Trifluoroacetic Acid-Mediated Hydroarylation:  Synthesis of Dihydrocoumarins and Dihydroquinolones

Li, Kelin; Foresee, Lindsay N.; Tunge, Jon A.

doi:10.1021/jo0477650

Cited by 136 publications

(55 citation statements)

References 10 publications

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“…NMR experiments were obtained on Bruker Avance-300 MHz instrument with tetramethylsilane (TMS) as internal standard. All the 1 H and necessary 13 C spectral data are reported. Electrospray ionization (ESI) mass spectra were recorded on Shimadzu LC-MS after dissolving the compounds in methanol.…”

Section: Methodsmentioning

confidence: 99%

“…6 was stirred with 3,4,5-trimethoxycinnamic acid methyl ester (10a) in trifluoroacetic acid at room temperature for 24 h to produce the desired product (12) in 34% yield. 13) Similarly, various other phenols such as 3-methoxyphenol, 3,5-dimethoxyphenol, 3,4-dimethoxyphenol, 6-methoxy-2-naphthol, and estrone were used to produce the corresponding neoflavonoids (24-28).…”

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Design and Synthesis of C-Ring Lactone- and Lactam-Based Podophyllotoxin Analogues as Anticancer Agents

et al. 2010

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Podophyllotoxin (1, PDT, Fig. 1) is a well known naturally occurring potent cytotoxic aryltetralin lignan isolated from the genus Podophyllum (family: Berberidaceae). 1) Two of its known analogues etoposide (2) and teniposide (3) show DNA topoisomerase II inhibition activity 2) and are among the frontline antitumour drugs against various cancers, including small cell lung cancer, testicular carcinoma, and Kaposi's sarcoma.3) A different mode of action of 2 and 3 by minor structural modifications of 1 has been attributed to pdemethylation in E-ring, inversion of stereochemistry at C-4 position, and addition of a sugar unit. 4) Furthermore, the replacement of C-4 sugar unit of etoposide with a heteroatom (O, N, or S) linked moieties helped in overcoming the problem of drug resistance to etoposide. 5) Subsequently, a large number of analogues have been reported exhibiting comparable or better activity than 2 and 3. 6)The present study was aimed at designing potential cytotoxic PDT analogues taking lactone and lactam moieties as targets. A series of neo-flavonoids was prepared in which the lactone moiety was shifted from ring D to ring C to fulfil the structural requirements (Prototype-I). Alternatively, some lactams (Prototype-II) were also synthesized to replace the oxygen by a nitrogen unit, since N-linked congeners were reported to have better activity than O-linked and S-linked11) Some PDT analogues devoid of ring A were also synthesized.Chemistry The strategy to synthesize lactones and lactams is depicted in Chart 1 in which piperonal (4) was used as starting material. The aldehydic group of piperonal was oxidized to formate ester (5) by Baeyer-Villiger oxidation using m-chloroperbenzoic acid (m-CPBA) in dichloromethane at room temperature in 22% yield.12) The formate ester (5) was hydrolyzed with 5% aqueous methanolic KOH to produce the corresponding phenol (6) in 82% yield. However, due to poor yield in the first step, piperonal was replaced with 3,4-methylenedioxyacetophenone (7). 7 on Baeyer-Villiger oxidation with m-CPBA yielded the corresponding acetate ester (8) in 47% yield. On alkaline hydrolysis, 8 yielded 3,4-methylenedioxyphenol (6) in 95% yield. 6 was stirred with 3,4,5-trimethoxycinnamic acid methyl ester (10a) in trifluoroacetic acid at room temperature for 24 h to produce the desired product (12) in 34% yield.13) Similarly, various other phenols such as 3-methoxyphenol, 3,5-dimethoxyphenol, 3,4-dimethoxyphenol, 6-methoxy-2-naphthol, and estrone were used to produce the corresponding neoflavonoids (24-28).To produce lactams as per prototype-II, 3,4,5-trimethoxycinnamic acid (10b) was condensed with 3,4-methylenedioxyaniline in presence of N-(3-dimethylaminopropyl)-NЈ-ethylcarbodiimide hydrochloride (EDC), 4-(dimethylamino)pyridine (DMAP) and N-hydroxybenzotriazole (HOBt) in N,N-dimethylformamide (DMF) to yield a corresponding amide (16). Amide (16) on stirring in trifluoroacetic acid (TFA) for 72 h yielded the corresponding lactam (18). 13)The p-demethylated lactone (13) was synthesized by stirr...

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Section: Methodsmentioning

confidence: 99%

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Design and Synthesis of C-Ring Lactone- and Lactam-Based Podophyllotoxin Analogues as Anticancer Agents

et al. 2010

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“…It is possible that dihydrocoumarin, which attaches ferrocenyl, will increase its biological activity. 3,4-Dihydroquinolin-2(1H)-one can be prepared in good yield in the presence of acid catalyst by coupling anilines with cinnamic acids prior to hydroarylation [19][20] . The synthesis of dihydroquinolin with attached ferrocenyl has never been reported.…”

Section: Introductionmentioning

confidence: 99%

A synthesis of ferrocenyl dihydrocoumarin and ferrocenyl dihydroquinolin-2(1H)-ones

Wang¹,

Fan²,

Luo³

et al. 2011

Arkivoc

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A series of phenols have been used to react with ferrocenyl cinnamic acid, and the results of 1 H NMR and crystal structures have shown that only resorcinol and 2-naphthalenol can get ring closure products, while the others only get esterified products. This is because resorcinol and 2-naphthalenol have higher electronic density in ortho-site of hydroxyl than other phenols used in this work. Ten ferrocenyl dihydroquinolin-2(1H)-ones are synthesized by hydroarylation of ferrocenyl acrylic amides in the presence of TFA, and an interpretation is also given to the experimental fact that strong acid can not catalyze hydroarylation of acrylic anilides to dihydroquinolones.

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Analysis of hydrogen-bond patterns of a new coumarin ester

Napolitano¹,

Silva²,

Aquino³

2013

Acta Cryst Sect A

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[1,2] It has been discovered a wide range of biological activities for the derivatives of cinnamic acid. There are reports that the derivatives transcinnamic acid possess hepatoprotective activity, antimalarial, antimicrobial, antioxidant and α-glucosidase. The cinnamic esters are also important intermediates in chemical reactions, such as hydroarylation in the presence of strong acid and Phenol forming the dihydrocoumarins [3] . The single crystals of the Ethyl-(2E)-3-(4-hydroxy-3,5-dimethoxyphenyl)-prop-2 enoate (C 13 H 16 O 5 ) were obtained by slow evaporation technique using ethyl ether as solvent. The structure was solved by Direct Methods and refined by full matrix Least Square methods on F 2 , using WINGX package. Non H atoms were refined anisotropically and all H atoms were placed geometrically, except those of the water molecule and hydroxyl, that were placed by D.W. Smith method. The compound crystallizes in the C2/c monoclinic space group with 23018 measured reflections and 4279 unique and 2587 observed [I > 2σ(I)]. The final residual factor R1 is 0.0607 for 181 refined parameters using 25 restraints. In the asymmetric unit there is a disordered water molecule that causes a partial disorder on the ester molecule. The water molecule of this compound does five intramolecular hydrogen bonds and three of them are significantly smaller than the sum of their van der Waals radii [4] , indicating one strong intra molecular interaction between the oxygen charge centers, and another one of this bonds is directed to a hydroxyl of the ester molecule.Throughout the electron density map we observed two peaks of residual electron density instead of one around the oxygen atom of this hydroxyl, suggesting that the hydrogen of this hydroxyl was also occupying two site positions. The observed disorder may be caused by a repulsive interaction between the hydrogen of the water molecule and the hydroxyl of the coumarin ester. The importance of it is due its harmonic characteristic that the atoms involved in the disorder show all the components in the disorder have the same site occupancy factor (about 48% through 52%) for each group, that may be indicating a resonance along the structure. Finally, the watercoumarin calculations using the DFT method have strengthened this structural finding, since our theoretical approaches also suggest two welldefined conformations of similar energies which resemble the molecular geometries determined by X-ray diffraction.

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Trifluoroacetic Acid-Mediated Hydroarylation: Synthesis of Dihydrocoumarins and Dihydroquinolones

Cited by 136 publications

References 10 publications

Design and Synthesis of C-Ring Lactone- and Lactam-Based Podophyllotoxin Analogues as Anticancer Agents

Design and Synthesis of C-Ring Lactone- and Lactam-Based Podophyllotoxin Analogues as Anticancer Agents

A synthesis of ferrocenyl dihydrocoumarin and ferrocenyl dihydroquinolin-2(1H)-ones

Analysis of hydrogen-bond patterns of a new coumarin ester

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