865. Synthetic aspects of free-radical addition. Part I. Radical-alkylation of malonic ester and related compounds

Allen, Joseph C.; Cadogan, J. I. G.; Harris, Betty W.; Hey, D. H.

doi:10.1039/jr9620004468

Cited by 15 publications

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“…The crude oily residue was purified by flash chromatography (CHCl 3 /acetone) to give 31a as a pale yellow oil (3.1 g; 37%). (Lit . bp 0.4 79–83 °C); R f : 0.68 (CHCl 3 ); 1 H NMR (400 MHz; DMSO- d 6 ) δ H : 0.86 (t, 3H, CH 3 , J = 6.7 Hz), 1.18 (t, 3H, CH 2 C H 3 , J = 7.3 Hz), 1.23–1.75 (m, 12H, 6 × CH 2 ), 2.06 (s, 3H, CH 3 CO), 2.39 (q, 2H, 3-CH 2 , J = 7.3 Hz), 3.61 (t, 1H, 2H, J = 6.7 Hz) and 4.12 (q, 2H, C H 2 CH 3 , J = 7.1 Hz); MS (FAB + ) m / z : 243.2 [100, (M + H) + ]; MS (FAB – ) m / z : 241.2 [100, (M – H) − ]; Acc.…”

Section: Methodsmentioning

confidence: 99%

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C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

et al. 2018

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Synthetic routes to potent bicyclic nonsteroidal sulfamate-based active-site-directed inhibitors of the enzyme steroid sulfatase (STS), an emerging target in the treatment of postmenopausal hormone-dependent diseases, including breast cancer, are described. Sulfamate analogs 9–27 and 28–46 of the core in vivo active two-ring coumarin template, modified at the 4- and 3-positions, respectively, were synthesized to expand structure–activity relationships. α-Alkylacetoacetates were used to synthesize coumarin sulfamate derivatives with 3-position modifications, and the bicyclic ring of other parent coumarins was primarily constructed via the Pechmann synthesis of hydroxyl coumarins. Compounds were examined for STS inhibition in intact MCF-7 breast cancer cells and in placental microsomes. Low nanomolar potency STS inhibitors were achieved, and some were found to inhibit the enzyme in MCF-7 cells ca. 100–500 more potently than the parent 4-methylcoumarin-7-O-sulfamate 3, with the best compounds close in potency to the tricyclic clinical drug Irosustat. 3-Hexyl-4-methylcoumarin-7-O-sulfamate 29 and 3-benzyl-4-methylcoumarin-7-O-sulfamate 41 were particularly effective inhibitors with IC50 values of 0.68 and 1 nM in intact MCF-7 cells and 8 and 32 nM for placental microsomal STS, respectively. They were docked into the STS active site for comparison with estrone 3-O-sulfamate and Irosustat, showing their sulfamate group close to the catalytic hydrated formylglycine residue and their pendant group lying between the hydrophobic sidechains of L103, F178, and F488. Such highly potent STS inhibitors expand the structure–activity relationship for these coumarin sulfamate-based agents that possess therapeutic potential and may be worthy of further development.

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Section: Methodsmentioning

confidence: 99%

“…(Lit. 63 . This was prepared by general method using resorcinol (910 mg; 8.26 mmol), 31a (2.0 g; 8.3 mmol), and a mixture of CF 3 COOH (1.27 mL; 16.3 mmol) and conc.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

et al. 2018

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“…Diethyl 2-cyclohexylmalonate (2h) was prepared from 1-bromocyclohexane and diethyl malonate as described in ref. [19]. Diethyl 2-heptylmalonate (2i) was prepared from 1-bromoheptane and diethyl malonate as described in ref.…”

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Synthesis and ring closure reactions of pyrido[3,2,1-jk]carbazol-6-ones

Dang

Knobloch

Habib

et al. 2005

Journal of Heterocyclic Chemistry

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4-Hydroxy-5-phenylpyrido[3,2,1-jk]carbazol-6-ones (4, 5), which were obtained from carbazoles 1 and malonates 2 or 3, were converted to reactive intermediates such as 4-chlorides 9 or 4-tosylates 10, which gave in turn 4-azido-5-phenyl derivatives 11. 5-Alkyl-4-azides 11 were not obtained in this manner; however a new one-pot azidation reaction was developed starting from 4-hydroxy derivatives 4 which gave azides 11 in good yields. 4-Azido-5-phenyl derivative 11f cyclized on thermolysis to the indole 12. The thermal behaviour of the azides 11 was studied by thermoanalytical methods (DSC).J. Heterocyclic Chem., 42, 85 (2005).Pyrido[3,2,1-jk]carbazol-6-one is part of the heterocyclic skeleton of many natural products (e.g., strychnos alkaloids such as strychninolones and brucinolones [2], picrasidin Q [3] and olivacine alkaloids [4]). It possesses the biologically interesting combination of indole and 2-pyridone structures. Moreover, some derivatives have found interest in pharmacological [5] or in dye chemistry [6]. Our interest is focused to 4-hydroxy-5-substituted pyrido[3,2,1-jk]carbazol-6-ones (4, 5) which possess 2 reactive positions: the hydroxy group at C-4, which can be substituted by various nucleophiles, and the CH-acidic proton at C-5, which reacts with a large number of electrophiles. In this contribution we want to report an improved synthesis of 4-hydroxy-5-substituted pyrido-[3,2,1-jk]carbazol-6-ones, the acetylation, tosylation and the nucleophilic exchange of the hydroxy groups.The synthesis of some 4-hydroxy-5-substituted pyrido[3,2,1-jk]carbazol-6-ones 4 is described in the literature in a few cases either by thermal condensation of malonates 2 with carbazole 1a at about 300 °C with moderate yields [7], or by thermal condensation of dichlorophenylmalonates with carbazole 1 at 260 °C with good yields [8]. We adopted the cyclocondensation methods of malonates with 1,3-dinucleophiles earlier described for quinolones and related compounds [9] for the synthesis of 4-hydroxy-5-substituted pyrido[3,2,1-jk]carbazol-6-ones 4 and 5. The first reaction step leads in a condensation reaction at about 200 °C to the monoanilides of the carbazole 1a with the malonates 2; the end of this reaction step can be easily observed by the end of ethanol evolution; further thermolysis at higher temperatures (300-350 °C) gives, by elimination of the second equivalent of ethanol, an intermediate α-oxo ketene which attacks in an electrophilic reaction the ortho-position of the aromatic ring to cyclize to the pyrido[3,2,1-jk]carbazol-6-ones 4. The yields of this reaction type are within 60-90% except with the octadecyl malonate 2j; in this case only 24% of 4j was obtained. It was also possible to carry out this reaction in one step without interruption when a 1:1 mixture of the malonate and the carbazole 1a was heated for 12 hours in refluxing diphenyl ether solution which limits the thermolysis temperature to 253 °C. The yields are within 60-80% comparable to the stepwise reaction; the workup however is easier and the purit...

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“…°C for 7 h. After evaporation of the solvent under reduced pressure, the residue was purified by a silica gel column chromatography (1.1 X 15 cm), eluting with hexane/ethyl acetate (3:1), to give a mixture (10.3 mg) of the chromenol derivative 11 and its 9-epimer: NMR (CDC13) 1.00 (3 H, d, J = 7 Hz), 1.01 (3 H, s), 1.46 (3 H, s), 2.31 (1 H, m), 3.77 (3 H, s), 3.80 (3 H, s), 4.65 (0.5 H, s), 4.66 (0.5 H, s), 4.70 (0.5 H, s), 4.72 (0.5 H, s), 5.19 (1 H, s), 5.72 (1 H, d, J = 9.9 Hz), 6.47 (1 H, s), and 6.56 (1 H, d, J = 9.9 Hz); EIMS, m/z 372 (M+), 221, 207, and 191. The mixture (8.3 mg) of 11 and 9-ep¿-ll was treated with an excess of diazomethane in an ether solution (15 mL) in the presence of silica gel (Wako gel C-300, 4 mg) at room temperature for 19 h. Evaporation of the solvent and purification by a silica gel column chromatography (1.1 X 17 cm), eluting with hexane/ethyl acetate (4:1), afforded a mixture (1.8 mg) of trimethoxychromenol derivative 9 and its 9-epimer: NMR (CDC13) 1.01 (3 H, s), 1.02 (3 H, d, J = 6.4 Hz), 1.45 (3 H, s), 3.79 (3 H, s), 3.83 (3 H, s), 3.84 (3 H, s), 4.66 (0.5 H, s), 4.67 (0.5 H, s), 4.72 (0.5 H, s), 4.73 (0.5 H, s), 5.68 (1 H, d, J -10.1 Hz), 6.47 (1 H, s), and 6.67 ( Bioassay Methods. Rabbits (2-3 kg) were sacrificed by cervical dislocation and the hearts were excised in cold Krebs-Ringer bicarbonate solution of the following composition (mM): NaCl, 120; KC1, 4.8; CaCl2,1.2; MgS04,1.3; KH2P04,1.2; NaHC03, 25.2; and glucose, 5.8; pH 7.4.…”

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confidence: 99%

A simple direct procedure for the regiospecific preparation of chloro aromatic compounds

Bay¹,

Timony²,

Leone-Bay³

1988

J. Org. Chem.

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865. Synthetic aspects of free-radical addition. Part I. Radical-alkylation of malonic ester and related compounds

Cited by 15 publications

References 0 publications

C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

C-3- and C-4-Substituted Bicyclic Coumarin Sulfamates as Potent Steroid Sulfatase Inhibitors

Synthesis and ring closure reactions of pyrido[3,2,1-jk]carbazol-6-ones

A simple direct procedure for the regiospecific preparation of chloro aromatic compounds

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