Straightforward Synthesis of 3‐Aminothiophenes Using Activated Amides

Herein, we describe a facile approach towards the synthesis of diversely substituted 3‐aminothiophenes. A wide range of functional groups can be incorporated at the C(2), C(4), and C(5) positions of the thiophenes, and this route is also suitable for the synthesis of fused bicyclic heterocycles such as 3‐aminotetrahydrobenzothiophenes. This methodology relies on a 6π‐electrocyclization involving a vinyl sulfide linked to a keteniminium salt, the latter being formed in‐situ through activation of the corresponding amide with triflic anhydride.     

Copper‐Catalyzed Domino Synthesis of 2‐Imino‐1H‐imidazol‐5(2H)‐ones and Quinoxalines Involving CC Bond Cleavage with a 1,3‐Dicarbonyl Unit as a Leaving Group

Although 2‐imino‐1H‐imidazol‐5(2H)‐ones have important biological activities in metabolism, their synthesis has rarely been investigated. Quinoxalines as “privileged scaffolds” in medicinal chemistry have been extensively investigated, but the development of novel and efficient synthetic methods remains very attractive. Herein, we have developed two copper‐catalyzed domino reactions for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones and quinoxalines involving C?C bond‐cleavage with a 1,3‐dicarbonyl unit as a leaving group. The domino sequence for the synthesis of 2‐imino‐1H‐imidazol‐5(2H)‐ones includes aza‐Michael addition, intramolecular cyclization, C?C bond‐cleavage, 1,2‐rearrangement, and aerobic dehydrogenation reaction, whereas the domino sequence for the synthesis of quinoxalines includes aza‐Michael addition, intramolecular cyclization, elimination reaction, and C?C bond‐cleavage reaction. The two domino reactions have significant advantages including high efficiency, mild reaction conditions, and high tolerance of various functional groups.     

5-Aminooxazole as an internal traceless activator of C-terminal carboxylic acid: rapid access to diversely functionalized cyclodepsipeptides

A conceptually novel macrolactonization protocol has been developed. It is a domino process involving a sequence of: 1) protonation of 5-aminooxazole leading to the electrophilic iminium salt; 2) trapping of the iminium species by the neighboring C-terminal carboxylic acid leading to a putative spirolactone; and 3) intramolecular nucleophilic addition of the tethered alcohol to the spirolactone followed by fragmentation. The strategically incorporated 5-aminooxazole serves as an internal traceless activator of the neighboring C-terminal carboxylic acid, since it became an integral part of the peptide backbone after cyclization. No coupling reagent is required and the entire sequence is triggered by just a few equivalents of trifluoroacetic acid under very mild conditions (MeCN as the solvent at room temperature). The spirolactone as an activated form of the carboxylic acid has been evidenced by a sulfur-migration experiment. By combining with a three-component synthesis of 5-aminooxazole, a two-step synthesis of structurally complex cyclodepsipeptides from readily accessible starting materials was developed.     

A Domino Fusion of an Organic Ligand Depended on Metal-Induced and Oxygen Insertion,Unraveled by Crystallography,Mass Spectrometry,and DFT Calculations

Herein, the reaction of (1-methyl-1 H-benzo[d]imidazol-2-yl)methanamine ( L1 ) with Co(H₂O)₆Cl₂, in CH₃CN at 120 °C, leading to the 2,3,5,6-tetrakis(1-methyl-1 H-benzo[d]imidazol-2-yl)pyrazine ( 3 ), isolated as a dimeric cluster {[Co^II₂( 3 )Cl₄] ⋅ 2 CH₃CN} ( 2 ), is reported. When O₂ and H₂O are present, (1-methyl-1 H-benzo[d]imidazole-2-carbonyl)amide (H L1′ ) is first formed and crystallized as [Co^III( L1 )₂( L1′ )]Cl₂ ⋅ 2 H₂O ( 4 ) before fusion of H L1′ with L1 , giving 1-methyl-N-(1-methyl-1 H-benzo[d]imidazol-2-carbonyl)-1 H-benzo[d]imidazol-2-carboxamide (H L2′′ ) forming a one-dimensional (1D) chain of [Co^II₃( L2′′ )₂Cl₄]_n ( 5 ). The combination of crystallography and mass spectrometry (ESI-MS) of isolated crystals and the solutions taken from the reaction as a function time reveal seven intermediate steps leading to 2 , but six steps for 5 , for which a different sequence takes place. Control and isotope labeling experiments confirm the two carbonyl oxygen atoms in 5 originate from both air and water. The dependence on the metals, compared with FeCl₃ ⋅ 6 H₂O leading to a stable triheteroarylmethyl radical, is quite astounding, which could be attributed to the different oxidation states of the metals and coordination modes confirmed by DFT calculations. This metal and valence dependent process is a very useful way for selectively obtaining these large molecules, which are unachievable by common organic synthesis.     

Protecting‐Group‐Free Total Synthesis of Isoquinoline Alkaloids by Nickel‐Catalyzed Annulation of o‐Halobenzaldimine with an Alkyne as the Key Step

An efficient short total synthesis of benzo[c]phenanthridine alkaloids including oxyavicine, oxynitidine, and oxysanguinarine is described. Thus, N‐methyl‐o‐bromobenzaldimines 1 b – d undergo regioselective cyclization with 4‐(benzo[d][1,3]dioxol‐5‐yl)but‐3‐yn‐1‐ol ( 2 b ) in the presence of [Ni(cod)₂] (cod=1,5‐cyclooctadiene). In situ oxidation of the resultant isoquinolinium salts gives isoquinolinone derivatives 5 b – d with benzo[d][1,3]dioxol‐5‐yl substitution at the C₃ atom and a (CH₂)₂OH group at the C₄ atom. Later, oxidation of the alcohol group in 5 b – d to the aldehyde moiety followed by acid‐catalyzed cyclization and dehydration completes the total syntheses to give oxyavicine, oxynitidine, and oxysanguinarine in 67, 65, and 60 % yields, respectively. The synthesis requires four steps from o‐bromobenzaldehyde derivatives. Transformations of these alkaloids to the other alkaloids in this family are also discussed herein.     

Derailed Ohira-Bestmann Reaction of γ,δ-Unsaturated Aldehydes for the Stereoselective Synthesis of Cyclopenta[c]pyrazoles

The synthesis of cyclopenta[c]pyrazoles from γ,δ-unsaturated aldehydes by a domino sequence involving one-carbon homologation and intramolecular azomethine imine 1,3-dipolar cycloaddition is disclosed. The fused pyrazoles bearing aromatic and aliphatic substituents are obtained in good yields and excellent diastereomeric purity. Additionally, the synthetic utility of the pyrazole products generated by this method has been highlighted in a series of functionalization reactions. The method presented opens strategic opportunities for the synthesis of pyrazole-containing biologically active compounds.     

Three Complementary One-Pot Four-Component Reaction Sequences for Rapid,General and Direct Spiropyran Synthesis

Three one-pot three-step four-component reaction sequences for spiropyran synthesis have been developed, based around three different methods for in situ generation of 1,2,3-trisubstituted indoles (indole N-alkylation, Fischer indolisation and indole C-alkylation). The reaction sequences give access to a broad swathe of spiropyran structures. Each sequence is operationally straightforward, rapid and high yielding. We have synthesized 58 structurally diverse spiropyrans bearing a wide range of useful functional groups, and their utility were demonstrated in the targeted synthesis of potential ratiometric fluorescence probes for metal ions and spiropyran-cholesterol conjugates. Finally, we showed that our one-pot N-alkylation-C-alkylation-condensation sequence can underpin combinatorial spiropyran synthesis through generation of a 16-member spiropyran library.     

Synthesis of Benzo[a]carbazoles through Visible Light-Induced Cycloaromatization

We report herein a synthesis of 5,6-diarylbenzo[a]carbazoles by a sequence of 6π-electrocyclization followed by β-elimination. The highly functionalized 2,3-disubstituted indoles used for this cycloaromatization process are prepared by Pd-catalyzed cyclizative cross-coupling of ortho-alkynylanilines with ortho-alkynylbenzamides. The combination of these two reactions allows us to develop a facile synthesis of benzo[a]carbazoles directly from two easily accessible internal alkynes without isolation of the indole intermediates.     

gem‐Dihalocyclopropanes as Building Blocks in Natural‐Product Synthesis: Enantioselective Total Syntheses of ent‐Erythramine and 3‐epi‐Erythramine

ent‐Erythramine ((?)‐ 1 ), the enantiomer of the alkaloid erythramine, was prepared in 15 steps from known compounds. The first of three pivotal bond‐forming steps in the synthesis was a Suzuki–Miyaura cross‐coupling reaction of the starting materials to give a bis‐silyl ether. The second involved silver(I)‐induced electrocyclic ring opening of the gem‐dichlorocyclopropane formed in the next step and trapping of the ensuing π‐allyl cation by the tethered nitrogen atom to give, following cleavage of the allyloxycarbonyl protecting group, an approximately 5:6 mixture of the chromatographically separable diastereoisomeric spirocyclic products. In the third critical bond‐forming reaction, the iodide formed from one of the diastereoisomers underwent a radical‐addition/elimination reaction sequence that led to (?)‐ 1 in 89 % yield. The application of the same sequence of transformations to the other diastereoisomer afforded 3‐epi‐(+)‐erythramine (3‐epi‐(+)‐ 1 ).     

Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry

Iron-based catalysts were applied in cascade-type reactions for the synthesis of different carbonyl compounds. The reactions proceeded by a new iron-catalyzed cascade of alkynylation/hydration by using both the σ- and π-Lewis acid properties of iron salts. The alkynylation reactions of several endo and exocyclic acetoxylactams were achieved with three different catalysts including FeCl₃ ⋅ 6H₂O, FeCl₃, and Fe(OTf)₃ showing the efficiency of σ-Lewis acidity of iron (III) salts in catalyzing the alkynylation reaction. We also demonstrated that the reaction sequence could be shortened by the direct use of hydroxylactams, leading to an environmentally friendly protocol, avoiding the need to perform unnecessary lengthy steps. A combination of the hard/soft iron Lewis acid properties was then used to implement an unprecedented tandem intermolecular alkynylation/intramolecular hydration sequence allowing expedient access to a new carbonyl structures from trivial materials.     

Generation of Glycosyl Radicals from Glycosyl Sulfoxides and Its Use in the Synthesis of C‐linked Glycoconjugates

We here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C‐linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate‐DNA conjugates.     

Microwave-mediated synthesis of a cyclic heptapeptoid through consecutive Ugi reactions

The combination of consecutive Isocyanide-based Multicomponent Reactions (IMCRs) allowed the synthesis of a cyclic heptapeptoid in a reduced number of steps. Herein, we describe this efficient approach using four consecutive Ugi reactions, being three Ugi four-center, four-component reactions, and one Ugi four-center, three-component reaction. Our strategy involved eight steps of which seven in a row were microwave-assisted with reaction times of 3–5?min and yields ranging from 88 to 98%.     

Ce-Doped Ordered Mesoporous Cobalt Ferrite Phosphides as Robust Catalysts for Water Oxidation

Controllable synthesis and rational design of ordered nanostructures are crucial for their renewable energy applications. In this work, a mesoporous CoP/Fe₂P doped with 5 % Ce by a simple nanocasting method is designed as a superior electrocatalyst for the oxygen evolution reaction (OER). The well-designed composite delivers an efficient electrocatalytic activity with a low overpotential of 250 mV at 10 mA cm⁻² and excellent long-term stability with no degradation after 10 h of electrochemical OER test, superior to that of the state-of-the-art RuO₂ electrocatalyst in alkaline electrolyte. A comprehensive analysis demonstrates that the outstanding OER performance is due to the desirable combination of the highly exposed active centers in the Ce-doped bimetallic phosphides, efficient mass transfer, and effective electron conduction owing to the hierarchically mesoporous hybridization. Furthermore, the synergistic effect between Ce and CoP/Fe₂P accelerates the migration rate of electrons/ions and increases the electrochemical active area. This excellent OER performance observed by Ce doping of CoP/Fe₂P makes them possible candidates toward OER in alkaline electrolytes.     

A bio-inspired cascade and a late-stage directed sp3 CH lithiation enables a concise total synthesis of (−)-virosaine A

The asymmetric total synthesis of (?)-virosaine A was achieved in 9% overall yield from commercially/readily available starting materials. Inspired by an intriguing biosynthetic proposal, a novel cascade reaction sequence was developed to efficiently construct the caged polycyclic core of virosaine A. The pivotal cascade precursor was readily available in enantiopure form via a robust route that featured an enantioselective one-pot Diels-Alder cycloaddition/organolithium addition. Several contemporary methods of CH functionalization were applied to the cascade product and yielded a diverse set of novel complex polycycles. Ultimately, a combination of NMR and computational analyses laid the groundwork for a successful directed lithiation strategy to selectively functionalize the caged core and complete the total synthesis of virosaine A.     

Topologically driven tandem radical cyclization-based strategy for the synthesis of oxa- and aza-cages

Tandem radical cyclization-based strategy for the synthesis of oxa- and aza-cage compounds is described. The aryl iodides 1 and N-tosyl propargylated amine 8 lead to oxa- and aza-cages, respectively, after two tandem 5-exo-trig radical cyclizations. The alcohols 11 on reaction with ⁿBu₃SnH and AIBN give rise to the oxa-cages 14 bearing the tributyltin moiety after three tandem 5-exo-trig cyclizations. On the other hand, reaction of the propargyl ether 16 under similar conditions furnishes the oxa-cage 17 by a 5-exo-trig, 4-exo-trig, 5-exo-trig tandem radical cyclization sequence.     

Divergent Dendrimer Synthesis via the Passerini Three‐Component Reaction and Olefin Cross‐Metathesis

The combination of the Passerini reaction and olefin cross‐metathesis is shown to be a very useful approach for the divergent synthesis of dendrimers. Castor oil‐derived platform chemicals, such as 10‐undecenoic acid and 10‐undecenal, are reacted in a Passerini reaction with an unsaturated isocyanide to obtain a core unit having three terminal double bonds. Subsequent olefin cross‐metathesis with tert‐butyl acrylate, followed by hydrogenation of the double bonds and hydrolysis of the tert‐butyl ester, leads to an active core unit bearing three carboxylic acid groups as reactive sites. Iterative steps of the Passerini reaction with 10‐undecenal and 10‐isocyanodec‐1‐ene for branching, and olefin cross‐metathesis with tert‐butyl acrylate, followed by hydrogenation and hydrolysis allow the synthesis of a third‐generation dendrimer. All steps of the synthesis are carefully characterized by NMR, GPC, MS, and IR.

     

Heck-mediated synthesis and photochemically induced cyclization of [2-(2-styrylphenyl)ethyl]carbamic acid ethyl esters and 2-styryl-benzoic acid methyl esters: total synthesis of naphtho[2,1f]isoquinolines (2-azachrysenes)

We describe two new closely related total syntheses of naphtho[2,1-f]isoquinolines. The first synthesis consists of a Heck coupling reaction between trifluoromethanesulfonic acid 2-(2-ethoxycarbonylaminoethyl)phenyl esters and styrenes to give [2-(2-styrylphenyl)ethyl]carbamic acid ethyl esters. These compounds cyclize to give (2-phenanthren-1-yl-ethyl)carbamic acid ethyl esters, from which 2-azachrysenes can be obtained in a three-step sequence. The second synthesis includes a new total synthesis of 2-styrylbenzoic acid methyl esters by Heck coupling of methyl o-iodobenzoates to styrenes, followed by the transformation of the resulting benzoic acid derivatives into phenanthrene-1-carboxylic acid methyl esters and then into the target compounds by a six-step sequence including a Bischler-Napieralski cyclization.     

Recent advances in the synthesis,structural diversity,and applications of mesoionic 1,2,3-triazol-5-ylidene metal complexes

Beyond the classic N-heterocyclic carbenes (NHCs) there is a subclass of NHCs called mesoionic carbenes (MICs). This review focuses on recent advances in the area of 1,2,3-triazol-5-ylidenes as the most abundant class of MICs and their metal complexes. The study of mesoionic 1,2,4- and 1,3,4-trisubstituted 1,2,3-triazol-5-ylidene transition metal complexes is a research area with a history of just ～10 years. During this relatively short period, hundreds of these complexes have appeared in the literature, reflecting their high stability and simpler synthesis compared with NHCs. Specifically, this review is focused on advances in the synthesis of 1,2,3-triazol-5-ylidene metal complexes derived from palladium, silver, gold, ruthenium, iridium, rhodium, iron, molybdenum, cobalt, nickel, platinum, and osmium, together with their catalytic, medicinal, and photophysical applications.     

A Visible‐Light‐Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist

A visible‐light‐mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem‐difluoro group present in an opioid receptor‐like 1 (ORL‐1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables the direct and efficient introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems, representing a new disconnection for the synthesis of this versatile moiety. When applied to the target compound, the photochemical step could be conducted on 15 g scale using industrially relevant [Ru(bpy)₃Cl₂] catalyst loadings of 0.01 mol %. This transformation is part of an overall five‐step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.     

Multistate Photoswitches: Macrocyclic Dihydroazulene/Azobenzene Conjugates

Molecules comprised of three covalently linked bi‐stable switches can exist in states described by a combination of binary numbers, one for each individual switch: ?000?, ?001?, etc. Here we have linked three photo‐/thermoswitches together in a rigid macrocyclic structure, one azobenzene (bit no 1) and two dihydroazulenes (DHAs; bits no 2 and 3) and demonstrate how electronic interactions and unfavorable strain in some states can be used to control the speed by which a certain state is reached. More specifically, upon irradiation of state ?000?, the AZB isomerizes from trans to cis and the two DHAs to vinylheptafulvenes (VHFs), generating ?111?. The thermal VHF‐to‐DHA back‐reactions from this state also occur stepwise and can be accelerated by photo‐induced AZB cis‐to‐trans conversion, proceeding via ?011? to ultimately furnish ?000?. Overall, the accessibility to a specific state of one bit was found to depend on the states of its neighboring bits.