organic light‐emitting diodes since 1997. The functionalization of PQ causes changes in various parameters, for example, HOMO and LUMO levels, which are important for the adjustment of fabricated organic light‐emitting diodes. One of the easiest methods of PQ preparation, namely, the condensation of substituted anilines with 5‐chloro‐1H‐pyrazole‐4‐carbaldehydes, is not regioselective. The method described in this study allows synthesizing of 1H‐pyrazolo[3,4‐b]quinolines with good yields and high selectivity – only the expected isomer is obtained. As various different 2‐fluorobenzaldehydes are commercially available, and 1H‐pyrazol‐5‐amines with different substituents are easy to prepare, the method could be a good alternative to the already known procedures. All possible mechanisms of the reaction were also thoroughly studied.

ChemInform Abstract: Highly Efficient Synthesis of Chalcones from Poly Carbonyl Aromatic Compounds Using BF3—Et2O via a Regioselective Condensation Reaction.

A new, simple, highly efficient method for the synthesis of different types of carbonyl chalcones through a regioselective condensation reaction of appropriate 5-acetyl-2-hydroxybenzaldehyde with various substituted acetophenones and 4-hydroxyisothalaldehyde with various substituted aldehydes using BF3-Et2O as a reagent is described.

Antineoplastic Isoflavonoids Derived from Intermediate ortho-Quinone Methides Generated from Mannich Bases.

The regioselective condensations of various 7-hydroxyisoflavonoids with bis(N,N-dimethylamino)methane in a Mannich reaction provided C-8 N,N-dimethylaminomethyl-substituted isoflavonoids in good yield. Similar condensations of 7-hydroxy-8-methylisoflavonoids led to the C-6-substituted analogs. Thermal eliminations of dimethylamine from these C-6 or C-8 N,N-dimethylaminomethyl-substituted isoflavonoids generated ortho-quinone methide intermediates within isoflavonoid frameworks for the first time. Despite other potential competing outcomes, these ortho-quinone methide intermediates trapped dienophiles including 2,3-dihydrofuran, 3,4-dihydro-2H-pyran, 3-(N,N-dimethylamino)-5,5-dimethyl-2-cyclohexen-1-one, 1-morpholinocyclopentene, and 1-morpholinocyclohexene to give various inverse electron-demand Diels-Alder adducts. Several adducts derived from 8-N,N-dimethylaminomethyl-substituted isoflavonoids displayed good activity in the 1-10 μm concentration range in an in vitro proliferation assay using the PC-3 prostate cancer cell line.

Highly Efficient Synthesis of Chalcones from Poly Carbonyl Aromatic Compounds Using BF<sub>3</sub>–Et<sub>2</sub>O <i>via</i> a Regioselective Condensation Reaction

A new, simple, highly efficient method for the synthesis of different types of carbonyl chalcones through a regioselective condensation reaction of appropriate 5-acetyl-2-hydroxybenzaldehyde with various substituted acetophenones and 4-hydroxyisothalaldehyde with various substituted aldehydes using BF3-Et2O as a reagent is described.

ChemInform Abstract: Transition‐Metal‐Free Approach to 4‐Ethynylpyrimidines via Alkenynones.

A practical approach to the synthesis of 4-ethynylpyrimidines by the condensation of arylamidines with 2-aryl-1-ethoxy-5-(trimethylsilyl)pent-1-en-4-yn-3-ones has been developed. As these latter ketones are easily accessible from bis(trimethylsilyl)acetylene and arylacetyl chlorides, the regioselective condensation reported herein provides a facile access to both TMS-protected and unprotected 4-ethynylpyrimidines in yields of up to 85 %.

Heteroaromatic Belts through Fold‐in Synthesis: Mechanistic Insights into a Macrocycle‐Templated Friedel–Crafts Alkylation

Direct alkylation of 9,9',9''-triethyl[2.2.2](2,7)carbazolophane with dimethoxymethane or paraformaldehyde affords a belt-like heteroaromatic structure, which forms as a kinetic product in acid-catalyzed condensations. In a competing, thermodynamically favored process, polymeric structures are formed by a largely regioselective condensation of stereochemically rigid "semi-belts". The relationship between these reactivity routes is rationalized in terms of strain release and differential reversibility of consecutive condensation steps.

Transition‐Metal‐Free Approach to 4‐Ethynylpyrimidines via Alkenynones

AbstractA practical approach to the synthesis of 4‐ethynylpyrimidines by the condensation of arylamidines with 2‐aryl‐1‐ethoxy‐5‐(trimethylsilyl)pent‐1‐en‐4‐yn‐3‐ones has been developed. As these latter ketones are easily accessible from bis(trimethylsilyl)acetylene and arylacetyl chlorides, the regioselective condensation reported herein provides a facile access to both TMS‐protected and unprotected 4‐ethynylpyrimidines in yields of up to 85 %.

A Regioselective Synthesis of the Dephospho DIthiolene Protected Molybdopterin.

The molybdopterin (MPT) is a complex molecule, made out of three distinctly different components. A retrosynthetic analysis provides a possible route for its synthesis that utilizes the coupling of a diamine with an osone analog. A regioselective condensation of the diamine with an osone affords the dephospho MPT, which has been characterized by NMR and IR spectroscopies, as well as high-resolution mass spectrometry.

Effect of Substituents on the Regioselectivity of the Reaction of α‐Tosyloxyketones with Thioureas in Acidic Medium: Access to 2‐Aminothiazoles and 2‐Imino‐2,3‐dihydrothiazoles

Regioselective condensation of α‐tosyloxyacetophenones 1 and N‐substituted thioureas 2 in acidic medium to give regioisomers 2‐aminothiazoles I and 2‐imino‐2,3‐dihydrothiazoles II is largely influenced by the substituents present on 1 and 2. A mechanism, supported by DFT calculations has been proposed to explain the observed regioselectively.

ChemInform Abstract: From Regioselective Condensation to Regioselective N‐Alkylation: A Novel and Environmentally Benign Strategy for the Synthesis of N,N′‐Alkyl Aryl Ureas and N,N′‐Dialkyl Ureas.

A protocol for the synthesis of N,N′-alkyl aryl ureas and N,N′-dialkyl ureas by transition metal-catalyzed regioselective N3-alkylation of the N-monosubstituted ureas with alcohols was proposed and accomplished. In the presence of an iridium/base system, the desired N,N′-alkyl aryl ureas and N,N′-dialkyl ureas were obtained with 70–93 % yields, and no isomeric N1-alkylated and N3-dialkylated products were formed in all cases. From both synthetic and environmental point of views, the reaction is highly attractive because of easily available starting materials, high atom efficiency and the formation of water as the only side product. Apparently, the research opens up the design of regioselective N-alkylation of amines with alcohols based on the regioselective condensation of amines with aldehydes, facilitating the progress of the “hydrogen autotransfer” (or “hydrogen-borrowing”) process.