Palladium‐Catalyzed Hydrolytic Cleavage of Aromatic C−O Bonds

Metallic palladium surfaces are highly selective in promoting the reductive hydrolysis of aromatic ethers in aqueous phase at relatively mild temperatures and pressures of H₂. At quantitative conversions, the selectivity to hydrolysis products of PhOR ethers was observed to range from 50 % (R=Ph) to greater than 90 % (R=n ‐C₄H₉, cyclohexyl, and PhCH₂CH₂). By analysis of the evolution of products with and without incorporation of H₂¹⁸O, the pathway was concluded to be initiated by palladium metal catalyzed partial hydrogenation of the phenyl group to an enol ether. Water then rapidly adds to the enol ether to form a hemiacetal, which then undergoes elimination to cyclohexanone and phenol/alkanol products. A remarkable feature of the reaction is that the stronger Ph−O bond is cleaved rather than the weaker aliphatic O−R bond.     

Photocatalytic Dehydrogenative Cross‐Coupling of Alkenes with Alcohols or Azoles without External Oxidant

Direct cross‐coupling between alkenes/R‐H or alkenes/RXH is a dream reaction, especially without external oxidants. Inputting energy by photocatalysis and employing a cobalt catalyst as a two‐electron acceptor, a direct C−H/X−H cross‐coupling with H₂ evolution has been achieved for C−O and C−N bond formation. A new radical alkenylation using alkene as the redox compound is presented. A wide range of aliphatic alcohols—even long chain alcohols—are tolerated well in this system, providing a new route to multi‐substituted enol ether derivatives using simple alkenes. Additionally, this protocol can also be used for N ‐vinylazole synthesis. Mechanistic insights reveal that the cobalt catalyst oxidizes the photocatalyst to revive the photocatalytic cycle.     

(E)‐6‐Methoxy‐3‐(α‐methoxybenzyl­idene)benzo[b]furan‐2(3H)‐one at 173 K

The title compound, C₁₇H₁₄O₄, is an unprecedented new synthetic isoaurone‐type enol ether that has the E configuration. The planar furanone ring is fused to a methoxy­benzene ring system, with an interplanar angle of 175.7 (1)°. Due to this ring fusion, the six‐membered ring has a significant amount of ring strain, as shown by the internal ring angle range of 115.8 (1)–124.7 (1)°, whereas the vinylic phenyl ring has internal angles between 119.7 (1) and 120.2 (1)°. The mol­ecules form infinite hydrogen‐bonding layers along the b direction of the form C—H?O, where the keto O atom acts as a bifurcated acceptor. These layers are connected along the c direction by another hydrogen bond with a methoxy H atom as donor. In addition to this connection, the layers are stacked via centres of symmetry by a pair of symmetry‐related benzo­furan­one ring systems.     

Oxidation and β‐Alkylation of Alcohols Catalysed by Iridium(I) Complexes with Functionalised N‐Heterocyclic Carbene Ligands

The borrowing hydrogen methodology allows for the use of alcohols as alkylating agents for C?C bond forming processes offering significant environmental benefits over traditional approaches. Iridium(I)‐cyclooctadiene complexes having a NHC ligand with a O‐ or N‐functionalised wingtip efficiently catalysed the oxidation and β‐alkylation of secondary alcohols with primary alcohols in the presence of a base. The cationic complex [Ir(NCCH₃)(cod)(MeIm(2‐ methoxybenzyl))][BF₄] (cod=1,5‐cyclooctadiene, MeIm=1‐methylimidazolyl) having a rigid O‐functionalised wingtip, shows the best catalyst performance in the dehydrogenation of benzyl alcohol in acetone, with an initial turnover frequency (TOF₀) of 1283 h^?1, and also in the β‐alkylation of 2‐propanol with butan‐1‐ol, which gives a conversion of 94 % in 10 h with a selectivity of 99 % for heptan‐2‐ol. We have investigated the full reaction mechanism including the dehydrogenation, the cross‐aldol condensation and the hydrogenation step by DFT calculations. Interestingly, these studies revealed the participation of the iridium catalyst in the key step leading to the formation of the new C?C bond that involves the reaction of an O‐bound enolate generated in the basic medium with the electrophilic aldehyde.     

(1‐Pyridinio)perfluorophenacylide: a new stable pyridinium ylide in the enol form

The title compound, C₁₃H₆F₅NO, exists in the enol form and adopts the E configuration about the enol double bond. It is the first example of an enol‐type pyridinium ylide. The enol structure was unambiguously determined on the basis of the significantly longer C—O bond and shorter C—C bond. Intramolecular C—H...O and C—H...F hydrogen bonds are responsible for promotion of the enol form and for the stability of this compound.     

Chemo‐ and Regioselective Hydrogenolysis of Diaryl Ether C−O Bonds by a Robust Heterogeneous Ni/C Catalyst: Applications to the Cleavage of Complex Lignin‐Related Fragments

We report the chemo‐ and regioselective hydrogenolysis of the C?O bonds in di‐ortho‐substituted diaryl ethers under the catalysis of a supported nickel catalyst. The catalyst comprises heterogeneous nickel particles supported on activated carbon and furnishes arenes and phenols in high yields without hydrogenation. The high thermal stability of the embedded metal particles allows C?O bond cleavage to occur in highly substituted diaryl ether units akin to those in lignin. Preliminary mechanistic experiments show that this catalyst undergoes sintering less readily than previously reported catalyst particles that form from a solution of [Ni(cod)₂].     

Tandem Insertion–[1,3]‐Rearrangement: Highly Enantioselective Construction of α‐Aminoketones

An enantioselective synthesis of α‐aminoketone derivatives were readily available through a tandem insertion–[1,3] O‐to‐C rearrangement reaction. The rhodium salt and chiral N,N′‐dioxide‐indium(III) complex make up relay catalysis, which enables the O?H insertion of benzylic alcohols to N‐sulfonyl‐1,2,3‐triazoles, and asymmetric [1,3]‐rearrangement of amino enol ether intermediates, subsequently. Preliminary mechanistic studies suggested that the [1,3] O‐to‐C rearrangement step proceeded through an ion pair pathway.     

1,4‐Addition of Bis(iodozincio)methane to α,β‐Unsaturated Ketones: Chemical and Theoretical/Computational Studies

1,4‐Addition of bis(iodozincio)methane to simple α,β‐unsaturated ketones does not proceed well; the reaction is slightly endothermic according to DFT calculations. In the presence of chlorotrimethylsilane, the reaction proceeded efficiently to afford a silyl enol ether of β‐zinciomethyl ketone. The C? Zn bond of the silyl enol ether could be used in a cross‐coupling reaction to form another C? C bond in a one‐pot reaction. In contrast, 1,4‐addition of the dizinc reagent to enones carrying an acyloxy group proceeded very efficiently without any additive. In this case, the product was a 1,3‐diketone, which was generated in a novel tandem reaction. A theoretical/computational study indicates that the whole reaction pathway is exothermic, and that two zinc atoms of bis(iodozincio)methane accelerate each step cooperatively as effective Lewis acids.     

Total Synthesis of 11‐Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage‐Gated Sodium Channels

11‐Saxitoxinethanoic acid (SEA) is a member of the saxitoxin (STX) family of paralytic shellfish poisons, and contains an unusual C?C bond at the C11 position. Reported herein is a total synthesis of SEA. The key to our synthesis lies in a Mukaiyama aldol condensation reaction of silyl enol ether with glyoxylate in the presence of an anhydrous fluoride reagent, [Bu₄N][Ph₃SnF₂], which directly constructs the crucial C?C bond at the C11 position in SEA. The Na_VCh‐inhibitory activities of SEA and its derivatives were evaluated by means of cell‐based assay. SEA showed an IC₅₀ value of (47±12) nm , which is approximately twice as potent as decarbamoyl‐STX (dcSTX).     

The Ireland-Claisen rearrangement as a probe for the diastereoselectivity of nucleophilic attack on a double bond adjacent to a stereogenic centre carrying a silyl group

The E- and Z-silyl enol ethers 4 derived from allyl 3-R-3-dimethyl(phenyl)silylpropanoate (R = Me, Pr(i) and Ph) and the Z-silyl enol ethers 7 derived from 4-R-4-dimethyl(phenyl)silylbut-2-enyl acetate (R = Me and Pr(i)) undergo Ireland-Claisen rearrangements largely in the same stereochemical sense, with C-C bond formation taking place anti to the silyl group in the conformations 22, 23 and 24 in which the hydrogen atom on the stereogenic centre is inside, more or less eclipsing the double bond. The E-silyl enol ether E-7a derived from 4-methyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the alternative sense, probably because C-C bond formation takes place anti to the silyl group in the conformation 26 with the methyl group inside, but the silyl enol ether E-7b derived from 4-isopropyl-4-dimethyl(phenyl)silylbut-2-enyl acetate shows low diastereoselectivity in the normal sense. The E- and Z-silyl enol ethers 33 derived from cis-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate and the E-silyl enol ether 39 derived from trans-crotyl 3-phenyl-3-dimethyl(phenyl)silylpropanoate undergo Ireland-Claisen rearrangements largely in the same stereochemical sense as their allyl counterparts, but with moderately high levels of diastereocontrol in setting up the third stereogenic centre following from chair-like transition structures.     

Comparison of the crystal structures of the potent anticancer and anti‐angiogenic agent regorafenib and its monohydrate

Regorafenib {systematic name: 4‐[4‐({[4‐chloro‐3‐(trifluoromethy)phenyl]carbamoyl}amino)‐3‐fluorophenoxy]‐1‐methylpyridine‐2‐carboxamide}, C₂₁H₁₅ClF₄N₄O₃, is a potent anticancer and anti‐angiogenic agent that possesses various activities on the VEGFR, PDGFR, raf and/or flt‐3 kinase signaling molecules. The compound has been crystallized as polymorphic form I and as the monohydrate, C₂₁H₁₅ClF₄N₄O₃·H₂O. The regorafenib molecule consists of biarylurea and pyridine‐2‐carboxamide units linked by an ether group. A comparison of both forms shows that they differ in the relative orientation of the biarylurea and pyridine‐2‐carboxamide units, due to different rotations around the ether group, as measured by the C—O—C bond angles [119.5 (3)° in regorafenib and 116.10 (15)° in the monohydrate]. Meanwhile, the conformational differences are reflected in different hydrogen‐bond networks. Polymorphic form I contains two intermolecular N—H…O hydrogen bonds, which link the regorafenib molecules into an infinite molecular chain along the b axis. In the monohydrate, the presence of the solvent water molecule results in more abundant hydrogen bonds. The water molecules act as donors and acceptors, forming N—H…O and O—H…O hydrogen‐bond interactions. Thus, R₄²(28) ring motifs are formed, which are fused to form continuous spiral ring motifs along the a axis. The (trifluoromethyl)phenyl rings protrude on the outside of these motifs and interdigitate with those of adjacent ring motifs, thereby forming columns populated by halogen atoms.     

Methyl 3‐(4‐methoxyphenyl)prop‐2‐enoate

The title mol­ecule, C₁₁H₁₂O₃, is almost planar, with an average deviation of the C and O atoms from the least‐squares plane of 0.146 (4) Å. The geometry about the C=C bond is trans. The phenyl ring and –COOCH₃ group are twisted with respect to the double bond by 9.3 (3) and 5.6 (5)°, respectively. The endocyclic angle at the junction of the propenoate group and the phenyl ring is decreased from 120° by 2.6 (2)°, whereas two neighbouring angles around the ring are increased by 2.3 (2) and 0.9 (2)°. This is probably associated with the charge‐transfer interaction of the phenyl ring and –COOCH₃ group through the C=C double bond. The mol­ecules are joined together through C—H?O hydrogen bonds between the methoxy and ester groups to form characteristic zigzag chains extended along the c axis.     

Activation of CH Bonds through Oxidant‐Free Photoredox Catalysis: Cross‐Coupling Hydrogen‐Evolution Transformation of Isochromans and β‐Keto Esters

The direct and controlled activation of a C(sp³)?H bond adjacent to an O atom is of particular synthetic value for the conventional derivatization of ethers or alcohols. In general, stoichiometric amounts of an oxidant are required to remove an electron and a hydrogen atom of the ether for subsequent transformations. Herein, we demonstrate that the activation of a C?H bond next to an O atom could be achieved under oxidant‐free conditions through photoredox‐neutral catalysis. By using a commercial dyad photosensitizer (Acr⁺‐Mes ClO₄^?, 9‐mesityl‐10‐methylacridinium perchlorate) and an easily available cobaloxime complex (Co(dmgBF₂)₂?2 MeCN, dmg=dimethylglyoxime), the nucleophilic addition of β‐keto esters to oxonium species, which is rarely observed in photocatalysis, leads to the corresponding coupling products and H₂ in moderate to good yields under visible‐light irradiation. Mechanistic studies suggest that both isochroman and the cobaloxime complex quench the electron‐transfer state of this dyad photosensitizer and that benzylic C?H bond cleavage is probably the rate‐determining step of this cross‐coupling hydrogen‐evolution transformation.     

Direct Synthesis of Benzofuro[2,3‐b]pyrroles through a Radical Addition/[3,3]‐Sigmatropic Rearrangement/Cyclization/Lactamization Cascade

A straightforward synthetic method for the construction of benzofuro[2,3‐b]pyrrol‐2‐ones by a novel domino reaction through a radical addition/[3,3]‐sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O‐phenyl‐conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C?C bonds, a C?O bond, and a C?N bond in a single operation, leading to pyrrolidine‐fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3‐b]pyrrol‐2‐one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.     

5‐Amino‐4‐(4‐diethyl­amino­phenyl)‐2‐(4‐hydroxy­phenyl)‐7‐(pyrrolidin‐1‐yl)‐1,6‐naphthyridine‐8‐carbo­nitrile

In the title compound, C₂₉H₃₀N₆O, the naphthyridine moiety is planar with a dihedral angle between the fused rings of 1.9 (1)°. The phenol ring is nearly coplanar, while the diethyl­amino­phenyl substituent is orthogonal to the central naphthyridine ring and the pyrrolidine ring makes an angle of 11.2 (1)° with it. The O atom of the hydroxy substituent is coplanar with the phenyl ring to which it is attached. The molecular structure is stabilized by a C—H?N‐type intramolecular hydrogen bond and the packing is stabilized by intermolecular C—H?π, O—H?N and N—H?O hydrogen bonds.     

The Mechanism of NO Bond Cleavage in Rhodium‐Catalyzed CH Bond Functionalization of Quinoline N‐oxides with Alkynes: A Computational Study

Metal‐catalyzed C?H activation not only offers important strategies to construct new bonds, it also allows the merge of important research areas. When quinoline N‐oxide is used as an arene source in C?H activation studies, the N?O bond can act as a directing group as well as an O‐atom donor. The newly reported density functional theory method, M11L, has been used to elucidate the mechanistic details of the coupling between quinoline N?O bond and alkynes, which results in C?H activation and O‐atom transfer. The computational results indicated that the most favorable pathway involves an electrophilic deprotonation, an insertion of an acetylene group into a Rh?C bond, a reductive elimination to form an oxazinoquinolinium‐coordinated Rh^I intermediate, an oxidative addition to break the N?O bond, and a protonation reaction to regenerate the active catalyst. The regioselectivity of the reaction has also been studied by using prop‐1‐yn‐1‐ylbenzene as a model unsymmetrical substrate. Theoretical calculations suggested that 1‐phenyl‐2‐quinolinylpropanone would be the major product because of better conjugation between the phenyl group and enolate moiety in the corresponding transition state of the regioselectivity‐determining step. These calculated data are consistent with the experimental observations.     

The Critical Role of Reductive Steps in the Nickel‐Catalyzed Hydrogenolysis and Hydrolysis of Aryl Ether C−O Bonds

The hydrogenolysis of the aromatic C?O bond in aryl ethers catalyzed by Ni was studied in decalin and water. Observations of a significant kinetic isotope effect (k_H/k_D=5.7) for the reactions of diphenyl ether under H₂ and D₂ atmosphere and a positive dependence of the rate on H₂ chemical potential in decalin indicate that addition of H to the aromatic ring is involved in the rate‐limiting step. All kinetic evidence points to the fact that H addition occurs concerted with C?O bond scission. DFT calculations also suggest a route consistent with these observations involving hydrogen atom addition to the ipso position of the phenyl ring concerted with C?O scission. Hydrogenolysis initiated by H addition in water is more selective (ca. 75 %) than reactions in decalin (ca. 30 %).     

Palladium‐Catalyzed Formal Cross‐Coupling of Diaryl Ethers with Amines: Slicing the 4‐O‐5 Linkage in Lignin Models

Lignin is the second most abundant organic matter on Earth, and is an underutilized renewable source for valuable aromatic chemicals. For future sustainable production of aromatic compounds, it is highly desirable to convert lignin into value‐added platform chemicals instead of using fossil‐based resources. Lignins are aromatic polymers linked by three types of ether bonds (α‐O‐4, β‐O‐4, and 4‐O‐5 linkages) and other C?C bonds. Among the ether bonds, the bond dissociation energy of the 4‐O‐5 linkage is the highest and the most challenging to cleave. To date, 4‐O‐5 ether linkage model compounds have been cleaved to obtain phenol, cyclohexane, cyclohexanone, and cyclohexanol. The first example of direct formal cross‐coupling of diaryl ether 4‐O‐5 linkage models with amines is reported, in which dual C(Ar)?O bond cleavages form valuable nitrogen‐containing derivatives.     

Quenching of metal‐catalyzed living radical polymerization with silyl enol ethers

Various silyl enol ethers were employed as quenchers for the living radical polymerization of methyl methacrylate with the R Cl/RuCl₂(PPh₃)₃/Al(Oi–Pr)₃ initiating system. The most effective quencher was a silyl enol ether with an electron‐donating phenyl group conjugated with its double bond [CH₂C(OSiMe₃)(4‐MeOPh) ( 2a )] that afforded a halogen‐free polymer with a ketone terminal at a high end functionality [F̄_n ∼ 1]. Such silyl compounds reacted with the growing radical generated from the dormant chloride terminal and the ruthenium complex to give the ketone terminal via the release of the silyl group along with the chlorine that originated from the dormant terminal. In contrast, less conjugated silyl enol ethers such as CH₂C(OSiMe₃)Me were less effective in quenching the polymerization. The reactivity of the silyl compounds to the poly(methyl methacrylate) radical can be explained by the reactivity of their double bonds, namely, the monomer reactivity ratios of their model vinyl monomers without the silyloxyl groups. The lifetime of the living polymer terminal was also estimated by the quenching reaction mediated with 2a . © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4735–4748, 2000     

Single‐Crystal X‐ray Diffraction Structure of the Stable Enol Tautomer Polymorph of Barbituric Acid at 224 and 95 K

The thermodynamically stable enol crystal form of barbituric acid, previously prepared as powder by grinding or slurry methods, has been obtained as single crystals by slow cooling from methanol solution. The selection of the enol crystal was facilitated by a density‐gradient method. The structure at 224 and 95 K confirms the enol inferred on the basis of powder data. The enol has bond lengths that are consistent with the expected bond order and with DFT calculations that include treatment of hydrogen bonding. In isolation, the enol is higher in energy than the tri‐keto form by 50 kJ mol^?1 which must be more than compensated by enhanced hydrogen bonding. Both crystal forms have four normal H‐bonds; the enol has two additional H‐bonds with O–O distances of 2.49 Å. Conversion into the enol form occurs spontaneously in the solid state upon prolonged storage of the commercial tri‐keto material. Slurry conversion of tri‐one to enol in ethanol is reversed in direction in ethanol‐D₁.