P-quinone Methide Research Articles

Catalyst-Enabled Chemodivergent Construction of Alkynyl- and Vinyl-Substituted Diarylmethanes from p-Quinone Methides and Alkynes.

Here, a catalyst-controlled chemodivergent 1,6-addition of p-quinone methides with alkynes was developed, affording diverse alkynyl- and vinyl-substituted diarymethanes. In this transformation, copper catalyzed the direct 1,6-addition of p-QMs with alkynes, while iron promoted the three components reaction of p-QMs, alkynes, and halogens from iron salts or added HX acid. The salient features of this transformation include completely controllable chemoselectivity, mild conditions, inexpensive catalysts, and good substrates scopes.

CuH-Catalyzed Asymmetric 1,6-Conjugate Reduction of p-Quinone Methides: Enantioselective Synthesis of Triarylmethanes and 1,1,2-Triarylethanes.

The first copper hydride (CuH)-catalyzed asymmetric 1,6-conjugate reduction of p-quinone methides is reported. This protocol provides a new method to access a variety of triarylmethanes and 1,1,2-triarylethanes in good yields with excellent enantioselectivities and broad functional group tolerance.

Diastereo- and Enantioselective 1,6-Conjugate Addition of 2-Azaarylacetamides to para-Quinone Methides.

A chiral Mg(II)/N,N'-dioxide complex was found to be highly effective in promoting the diastereo- and enantioselective 1,6-conjugate addition of various azaarylacetamides to p-quinone methides under mild reaction conditions. Various chiral azaarene derivatives containing gem(1,1)-diaryl skeletons were obtained in good yields, dr, and excellent ee values. Meanwhile, on the basis of insight gained from the control experiments as well as the single-crystal structure of the Mg(II)/N,N'-dioxide complex and product, a possible transition state was proposed to explain the origin of coordination and stereoinduction.

Visible-light mediated trifluoromethylation of p-quinone methides by 1,6-conjugate addition using pyrylium salt as organic photocatalyst

A transition metal free visible light mediated organo photoredox catalyzed trifluoromethylation of p-quinone methides (p-QMs) to construct fluoro-analogs of dichlorodiphenyltrichloroethane (DDT) is reported using a bench stable, inexpensive Langlois reagent as a trifluoromethyl radical source. This protocol could generate a benzylic C(sp3)-CF3 bond with excellent yield under mild reaction conditions using 1,6-conjugate addition/aromatization of trifluoromethyl radical in the absence of any external additives. Further, we demonstrate di-trifluoromethylation and gram scale synthesis of this reaction.

Stereoselective Formation of β-O-4 Structures Mimicking Softwood Lignin Biosynthesis: Effects of Solvent and the Structures of Quinone Methide Lignin Models.

p-Quinone methide (QM) is formed as an intermediate during lignin biosynthesis. The aromatization of the QM by the attack of a nucleophile at the α-position of its side chain generates a phenolic hydroxy group in a growing polymer and creates stereoisomeric forms in the side chain. A series of β-O-4-aryl ether QMs was reacted with water at 25 °C to replicate the formation of p-hydroxyphenyl (H) and guaiacyl (G) β-O-4 structures in plant cell walls. Water addition occurred in 3-methoxy-substituted QMs (G-type QMs) with half-lives ( t1/2) between 13 and 15 min, at pH 7, in 50% water solution (dioxane-water, 1:1). The rate increased as the water concentration increased to 99% ( t1/2, 1.2-1.4 min). Similar solvent effects were observed for more reactive nonsubstituted QMs (H-type QMs with t1/2 of <1 min). Consequently, t1/2 of the H-type QMs was shorter than that of the G-type QMs under every solvent condition. Upon increasing the water concentration, the variation in the erythro/ threo ratios of the four dimeric β-O-4 products increased. Interestingly, the effect of pH on the stereopreference, which was observed in 50% water solution, was small and became imperceptible as the water concentration increased to 99%, suggesting that the effect of the solvent, as well as the effect of the pH, plays an important role in understanding the reaction conditions in cell walls during lignin biosynthesis. The threo isomer was preferentially formed in the four dimeric β-O-4 structures, which is inconsistent with the structural features of compression wood lignin rich in H-units. However, the erythro-selective formation was attained in an H-type QM at every pH studied (pH 3.5-7) by introducing a biphenyl structure into the β-etherified ring moiety.

Catalytic Asymmetric Conjugate Addition of Indoles to para-Quinone Methide Derivatives.

A catalytic asymmetric conjugate addition of indoles to o-hydroxyphenyl substituted p-quinone methides has been established in the presence of chiral phosphoric acid, which afforded chiral indole-containing triarylmethanes in generally high yields (54-98%) and good enantioselectivities (90:10-96:4 enantiomeric ratio). The control experiments indicated that o-hydroxyphenyl substituted p-quinone methides had a high possibility to transform into o-quinone methides in the presence of chiral phosphoric acid, and the formation of o-quinone methides might be a necessity for the reaction. This reaction will not only contribute to the research field of catalytic asymmetric transformations of p-quinone methides and o-quinone methides but also provide a useful method for the construction of enantioenriched triarylmethane frameworks.

A Case of Serendipity: Synthesis, Characterization, and Unique Chemistry of a Stable, Ring-Unsubstituted Aliphatic p-Quinone Methide.

We report the serendipitous synthesis of an indefinitely solution-stable ring-unsubstituted aliphatic p-quinone methide (p-QM) and detail its remarkable reaction chemistry through three archetypical chemical transformations: hydrogenation, hydride reduction, and nucleophilic addition. For example, the p-QM hydrogenates in a counterintuitive way; it resists all attempts at aromatization by catalytic reduction. Paradoxically, it does undergo aromatization/rearrangement upon reduction with LiAlH4. Nucleophilic addition of thiol results in an unanticipated rearrangement instead of the expected 1,6-conjugate addition. We hope that this highly stable p-QM and its unique reactivity provide some new insights into the chemistry of this important class of organic molecules.

Deacylative 1,6-addition of Bestmann-Ohira reagent to p-quinone methides for the synthesis of α-diazo-β-diarylphosphonates and cis-stilbenyl phosphonates

The role of Bestmann-Ohira Reagent (BOR) as a conjugate addition partner is reported for the first time. Deacylation of BOR in the presence of ethanolic KOH and 1,6-addition of the resulting diazophosphonate anion to p-quinone methides (PQMs) provides β-disubstituted α-diazophosphonates in good to excellent yields in most cases. Such 1,6-adducts further undergo Rh-catalyzed elimination of the diazo group and 1,2-migration of the phenolic group to afford cis-stilbenylphosphonates with high E-selectivity. The migration of the phenolic group presumably takes place via a spirocyclopropane intermediate derived from the Rh-carbenoid.

Identification of Boronic Acid Derivatives as an Active Form of N-Alkylaminoferrocene-Based Anticancer Prodrugs and Their Radiolabeling with 18F.

N-Alkylaminoferrocene (NAAF)-based prodrugs are activated in the presence of elevated amounts of reactive oxygen species (ROS), which corresponds to cancer specific conditions, with formation of NAAF and p-quinone methide. Both products act synergistically by increasing oxidative stress in cancer cells that causes their death. Though it has already been demonstrated that the best prodrugs of this type retain their antitumor activity in vivo, the effects were found to be substantially weaker than those observed in cell cultures. Moreover, the mechanistic studies of these compounds in vivo are missing. For clarification of these important questions, labeling of the prodrugs with radioactive moieties would be necessary. In this paper, we first observed that the representative NAAF-based prodrugs are hydrolyzed in dilute aqueous solutions to the corresponding arylboronic acids. We confirmed that these products are responsible for ROS amplification and anticancer properties of the parent prodrugs. Next, we developed the efficient synthetic protocol for radiolabeling the hydrolyzed NAAF-based prodrugs by [18F]fluoroglucosylation under the conditions of the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition and used this protocol to prepare one representative hydrolyzed NAAF-based prodrug radiolabeled with 18F. Finally, we studied the stability of the 18F-labeled compound in human serum in vitro and in rat blood in vivo and obtained preliminary data on its biodistribution in vivo in mice carrying pancreatic (AR42J) and prostate (PC3) tumors by applying PET imaging studies. The compound described in this paper will help to understand in vivo effects (e.g., pharmacokinetics, accumulation in organs, the nature of side effects) of these prodrugs that will strongly contribute to their advancement to clinical trials.

Phosphine Sequentially Catalyzed Domino 1,6-Addition/Annulation: Access to Functionalized Chromans and Tetrahydroquinolines with an Ethynyl-Substituted All-Carbon Quaternary Center.

A novel phosphine sequentially catalyzed domino 1, 6-addition/annulation process has been developed using p-quinone methides ( p-QMs) and α-substituted allenoates which generates a series of chroman and tetrahydroquinoline derivatives containing an ethynyl-substituted all-carbon quaternary center with up to 97% yield and 20:1 dr. value. In this reaction, allenoates act as C2 synthons.

Lignin-Biosynthetic Study: Reactivity of Quinone Methides in the Diastereopreferential Formation of p-Hydroxyphenyl- and Guaiacyl-Type β- O-4 Structures.

p-Quinone methides are involved in lignin biosynthesis as transient intermediates, and the aromatization step has a great impact on the chemical structure of the resulting lignin. A series of quinone methides (QMs) were synthesized and allowed to react with water in pH 3-7 buffers at 25 °C to mimic the formation of p-hydroxyphenyl- and guaiacyl-type (H- and G-type, respectively) β- O-4 structures in gymnosperm-plant cell walls. Water addition occurred in 3-methoxy-substituted QMs (G-type QMs) with half-lives of 1.4-15 min. In contrast, nonsubstituted QMs (H-type QMs) were very labile; they were aromatized to β- O-4 products with half-lives of only 10-40 s. The rapid aromatization in H-type QMs may provide an advantage over G-type species for efficiently driving the lignin-polymerization cycle, which possibly contributes to the development of highly lignified compression wood. In the water-addition reaction, the threo isomers of the β- O-4 products were stereopreferentially formed more than the erythro isomers from both G- and H-type QMs ( erythro/ threo ratios of 24:76 and 50:50, respectively). The proportion of erythro isomers was higher at lower-pH conditions. This pH-dependent trend agrees with findings from a previous study on 3,5-dimethoxy-substituted (syringyl-type, S-type) QMs; thus, this pH-dependent trend is common in H-, G-, and S-type lignin-related QMs. Higher threo-selectivity was obtained by changing the β-etherified aromatic rings from G- to H-type. A similar but weaker effect was also observed by changing the QM moiety from G- to H-type.

Metal Enolates – Enamines – Enol Ethers: How Do Enolate Equivalents Differ in Nucleophilic Reactivity?

The kinetics of the reactions of trimethylsilyl enol ethers and enamines (derived from deoxybenzoin, indane-1-one, and α-tetralone) with reference electrophiles (p-quinone methides, benzhydrylium and indolylbenzylium ions) were measured by conventional and stopped-flow photometry in acetonitrile at 20 °C. The resulting second-order rate constants were subjected to a least-squares minimization based on the correlation equation lg k = s N(N + E) for determining the reactivity descriptors N and s N of the silyl enol ethers and enamines. The relative reactivities of structurally analogous silyl enol ethers, enamines, and enolate anions towards carbon-centered electrophiles are determined as 1, 107, and 1014, respectively. A survey of synthetic applications of enolate ions and their synthetic equivalents shows that their behavior can be properly described by their nucleophilicity parameters, which therefore can be used for designing novel synthetic transformations.

Metal-free, radical 1,6-conjugated addition of cyclic ethers with para-quinone methides (p-QMs).

An efficient method for metal-free C-C bond formation between p-quinone methides (p-QMs) and cyclic ethers via a radical pathway to afford substituted diarylmethanes and triarylmethanes or to effect the α-alkylation of the cyclic ethers has been developed. Also, the synthesis of 3,3'-disubstituted oxindoles with stereogenic quaternary carbon centers was successfully achieved under mild reaction conditions.

Diastereoselective construction of 3-aryl-substituted indolines via annulation of in situ generated p-quinone methides.

A highly diastereoselective [4 + 1] annulation reaction of in situ generated p-quinone methides for the synthesis of 3-aryl-substituted indolines has been developed. Employing commercial manganese dioxide as the oxidant, a series of ortho-tosylaminophenyl-substituted p-QMs could be generated in situ. This new protocol is based on an unprecedented 1,6-conjugate addition/annulation cascade reaction, without the need for pre-synthesized p-QMs, and enables the easy preparation of a variety of 3-aryl-2,3-dihydroindoles in good to excellent yields.

Catalyst- and reagent-free 1,6-hydrophosphonylation of p-quinone methides: a practical approach for the synthesis of diarylmethyl phosphine oxides.

We developed a catalyst-, reagent-, and additive-free protocol with 100% atom economy for the synthesis of diarylmethyl phosphine oxides via 1,6-hydrophosphonylation of p-quinone methides using water as a green solvent. The reaction showed broad scope with excellent functional group tolerance. The practicability of this method was demonstrated by carrying out the reaction on the gram scale whereby product was obtained in high yield by the filtration technique avoiding chromatographic purification.

Organocatalytic [4 + 2] cyclizations of para-quinone methide derivatives with isocyanates.

The first [4 + 2] cyclizations of para-quinone methide derivatives with isocyanates have been established under the catalysis of Brønsted acids or Brønsted bases, which efficiently constructed benzoxazin-2-one frameworks in generally high yields (up to 95%). This reaction will not only enrich the research contents of para-quinone methide-involved cyclization reactions but also provide a useful method for constructing biologically important benzoxazin-2-one frameworks.

1,6-Conjugate addition of C-nucleophiles to p-quinone methide surrogate: Synthesis of diarylpropanes

1,6-Conjugate addition of various carbon nucleophiles to p-quinone methide surrogate is reported. The active methylene containing C-nucleophiles such as 1,3-diketones, diesters and ketoesters underwent two consecutive additions leading to bis-addition products, diarylpropanes. Whereas, nitroalkanes proceeded to contribute mono-addition products. Surprisingly, bromo analogue of p-quinone methide surrogate underwent halophilic dimerization reaction with excellent yield. The reported strategy provides an efficient synthesis of 1,3-diarylpropane derivatives bearing pharmacophoric ortho-methoxy phenol moiety under mild reaction conditions.

Asymmetric Synthesis of Griffipavixanthone Employing a Chiral Phosphoric Acid-Catalyzed Cycloaddition.

Asymmetric synthesis of the biologically active xanthone dimer griffipavixanthone is reported along with its absolute stereochemistry determination. Synthesis of the natural product is accomplished via dimerization of a p-quinone methide using a chiral phosphoric acid catalyst to afford a protected precursor in excellent diastereo- and enantioselectivity. Mechanistic studies, including an unbiased computational investigation of chiral ion-pairs using parallel tempering, were performed in order to probe the mode of asymmetric induction.

Base-Catalyzed 1,6-Conjugate Addition of Nitroalkanes to p-Quinone Methides under Continuous Flow.

A mild base-catalyzed protocol for the synthesis of substituted nitroalkane derivatives has been developed under continuous flow using a microreaction technique. This transformation basically involves the 1,6-conjugate addition of nitroalkanes to p-quinone methides, leading to the substituted nitroalkanes in good to excellent yields.

Diastereoselective Synthesis of Tetrahydroquinolines via [4 + 2] Annulation between in Situ Generated p-Quinone Methides and Nitroalkenes.

A formal [4 + 2] annulation reaction between in situ generated p-quinone methides and nitroalkenes via an aza-Michael/1,6-conjugate addition reaction sequence has been developed in which manganese dioxide is used as the oxidant to promote in situ formation of o-tosylaminophenyl-substituted p-QMs. Under mild conditions, this unprecedented cascade reaction readily occurs in good yield, providing straightforward access to a series of 4-aryl-substituted tetrahydroquinolines.