The chemistry of coumarin derivatives. Part 3. Synthesis of 3-alkyl-4-hydroxycoumarins by reductive fragmentation of 3,3′-alkyiidene-4,4′-dihydroxybis[coumarins]

Treatment of 3,3′-alkylidene-4,4′-dihydroxybis[coumarins] 1 with NaBH₃CN in refluxing MeOH affords 3-alkyl-4-hydroxycoumarins 2 and 4-hydroxycoumarin ( 3 ; Scheme 1). The reaction might take place via hydride trapping of alkylidenechromandiones C formed from 1 in a retro-Michael reaction. Such a retro-Michael reaction of 1 might be biologically relevant. The presence of C during the reductive fragmentation 1 → 2 is suggested by Diels-Alder and nucleophilic trapping of the alkylidenechromandiones C as well as from cross-over experiments with coumarins other than 3 (see Scheme 2). The reductive fragmentation of 1 allows the chemo- and regioselective synthesis of a variety of 3-alkyl-4-hydroxycoumarins 2 (see Table).     

Solid-supported acid-catalyzed C3-alkylation of 4-hydroxycoumarins with secondary benzyl alcohols: access to 3,4-disubstituted coumarins via Pd-coupling

An efficient and operationally simple method for C3-alkylation of 4-hydroxycoumarins has been developed under acidic medium giving good yields of the products. In the present method, a reusable Amberlite^® IR-120 (H⁺ form) was used as an acid catalyst and secondary benzyl alcohols were used as alkylating agents. The obtained 3-alkylated-4-hydroxycoumarins offered an easy access for the synthesis of 3,4-disubstituted coumarins by way of Pd-catalyzed coupling reactions.     

Yb(OTf)3-catalyzed propargylation and allenylation of 1,3-dicarbonyl derivatives with propargylic alcohols: one-pot synthesis of multi-substituted furocoumarin

A highly efficient and mild Lewis acid-catalyzed coupling reaction of 1,3-dicarbonyl compounds with propargylic alcohols has been established. Selective propargylation or allenylation products are obtained depending on the nature of propargylic alcohols. In addition, catalytic quantities of Yb(OTf)₃ can also effectively promote the propargylation and allylation of 4-hydroxycoumarins at the 3-position. By applying this reaction as the key step, a multi-substituted furocoumarin can easily be synthesized in a one-pot procedure. The advantages of this method are broad scope, mild conditions, and easy handling since water is the only side product.     

Phenyliodonium zwitterion as an efficient electrophile in the palladium-catalyzed suzuki-type reaction: a novel method for the synthesis of 3-aryl-4-hydroxycoumarins

[reaction: see text] A palladium-catalyzed coupling reaction of phenyliodonium zwitterions with aryl boronic acids has been developed. The unique characteristics of the mild reaction conditions and convenient synthetic accessibility of phenyliodonium zwitterions make this method a valuable tool for generating diversified 3-aryl-4-hydroxycoumarins.     

I2-promoted tandem cyclization to synthesize polysubstituted pyrano[3,2-c]chromene-2,5-diones

An efficient and convenient method for the synthesis of various substituted pyrano[3,2-c]chromene-2,5-diones was developed via the I₂-promoted tandem cyclization of commercially available aryl methyl ketones and 4-hydroxycoumarins. Preliminary mechanism studies indicated that the reaction involved a consecutive iodination/Kornblum oxidation/annulation process. HI produced in the I₂-DMSO system acted as an important promoter, accelerating the annulation protocol.     

HBr/H2O2-mediated formation of C–S bond with thiosulfates

A novel, efficient, and green protocol to construct C–S bond has been developed via HBr/H₂O₂-mediated sulfenylation of styrenes and 4-hydroxycoumarins leading to unsymmetrical sulfides. Various unsymmetrical sulfides were prepared in one step with moderate to good yields using environmentally-friendly H₂O₂ as oxidant and HBr as catalyst. Based on the preliminary experimental results, a plausible reaction mechanism was proposed for HBr/H₂O₂-mediated formation of C–S bond with thiosulfates.     

Condensation of propargylic alcohols with 1,3-dicarbonyl compounds and 4-hydroxycoumarins in ionic liquids (ILs)

Propargylic alcohols are activated toward 1,3-diketones by Lewis or Brønsted acidic ionic liquids (ILs) without an added catalyst, but significantly better conversions are achieved with metallic triflates [in particular Sc(OTf)₃ and Ln(OTf)₃] and bismuth nitrate in imidazolium ILs. The scope of this condensation reaction was investigated with a variety of propargylic alcohols and a host of acyclic and cyclic dicarbonyl compounds. Concomitant cycloisomerization leading to tetrasubstituted furans was observed with the propargylic alcohols 1b and 1c in reaction with 1,3-diketone 2b and the β-ketoester 2c. With propargylic alcohol 1c, propargylation, cycloisomerization, or dienone formation were observed, depending on the structure of the 1,3-dicarbonyl compound. The [BMIM][PF₆]/Bi(NO₃)₃·5H₂O system proved efficient for propargylation, vinylation, and alkylation of 4-hydroxycoumarins. The recycling and reuse of the IL are added advantages of this method.     

Synthesis and study of the properties of 4-substituted 3-aminomethylcoumarins

The aminomethylation of 4-hydroxycoumarin gave 3-pyrrolidinomethyl- and 3-piperidinomethyl-4-hydroxycoumarins, which were converted to 4-chloro derivatives by the action of phosphorus oxychloride. A number of 3-pyrrolidinomethyl- and 3-piperidinomethyl-4-aminocoumarins were synthesized by reaction of the 4-chloro derivatives with various amines, and some of their properties were studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 896–899, July, 1982.     

Solid phase synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins

A solid phase strategy has been developed for the synthesis of 3-(5-arylpyridin-2-yl)-4-hydroxycoumarins. The key transformation is an intramolecular ipso substitution reaction which forms the coumarin heterocycle and culminates with cleavage of product from the polymer support. The pyridine moiety at C3 can be further modified with Suzuki coupling. A sample library with two diversity elements has been synthesized to demonstrate this ipso substation-based cyclo-elimination strategy.     

Convenient Michael addition/β-elimination approach to the synthesis of 4-benzyl- and 4-aryl-selenyl coumarins using diselenides as selenium sources

A concise and efficient, two-step approach toward 4-organoselenyl coumarin derivatives from the easily available 4-hydroxycoumarins, is reported. The synthesis was based on conventional tosylation followed by a tandem selena-Michael addition/β-elimination reaction of an aryl-/benzyl-selenolate anion on the corresponding 4-tosyloxycoumarins. The selenolate anions were conveniently generated in situ by exposure of the corresponding diselenides to NaBH₄. Selected compounds demonstrated to exhibit antioxidant properties in mice cortex and hippocampus.     

Aminomethylation of cytisine by 3-hetaryl-7-hydroxycoumarins

8-Aminomethyl derivatives of 7-hydroxycoumarins were prepared by reaction of methylene-bis-cytisine and substituted 7-hydroxycoumarins. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 145–148, March–April, 2007.     

Synthesis and structure of 4-hydroxy-3-pyridylcoumarins

The reaction of substituted 3-cinnamoyl-4-hydroxycoumarins with pyridinium salts of various bromomethyl ketones gives the corresponding 4-hydroxy-3-pyridylcoumarins. The use of microwave radiation decreases the time required and improves the yield of this reaction. The products obtained do not display solvatochromic properties or photochemical activity.     

Synthesis of zwitterionic 4-hydroxycoumarin derivatives through a unique reaction of 4-hydroxycoumarins with p- benzoquinone and pyridine

[reaction: see text] A unique reaction of 4-hydroxycoumarins with p-benzoquinone and pyridine was found, and through the reaction, six zwitterionic 4-hydroxycoumarin derivatives were synthesized. The structures of these compounds were determined by IR, MS(ESI), 1H NMR, 13C NMR, and single-crystal X-ray diffraction studies.     

A different route to 3-aryl-4-hydroxycoumarins

We herein report the simple and direct arylation of 4-hydroxycoumarins by photoinduced reaction with aryl halides (iodobenzene, iodonaphthalene, 4-iodoanisole, 2-iodoanisole). Good yields of 3,4-disubstituted coumarins were obtained in these reactions (>60%). Extension of the procedure to the reaction with o-dihalobenzenes leads to the synthesis of ring closure products which bear a tetracyclic aromatic-condensed ring system, although in lower overall yields (≈45%).     

Condensation of 2-hydroxyacetophenones with trichloroacetonitrile as a route to 2-trichloromethylchromones and 4-hydroxycoumarins

Condensation of 2-hydroxyacetophenones with trichloroacetonitrile in the presence ofN-methylanilinomagnesium bromide affords hydroxyaryl β-amino-β-trichloromethylvinyl ketones, which are converted into 2-trichloromethylchromones upon treatment with concentrated HCl. The resulting compounds react with alcoholic solutions of NH₃ or KOH to form 3-amino-1-(2-hydroxyaryl)-4,4,4-trichlorobut-2-en-1-ones and 4-hydroxycoumarins, respectively. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 476–479, March, 2000.     

Synthesis and properties of 4-chloromethyl-6-hydroxy-coumarins and 4-(2-benzofuryl)-6-hydroxycoumarins

New 4-chloromethyl-6-hydroxycoumarins have been obtained by the condensation of hydroquinone derivatives with 4-chloroacetoacetic ester, and have been used for the synthesis of 4-(2-benzofuryl)-6-hydroxycoumarins. Alkylation and acylation of the phenolic hydroxyl of the synthesized 4-(2-benzo-furyl)coumarins have been investigated. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 361–369, March, 2009.     

Structure and stereochemistry of the coumarins ofFerula lehmannii

Two new 7-hydroxycoumarins have been isolated from the roots ofFerula lehmannii (Lehmann's giant fennel): lehmferidin (I), C₂₄H₂₈O₄, M⁺ 380, mp 173–174°C, and lehmferin (II), C₂₄H₃₀O₄, M⁺ 382, mp 118–119°C; and badrakemin (III) has also been identified. The structures and configurations of the asymmetric centers of the new coumarins have been established on the basis of spectral characteristics and conversion into known substances.Institute of the Chemistry of Plant Substances, Academy of Sciences of the Uzbek SSR, Tashkent. Translated from Khimiya Prirodnykh Soedinenii, No. 6, pp. 709–712, November–December, 1983.     

Synthesis of some 3-substituted 4-methyl-7-hydroxycoumarins

The Pechmann condensation reaction was used to synthesize a number of 4-methyl-7-hydroxycoumarins possessing a chain of three carbon atoms at position 3.     

Selective solution-phase synthesis of BiOCl, BiVO4 and δ-Bi2O3 nanocrystals in the reaction system of BiCl3-NH4VO3-NaOH

In this study, we demonstrate a straightforward solution-phase method for the selective synthesis of BiOCl, BiVO₄ and δ-Bi₂O₃ nanocrystals by simply manipulating the reaction temperature and the BiCl₃-to-NaOH mole ratio in the reaction system of BiCl₃-NH₄VO₃-NaOH. The experimental results revealed that BiOCl, as the sole product, was prepared when designating the reaction temperature ranging from room temperature to 100 °C, regardless of the BiCl₃-to-NaOH mole ratio; on the other hand, BiOCl, BiVO₄, and δ-Bi₂O₃ nanocrystals could be selectively prepared at 140-180 °C, depending on the BiCl₃-to-NaOH mole ratio in solution. Significantly, we first report on fabricating δ-Bi₂O₃ sample, the high-temperature cubic phase commonly stabilized at 730-824 °C, at the low reaction temperature of 140-180 °C under solution-phase synthetic conditions. In addition, the δ-Bi₂O₃ sample exhibits strong emission at room temperature.     

Reactions of 5,6,7,8-tetrafluoro-4-hydroxycoumarin derivatives with benzylamine and aniline

5,6,7,8-Tetrafluoro-4-hydroxycoumarin reacted with benzylamine under mild conditions to give a stable salt, while its refluxing with aniline or benzylamine in xylene afforded 5,6,7,8-tetrafluoro-4-phenyl(benzyl)aminocoumarins. Reactions of 3-acetyl(acetimidoyl)-5,6,7,8-tetrafluoro-4-hydroxycoumarins with benzylamine followed different pathways, depending on the solvent. Condensation at the acyl substituent can be accompanied by replacement of the F atom in position 7. 3-Acetylcoumarin formed a salt, while 3-acetimidoylcoumarin yielded a 7-monosubstituted product. 3-Acetyl(acetimidoyl)-5,6,7,8-tetrafluoro-4-hydroxycoumarins reacted with aniline to give only 5,6,7,8-tetrafluoro-4-hydroxy-3-(N-phenylacetimidoyl)coumarin. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1170–1174, July, 2006.