Alcohol Research Articles

Catalytic Asymmetric Barbier Reaction of Ketones with Unactivated Alkyl Electrophiles.

The Barbier reaction is a reductive-type addition of an aldehyde or ketone with an organic electrophile in the presence of a terminal metal reductant, providing a straightforward and efficient method for carbon-carbon bond formation. This reaction possesses the advantage of circumventing the preparation of moisture- and air-sensitive organometallic reagents. However, the catalytic Barbier reaction of ketones to construct tetrasubstituted stereogenic centers is largely underdeveloped, despite its great potential for accessing synthetically challenging chiral tertiary alcohol. Particularly, the leveraging of unactivated alkyl electrophiles as coupling components is still rarely exploited. Herein, we disclose a photoredox-assisted cobalt-catalyzed asymmetric alkylative Barbier-type addition reaction of ketones to address the aforementioned challenges, thereby allowing for the construction of highly congested tetrasubstituted carbon centers. The alkyl addition fragments could be either readily accessible unactivated alkyl halides or redox-active esters generated through a decarboxylative pathway. Both types of alkyl electrophiles include primary, secondary, and tertiary ones, thus affording diverse enantioenriched tertiary alcohols with a broad substrate scope. This enantioselective protocol is applied for the expedient synthesis of core structure of Sofdra, a very recent FDA-approved drug in 2024. The newly developed bisoxazolinephosphine (NPN) ligand enables high enantioselectivity in this asymmetric reductive addition process.

Phase equilibria and volumetric properties of mixtures of highly fluorinated alcohols and water

New thermodynamic data are reported for aqueous solutions of highly fluorinated alcohols of different chain lengths. The liquid-liquid equilibrium (LLE) T-x diagram of the binary mixture (1H,1H-perfluoropropanol + water) was determined, as well as the LLE phase diagram of the ternary mixture (1H,1H-perfluoropropanol + 1-propanol + water) at 298.15 K and atmospheric pressure. The mutual solubilities of water with several linear perfluorinated alcohols (CF3(CF2)nCH2OH, n = 1–5) and the tertiary alcohol perfluoro-t-butanol ((CF3)3COH) were also measured at 298.15 K. Finally, volumetric properties such as the excess molar volumes and partial molal volumes at infinite dilution of the different fluorinated alcohols in water were also determined and discussed comparing with equivalent data from the literature for the corresponding hydrogenated alcohols.

An acid-mediated synthesis of substituted naphthalenes from ortho-alkynyl tertiary benzylic alcohols

We present an efficient, acid-mediated cascade strategy for the construction of 1,3- and 1,2,3-substituted naphthalenes from readily accessible starting materials. This method employs ortho-alkynyl or arynyl tertiary benzylic alcohols as the substrates, which undergo a Lewis acid-triggered dehydration to form ortho-(alkynyl)-styrene intermediates. These intermediates subsequently undergo intramolecular cycloaromatization, resulting in the formation of substituted naphthalenes in a one-pot reaction. A significant advantage of this approach is its ability to proceed under sustainable and neat reaction conditions using ZnCl₂ as the sole Lewis acid, highlighting the simplicity and practicality of the process. Additionally, the strategy exhibits a broad substrate scope, efficiently yielding the desired naphthalene derivatives with practical and consistent yields. This method not only simplifies the synthetic pathway but also aligns with green chemistry principles by minimizing the use of solvents and reagents.

Biocatalytic asymmetric aldol addition into unactivated ketones.

Enzymes are renowned for their catalytic efficiency and selectivity, but many classical transformations in organic synthesis have no biocatalytic counterpart. Aldolases are prodigious C-C bond-forming enzymes, but their reactivity has only been extended past activated carbonyl electrophiles in special cases. To probe the mechanistic origins of this limitation, we use a pair of aldolases whose activity is dependent on pyridoxal phosphate. Our results reveal how aldolases are limited by kinetically favourable proton transfer with solvent, which undermines aldol addition into ketones. We show how a transaldolase can circumvent this limitation, enabling efficient addition into unactivated ketones. The resulting products are highly sought non-canonical amino acids with side chains that contain chiral tertiary alcohols. Mechanistic analysis reveals that transaldolase activity is an intrinsic feature of pyridoxal phosphate chemistry and identifies principles for extending aldolase catalysis beyond its previous limits to enable convergent, enantioselective C-C bond formation from simple starting materials.

Total Synthesis of Chalaniline A: An Aminofulvene Fused Chromone from Vorinostat-Treated Fungus Chalara sp. 6661.

Chalaniline A, an aminofulveno[1,2-b]chromone derivative previously isolated from a vorinostat-treated ascomycete Chalara sp., was prepared in nine steps from orcinol (3,5-dihydroxytoluene). In a key transformation, the tricyclic ring system of the target was generated by a pyrrolidine-catalyzed double annulation between α-(methylsulfinyl)-2,6-dihydroxy-4-methylacetophenone and the ketaldoester, methyl 2,5-dioxopentanoate. The resulting tertiary alcohol (coniochaetone H) was further converted to chalaniline A by operations including dehydration (to yield a hydroxyfulvene), Vilsmeier reaction, and enamine exchange.

Electrocatalytic Aromatic Alcohols Splitting to Aldehydes and H2 Gas.

Selective electrocatalytic transformation of alcohols to aldehydes offers an efficient and environmentally friendly platform for the simultaneous production of fine chemicals and pure hydrogen gas. However, traditional alcohol oxidation reactions (AORs) in aqueous electrolyte unavoidably face competitive reactions (e.g., water oxidation and overoxidations reactions) for the presence of active oxygen species from water oxidation, causing an unwanted decrease in final efficiency and selectivity. Here, we developed an integrated all-solid proton generator-transfer electrolyzer to trigger the pure alcohol splitting reaction (ASR). In this splitting process, only O-H and C-H bonds can be cleaved at the proton generator (Pt nanoparticles), thereby completely avoiding all competitive reactions involving oxygen active species to give a > 99% selectivity to aldehydes. The as-generated protons are transported to the cathode by a three-dimensional (3D) conducting network (assemblies of ionomers and carbon spheres) for efficient hydrogen production. Unlike the poor selectivity (<22%) and durability (<3 h) of a conventional AOR electrolyzer, this ASR electrolyzer could be continuously operated at a low cell voltage of 1.2 V for at least 10 days to give a high Faradaic efficiency of 80-93% for aldehyde production.

Iridium‐Pyrazolato Complex Catalyzed Dehydrogenative Alkylation of Ketones and Arylacetonitriles with Primary Alcohols

Herein, we report the use of an air‐stable iridium pyrazolato complex as an effective catalyst for the α‐alkylation of ketones and arylacetonitriles with primary alcohols, employing borrowing hydrogen strategy. The alkylation reactions were efficiently conducted at 120 °C in toluene utilizing a very low catalyst loading (0.1 mol%). A broad range of ketones and arylacetonitriles, in combination with various aromatic and aliphatic primary alcohols, were successfully transformed into the corresponding α‐alkylated products. Additionally, quinoline derivatives were synthesized from 2‐aminobenzylalcohol and ketones using dehydrogenative coupling strategy. A mechanistic investigation unveiled that the key step involved alcohol activation via metal‐ligand cooperation.

Catalyst-free synthesis of novel α-trifluoromethylated tertiary alcohols bearing azaarenes as potential antifungal agents

Herein, α-trifluoromethylated tertiary alcohols bearing azaarenes were successfully synthesized via the reaction of 2-methyl azaarenes and CF3-substituted 1,3-diols with high yields under catalyst-free, mild conditions. The antifungal activities against Gaeumannomyces graminis var tritici, Rhizoctonia cerealis, Fusarium graminearum, Rhizoctonia solani, Fusarium moniliforme, Sclerotium rolfsii Sacc were investigated. The bioassay results indicated that the antifungal activity against Gaeumannomyces graminis var tritici was obviously better compared to other five fungi and compound 3dd displayed the highest activity, with an EC50 value of 27.73 μg/mL in vitro.

Modular Synthesis of Heterobenzylic Amines via Carbonyl Azinylative Amination

AbstractTransformations enabling the synthesis of α‐alkyl, α′‐2‐azinyl amines by addition of 2‐heteroaryl‐based nucleophiles to in situ‐generated and non‐activated alkyl‐substituted iminium ions are extremely rare. Approaches involving classical 2‐azinyl organometallics, such as the corresponding Grignard reagents, often fail to produce the desired products. Here, we report an operationally straightforward solution to this problem through the development of a multicomponent coupling process wherein a soft 2‐azinyl indium nucleophile, generated in situ from the corresponding 2‐iodo heteroarene and indium powder, adds to an iminium ion that is also formed directly in the reaction. This modular carbonyl azinylative amination (CAzA) displays a broad scope and only a metal reductant is needed to generate a reactive 2‐azinyl nucleophile. Beyond the addition to iminium ions, the 2‐azinyl addition to polyfluoromethyl ketones forms the corresponding tertiary alcohols. Together, the products of these reactions possess a high degree of functionality, are typically challenging to synthesize by other methods, and contain motifs recognized as privileged in the context of pharmaceuticals and agrochemicals.

Chemoselective Synthesis of α-Tertiary Hydroxy Oximes via Photochemical 1,3-Boronate Rearrangement.

Tertiary alcohols with adjacent nucleophilic labile groups are prevalent in bioactive molecules but are challenging to synthesize. Herein we introduce a direct, protecting group-free method to access α-tertiary hydroxy oximes via photochemical 1,3-boronate rearrangement. This reaction delivers high yields (up to 94%) using readily available boronic acids, is scalable to gram quantities, and allows for further derivatization to other nitrogen-containing molecules.

Visible Light‐Switchable Lattice Oxygen Sites for Selective C−H and C(O)−C Bond Electrooxidation

Lattice‐oxygen is highly oxidizable, ideal for electrocatalytic C−H oxidation but insufficient alone for C(O)−C bond cleavage due to the non‐removable nature of lattice sites. Here, we present a visible light‐assisted electrochemical method of in‐situ formulating removable lattice‐oxygen sites in a nickel‐oxyhydroxide (ESE‐NiOOH) electrocatalyst. This catalyst efficiently converts aromatic alcohols and carbonyls with C(O)−C fragments from lignin and plastics into benzoic acids (BAs) with high yields (83–99%). Without light irradiation, ESE‐NiOOH’s intrinsic lattice‐oxygen is non‐removable and inert for C(O)−C bond cleavage. In‐situ characterizations show light‐induced lattice‐oxygen removal and regeneration via OH– refilling. Theoretical calculations identify the nucleophilic oxygen attack on ketone‐derived carbanion as a rate‐determining step, which can be remarkably facilitated by removable lattice‐oxygen to activate α‐C−H bonds. As a proof‐of‐concept, an “electrochemical funnel” strategy is developed for high‐efficiency upgrading aromatic mixtures with C(O)−C moieties into BA with up to 94% yield. This in‐situ removal‐regeneration approach for lattice sites opens an avenue for the tailored design of interfacial electrocatalysts to selectively upcycle waste carbon sources into valuable products.

Visible Light-Switchable Lattice Oxygen Sites for Selective C-H and C(O)-C Bond Electrooxidation.

Lattice-oxygen is highly oxidizable, ideal for electrocatalytic C-H oxidation but insufficient alone for C(O)-C bond cleavage due to the non-removable nature of lattice sites. Here, we present a visible light-assisted electrochemical method of in-situ formulating removable lattice-oxygen sites in a nickel-oxyhydroxide (ESE-NiOOH) electrocatalyst. This catalyst efficiently converts aromatic alcohols and carbonyls with C(O)-C fragments from lignin and plastics into benzoic acids (BAs) with high yields (83-99%). Without light irradiation, ESE-NiOOH's intrinsic lattice-oxygen is non-removable and inert for C(O)-C bond cleavage. In-situ characterizations show light-induced lattice-oxygen removal and regeneration via OH- refilling. Theoretical calculations identify the nucleophilic oxygen attack on ketone-derived carbanion as a rate-determining step, which can be remarkably facilitated by removable lattice-oxygen to activate α-C-H bonds. As a proof-of-concept, an "electrochemical funnel" strategy is developed for high-efficiency upgrading aromatic mixtures with C(O)-C moieties into BA with up to 94% yield. This in-situ removal-regeneration approach for lattice sites opens an avenue for the tailored design of interfacial electrocatalysts to selectively upcycle waste carbon sources into valuable products.

Leveraging Natural Product-Inspired Antifungals to Investigate the Mechanism of Action of Peniciaculin A.

Ubiquinone mimics known as quinone outside inhibitors (QoIs) are one of the most prominent fungicides used to protect crops in the agricultural industry. Due to chemotype similarities with known QoIs, peniciaculin A, a triaryl natural product, was proposed to exhibit similar broad spectrum antifungal activity against phytopathogens. Instability of the tertiary alcohol and phenol motif, however, prompted exploration of the antifungal properties of simplified analogues to probe possible overlap in mechanism of action between the natural product and QoIs. Peniciaculin A inspired analogues mimicking known QoI scaffolds displayed broad spectrum antifungal activity while those containing scaffolds dissimilar to QoIs possessed negligible bioactivity. These activity profiles suggest peniciaculin A is likely acting as a QoI.

Pyridine-Catalyzed Chemoselective Four-Component Cascade Reaction of Aromatic Aldehydes, Malononitrile/Cyanoacetates, MBH Carbonates, and Alcohols.

An efficient pyridine-catalyzed chemoselective four-component cascade reaction of aromatic aldehydes, malononitrile/cyanoacetates, Morita-Baylis-Hillman (MBH) carbonates, and alcohols has been established. This one-pot reaction progressed in an unusual reaction with solvent participation via a Knoevenagel condensation/oxa-Michael addition/SN2' substitution sequence. This method allowed for facile access to an array of functionalized chain alkylbenzenes and dihydroquinolinones bearing one all-carbon quaternary center in moderate to excellent yields. It is worth noting that the configuration of the all-carbon quaternary center could be modulated by changing only the electron-withdrawing groups via a tandem reduction/cyclization reaction.

Catalytic Appel Reaction Accessing the Mesoporous Substructure of a Robust and Heterogeneous Polyphosphamide

AbstractPolyphosphamides are normally good flame retardants. Herein a mesoporous polyphosphamide (p‐PPA) with an accessible average pore diameter of &lt;10 nm and a surface area of 1.773 m2/g has been synthesized via condensation of 1,3‐diamino benzene (DAB) and phenyl phosphinic dichloride (PPDC). 31P, 13C CP‐MAS solid‐state NMR, Raman, and X‐ray photoelectron spectroscopic (XPS) characterizations confirm the presence of ‐{PV(O)‐NH}‐ in the repeating unit of the p‐PPA that is further used as a catalytic mediator to perform the Appel reaction i. e., conversion of alcohols to halides with a broad substrate scope and high TON (561). The heterogeneity of p‐PPA allows easy recovery of organic halides and recycling of the catalyst many times. Mesoporous p‐PPA has further given a scope to perform shape‐selective conversion of primary alcohols with linear alkyl chain (1‐dodecanol) while a low conversion for the bulky secondary (cyclo‐hexanol) and tertiary alcohol (tert‐butanol) is observed. Perhaps, the phosphamide units present inside the porous channel are non‐preferable sites for bulkier alcohols, as evident from the competitive experiments. A comparatively less catalytic conversion obtained with an analogous non‐porous n‐PPA, made of tris(2‐aminoethyl)amine (TREN) linker, highlights the role of porosity in p‐PPA to enhance the accessibility of numerous ‐{PV(O)‐NH}‐ reactive units to increase the TON.

Magnetic Ru nanocatalysts for green solvent-free oxidation reactions of aromatic alcohols

A kind of magnetic hybrid organic-inorganic nanoparticles containing Ru metal (Fe3O4@SiO2-FPBA-Ru) was prepared. It was spherical with the characteristic lattice fringe of ruthenium atom. The size was in the range of 5–15 nm and it contained 0.30 mmol/g Ru. Its saturation magnetization value was 15.95 emu/g, which could be easily and efficiently recovered from solution through an external magnet. It was also stable below 240°C and hot filtration experiment proved Ru wasn't leaked from Fe3O4@SiO2-FPBA-Ru in 70°C oxidation reaction. It could be recovered and reused at least 7 cycles. The low amount of Fe3O4@SiO2-FPBA-Ru (75 mmol%) could convert the 99 % of 1-phenylethanol to acetophenone under solvent-free system, which verified its green and environment-friendly properties. The yield was exceed that of homogeneous (RuCl3, 85 %). Beside this, the TON (5181), TOF (7430 h−1) in oxidation of 1-phenylethanol and high conversion yields for a series of oxidation reactions of aromatic secondary alcohols proved the high catalytic ability of Fe3O4@SiO2-FPBA-Ru. These laid a foundation for its industrial applications.

Friedel–crafts alkylations of indoles, furans, and thiophenes with arylmethyl acetates promoted by trimethylsilyl trifluoromethanesulfonate

Various indoles undergo Friedel–Crafts alkylation at the 3-position when treated with secondary arylmethyl acetates in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine. Tertiary benzylic alcohols are also effective alkylating agents, undergoing TMSOTf-promoted activation to yield alkylated indoles that feature quaternary centers. A related study shows that benzofuran reacts under similar conditions to yield 2-alkylated benzofurans when treated with similar alkylating agents, and the reaction has been extended to include other representative heteroarenes. Yields for these Friedel–Crafts alkylation products range from 43%–99% over a wide range of substrate combinations.

Catalyst-Free Dearomative Allylboration of Ketones with Benzo[b]thiophenylmethyl Boronic Acids.

A novel approach to the dearomative allylboration of ketones with benzo[b]thiophenylmethyl boronic acids has been developed. By leveraging the inherent reactivity of the boronic acid unit, this process occurs under mild reaction conditions without the need for a catalyst, leading to the efficient formation of homoallylic tertiary alcohols accompanied by the construction of three-dimensional sulfur-containing alicyclic scaffolds in high yields with excellent stereoselectivities.

Catalytic Generation of Benzyl Anions from Aryl Ketones Utilizing [1,2]-Phospha-Brook Rearrangement and Their Application to Synthesis of Tertiary Benzylic Alcohols.

A synthetic method of tertiary alcohols was developed based on the formal umpolung addition of aryl ketones with electrophiles utilizing the [1,2]-phospha-Brook rearrangement under Brønsted base catalysis. The addition reaction of α-hydroxyphosphonates, derived from alkyl aryl- and diaryl ketones, with electrophiles such as phenyl vinyl sulfone, afforded phosphates having a tertiary alkyl group, which were readily convertible to the corresponding tertiary benzylic alcohols. This operationally simple protocol provides efficient complementary access to tertiary alcohols that are difficult to synthesize by conventional methods.

Solvent-free oxidation of alcohols by a heterogeneous Fe3O4@SiO2-DTPA-Ru nanocatalyst

A novel magnetic heterogeneous ruthenium catalyst (Fe3O4@SiO2-DTPA-Ru) was prepared by using magnetic silicon spheres as support, ethylenediaminepentaacetic acid (DTPA) as functional ligands, ruthenium chloride as catalyst precursor. The results obtained after a series of characterizations showed that the catalyst Fe3O4@SiO2-DTPA-Ru was 5–15 nm in size with a 0.205 nm lattice and contained 0.31 mmol Ru/g catalyst. It also had a good thermal stability under 232°C which was verified by thermal filtration method. Besides, the saturation magnetic intensity was as high as 20.54 emu/g. The catalyst Fe3O4@SiO2-DTPA-Ru was applied for the first time into thirteen oxidation reactions of aromatic alcohols and showed good catalytic activity even the yields of eleven aromatic alcohols were all over 90%. In catalyzing 1-phenylethanol to acetophenone, its TOF and TON were 9677 h−1 and 6991, respectively. The Fe3O4@SiO2-DTPA-Ru catalyst could still maintain good reusability and catalytic performance after 15 cycles of 1-phenylethanol oxidation, which was superior to many reported catalysts and had great potential in future industrial production.