Synthesis of new chlorine-substituted derivatives of 2-tetralone

Rosowsky, A.; Battaglia, Josephine; Chen, Katherine K. N.; Modest, Edward J.

doi:10.1021/jo01275a069

Cited by 33 publications

(12 citation statements)

References 2 publications

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“…6-Chloro-2-tetralone (1c) was prepared by the reaction of 4-chlorophenylacetyl chloride (8.93 g, 47.2 mmol) with excess ethylene and anhydrous AlCl 3 (13 g) in anhydrous dichloromethane (120 mL). , Column chromatography (silica, Merck 60, CH 2 Cl 2 ), followed by recrystallization gave pure 1c (7.11 g, 84%), mp 67.0−67.5 °C (lit. : 68−70 °C) . TLC (CH 2 Cl 2 ), R f = 0.24.…”

Section: Methodsmentioning

confidence: 99%

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Transition State Imbalance in the Deprotonation of Substituted 2-Tetralones by Hydroxide Ion

et al. 1997

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Rate and equilibrium constants for the deprotonation of a series of phenyl-substituted 2-tetralones in aqueous sodium hydroxide have been determined. A Brønsted plot of log k for deprotonation vs pK a of the appropriate 2-tetralone is linear with a slope (−α) of −0.60 ± 0.01, except for the point corresponding to 6-nitro-2-tetralone (1b). The negative deviation of 1b from the correlation indicates that the transition state for deprotonation of 2-tetralone is imbalanced, with delocalization of charge into the phenyl ring lagging behind proton transfer. A semiquantitative assessment of the charge distribution in both the fully formed anion and the transition state for deprotonation was calculated from these results and 13C NMR spectra of the 2-tetralone anion in methanol/water mixtures. Although approximately twice as much negative charge is localized on the oxygen than on the enolate carbon in the anion, slightly more charge is on the enolate carbon in the transition state.

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Section: Methodsmentioning

confidence: 99%

“…7-Chloro-2-tetralone (1f). 3-Chlorophenylacetyl chloride (5.54 g, 32.5 mmol) was reacted with ethylene and anhydrous AlCl 3 (8 g) in anhydrous dichloromethane (120 mL) as for 1c …”

Section: Methodsmentioning

confidence: 99%

Transition State Imbalance in the Deprotonation of Substituted 2-Tetralones by Hydroxide Ion

et al. 1997

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“…3-Amino-9-ethylbenzo[/]quinazolin-l(2£7)-one (22). A solution of 3-amino-9-vinylbenzo [/] quinazolin-1 (27í)-one (0.060 g, 0.25 mmol) and 10% palladium on carbon (0.10 g) (Aldrich) in ethanol (200 mL) was shaken under hydrogen (40 psi) for 1 h and then filtered through Celite and concentrated in vacuo.…”

Section: -Amino-6-(methoxymethyl)benzo[/]quinazolin-l(2fl)one (4bb) (...mentioning

confidence: 99%

Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some 3-amino- and 3-methylbenzo[f]quinazolin-1(2H)-ones

Pendergast¹,

Johnson²,

Dickerson³

et al. 1993

J. Med. Chem.

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The synthesis and thymidylate synthase (TS) inhibitory activity of a series of simple benzo[f]-quinazolin-1(2H)-ones are described. Fully aromatic 3-amino compounds with compact lipophilic substituents in the 9-position were found to have I50 values as low as 20 nM on the isolated enzyme, and represent the first examples of potent, folate-based TS inhibitors that completely lack any structural feature corresponding to the (p-aminobenzoyl)glutamate moiety of the cofactor. A number of the compounds also showed moderate growth inhibitory activity against a human colon adenocarcinoma cell line (SW480), with IC50 values as low as 2 microM.

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“…2-Aminotetralins 19 and 20 (class H) were synthesized (Scheme IV) starting from 6,7-dichloro-2-tetralone (54). 21 Reductive amination of 54 with l-(2-aminoethyl)pyrrolidine and NaCNBHg in the presence of CH3COOH gave 19 in 55% yield. This was readily transformed to its iV-methyl derivative 20. The characterization of most of the compounds reported herein is summarized in Table IV.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and evaluation of conformationally restricted N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamines at .sigma. receptors. 2. Piperazines, bicyclic amines, bridged bicyclic amines, and miscellaneous compounds

Costa¹,

He²,

Linders³

et al. 1993

J. Med. Chem.

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As a continuation of our earlier study (J. Med. Chem. 1992, 35, 4334-4343) we conformationally restricted the sigma-receptor ligand 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylamine (1) by incorporating it into a series of homologous piperazines 3-9 and homopiperazines 10 and 11, diazabicyclononanes and decanes, bridgehead bicyclooctanes and nonanes as well as other miscellaneous compounds. sigma-Receptor binding affinities were obtained using [3H](+)-pentazocine in guinea pig brain membrane sigma 1 sites. The studies suggest that the nitrogen lone pair orientation found in the piperazines affords the strongest binding interaction. Other nitrogen lone pair orientations or compounds representing unlikely staggered conformations of 1 [ as in 4-[2-(3,4-dichlorophenyl)ethyl]-1,4-diazabicyclo[3.2.2]nonane (16)] show very weak sigma interaction. Comparison of the binding data of different N-substituted homologues of 1 with those of the 1-[2-(3,4-dichlorophenyl)ethyl]-4-alkylpiperazines suggests that the two nitrogen atoms of 1 are working in opposition to one another in terms of their sensitivity to steric bulk. The high binding affinity of the 1,4-diazabicyclo[4.3.0]nonanes 12 suggests that these may approximate the methyl and pyrrolidine ring conformations found in 1 when it is bound to the sigma receptor. Compound 12 exhibited a 4-fold enantioselectivity favoring (+)-12. The synthesis of 6,7-dichloro-2-[[2-(1-pyrrolidinyl)ethyl]amino]tetralin (19) and its desmethyl derivative 20 permitted constraint of the 3,4-dichlorophenyl and N-methyl moieties of 1 into a gauche orientation. The binding data suggests that this conformation in 1 favors strong binding interaction at sigma-receptors. sigma-Receptor Ki's ranged from 0.55 nM for 1-[2-(3,4-dichlorophenyl)ethyl]-4-n-butylpiperazine (7) to 654 nM for 16. Overall comparison of the results indicate that 1 is subject to considerable conformational freedom and suggests that the sigma receptor is not subject to rigid stereochemical restraints with 1. These results add to our earlier study where we restrained 1 using simple monocyclic heterocycles.

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Synthesis of new chlorine-substituted derivatives of 2-tetralone

Cited by 33 publications

References 2 publications

Transition State Imbalance in the Deprotonation of Substituted 2-Tetralones by Hydroxide Ion

Transition State Imbalance in the Deprotonation of Substituted 2-Tetralones by Hydroxide Ion

Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some 3-amino- and 3-methylbenzo[f]quinazolin-1(2H)-ones

Synthesis and evaluation of conformationally restricted N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamines at .sigma. receptors. 2. Piperazines, bicyclic amines, bridged bicyclic amines, and miscellaneous compounds

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