Cyclopropanation of Alkenes with Halodiazirines as Halocarbene Precursors in Continuous Flow.

The cyclopropanation reaction of alkenes with photolytically-generated chlorocarbenes from chlorodiazirines is reported as an effective way to prepare substituted 3-chloro-3-aryl-cyclopropanes. This practical and efficient approach allows the synthesis of various 3-chloro-3-aryl-cyclopropanes (32 examples) in continuous flow in 5-minute residence time under light-emitting diode (LED) irradiation. The conditions using 380 nm LED irradiation were successfully extended to the synthesis of substituted 3-bromo-3-aryl-cyclopropanes (3 examples).

Eco-Friendly Homo- and Cross-Etherification of Benzyl Alcohols Catalyzed by Iron(II/III) Chloride in Propylene Carbonate as a Green and Recyclable Solvent.

A new catalytic approach toward the symmetrical and nonsymmetrical etherification of benzyl alcohols was developed. The symmetrical etherification reaction was carried out in the presence of FeCl3·6H2O (5 mol %) as the catalyst and propylene carbonate as a green and recyclable solvent and led to the corresponding symmetrical ethers in 53 to 91% yields. The nonsymmetrical etherification of benzylic alcohols was achieved by using FeCl2·4H2O (10 mol %) in the presence of a pyridine bis-thiazoline ligand (12 mol %) and allowed for high selectivity and in 52 to 89% yields. These methods take advantage of eco-friendly conditions.

Eco-friendly and efficient catalyst-free synthesis of N-sulfonylimines from sulfonamides and aldehydes: crucial role of Al2O3 as a reusable dehydrating agent.

A green synthetic method for the synthesis of N-sulfonylimines was developed involving the straightforward condensation of sulfonamides with aldehydes under green and catalyst-free conditions, mediated by neutral Al2O3 as an efficient and reusable dehydrating agent. N-Sulfonylimines were produced in high yields and purity under simple experimental procedures.

Fluorine in metal-catalyzed asymmetric transformations: the lightest halogen causing a massive effect.

This review aims at providing an overview of the most significant applications of fluorine-containing ligands reported in the literature starting from 2001 until mid-2021. The ligands are classified according to the nature of the donor atoms involved. This review highlights both metal-ligand interactions and the structure-reactivity relationships resulting from the presence of the fluorine atom or fluorine-containing substituents on chiral catalysts.

Convenient synthesis of tricyclic N(1)-C(2)-fused oxazino-indolones via [Au(I)] catalyzed hydrocarboxylation of allenes.

A new [Au(I)] catalyzed intramolecular hydrocarboxylation of allenes is presented as a valuable synthetic route to oxazino-indolones. The use of 3,5-(CF3)2-C6H3-ImPyAuSbF6 as the optimal catalyst (5 mol%) was necessary to guarantee (i) wide tolerance of functional groups, (ii) mild reaction conditions (r.t., 16 h), and (iii) high yields (up to 90%). Preliminary attempts towards an enantioselective version (81 : 19 er) are also documented by means of a new family of chiral C1-symmetric ImPyAuCl complexes.

Electrosynthesis of Stabilized Diazo Compounds from Hydrazones.

An electrochemical synthesis of diazo compounds from hydrazones in yields as high as 99% was performed. This method was elaborated as a useful synthetic method and demonstrated on various diazo compounds (24 examples). Apart from exhibiting an efficiency that matched that of commonly used harsh and toxic chemical oxidants, this reaction is practically simple to set up, requires mild conditions, and is highly electron efficient (3 F/mol).

Catalytic Bismuth(V)-Mediated Oxidation of Hydrazones into Diazo Compounds.

A new bismuth(V) oxidative catalytic system has been developed and applied for the conversion of hydrazones into diazo compounds. With the use of low catalytic amounts of Ph3Bi and AcOH with NaBO3·H2O as a terminal oxidant, the in situ formation of Ph3Bi(OAc)2 is capable of oxidizing hydrazones in excellent yields. The reaction was applied for the synthesis of diazocarbonyls and 2,2,2-trifluoromethyl diazoalkanes in good to excellent yields.

C2-Symmetric 2,2'-Bipyridine-α,α'-1-adamantyl-diol Ligand: Bulky Iron Complexes in Asymmetric Catalysis.

The synthesis of a chiral 2,2'-bipyridine-α,α'-1-adamantyl-diol ligand was achieved starting from commercially available materials. The bulky ligand was synthesized in three steps in 40% overall yield with stereoselectivities of 98% de and >99.5% ee for the S,S enantiomer. The absolute configuration of and structural insights into a heptacoordinated 2,2'-bipyridine-α,α'-1-Ad-diol/FeII chiral complex were obtained from single-crystal diffraction analyses. The newly synthesized ligand was used in iron-catalyzed asymmetric Mukaiyama aldol, thia-Michael, and Diels-Alder reactions.

Emerging Applications of Aryl Trifluoromethyl Diazoalkanes and Diazirines in Synthetic Transformations.

Aryl trifluoromethyl diazoalkanes and diazirines have become unique as reactants in synthetic methodology. As privileged compounds containing CF3 groups and ease of synthetic access, aryl trifluoromethyl diazoalkanes and diazirines have been highlighted for their versatility in applications toward a wide range of synthetic transformations. This Perspective highlights the synthetic applications of these reactants as precursors of stabilized metal carbenes, i.e., donor-acceptor-substituted ones.

Anodic Oxidation of Aminotetrazoles: A Mild and Safe Route to Isocyanides.

A new electrochemical method for the preparation of isocyanides from easily accessible aminotetrazole derivatives has been developed, which tolerates an unprecedented range of functional groups. The use of chemical, rather than electrochemical, oxidation to afford isocyanides was also demonstrated, which provides access to these compounds for those without electrosynthesis equipment. The practicality of scale-up using flow electrochemistry has been demonstrated, in addition to the possibility of using electrochemically generated isocyanides in further reactions.

2,2'-Bipyridine-α,α'-trifluoromethyl-diol ligand: synthesis and application in the asymmetric Et2Zn alkylation of aldehydes.

A chiral 2,2'-bipyridine ligand (1) bearing α,α'-trifluoromethyl-alcohols at 6,6'-positions was designed in five steps affording either the R,R or S,S enantiomer with excellent stereoselectivities, i.e. 97% de, >99% ee and >99.5% de, >99.5% ee, respectively. The key step for reaching high levels of stereoselectivity was demonstrated to be the resolution of the α-CF3-alcohol using (S)-ibuprofen as the resolving agent. An initial application for the 2,2'-bipyridine-α,α'-CF3-diol ligand was highlighted in the ZnII-catalyzed asymmetric ethylation reaction of aromatic, heteroaromatic, and aliphatic aldehydes. Synergistic electron deficiency and steric hindrance properties of the newly developed ligand afforded the corresponding alcohols in good to excellent yields (up to 99%) and enantioselectivities (up to 95% ee). As observed from single crystal diffraction analysis, the complexation of the 2,2'-bipyridine-α,α'-CF3-diol ligand generates an unusual hexacoordinated ZnII.

Fluoride-Triggered Synthesis of 1-Aryl-2,2-difluoroalkenes via Desilylative Defluorination of (1-Aryl)-2,2,2-trifluoroethyl-silanes.

An efficient route for the synthesis of 1-aryl-2,2-difluoroalkenes via 1,2-desilylative defluorination is disclosed. Only a catalytic amount of fluoride source is required to initiate the desilylation and afford gem-difluoroalkenes in very good to quantitative yields, using mild reaction conditions in dimethyl carbonate as a green solvent. This reaction uses (1-aryl)-2,2,2-trifluoroethyl-silanes, which are easily prepared via the insertion reaction of trifluoroethyl diazo alkanes into the Si-H bond of tertiary organosilanes. (1-Aryl)-perfluoroalkyl-silanes cleanly afford the corresponding (Z)-1-benzylideneperfluoroalkanes, which upon hydrodefluorination furnish the (E)-ß(perfluoroalkyl)styrene derivatives with excellent yield and complete stereoselectivity. A one-pot system involving sequential insertion and desilylative-defluorination is also suitable for this transformation. This method demonstrates the usefulness of organosilanes toward the preparation of fluorinated alkenes as synthetically useful targets.

Photochemical Cyclopropenation of Alkynes with Diazirines as Carbene Precursors in Continuous Flow.

An efficient synthesis of 3-trifluoromethyl-3-aryl-cyclopropenes via the cyclopropenation reaction of alkynes with photolytically generated carbenes from diazirine compounds is described. This reaction is performed in continuous flow using readily available LEDs under mild reaction conditions. This new and efficient method describes the synthesis of 25 examples of 3-trifluoromethyl-3-aryl-cyclopropenes with yields up to 97%, achieved in continuous flow with a 5 min residence time. Control experiments highlighted that diazirines are more efficient than diazo compounds for this transformation.

Synthesis of homochiral sulfanyl- and sulfoxide-substituted naphthyltriazoles and study of the conformational stability.

The preparation of a series of novel homochiral atropisomeric sulfanyl- and sulfoxide-substituted naphthyltriazoles is described. The triazolization methodology used presents a new way towards novel and highly stable 1,2,3-triazole-based atropisomers, and introduces a new and complementary synthetic pathway towards 4-sulfanyl substituted 1,2,3-triazoles. Starting from sulfanyl-substituted naphthyl ketones, enantiopure amines, and 4-nitrophenyl azide, a collection of 16 sulfanyl-substituted naphthyltriazoles were obtained via the triazolization reaction in which the homochiral diastereomers are readily isolated. Subsequent monooxidation results in the preparation of several sulfoxide-substituted naphthyltriazoles. The absolute configuration of a set of diastereomeric sulfanyl- and sulfoxide-appended naphthyltriazoles was deduced via X-ray crystallography. Furthermore, the conformational stability of the atropisomers was determined experimentally, and further confirmed and analyzed with the aid of computational DFT calculations.

Bridging Lab and Industry with Flow Electrochemistry.

A revitalization of organic electrosynthesis has incited the organic chemistry community to adopt electrochemistry as a green and cost-efficient method for activating small molecules to replace highly toxic and expensive redox chemicals. However, many of the critical challenges of batch electrosynthesis, especially for organic synthesis, still remain. The combination of continuous flow technology and electrochemistry is a potent means to enable industry to implement large scale electrosynthesis. Indeed, flow electrosynthesis helps overcome problems that mainly arise from macro batch electro-organic systems, such as mass transfer, ohmic drop, and selectivity, but this is still far from being a flawless and generic applicable process. As a result, a notable increase in research on methodology and hardware sophistication has emerged, and many hitherto uncharted chemistries have been achieved. To better help the commercialization of wide-scale electrification of organic synthesis, we highlight in this perspective the advances made in large-scale flow electrosynthesis and its future trajectory while pointing out the main challenges and key improvements of current methodologies.

Asymmetric CuI-Catalyzed Insertion Reaction of 1-Aryl-2,2,2-trifluoro-1-diazoethanes into Si-H Bonds.

An asymmetric copper(I)-catalyzed Si-H insertion reaction of 1-aryl-2,2,2-trifluoro-1-diazoethanes in dimethyl carbonate as a green solvent alternative was developed. A C2-symmetric copper(I) diimine complex enabled the asymmetric insertion reaction to give enantioenriched (1-aryl-2,2,2-trifluoroethyl)silanes with excellent stereoselectivities (up to 98:2 er). Successful conversion of the silanes into the corresponding alcohols was performed with retention of stereochemistry. Mechanistic studies and DFT calculations support the proposed model for the observed stereoselectivities.

Synthesis of Imidazolidinone, Imidazolone, and Benzimidazolone Derivatives through Oxidation Using Copper and Air.

A new synthetic method of urea derivatives using copper and air was developed. These mild conditions provided moderate to very good yields for 15 examples (53-93%), while low yields were obtained with sterically hindered substrates (3 examples). The reaction was found to go through an in situ generated copper- N-heterocyclic carbene, which was then oxidized into cyclic urea derivatives possessing alkyl, benzyl, aryl, hydroxy, Boc-protected, and tertiary amine groups.

α-Thiocarbonyl synthesis via the FeII-catalyzed insertion reaction of α-diazocarbonyls into S-H bonds.

Fe(OTf)2 was used to catalyze the insertion reaction of α-diazocarbonyls into S-H bonds at 40 °C. A wide range of α-thioesters were obtained in yields up to 96% within 24-48 h from their corresponding α-diazoesters. A variety of thiols were used for the unprecedented insertion reaction with an α-diazoketone, leading to yields up to 85% of α-thioketones.

Transition-Metal-Free α-Vinylation of Enolizable Ketones with ß-Bromostyrenes.

An α-vinylation of enolizable ketones has been developed by using ß-bromostyrenes and a KO tBu/NMP system. ß,γ-Unsaturated ketones of E configuration were obtained in excellent yield and selectivity. Further synthetic possibilities are highlighted by one-pot functionalization via trapping of intermediate dienolates with alkyl, allyl, benzyl, and propargyl halides to generate quaternary centers. The reported transformation is believed to involve phenylacetylene and propargylic alcohol derivatives.

Recyclable iron(ii) caffeine-derived ionic salt catalyst in the Diels-Alder reaction of cyclopentadiene and α,ß-unsaturated N-acyl-oxazolidinones in dimethyl carbonate.

Iron(ii) triflate was used in combination with caffeine-derived salts as recyclable catalysts for the Diels-Alder reaction run in dimethyl carbonate (DMC) as a green solvent. The catalyst was prepared as an ionic salt from a xanthinium salt and Fe(OTf)2. Various substrates including α,ß-unsaturated carbonyl and N-acyloxazolidinone derivatives were reacted with cyclopentadiene using this recyclable catalyst. The use of a low catalyst loading (1 mol%) afforded high yields (up to 99%) of the corresponding cycloadducts. The recycling and the efficiency of the catalyst were demonstrated for several runs.