Intramolecular Wittig Reaction Research Articles

A convergent synthetic study of biologically active benzofuran derivatives

In order to construct a benzofuran library, we developed a model study of benzbromarone. Synthesis has been achieved in 53% overall yield, starting from phenol via the key intermediate 2-ethylbenzofuran which was afforded by intramolecular Wittig reaction.

Novel Benzofuran Derivatives for PET Imaging of β-Amyloid Plaques in Alzheimer's Disease Brains

A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.

Pyrrolotriazine-5-carboxylate ester inhibitors of EGFR and HER2 protein tyrosine kinases and a novel one-pot synthesis of C-4 subsitituted pyrrole-2,3-dicarboxylate diesters

Pyrrolotriazines with an ester group at C-5 were prepared and evaluated as inhibitors of the EGFR and HER2 receptor tyrosine kinases, validated targets for cancer therapy. The C-5 ester (15) was at least as potent as its C-6 ester analogue (17), an example of a known series of pyrrolotriazine EGRF/HER2 kinase inhibitors that show good biochemical and cellular activity. The C-5 esters were synthesized from pyrrole 2,3-diesters that were made by a new, one-pot procedure. This involved reaction of readily available N-tosyl derivatives of α-amino acid esters or ketones with triphenylphosphine and diethyl acetylenedicarboxylate to form 3-pyrrolines via an intramolecular Wittig olefination. The 3-pyrroline intermediates were not isolated but treated directly with base to eliminate toluenesulfinic acid and generate the pyrrole 2,3-diesters in good yield.Key words: pyrrolotriazine, EGFR, HER2, pyrrole, intramolecular Wittig reaction.

Highly functionalized dihydrofuran derivatives: Synthesis by diastereoselective intramolecular Wittig reaction

Abstract3a,8a‐Dihydroxy‐1,3,3a,8a‐tetrahydro‐ indeno[1,2‐d]imidazole‐2,8‐dione 3 reacts with dialkyl acetylenedicarboxylates in the presence of triphenylphosphine to produce some novel interesting dihydrofuran derivatives diastereoselectively. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:277–279, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20202

Synthesis of Diastereomeric Phosphorus Ylides: A Facile Route to Dialkyl‐(E)‐2‐{1‐[2‐oxodihydro‐3(2H)‐furanyliden]ethyl}‐2‐butenedioate.

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Synthesis of dimethyl-1-(trifluoromethyl)-3H-pyrrolizine-2,3-dicarboxylate using phosphorus compounds

A general and practical route for the synthesis of phosphorus compounds containing trifluoromethyl or trichloromethyl groups by a one-pot condensation triphenylphosphine and dialkyl acetylenedicarboxylate in the presence of an NH-acid such as 2,2,2-trifluoro-1-(1H- pyrrol-2-yl)ethanone or 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone is described. The product obtained from the fluorinated compound undergoes an intramolecular Wittig reaction in boiling THF. This method offers a simple procedure for the preparation of dimethyl 1-(trifluoromethyl)- 3H-pyrrolizine-2, 3-dicarboxylate.

One‐Step Stereoselective Synthesis of Dialkyl 1,1‐Diacetyl‐8a‐hydroxy‐8‐oxo‐1,2,8,8a‐tetrahydrocyclopenta [a]indene‐2,3‐dicarboxylates from the Reaction of Dialkyl 2‐(1‐Acetyl‐2‐oxopropyl)‐3‐(tributylphosphoranylidene) Succinates with Indene‐1,2,3‐trione.

Protonation of the highly reactive 1:1 intermediates produced in the reaction between tributylphosphine and dialkyl acetylenedicarboxylates by acetylacetone leads to sterically congested phosphorus ylides that undergo an intermolecular addition reaction with indene-1,2,3-trione and concomitant intramolecular Wittig reaction in CH 2 Cl 2 at room temperature to produce dialkyl 1,1-diacetyl-8a-hydroxy-8-oxo-1,2,8,8a-tetrahydrocyclopenta[a]indene-2,3-dicarboxylates in fairly good yields.

Synthesis of Diastereomeric Phosphorus Ylides: A Facile Route to Dialkyl-(E)-2- { 1-[2-oxodihydro-3(2H)-furanyliden]ethyl }-2-butenedioate

2-acetylbutyrolactone undergoes a smooth reaction with triphenylphosphine and dialkyl acetylenedicarboxylates to produce dialkyl 2-(3-acetyl-2-oxotetrahydro-3-furanyl)-3-(1,1,1-triphenyl-1 5 -phosphanilidene) succinate. These compounds undergo an intramolecular Wittig reaction to produce highly strained spiro compounds in boiling benzene, which spontaneously undergo ring-opening reactions to produce dialkyl (E)-2-{1-[2-oxodihydro-3(2H)-furaniliden]ethyl}-2-butenedioates.

One-Pot, Three-Component Synthesis of Dialkyl 1,2-Dihydroquinoline-2,3-Dicarboxylates from Triphenylphosphine, Acetylenic Esters, and Amide Derivatives of 2-Aminobenzaldehyde in Aqueous Acetone

Protonation of the highly reactive 1:1 intermediates, produced in the reaction between triphenylphosphine and dialkyl acetylenedicarboxylates by amide derivatives of 2-aminobenzaldehyde in the mixture of acetone-water (3:1) leads to vinyltriphenylphosphonium salts, which undergo a Michael addition reaction with a conjugate base to produce the corresponding stabilized phosphorus ylides. An intramolecular Wittig reaction of the stabilized phosphorus ylide group with the aldehyde group leads to the corresponding dialkyl 1,2-dihydroquinoline-2,3-dicarboxylates.

One-Step Stereoselective Synthesis of Dialkyl 1,1-Diacetyl-8a-hydroxy-8-oxo-1,2,8,8a-tetrahydrocyclopenta[a]indene-2,3-dicarboxylates from the Reaction of Dialkyl 2-(1-Acetyl-2-oxopropyl)-3- (tributylphosphoranylidene) Succinates with Indene-1,2,3-trione

Protonation of the highly reactive 1:1 intermediates produced in the reaction between tributylphosphine and dialkyl acetylenedicarboxylates by acetylacetone leads to sterically congested phosphorus ylides that undergo an intermolecular addition reaction with indene-1,2,3-trione and concomitant intramolecular Wittig reaction in CH 2 Cl 2 at room temperature to produce dialkyl 1,1-diacetyl-8a-hydroxy-8-oxo-1,2,8,8a-tetrahydrocyclopenta[a]indene-2,3-dicarboxylates in fairly good yields.

A Novel Synthesis of Flavones from 2-Methoxybenzoic Acids

The flavones (2-phenylchromones) are widely distributed in vascular plants and have attracted a lot of attention because they possess biological activities, such as antioxidant effect, antiviral activity, and anticarcinogenic effect. The main synthetic methods known for the flavones are the cyclodehydration of 1-(2-hydroxyphenyl)-3-phenyl-1,3propanediones, the oxidative cyclization of 2'-hydroxychalcones, and synthesis via an intramolecular Wittig reaction. The rearrangement of benzoyl esters of 2'hydroxyacetophenones (Baker-Venkataraman process) and the direct benzoylation of 2'-hydroxyacetophenones with benzoyl chlorides or methyl benzoates affords 1-(2hydroxyphenyl)-3-phenyl-1,3-propanediones, which are cyclodehydrated to give flavones in acidic conditions. The treatment of 2'-hydroxychalcones which are prepared from 2'-hydroxyacetophenones and benzaldehydes in the presence of 2 equiv of lithium diisopropylamide with oxidizing agents also affords flavones at high temperature. Alternatively Wittig reaction involves the intramolecular olefination of phosphoranes obtained from triphenylphosphine and 2-acetoxyphenacyl bromides, a four step process from 2'-hydroxyacetophenones. A common feature in all these methods is that they invariably use 2'hydroxyacetophenones as the starting material. However, there are no reports of the synthesis of flavones from 2'-methoxyacetophenones. Although 1-(2-methoxyphenyl)-3-methyl-1,3-propanedione is cyclized with boiling HI to give 2-methylchromone, the scope of the reaction is not fully investigated and there are no reports on the synthesis of flavones with 2-substituted phenyl group. Furthermore, it has been reported that the condensation of 2'-methoxyacetophenone with methyl 2-methoxybenzoate using sodium or sodium hydride failed to produce the corresponding 1,3-diketone. As part of our continuing studies of flavonoids, we report that flavones can be newly synthesized in two steps via 1-(2-methoxyphenyl)-3-phenyl-1,3-propanediones from 2'-methoxyacetophenones cheaper than 2'-hydroxyacetophenones in general. 2'-Methoxyacetophenones 2 were readily prepared by the treatment of 2-methoxybenzoic acids 1 with 2 equiv of methyllithium in THF for 2 h at −78 C (Scheme 1). The reaction proceeded smoothly to give 2 free from the corresponding tertiary alcohols after acidic hydrolysis (R, R, R=H; 92%, R1=OCH3, R , R=H; 93%, R, R=H, R2=OCH3; 88%). However, the reaction of 2,6dimethoxybenzoic acid with methyllithium proceeded sluggish due to the steric effect and thus 2',6'-dimethoxyacetophenone was prepared by the treatment of N-methoxyN-methyl 2,6-dimethoxybenzamide with methyl magnesium bromide at room temperature in 75% yield. The key intermediates, 1-(2-methoxyphenyl)-3-phenyl1,3-propanediones 4, for the synthesis of flavones 5 were readily prepared by the condensation of the lithium enolates of 2 with benzoyl cyanides. To find out the optimum reagent

One‐Pot Synthesis of Fluorine Containing 3‐Cyano/Ethoxycarbonyl‐2‐methyl‐benzo[b]furans.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diastereoselective synthesis of dialkyl 4,5,5-triacetyl-3-methylcyclopent-3-ene-1,2-dicarboxylates

Tetraacetylethane (3,4-diacetylhexane-2,5-dione) undergoes a smooth reaction with dialkyl acetylenedicarboxylates in the presence of triphenylphosphine to produce phosphorus ylide intermediates, which undergo a diastereoselective intramolecular Wittig reaction to produce dialkyl 4,5,5-triacetyl-3-methylcyclopent-3-ene-1,2-dicarboxylates in good yields.

An Efficient and Novel Protocol for the Synthesis of Pyrazolo[5,1‐a]isoindole Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Triphenylphosphine‐Mediated Chemoselective Synthesis of Functionalized Spiro‐imidazol‐4‐ones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

One-pot synthesis of fluorine containing 3-cyano/ethoxycarbonyl-2-methyl-benzo[ b]furans

Fluoro-substituted 3-cyano-2-methyl-benzo[ b]furans and ethyl 2-methyl-benzo[ b]furan-3-carboxylates are conveniently prepared in a single step in good yield by the microwave induced tandem intramolecular Wittig and Claisen rearrangement reactions of the corresponding [(aryloxyacetyl) (cyano) methylene] triphenylphosphorane and [(aryloxyacetyl) (ethoxycarbonyl) methylene] triphenylphosphoranes, respectively.

A Route to the Synthesis of Novel Coumarins.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereoselective Synthesis of Highly Functionalized Trifluoromethylated Cyclobutenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

TRIPHENYLPHOSPHINE-MEDIATED CHEMOSELECTIVE SYNTHESIS OF FUNCTIONALIZED SPIRO-IMIDAZOL-4-ONES

Stabilized phosphoranes, obtained from the three-component reaction between dialkyl acetylenedicarboxylates and spiro-hydantoins in the presence of triphenylphosphine, undergo a smooth intramolecular Wittig reaction in boiling toluene to produce functionalized spiro-imidazol-4-ones in good yields.

Synthetic studies related to the akuammiline alkaloids

Ethyl-2,3-dihydro-1-phenyl-1H-pyrrolizine 19 and 1-(2-aminophenyl)-6-ethyl-2,3-dihydro- 1H-pyrrolizine 30 were synthesized starting from the pyrroles 4-acetylpyrrol-2-yl phenyl ketone 13 and 4-acetylpyrrol-2-yl 2-(dimethylaminomethylenamino)phenyl ketone 26, respectively, using vinyltriphenylphosphonium bromide in an intramolecular Wittig reaction for the formation of the second five-membered ring.