Synthesis and spectral properties of phthalimidines and phthalides

Alkaline hydrolysis of substituted 2-cyanocinnamic acids leads to the corresponding substituted 3-carboxymethylpthalimidines; acid hydrolysis of the same acids results in the formation of phthalides with an analogous structure. NMR and mass spectrometric data are examined critically.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 472–476, April, 1992.     

Quinine-derived thiourea promoted enantioselective Michael addition reactions of 3-substituted phthalides to maleimides

A highly diastereoselective and enantioselective Michael addition/desymmetrization reaction of maleimides with prochiral 3-substituted phthalides catalyzed by quinine-derived bifunctional thiourea was realized. A broad range of the 3,3′-disubstituted phthalides bearing vicinal quaternary-tertiary stereogenic centers were synthesized in moderate to good yields(up to 96%) with high diastereoselectivities(up to 19:1 dr) and enantioselectivities(up to 96:4 er).     

Ru-catalyzed synthesis of substituted phthalides through C–H bond activation and functionalization

Synthesis of substituted phthalides through a ruthenium-catalyzed reaction of phthalic anhydrides with acrylates is described. The reaction proceeds via CH bond activation and leads to the formation of vinylated phthalides through a successive double vinylation accompanied by decarboxylation and annulation reactions.     

Synthesis of phthalides and 3,4-dihydroisocoumarins using the palladium-catalyzed intramolecular benzannulation strategy

A novel method for the synthesis of phthalides and 3,4-dihydroisocoumarins via the palladium-catalyzed intramolecular benzannulation of bis-enyne and enyne-diyne systems is described. Various kinds of substituted phthalides 9 and 17 and 3,4-dihydroisocoumarins 19 were synthesized from 8, 16, and 18, respectively, in moderate to excellent yields. The benzannulation reaction proceeded chemoselectively to give the corresponding fused ring compounds A without the formation of the regioisomeric products B (eq 6). Furthermore, this methodology was applied to the synthesis of biologically active 3-n-butylphthalide 23.     

Expeditious synthesis of 3,4-dihydroisocoumarins and phthalides using the Heck-Matsuda reaction

Several 3,4-dihydroisocoumarins and phthalides were synthesized by an effective Heck-Matsuda reaction involving an ortho carboxybenzenediazonium salt with a series of styrenes bearing electron donating and electron withdrawing groups, methylvinyl ketone, and methyl acrylate. The reaction was carried out in an open-flask with 1% mol of palladium acetate in aqueous ethanol at ∼80 °C, giving the correspondent 3-aryl-3,4-dihydroisocoumarins and phthalides with good overall yields. The electronic nature of the group attached to the olefin is a key feature for the regioselectivity of the cyclization step.     

One-pot reaction of 2-formylbenzoates,hexamethyldisilazane, and diethyl phosphite in the presence of Yb(OTf)3: Synthesis of 3-phosphonate phthalides

Reaction of 2-formylbenzoates with hexamethyldisilazane and diethyl phosphite in the presence of Yb(OTf)₃ proceeded smoothly at room temperature to afford addition adducts, which were readily cyclized to 3-phosphonate phthalides by adding trifluoroacetic acid (TFA). The reactions employing Sc(OTf)₃ instead of Yb(OTf)₃ produced 3-phosphonate isoindolinones without addition of TFA.     

One-pot synthesis of phthalides via regioselective intramolecular cyclization from ortho-alkynylbenzaldehydes

A one-pot synthesis of phthalides via an intramolecular 5-exo-dig cyclization of ortho-alkynylbenzaldehydes under mild NaClO₂ oxidation conditions is described.     

Dibenzothiepins, phthalans and phthalides from 4-heterosubstituted dibenzothiins

The lithiation of 4-heterosubstituted dibenzothiins 1 (phenoxathiin, phenothiazine and thianthrene) with lithium and a catalytic amount of 4,4′-di-tert-butylbiphenyl (DTBB, 7.5% molar) in THF at temperatures ranging from −90 to −78°C gives the corresponding functionalised organolithium intermediate I, which by reaction with different electrophiles [H₂O, D₂O, Bu^tCHO, PhCHO, Ph(CH₂)₂CHO, Me₂CO, Et₂CO, (CH₂)₅CO, (CH₂)₇CO] at the same temperature, followed by hydrolysis, gives the expected functionalised thiols 2. Cyclisation of some thiols 2 under acidic conditions leads to the corresponding seven-membered dibenzo heterocycles 5. In the case of thianthrene 1c, after addition of a carbonyl compound as the first electrophile [MeCHO, Bu^tCHO, Me₂CO, Et₂CO, (CH₂)₅CO], the corresponding intermediate II can be lithiated again and react with a second electrophile. Diols 3 are obtained after hydrolysis when a carbonyl compound [Bu^tCHO, PhCHO, Ph(CH₂)₂CHO, Me₂CO, Et₂CO, (CH₂)₅CO] is used as the second electrophile. Acidic cyclisation of diols 3 gives substituted phthalans 6 in almost quantitative yields. Finally, in the case of using carbon dioxide as the second electrophile, phthalides 4 are obtained after acidic hydrolysis.     

Ring-chain tautomerism as a factor in the reaction between Grignard reagents and substituted phthalides

With phthalide two equivalents of Grignard reagent react rapidly in a reaction which could not be controlled to give stepwise addition. In contrast, 3,3- and 4,7-disubstituted phthalides react with only one equivalent of organometallic reagent. The primary addition product formed from one equivalent each of phthalide and Grignard reagent exists in a ring-chain tautomerism whose position is controlled by the interaction between the substituents present in the phthalide and the alkyl group introduced by the Grignard reagent. With substituted phthalides, ring opening of the primary addition product is prevented by these interactions and thus a second equivalent of Grignard reagent does not react. In the absence of substituents, ring opening and the reaction of a second equivalent occurs.Somewhat related effects appear to exist in the reaction between Grignard reagents and phthalic anhydride and in the dehydration of substituted phthalyl alcohols to their corresponding phthalans.     

Synthesis of novel antifungal phthalides produced by a wheat rhizosphere fungus

Two antifungal phthalides produced by a wheat rhizosphere fungus have been synthesized using the Alder-Rickert reaction to construct their common isobenzofuranone core structure. The absolute configuration of one of the two phthalides has been determined to be S by synthesizing its (S)- and (R)-enantiomer and comparing their optical rotations with that of the natural product.     

Fermi resonance in substitutedZ-3-methylene phthalides

Summary The absorption bands of the C=O Stretching vibrations of a series of thirty-nine substitutedZ-3-methylene phthalides (1a-s, 2a-h, 3a-f, 4a-c, and5a-c) were measured in CHCl₃ and CCl₄. The two-levelFermi resonance effect on the infrared spectra of the above compounds was investigated after deconvolution and band separation. The wave numbers of the unperturbed fundamental C=O stretching vibrations exhibit excellent linear correlations withHammet's constants of substituents and¹³C NMR chemical shifts of the C=O group.

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Fermi-Resonanz in substituiertenZ-3-Methylenphthaliden

Zusammenfassung Die Absorptionsbanden der C=O-Streckschwingung von 39 substituiertenZ-3-Methylenphthaliden (1a-s, 2a-h, 3a-f, 4a-c und5a-c) wurden in CHCl₃ und CCl₄ vermessen. Durch Dekonvolution und Bandentrennung konnte der EinflußFermi-Resonanz auf die Infrarotspektren der obengenannten Verbindungen untersucht werden. Die Wellenzahlen der ungestörten C=O-Streckschwingungen ergeben ausgezeichnete lineare Korrelationen mit denHammetschen Substituentenkonstanten und den¹³C-NMR-Verschiebungen der Carbonylgruppe.

     

Highly Efficient Synthesis of Unsymmetrical 3,3′‐Bis(1H‐indol‐3‐yl)methanes in Water

A simple and practical approach for the preparation of unsymmetric bis(indolyl)methanes (BIMs) was realized by Lewis acid InBr₃‐catalyzed Friedel‐Crafts reaction of indoles with 3‐indolyl‐substituted phthalides in water.     

Fast microwave promoted palladium-catalyzed synthesis of phthalides from bromobenzyl alcohols utilizing DMF and Mo(CO)6 as carbon monoxide sources

A fast method utilizing in situ generated CO for the synthesis of phthalides has been developed. DMF and Mo(CO)₆ were applied as two alternative CO-sources in these microwave promoted carbonylation-lactone formation reactions. Mo(CO)₆ was found to be the more generally applicable CO-source and provided phthalides as well as dihydroisocoumarin, dihydroisoindone, and phthalimide from the corresponding aryl bromide via an efficient CO insertion within a 1 h reaction time.     

Highly efficient synthesis of 3-indolyl-substituted phthalides via Friedel-Crafts reactions in water

An efficient and simple method for the synthesis of 3-indolyl-substituted phthalides via Friedel-Crafts reaction of indoles with 2-formylbenzoic acids in pure water has been developed. The reaction affords a wide range of 3-indolyl-substituted phthalides in good to excellent yields.     

Catalytic asymmetric 1,2‐Addition/Lactonization tandem reactions for the syntheses of chiral 3‐Substituted phthalides using organozinc reagents

Using chiral phosphoramide ligand 2d‐ Zn (II) complex derived from (1R,2R)‐1,2‐diphenylethylenediamine as the catalyst, we have developed efficient catalytic asymmetric 1,2‐addition/lactonization tandem reactions of diverse organozinc reagents with varied methyl 2‐formylbenzoates for the construction of optically enriched 3‐aryl or alkyl substituted phthalides, which are significant building blocks of many important chiral pharmaceuticals and natural products. The corresponding products could be afforded with good to excellent yields (up to 95%) and moderate to good enantioselectivities (up to 89%).     

Conversion of (±)‐3‐ethyl‐3‐methyl phthalides to 3,3‐dimethyl‐3,4‐dihydroisocoumarins. Synthesis of 3‐methylmellein

o‐Lithio yV‐methyl benzamides ( 1a‐f ) upon alkylation with ethyl methyl ketone gave (±)‐3‐ethyl‐3‐methyl phthalides ( 2a‐f ), which upon treatment with concentrated H₂SO₄ or anhydrous A1C1₃ furnished corresponding 3,3‐dimethyl‐3,4‐dihydroisocoumarins ( 3a‐f ) and 3‐methyl mellein ( 3g ).     

Organic-base-catalyzed synthesis of phthalides via highly regioselective intramolecular cyclization reaction

The organic-base-catalyzed 5-exo intramolecular cyclization reaction of o-alkynylbenzoic acid produces the corresponding phthalide regioselectively in good to excellent yields. The method provides a practical access to the phthalides, an important class of biologically active molecules.     

Characterization of the potential new phthalides in Ligusticum chuanxiong Hort. using ultra‐performance liquid chromatography coupled with quadrupole time of flight tandem mass spectrometry

The characterization of unknown compounds is still a great challenge currently. A strategy for deduction of potential new phthalides through the characterization of isomers based on ultra‐performance liquid chromatography coupled with quadrupole time of flight tandem mass spectrometry was proposed here to characterize the unknown compounds of Ligusticum chuanxiong Hort. (Chuanxiong). This proposed strategy consisted of four steps: (1) the high resolution MS data was collected, and the peaks were screened preliminarily by UNIFI^TM platform based on the in‐house database; (2) the fragmentation patterns and the characteristic fragments were summarized based on the representative standards; (3) the target compounds were identified based on the fragmentation rules, standards comparison and false positive exclusion; (4) the unknown components were structurally characterized according to the accurate mass and fragmentation patterns analysis. This strategy was successfully applied to the identification and deduction of phthalides in Chuanxiong. A total of 81 phthalides were detected. Fifty‐five known phthalides were identified, and 26 potential new phthalides were characterized. This research enriched the material basis of Chuanxiong, and provided a liquid chromatography tandem mass spectrometry‐oriented method for the discovery of the potential new compounds.     

Characterization of phthalides in Ligusticum chuanxiong by liquid chromatographic-atmospheric pressure chemical ionization-mass spectrometry

High-performance liquid chromatography (HPLC) with diode-array detection interfaced to atmospheric pressure chemical ionization (APCI)-mass spectrometry (MS) is applied to analyze phthalides from Chuanxiong (the rhizome of Ligusticum chuanxiong). This herb material, containing plenty of phthalide compositions, is selected as the analytical target in this paper for its hematological activity. Some of the phthalides are not stable and are difficult to analyze by gas chromatography-MS. Under optimized LC-MS-MS conditions, six phthalides in the methanol extract of Chuanxiong are unambiguously identified, and characteristic fragments are obtained using homemade reference standards. Ten other phthalides in the extract are confirmed by means of LC-APCI-MS with positive-negative ion mode and collision-induced dissociation in combination with UV spectrophotometry. The results show that LC-MS-MS is a method of choice for fast detection and detailed structural analysis of such mixtures in the crude extract of Chuanxiong.     

Dieckmann-Shapiro condensation of substituted phthalides with p-dimethylaminobenzaldehyde

Conclusion In the Dieckmann-Shapiro condensation of phthalides with p-dimethylaminobenzaldehyde the reaction rate decreases with an increase in the electron-donor effect of the substituent in the phthalide and becomes comparable to the rate of a competing reaction — Claisen condensation of ethyl acetate with the aldehyde.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khlmicheskaya, No. 8, pp. 1850–1855, August, 1986.The authors thank L. A. Sibel'dina's group for recording the PMR spectra.