Dihydrobenzofuran Derivatives Research Articles

Cascade Synthesis of 3-Alkylidene Dihydrobenzofuran Derivatives via Rhodium(III)-Catalyzed Redox-Neutral C-H Functionalization/Cyclization.

An efficient rhodium(III)-catalyzed coupling reaction of N-phenoxyacetamides with propargyl carbonates to yield 3-alkylidene dihydrobenzofuran derivatives via C-H functionalization/cascade cyclization has been developed. This transformation represents a redox-neutral process and features the formation of three new bonds under mild conditions.

Palladium‐Catalyzed Domino Mizoroki–Heck/Intermolecular C(sp3)–H Activation Sequence: An Approach to the Formation of C(sp3)–C(sp3) Bonds

AbstractA palladium‐catalyzed domino Mizoroki–Heck/intermolecular unactivated C(sp3)–H alkylation reaction has been developed. This simple palladium nanoparticle catalytic system shows good activity and affords the dimeric dihydrobenzofuran derivatives in moderate to good yields. Furthermore, this reaction provides a new method for the elaboration of domino reactions involving a C(sp3)–C(sp3) bond‐forming process.

Synthesis and structure–activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists

Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R1 attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R2. The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.

Electrochemically Active Crosslinking Reaction for Fluorescent Labeling

Crosslinking reaction is a valuable method for the integration of two or more functionalities or properties to facilitate the effective design and fabrication of bioconjugates and nanomaterials. In particular, crosslinking reactions using photoactive linkers or click-chemistry for fluorescent labeling offer versatile strategies to manufacture biomolecular probes, which allow surface modification through stable covalent bonds. Although electroorganic synthetic methods have produced a wide variety of useful intermediate species under mild conditions, their application to practical crosslinking is restricted due to the difficulty of mass transfer, i.e., the unstable reactive intermediate generated from the electrode must be transported to another location. To date, attempts in solid-phase electroorganic synthesis have been limited mostly to immobilization of substrates on an electrode or indirect electroorganic synthesis. Furthermore, solid-phase syntheses often require excess amounts of reagents to complete target reactions due to low reactivity, and typical electroorganic approaches therefore suffer from in situgeneration of unstable intermediates trapped within the solid-supports. Therefore, the development of electrochemically active crosslinkers for the modification of insoluble targets, nonconductive samples, and biomolecules remains a significant challenge. We have recently accomplished intermolecular carbon-carbon bond formation reactions with aliphatic alkenes viaanodically generated cation intermediates to afford a variety of polycyclic systems. Furthermore, less reactive alkenes could be coupled with electrochemically activated substrates, which can be trapped in a thermomorphic solution-phase, spatially separated from the electrode, by using cyclohexane-nitromethane as a medium. These solution-phase reaction systems effectively accelerated intermolecular interactions between the less reactive olefins and unstable cation intermediates. We hypothesized that this approach would allow selective, direct and stable modification of alkene-attached insoluble targets with electrochemically active species. The electrochemically active crosslinking system could also enable the construction of a fluorescent probe, triggered by the formation of a covalent linkage. This strategy addresses the time-consuming, multistep post-processing problems associated with fluorescent labeling, such as washing and purification, and reduces false signals arising from nonspecific adsorption of a fluorophore or its undesired cleavage in the detection environment.To study the selectivity of the functional groups in this reaction system, electrochemical coupling reactions were conducted using phenol 1 in the presence of terminal mono-substituted olefins and trialkyl-substituted olefin 2 (Table1). These results indicate that the phenoxonium cations anodically generated in the LiClO4-MeNO2 reaction system can be selectively trapped with trialkyl-substituted olefins to afford the cycloadduct as a fluorescent unit in high yields.Based on these results, we also attempted to synthesize a fluorescent probe composed of 2,7-dimethyl-6-octenoic acidon amino-modified silica and unactivated alkenes to confirm the lifetime of the phenoxonium cation. The size of the amino-silica particles was ca.0.6-0.7 μm and the amino group content was 0.4 mmol/g. After the reaction, the mixture was washed in water and collected by filtration. Fluorescence on the silica was observed by fluorescent microscopy. The reactive site of the alkenes cannot approach the electrode because the silica molecule is too large, and thus, it was assumed that the phenoxonium cation was stable until reacting on the silica surface.In conclusion, an electrochemically active crosslinking reaction was developed to attach fluorescent probes to aliphatic alkenes. Several dihydrobenzofuran derivatives formed via[3+2] cyclization reactions exhibited fluorescence properties. Furthermore, this approach allows the effective and stable modification of alkene-attached silica gel as an insoluble target with electrochemically active species, which enables the construction of fluorescent probes, triggered by the formation of a covalent linkage.ReferencesShokaku Kim, Kumi Hirose, Jumpei Uematsu, Yuzuru Mikami, Kazuhiro Chiba, Chem. Eur. J. , 2012, 18(20), 6284-6288.

Bifunctional Primary Amine‐Squaramide Catalyzed Enantioselective Intramolecular Michael Addition of Keto‐enones: A Convenient Process to the Stereocontrolled Construction of trans‐Dihydrobenzofuran Skeletons

AbstractA highly diasterero‐ and enantioselective intramolecular Michael addition of keto‐enones has been realized. By using the (R,R)‐1,2‐diphenylethane‐1,2‐diamine‐based bifunctional primary amine‐squaramide catalyst, the reaction proceeded smoothly to generate the corresponding trans‐2,3‐disubstituted dihydrobenzofuran derivatives in excellent yields with good to excellent diastereo‐ and enantioselectivities (up to 97:3 dr, up to >99 % ee).

Lewis‐Acid‐Promoted Arylation Reaction: Synthesis of Dihydrobenzofuran Derivatives from Aryltriazenes

AbstractA Lewis‐acid‐promoted approach to the synthesis of highly functionalized dihydrobenzofuran derivatives was developed. A diverse range of functional groups are tolerated in this type of reaction. The reaction mechanism investigation indicates that the highly reactive phenyl cation intermediate is probably involved in this process. The chirality of substrate is retained under the reaction conditions.

ChemInform Abstract: Electrochemically Active Cross‐Linking Reaction for Fluorescent Labeling of Aliphatic Alkenes.

AbstractElectrochemical [3 + 2] cyclization of phenolic compounds with various alkenes provides access towards dihydrobenzofuran derivatives as fluorescent probes.

Intramolecular Alkoxycyanation and Alkoxyacylation Reactions: New Types of Alkene Difunctionalizations for the Construction of Oxygen Heterocycles

Functionalized dihydrobenzofuran derivatives can be obtained by intramolecular alkoxycyanation and alkoxyacylation of alkenes (see scheme). In both transformations, selective activation of an OFG bond is accomplished by using a transition-metal catalyst. These transformations represent a conceptually new approach to metal-catalyzed alkene difunctionalization.

ChemInform Abstract: Stereoselective Synthesis of 2,3‐Disubstituted Dihydrobenzofuran Using Alkyne Prins Type Cyclization to Vinylogous Carbonates.

Abstracttrans‐2,3‐Disubstituted dihydrobenzofuran derivatives (VI) (13 examples) are stereoselectively obtained in an intramolecular, alkyne Prins‐type cyclization of vinylogous carbonates obtained from o‐alkynylphenols.

Electrochemically Active Cross‐Linking Reaction for Fluorescent Labeling of Aliphatic Alkenes

Although cross-linking reactions serve as a valuable tool for the integration of two or more functionalities or properties, the application of electrochemical synthesis to cross-linking reactions is restricted due to the difficulty of mass transfer. Thus, the primary purpose of this research is to explore electrochemical cross-linking systems to construct a fluorescent probe, triggered by the formation of a covalent linkage. The second purpose is to apply the probe to insoluble targets. Towards these goals, a combination of electrochemically active phenol derivatives and aliphatic alkenes were employed to form polycyclic compounds. Several of the dihydrobenzofuran derivatives formed through [3+2] cyclization reactions exhibited fluorescence. Furthermore, this approach allowed the effective modification of alkene-modified silica gel with electrochemically active species, which enables the construction of fluorescent probes that are triggered by C-C bond formation.

ChemInform Abstract: Synthesis of 5‐Substituted 2,3‐Dihydrobenzofurans in a One‐Pot Oxidation/Cyclization Reaction.

AbstractThe oxidation of N‐protected p‐aminophenol derivatives to quinone imides is combined with cycloaddition towards azadiene (II) in a one‐pot reaction to give dihydrobenzofuran derivatives in moderate to good yields.

ChemInform Abstract: [3 + 2] Coupling of Quinone Monoacetals by Combined Acid—Hydrogen Bond Donor.

AbstractThe method allows a new and efficient access to various dihydrobenzofuran derivatives.

ChemInform Abstract: Rhodium‐Catalyzed Olefin Isomerization/Enantioselective Intramolecular Alder‐Ene Reaction Cascade.

AbstractTreatment of substrates (I), (III), and (V) according to A) or B) allows an enantioselective access to dihydrobenzofuran derivatives.

Stereoselective synthesis of 2,3-disubstituted dihydrobenzofuran using alkyne Prins type cyclization to vinylogous carbonates

An intramolecular, alkyne Prins type cyclization of vinylogous carbonates derived from o-alkynyl phenols is developed for the stereoselective construction of trans-2,3-disubstituted dihydrobenzofuran derivatives. Strong Lewis acids like TMSOTf catalyse this reaction efficiently. The presence of mildly electron donating groups on aryl rings increases the efficiency of the reaction.

Enantioselective Cycloetherification in a Micellar Catalysis System

Abstract The enantioselective cycloetherification of substituted keto phenols into their corresponding dihydrobenzofuran derivatives was carried out using hydrogen peroxide and chiral quaternary ammonium iodide in micellar media. This approach increased the conversion rate of cycloetherification and also widened the scope of this particular reaction for various substituted keto phenols with electron withdrawing as well as electron donating functionalities. The use of a surfactant in the cycloetherification reaction increased the yield of the corresponding enantioselective dihydrobenzofuran four times. The conversion rate of keto phenols into their corresponding dihydrobenzofuran derivatives was proportional to the concentration of the surfactant used in the reaction.

ChemInform Abstract: Pd(II)‐Catalyzed Hydroxyl‐Directed C—H Activation/C—O Cyclization: Expedient Construction of Dihydrobenzofurans.

AbstractIntramolecular cyclization of tertiary phenylethanol derivatives, e.g. (I), (III) or (V), proceeds smoothly in the presence of Pd(II) catalyst and Ph‐I(O‐Ac)2 to give dihydrobenzofuran derivatives in good yields.

ChemInform Abstract: Regio- and endo-Selective [2 + 2] Photocycloadditions of Homobenzoquinones with Ethyl Vinyl Ether.

Irradiation of various meta- and para-substituted homobenzoquinones with ethyl vinyl ether gave the [2 + 2] photoadducts, tricyclic diones, regio- and endo-selectively and in good yields. The tricyclic skeleton has an anti-form built by the addition of ethyl vinyl ether from the less hindered side of homoquinones. All of the CH3, Cl, Br, and CH3O substituents at the reacting CC double bond afforded head-to-head (HH) addition predominantly. In the case of CH3, Cl, and Br, the ethoxy group was oriented in the endo-position, while the CH3O substituent led to a 1/5 mixture with the exo-isomer. It was also found that the Br-substituted [2 + 2] adducts undergo a facile skeletal rearrangement, being converted into dihydro-o-benzoquinone monomethide derivatives for para-substitution and dihydrobenzofuran derivatives for meta-substitution, probably under the influence of the in situ generated HBr. Intramolecular [2 + 2] photocycloaddition of an alkenylhomobenzoquinone afforded a tetracyclic dione.

Photochemistry of allyloxybenzophenones: a pseudo-Paternò–Büchi rearrangement accompanied by hydrogen transfer induced 1,5-cyclization

The solution photochemistry of the ortho allyloxy-substituted benzophenone has been investigated in detail. Product analysis revealed formation of a diastereomeric mixture of dihydrobenzofuran derivatives by cyclization via a short-lived intermediate 1,5-biradical and an unusual acetal by a pseudo-Paternò-Büchi rearrangement. The latter reaction pathway was supported by means of laser flash photolysis, where a long-lived intermediate with a maximum absorption band at 380 nm was observed. Besides, theoretical calculations (TD-DFT) of this UV-transient resulted in a band with maximum intensity at 390 nm showing a good correlation between experimental results and theoretical calculations. For comparison, the meta-substituent substrate was also investigated showing preferred triplet-triplet energy transfer.

ChemInform Abstract: Synthesis of Isochroman and Tetrahydroisoquinoline Derivatives from Baylis—Hillman Adducts by Radical Cyclization.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Isochroman and Tetrahydroisoquinoline Derivatives from Baylis-Hillman Adducts by Radical Cyclization

Recently we were interested in radical cyclizations of modified Baylis-Hillman adducts. We reported the synthesis of various heterocyclic compounds including 2,3dihydrobenzofuran derivatives using radical cyclization process. Meantime we reasoned that six-membered heterocyclic compounds such as isochroman and tetrahydroisoquinoline derivatives could be prepared by radical cyclization from suitably modified Baylis-Hillman adducts (vide infra, Scheme 1). Isochroman and tetrahydroisoquinoline derivatives are important backbone in many biologically interesting substances and their synthesis have been studied extensively. Especially, appropriately substituted tetrahydroisoquinolines are an important class of natural and synthetic compounds, which exhibit various biological activities including antitumor, antibacterial, antiplasmodial and β-adrenergic receptor antagonism. As an initial trial we examined the synthesis of isochroman derivative 4a as shown in Scheme 1. The starting material 3a was synthesized from the reaction of BaylisHillman acetate 1a and 2-bromobenzyl alcohol (2a) in good yield (82%). With this compound 3a in our hand we examined the radical cyclization under the influence of nBu3SnH/AIBN in benzene and we obtained desired 4,4disubstituted isochroman derivative 4a in 89% yield (Scheme 1). We did not observe the formation of sevenmembered ring compound or reduction product. Most of the radical cyclizations of aryl radical toward tethered unsaturated ester occurred at the β-position of unsaturated moiety. However, we observed the selective formation of sixmembered ring compound 4a presumably due to the special stability of the intermediate benzylic radical as in our previous synthesis of 2,3-dihydrobenzofuran. Encouraged by the results we prepared starting materials 3b-f (vide infra, Table 1 and Scheme 2) and carried out radical cyclizations under the same conditions, and the results are summarized in Table 1. As shown we prepared three isochroman derivatives 4a-c (entries 1-3) and two tetrahydroisoquinolines 4d and 4e (entries 4 and 5) in good yields (85-89%). However, unfortunately, radical cyclization was not completed in the case of nitrile derivative 3f and we isolated isochroman 4f and reduction compound 5 together (1:1 mixture based on H NMR) as a mixture. The separation of 4f and 5 was very difficult by column chromatography due to their same mobility on TLC. At this stage the reason for low yield of cyclized compound 4f is not clear. Synthesis of starting materials 3a-e required somewhat different synthetic approaches depending upon the substrates as shown in Scheme 2. Synthesis of 3a and 3b was carried out by the reaction of Baylis-Hillman acetate 1a and 2bromobenzyl alcohol (2a) in the presence of K2CO3 in acetonitrile (79-82%). The compound 3c was synthesized from cinnamyl alcohol 1b and 5-bromo-6-bromomethyl1,3-benzodioxole (2b) in moderate yield (56%) by using potassium tert-butoxide in DMF. The compounds 3d and 3e were prepared from the reaction of rearranged aza-BaylisHillman adduct 1c and 2b or 2-bromobenzyl bromide (2c) in the presence of K2CO3 in DMF in good yields (81-91%). Nitrile derivative 3f was prepared by the reaction of 2a and the corresponding Baylis-Hillman acetate in 79% yield by following the same procedure for the synthesis of 3a. In summary, we disclosed the synthesis of some isochroman and tetrahydroisoquinoline derivatives by the radical cyclization process starting from the Baylis-Hillman adducts.