Brønsted Acid Catalyzed,Conjugate Addition of β‐Dicarbonyls to In Situ Generated ortho‐Quinone Methides—Enantioselective Synthesis of 4‐Aryl‐4H‐Chromenes

We describe herein a catalytic, enantioselective process for the synthesis of 4H‐chromenes which are important structural elements of many natural products and biologically active compounds. A sequence comprising a conjugate addition of β‐diketones to in situ generated ortho‐quinone methides followed by a cyclodehydration reaction furnished 4‐aryl‐4H‐chromenes in generally excellent yields and high optical purity. A BINOL‐based chiral phosphoric acid was employed as a Brønsted acid catalyst which converted ortho‐hydroxy benzhydryl alcohols into hydrogen‐bonded ortho‐quinone methides and effected the carbon–carbon bond‐forming event with high enantioselectivity.     

Quinone‐Catalyzed Selective Oxidation of Organic Molecules

Quinones are common stoichiometric reagents in organic chemistry. Para‐quinones with high reduction potentials, such as DDQ and chloranil, are widely used and typically promote hydride abstraction. In recent years, many catalytic applications of these methods have been achieved by using transition metals, electrochemistry, or O₂ to regenerate the oxidized quinone in situ. Complementary studies have led to the development of a different class of quinones that resemble the ortho‐quinone cofactors in copper amine oxidases and mediate the efficient and selective aerobic and/or electrochemical dehydrogenation of amines. The latter reactions typically proceed by electrophilic transamination and/or addition‐elimination reaction mechanisms, rather than hydride abstraction pathways. The collective observations show that the quinone structure has a significant influence on the reaction mechanism and has important implications for the development of new quinone reagents and quinone‐catalyzed transformations.     

Regioselective α‐Addition of Deconjugated Butenolides: Enantioselective Synthesis of Dihydrocoumarins

The enantioselective α‐addition of deconjugated butenolides has rarely been exploited, in contrast to the well‐studied γ‐addition of deconjugated butenolides. In this study, an unprecedented asymmetric α‐addition/transesterification of deconjugated butenolides with ortho ‐quinone methides generated in situ afforded a series of functionalized 3,4‐dihydrocoumarins containing two contiguous stereogenic centers with excellent diastereo‐ and enantioselectivity. DFT calculations suggested that the rarely observed regioselectivity was due to the distortion energy that resulted from the interaction between the nucleophilic dienolate and the electrophilic ortho ‐quinone methide.     

N‐Heterocyclic‐Carbene‐Catalyzed Synthesis of 2‐Aryl Indoles

A convergent and efficient transition‐metal‐free catalytic synthesis of 2‐aryl‐indoles has been developed. The interception of a highly reactive and transient aza‐ortho‐quinone methide by an acyl anion equivalent generated through N‐hetereocyclic carbene catalysis is central to this successful strategy. High yields and a wide scope as well as the streamlined synthesis of a kinase inhibitor are reported.     

Catalytic Asymmetric Intramolecular [4+2] Cycloaddition of In Situ Generated ortho‐Quinone Methides

Herein, we describe the first catalytic asymmetric intramolecular [4+2] cycloaddition of in situ generated ortho‐quinone methides. In the presence of a confined chiral imidodiphosphoric acid catalyst, various salicylaldehydes react with dienyl alcohols to give transient ortho ‐quinone methide intermediates, which undergo an intramolecular [4+2] cycloaddition to provide highly functionalized furanochromanes and pyranochromanes in excellent diastereoselectivity and enantioselectivity.     

Catalytic Asymmetric (4+3) Cyclizations of In Situ Generated ortho‐Quinone Methides with 2‐Indolylmethanols

The first catalytic asymmetric (4+3) cyclization of in situ generated ortho‐quinone methides with 2‐indolylmethanols has been established, which constructed seven‐membered heterocycles in high yields (up to 95 %) and excellent enantioselectivity (up to 98 %). This approach not only represents the first catalytic asymmetric (4+3) cyclization of o‐hydroxybenzyl alcohols, but also enabled an unprecedented catalytic asymmetric (4+3) cyclization of 2‐indolylmethanols. In addition, a scarcely reported catalytic asymmetric (4+3) cyclization of para‐quinone methide derivatives was accomplished.     

Asymmetric Synthesis of Enantioenriched 2‐Aryl‐2,3‐Dihydrobenzofurans by a Lewis Acid Catalyzed Cyclopropanation/Intramolecular Rearrangement Sequence

A cyclopropanation/intramolecular rearrangement initiated by the Michael addition of in situ generated ortho‐quinone methides (o‐QMs) has been developed for the enantioselective synthesis of 2‐aryl‐2,3‐dihydrobenzofurans containing two consecutive stereogenic centers, including a quaternary carbon atom. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in excellent yields (up to 95 %) with excellent stereoselectivity (up to >99 ee, up to >20:1 d.r.).     

Kinetics and mechanism of the chain reaction between <Emphasis Type="Italic">N</Emphasis>-phenyl-1,4-benzoquinone monoimine and thiophenol

The kinetics of the reaction between N-phenyl-1,4-benzoquinone monoimine (quinone monoimine) and thiophenol is studied in chlorobenzene at 343 K. The reaction has the same mechanism proposed earlier for a similar reaction involving N,N'-diphenyl-1,4-benzoquinone diimine (quinone diimine). This mechanism has two paths: chain and nonchain. An important difference between the kinetics of the two reactions is the apparent reversible nature of the chain reaction in the quinone monoimine + thiophenol system. This nature reveals itself when the concentrations of thiophenol are comparable to or slightly higher than the concentrations of quinone imine. In light of this, kinetic research is conducted under conditions where the concentrations of thiophenol are significantly higher than those of quinone monoimine, allowing us to simplify the kinetic features and obtain interpretable data. The rate constants of the reaction’s elementary steps are estimated and found to be three to five times lower for the reaction involving quinone monoamine than for the one involving quinone diimine. Both reactions have relatively short chains whose lengths do not exceed several tens of units.     

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

The first catalytic asymmetric inverse‐electron‐demand (IED) oxa‐Diels–Alder reaction of ortho‐quinone methides, generated in situ from ortho‐hydroxybenzyl alcohols, has been established. By selecting 3‐methyl‐2‐vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho‐hydroxybenzyl alcohols as precursors of dienes and 3‐methyl‐2‐vinylindoles as dienophiles, as well as the hydrogen‐bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa‐Diels–Alder reaction.     

Synergistic Rhodium/Phosphoric Acid Catalysis for the Enantioselective Addition of Oxonium Ylides to ortho‐Quinone Methides

We report herein a powerful and highly stereoselective protocol for the domino‐type reaction of diazoesters with ortho‐quinone methides generated in situ to furnish densely functionalized chromans with three contiguous stereogenic centers. A transition‐metal and a Brønsted acid catalyst were shown to act synergistically to produce a transient oxonium ylide and ortho‐quinone methide, respectively, in two distinct cycles. These intermediates underwent subsequent coupling in a conjugate‐addition–hemiacetalization event in generally good yield with excellent diastereo‐ and enantioselectivity.     

Brønsted Acid‐Catalyzed,Highly Enantioselective Addition of Enamides to In Situ‐Generated ortho‐Quinone Methides: A Domino Approach to Complex Acetamidotetrahydroxanthenes

The highly enantioselective conjugate addition of enamides and enecarbamates to in situ‐generated ortho‐quinone methides, upon subsequent N,O‐acetalization, gives rise to acetamido‐substituted tetrahydroxanthenes with generally excellent enantio‐ and diastereoselectivities. A chiral BINOL‐based phosphoric acid catalyst controls the enantioselectivity of the carbon–carbon bond‐forming event. The products are readily converted into other xanthene‐based heterocycles.     

Brønsted Acid Catalyzed Addition of Enamides to ortho‐Quinone Methide Imines—An Efficient and Highly Enantioselective Synthesis of Chiral Tetrahydroacridines

The direct and highly enantioselective synthesis of tetrahydroacridines was achieved through the phosphoric acid catalyzed addition of enamides to in situ generated ortho‐quinone methide imines and subsequent elimination. This novel one‐step process constitutes a very efficient, elegant, and selective synthetic approach to valuable N‐heterocycles with a 1,4‐dihydroquinoline motif. By subsequent highly diastereoselective hydrogenation and N‐deprotection the reaction products were easily converted into free hexahydroacridines with a total of three new stereogenic centers.     

Studies on quinones. Part 40: Synthesis and cytotoxicity evaluation of anthraquinone epoxides and isomerization products

Aerobic oxidation of 1,4,4a,10a-tetrahydro-1,4-alkano-5,10-anthraquinones and thiophene-analogues in dichloromethane-DBU yielded the corresponding dihydroalkanoquinones which, depending on their structures, react with in situ generated hydroperoxide anion to give quinone epoxides and/or hydroperoxides. The calcium hydroxide-induced rearrangement of quinone epoxides yielded furan-containing angular quinones. The cytotoxic activities of quinone epoxides and their isomerization products were evaluated in vitro against normal human lung fibroblasts (MRC-5) and human cancer gastric epithelial cells (AGS).     

Catalytic Asymmetric N‐Alkylation of Indoles and Carbazoles through 1,6‐Conjugate Addition of Aza‐para‐quinone Methides

Catalytic asymmetric N‐alkylation of indoles and carbazoles represents a family of important but underdeveloped reactions. Herein, we describe a new organocatalytic strategy in which in situ generated aza‐para ‐quinone methides are employed as the alkylating reagent. With the proper choice of a chiral phosphoric acid and an N‐protective group, the intermolecular C−N bond formation with various indole and carbazole nucleophiles proceeded efficiently under mild conditions with excellent enantioselectivity and functional‐group compatibility. Control experiments and kinetic studies provided important insight into the reaction mechanism.     

2‐(Pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone and 2‐phenyl­sulfanyl‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone

The structure of 2‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone, C₁₄H_12.95Cl_0.05NO₂, (I), is actually a 0.95:0.05 mixture including 2‐chloro‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone as a minor impurity, but (I) was resolved as a single molecule containing a Cl atom with 5% occupancy at the 3‐position. Compound (I) was prepared from the fully chloro‐substituted analogue in an attempt to produce the disubstituted pyrrolidinyl derivative. 2‐Phenyl­sulfanyl‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone, C₂₀H₁₇NO₂S, (II), was also prepared from 2‐chloro‐3‐(pyrrolidin‐1‐yl)‐1,4‐naphtho­quinone, using a strong exocyclic nucleophile. The structure of (II) differs from previous structures of 2,3‐di­chloro‐1,4‐naphtho­quinone and its derivatives in that the naphtho­quinone ring is non‐planar.     

Convenient Synthesis of 2‐Amino‐4H‐chromenes from Photochemically Generated o‐Quinone Methides and Malononitrile

2‐Amino‐4H‐chromenes were synthesized in moderate to good yields by the reaction of o‐quinone methides photochemically generated from o‐(dimethylaminomethyl)phenols with malononitrile. This method was applicable to the synthesis of fluorinated chromenes that were difficult to obtain by other methods. In addition, o‐(hydroxymethyl)phenols could be used for the reaction in the presence of tertiary amine bases.     

A Catalyst‐Controlled Aerobic Coupling of ortho‐Quinones and Phenols Applied to the Synthesis of Aryl Ethers

ortho‐Quinones are underutilized six‐carbon‐atom building blocks. We herein describe an approach for controlling their reactivity with copper that gives rise to a catalytic aerobic cross‐coupling with phenols. The resulting aryl ethers are generated in high yield across a broad substrate scope under mild conditions. This method represents a unique example where the covalent modification of an ortho‐quinone is catalyzed by a transition metal, creating new opportunities for their utilization in synthesis.     

ECEC and ECE‐Type Mechanisms in Electrochemical Oxidation of 4‐Substituted Catechols in the Presence of 4‐Hydroxy‐6‐methyl‐2‐pyrone

Electrochemical oxidation of 3,4‐dihydroxybenzoic acid ( 1 ) and 4‐tert‐butylcatechol ( 5 ) in the presence of 4‐hydroxy‐6‐methyl‐2‐pyrone ( 2 ) as nucleophile in aqueous solution has been studied using cyclic voltammetry and controlled‐potential coulometry. The results indicate that 1 via Michael reaction under electro‐decarboxylation reaction converts to heterocyclic compound 4 , and the quinone derived from 4‐tert‐butylcatechol ( 5 ) participates in Michael reaction with 2 and through an ECE mechanism converts to the corresponding o‐quinone ( 6a ). The electrochemical synthesis of 4 and 6a has been successfully performed in an undivided cell.     

A simple and convenient procedure for the synthesis of naphthoquinone fused cyclic α‐aminophosphoryl chloride

The synthesis of a novel quinone fused phosphorus heterocycle, 2‐chloro‐3,3‐disubstituents‐3,4‐dihydro‐2H‐naphtho[2,3‐e][1,4,2]oxazaphosphinane‐5,10‐dione 2‐oxide ( 3a–g ), was described for the first time. These compounds, which have a readily leaving group Cl, can serve as intermediates of many quinone fused phosphorus heterocycles. The structures of 3a–g were characterized by using common spectroscopic methods. According to the X‐ray structure of 3a , these compounds may be used as DNA‐intercalators. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:359–362, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20306     

Catalytic Asymmetric Diels–Alder Reaction of Quinone Imine Ketals: A Site‐Divergent Approach

The catalytic asymmetric Diels–Alder reaction of quinone imine ketals with diene carbamates catalyzed by axially chiral dicarboxylic acids is reported herein. A variety of primary and secondary alkyl‐substituted quinone derivatives which have not been applied in previous asymmetric quinone Diels–Alder reactions could be employed using this method. More importantly, we succeeded in developing a strategy to divert the reaction site in unsymmetrical 3‐alkyl quinone imine ketals from the inherently favored unsubstituted C?C bond to the disfavored alkyl‐substituted C?C bond.