Cyclization Conditions Research Articles

Unanticipated synthesis of a C3 symmetrical tris-triazine under cyclization conditions of coumarinoyl thioureas with α-halo compounds

A new highly symmetric 1,3,5-triazine-2,4,6-sulfanediyl species, was obtained by trimerization of ethyl (Z)-3-oxo-2-((N-(2-oxo-2H-chromene-3-carbonyl)-N'-phenylcarbamimidoyl)thio) butanoate derivatives under basic conditions. The compound has been characterized by FT-IR, Raman, NMR and X-ray diffraction analysis. Triethyl 2,2′,2″-((1,3,5-triazine-2,4,6-triyl)tris(sulfanediyl))tris(3-hydroxybutanoate) crystallizes in the trigonal system with space group R-3. The sulfur atom is located in the same plane of the triazine ring, leading to a planar synthon involving the whole 1,3,5-triazine-2,4,6-triyl-tris(sulfanediyl) core. Furthermore, the crystal structure was stabilized by π-stacking interactions favored by the heterocyclic aromatic triazine ring. Hirshfeld surface analyses for visually analyzing intermolecular interactions in crystal structure employing molecular surface contours and 2D fingerprint plots have been used to examine molecular shapes. The enol tautomeric form is observed in the crystal, favored by a strong OH···O = C intramolecular hydrogen bond. This form was also clearly observed in solution, with minor contribution of the keto tautomer, the relative contribution between the enol:keto forms is ca. 0.7:0.3. A thorough computational investigation of the conformational space of the triazine under study led to twelve different minima, the all-enol tautomer being the most stable form, in good agreement with the experimental findings. The solid phase infrared and Raman spectra were recorded, and the vibrational properties interpreted in terms of highly C3-symmetrical species.

Synthesis of 10H-di(1-benzothiopheno)[2,3-b:3′,2′-d]pyrrole: re-investigation of the Cadogan cyclization route

Abstract The reaction of 2-nitro-3,3′-bi(1-benzothiophene) bearing ester groups at 7- and 7′-positions under the Cadogan cyclization conditions (PPh3, o-C6H4Cl2, refl.) afforded the targeted 10H-di(1-benzothiopheno)[2,3-b:3′,2′-d]pyrrole-1,8-dicarboxylate derivative in a low yield accompanied with a byproduct. On the other hand, the Cadogan reaction of 2-nitro-3,3′-bi(1-benzothiophene) without ester groups did not provide the corresponding pyrrole but gave a mixture of thiophene-ring-opening products, from which dibenzothiophenothiopyrans were isolated. The structures of these ring-opening products were fully characterized by spectroscopic and X-ray analyses and the generation mechanism giving the byproducts was deduced. Pristine 10H-di(1-benzothiopheno)[2,3-b:3′,2′-d]pyrrole could be prepared via another route, namely nitrosation followed by cyclization and reduction.

Total Synthesis of Cyanobactin Natural Product Balgacyclamide B.

Balgacyclamide A-C are a family of cyanobactin natural products isolated from freshwater cyanobacteria Microcystis aeruginosa. These macrocyclic peptides are characterized by their oxazoline-thiazole core, their 7 or 8 stereocenters, and their antiparasitic activities. Balgacyclamide B is known for its activity towards Plasmodium falciparum chloroquine-resistant strain K1, Trypanosoma brucei rhodesiense, and Leishmania donovani. In this report, the first total synthesis of Balgacyclamide B is described in a 17-steps pathway and a 2 % overall yield. The synthetic pathway toward balgacyclamide B can be adapted for the future syntheses of balgacyclamide A and C. In addition, a brief history background of oxazolines syntheses is shown to emphasize the importance of the cyclization conditions used to interconvert or retain configuration of β-hydroxy amides via dehydrative cyclization.

Discovery of a novel tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acid derivative as a potent and selective heparanase-1 inhibitor utilizing an improved synthetic approach

Heparanase-1 (HPSE1) is an endo-β-d-glucuronidase that catalyzes degradation of heparan sulfate proteoglycans. Inhibition of HPSE1 appears to be a useful therapeutic target against cancer and proteinuric kidney diseases. We previously reported tetrahydroimidazo[1,2-a]pyridine 2 as a potent HPSE1 inhibitor after optimization of the synthetic reaction. However, synthesis of 2 involves a total of 19 steps, including a cyclization process that accompanies a strong odor due to the use of Lawesson’s reagent and an epimerization reaction; furthermore, 2 exhibited insufficient selectivity for HPSE1 over exo-β-d-glucuronidase (GUSβ) and glucocerebrosidase (GBA), which also needed to be addressed. First, the cyclization reaction was optimized to synthesize tetrahydroimidazo[1,2-a]pyridine without using Lawesson’s reagent or epimerization, with reference to previous reports. Next, 16 and 17 containing a bulkier substituent at position 6 than the 6-methoxyl group in 2 were designed and synthesized using the improved cyclization conditions, so that the synthetic route of 16 and 17 was shortened by five steps as compared with that of 2. The inhibitory activities of 16 and 17 against GUSβ and GBA were reduced as compared with those of 2, that is, the compounds showed improved selectivity for HPSE1 over GUSβ and GBA. In addition, 16 showed enhanced inhibitory activity against HPSE1 as compared with that of 2. Compound 16 appears promising as an HPSE1 inhibitor with therapeutic potential due to its highly potent inhibitory activity against HPSE1 with high selectivity for HPSE1.

Investigation into a Conformationally Locked (Z)-Azidoxime.

High nitrogen compounds find wide use in the development of new propellants and explosives as well as pharmaceutical chemistry as bioisosteres, bacterial stains, and antifungal agents. A class of underexplored high-nitrogen materials includes azidoximes and their 1-hydroxytetrazole isomers. Azidoximes possess an energetic azide group and are quite sensitive to impact, spark, and friction. Therefore, these materials are generated in situ and cyclized under mild acidic conditions to their 1-hydroxytetrazole isomers. Recently, we synthesized a novel 1,2,4-triazine-derived azidoxime; however, upon subjecting this material to established cyclization conditions, no reaction was observed, even after prolonged reaction times with heating. Additional 1,2,4-triazine-derived azidoximes also displayed a similar lack of reactivities. This observation led us to probe the reactivity of these materials with both a DFT investigation and crystallographically based electrostatic potential mapping. In all, the lack of reactivity toward cyclization was found to be due to an inability of 1,2,4-triazine-based azidoximes to isomerize into the reactive (E)-conformation, requiring an activation energy of 26.4 kcal mol-1.

Stereochemical modulation of ketyl radical cyclization enabled by pyridine-boryl radicals: catalytic diastereoselective synthesis of trans-2-alkyl-1-indanols.

Previously available ketyl radical cyclization conditions suffer from low and uncontrollable diastereoselectivity because of the absence of reagent-substrate interactions. In this report, stereochemical modulation was accomplished by taking advantage of the pyridine-boryl radical, which leaves the synthetically modifiable boronate moiety on the carbonyl oxygen near the reacting center during the stereo-determining cyclization step. In consequence, a catalytic diastereoselective synthesis of trans-2-substituted-1-indanols was achieved in the presence of a sterically congested six-membered diboronic ester and an efficient hydrogen atom donor.

Synthesis and Anti-Leishmanial Properties of Quinolones Derived from Zanthosimuline.

Quinoline derivatives and especially quinolones are considered as privileged structures in medicinal chemistry and are often associated with various biological properties. We recently isolated a series of original monoterpenyl quinolones from the bark of Codiaeum peltatum. As this extract was found to have a significant inhibitory activity against a Leishmania species, we decided to study the anti-leishmanial potential of this type of compound. Leishmaniasis is a serious health problem affecting more than 12 million people in the world. Available drugs cause harmful side effects and resistance for some of them. With the aim of finding anti-leishmanial compounds, we developed a synthetic strategy to access natural quinolones and analogues derived from zanthosimuline. We showed the versatility of this natural compound toward cyclization conditions, leading to various polycyclic quinolone-derived structures. The natural and synthetic compounds were evaluated against amastigote forms of Leishmania infantum. The results obtained confirmed the interest of this family of natural compounds but also revealed promising activities for some intermediates deriving from zanthosimuline. Following the same synthetic strategy, we then prepared 14 new analogues. In this work, we identified two promising molecules with good activities against intramacrophage L. infantum amastigotes without any cytotoxicity. We also showed that slight changes in amide functional groups affect drastically their anti-parasitic activity.

Frustrated Lewis pairs in situ formation in B-based porous aromatic frameworks for efficient o-phenylenediamine cyclization

Benzimidazoles are very important chemical materials in the pharmaceutical industry, and the most common synthetic route is cyclization of o-phenylenediamine with carbon sources, in which utilization of inexpensive and abundant CO2 as C1 source is very impressive. Porous aromatic frameworks (PAFs) with highly desired skeletons have attracted great attentions in gas capture and catalysis. Herein, B-based PAF-165 and PAF-166 are designed and synthesized via Friedel-Crafts alkylation reaction, which present high surface areas as well as high stability. Benefiting from the abundant electron-deficient B centers, both PAFs exhibit excellent selective CO2 adsorption abilities. The presence of sterically hindered B units in PAFs can act as Lewis acid active sites for the frustrated Lewis pairs (FLPs) in situ formation with o-phenylenediamine, thus promoting the synthesis of benzimidazole. The optimal reaction conditions for o-phenylenediamine cyclization with PAF catalysts are explored, and the reaction mechanism is also proposed. This work provides feasible ideas for incorporating FLPs within porous materials as reusable heterogeneous catalysts for CO2 capture and conversion.

Stereoselective Synthesis of Allenyl Alcohols by Cobalt(III)‐Catalyzed Sequential C−H Bond Addition to 1,3‐Enynes and Aldehydes

AbstractAn efficient and stereoselective CoIII‐catalyzed sequential C−H bond addition to 1,3‐enynes and aldehydes is disclosed. This transformation represents the first example of sequential C−H bond additions to 1,3‐enynes and a second coupling partner and provides the first example of preparing allenes by C−H bond addition to 1,3‐enynes. A wide range of aldehydes, C−H bond substrates and 1,3‐enynes with large substituents on the alkynes are effective substrates. The allenyl alcohol products can be further converted to dihydrofurans with high stereoselectivity either in situ or under Ag‐mediated cyclization conditions. The allenyl silyl group can also be transferred to the adjacent alcohol by a Brook rearrangement. Moreover, a mechanism for the transformation is proposed supported by X‐ray structural characterization of a cobaltacycle intermediate.

Stereoselective Synthesis of Allenyl Alcohols by Cobalt(III)-Catalyzed Sequential C-H Bond Addition to 1,3-Enynes and Aldehydes.

An efficient and stereoselective CoIII -catalyzed sequential C-H bond addition to 1,3-enynes and aldehydes is disclosed. This transformation represents the first example of sequential C-H bond additions to 1,3-enynes and a second coupling partner and provides the first example of preparing allenes by C-H bond addition to 1,3-enynes. A wide range of aldehydes, C-H bond substrates and 1,3-enynes with large substituents on the alkynes are effective substrates. The allenyl alcohol products can be further converted to dihydrofurans with high stereoselectivity either in situ or under Ag-mediated cyclization conditions. The allenyl silyl group can also be transferred to the adjacent alcohol by a Brook rearrangement. Moreover, a mechanism for the transformation is proposed supported by X-ray structural characterization of a cobaltacycle intermediate.

Convenient Synthesis of Alternatively Bridged Tryptophan Ketopiperazines and Their Activities against Trypanosomatid Parasites.

There is an urgent need for the development of new treatments against trypanosomatid parasites; the causative agents of some of the most debilitating diseases in the developing world. This work targets an interesting 6-5-6-6 fused carboline scaffold, accessing a range of substituted derivatives through stereospecific intramolecular Pictet-Spengler condensation. Modification of the cyclisation conditions allowed retention of the carbamate protecting group and gave insight into the reaction mechanism. Compounds' bioactivities were measured against T. brucei, T. cruzi, L. major and HeLa cells. We have identified promising pan-trypanocidal lead compounds based on the core scaffold, and highlight key SAR trends which will be useful for the future development of these compounds as potent trypanocidal agents.

Diverse saturated heterocycles from a hydroacylation/conjugate addition cascade.

Rhodium-catalyzed hydroacylation using alkynes substituted with pendant nucleophiles, delivers linear α,β-unsaturated enone intermediates with excellent regioselectivity. These adducts are used to construct a broad range of diversely substituted, saturated O-, N- and S-heterocycles in a one-pot process. Judicious choice of cyclisation conditions enabled isolation of O-heterocycles with high levels of diastereoselectivity. A variety of derivatisation reactions are also performed, generating functionalised hydroacylation products. This sequence serves as a general approach for the synthesis of fully saturated heterocycles.

Optical and electrochemical properties of peripherally substituted chromium and manganese phthalocyanines

New chromium phthalocyanine complex peripherally substituted with 8-quinolinoxy group was synthesized from modified precursor 4-(8-quinolinoxy) phthalonitrile in presence of CrCl3·6H2O in DMAE, using zinc dust as the reducing agent. The product μ-oxodimer of Cr(III)QPc [Cr(III)QPc-O-Cr(III)QPc] exhibited green florescence, in contrary to the typical red emissive behaviour of phthalocyanines. The detailed study on the emission spectrum of Cr(III)QPc-O-Cr(III)QPc revealed dual peaks with abroad band situated at 510 nm and a narrow peak situated at 686 nm, where the former broad band was found to be responsible for the intense green emission. The emission at 686 nm was the expected ligand based transition of Pc core from excited state singlet to ground state, S1 → S0, while the abnormal peak at 510 nm was found to be due to the combined effect of radiative relaxation of second excited singlet state to ground state (S2 → S0) and the LMCT of Pc2- to Cr(III) metal center. The emission spectra of Cr(III)QPc-O-Cr(III)QPc also exhibited a reciprocal relationship in the intensity of the dual peaks when the excitation wavelength was varied from 350 to 440 nm. The presence of an isoemission point at 648 nm indicated that two emission bands were brought about by two different excitonic transitions. Substituted chromium phthalocyanines are very less reported to date with remarkable fluorescent features, and in this work, the modified cyclotetramerization method applied by using zinc dust have paved new ways for their preparation. The preparation of unstable manganese phthalocyanine, MnQPc, was also rarely reported owing to its aerobic oxidation to the more stable and often synthesized analogue, MnQPc(CH3COO). Here, the synthesis of MnQPc was achieved under normal cyclization conditions and the effect of acetic acid and chlorinated solvents on the oxidative stability of MnQPc were also studied.

Deacylation-Aided C─H Alkylative Annulation through C─C Cleavage of Unstrained Ketones.

Arene- and heteroarene-fused rings are pervasive in biologically active molecules. Direct annulation between a C─H bond on the aromatic core and a tethered alkyl moiety provides a straightforward approach to access these scaffolds; however, such a strategy is often hampered by the need of special reactive groups and/or less compatible cyclization conditions. It would be synthetically appealing if a common native functional group can be used as a handle to enable a general C─H annulation with diverse aromatic rings. Here, we show a deacylative annulation strategy for preparing a large variety of aromatic-fused rings from linear simple ketone precursors. The reaction starts with homolytic cleavage of the ketone α C─C bond via a pre-aromatic intermediate, followed by a radical-mediated dehydrogenative cyclization. Using widely available ketones as the robust radical precursors, this deconstructive approach allows streamlined assembly of complex polycyclic structures with broad functional group tolerance.

Calix[3]pyrrole: A Missing Link in Porphyrin-Related Chemistry.

A long-standing question in porphyrin chemistry is why pyrrole monomers selectively form tetrapyrrolic macrocycles, whereas the corresponding tripyrrolic macrocycles are never observed. Calix[3]pyrrole, a tripyrrolic porphyrinogen-like macrocycle bearing three sp3-carbon linkages, is a missing link molecule that might hold the key to this enigma; however, it has remained elusive. Here we report the synthesis and strain-induced transformations of calix[3]pyrrole and its furan analogue, calix[3]furan. These macrocycles are readily accessed from cyclic oligoketones. Crystallographic and theoretical analyses reveal that these three-subunit systems possess the largest strain energy among known calix[n]-type macrocycles. The ring-strain triggers transformation of calix[3]pyrrole into first calix[6]pyrrole and then calix[4]pyrrole under porphyrin cyclization conditions. The present results help explain the absence of naturally occurring three-pyrrole macrocycles and the fact that they are not observed as products or intermediate during classic porphyrin syntheses.

Synthesis of Anthracene‐Based Cyclic π‐Clusters and Elucidation of their Properties Originating from Congested Aromatic Planes

AbstractSynthesis and properties of anthracene‐based cyclic π‐clusters which possess two and four anthracene units are discussed. The optimal cyclization conditions were determined based on a nickel(0)‐mediated reaction that afforded a cyclic anthracene dimer as the major product. Bringing two anthracene planes in close proximity in a face‐to‐face manner resulted in red‐shifted absorption owing to the narrowing of the HOMO–LUMO gap. The cyclic anthracene dimer exhibits multi‐stimuli responsiveness due to high π‐congestion. For example, photoirradiation on the anthracene dimer affords its photoisomer having C−C bonds that are longer than 1.65 Å, which can undergo thermal reversion under gentle heating. This enabled mechanochromism of the photoisomer (colorless) to the original anthracene dimer (red). Photoisomerization was also observed in the crystalline state, accompanied by crystal jumping or collapsing, that is, the photosalient effect.

Synthesis of Anthracene-Based Cyclic π-Clusters and Elucidation of their Properties Originating from Congested Aromatic Planes.

Synthesis and properties of anthracene-based cyclic π-clusters which possess two and four anthracene units are discussed. The optimal cyclization conditions were determined based on a nickel(0)-mediated reaction that afforded a cyclic anthracene dimer as the major product. Bringing two anthracene planes in close proximity in a face-to-face manner resulted in red-shifted absorption owing to the narrowing of the HOMO-LUMO gap. The cyclic anthracene dimer exhibits multi-stimuli responsiveness due to high π-congestion. For example, photoirradiation on the anthracene dimer affords its photoisomer having C-C bonds that are longer than 1.65 Å, which can undergo thermal reversion under gentle heating. This enabled mechanochromism of the photoisomer (colorless) to the original anthracene dimer (red). Photoisomerization was also observed in the crystalline state, accompanied by crystal jumping or collapsing, that is, the photosalient effect.

Stereoselective Synthesis of Hexahydroimidazo[1,2-a]quinolines via SN2-Type Ring-Opening Hydroarylation-Hydroamination Cascade Cyclization of Activated Aziridines with N-Propargylanilines.

A novel synthetic approach for the construction of 1,2,3,3a,4,5-hexahydroimidazo[1,2-a]quinolines in good yields (up to 75%) with excellent stereoselectivity (dr up to 94:6, ee up to >99%) under one-pot domino ring-opening cyclization (DROC) conditions has been developed. The DROC protocol proceeds through a Lewis acid catalyzed SN2-type ring-opening of activated aziridines with N-propargylanilines followed by intramolecular cyclization comprising concomitant hydroarylation and hydroamination steps in a domino fashion.

Short path to a complex ring

Organic Chemistry Nucleotide analogs are valuable tools and therapeutics because of their ability to interfere with processes such as DNA synthesis, which are vital to rapidly dividing cells and replicating viruses. These molecules are challenging to synthesize chemically. Meanwell et al. developed a “ribose last” synthetic strategy in which a fluorinated acyclic nucleic acid is formed by an l- or d-proline–catalyzed aldol reaction (see the Perspective by Miller). This intermediate can then be cyclized to yield the nucleic acid analog in one pot with control of anomeric conformation based on cyclization conditions. Nucleotide analogs accessible by this strategy include those with modifications at C2′ and C4′, purines and pyrimidines, and locked and protected products. Science , this issue p. [725][1]; see also p. [623][2] [1]: /lookup/doi/10.1126/science.abb3231 [2]: /lookup/doi/10.1126/science.abd1283

A short de novo synthesis of nucleoside analogs.

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2'- and C4'-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.