Reduction of nitrogen heterocycles by lithium in liquid ammonia. III. Indoles and quinolines

Remers, William A.; Gibs, Gabriel J.; Pidacks, C.; Weiss, Martin J.

doi:10.1021/jo00801a009

Cited by 42 publications

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“…Comparison of the NMR-spectra of the intermediate 4,7-dihydroindoles of 6 and 10 with the spectrum of 4,7-dihydro-l-methyl-5-methoxy-indole 7 ) showed the same typical signals for the vinylic and aliphatic protons. The identity of the hydrolized indolones 6 and 10 was established by IH_ NMR spectroscopy and elemental analysis.…”

Section: Chemistrymentioning

confidence: 74%

“…phase was washed with saturated NaHC0 3 solution and dried (Na2S0.). After evaporation of the CH 2CI2 the residue was purified by column chromatography (Si~; CH~12 Schiller, von Angerer, and Schneider 2-(4-BenzyJoxyphenyl)-6-methoxy-3-methylindole (7) A solution of 35 mmol (11.17 g) of2-bromo-(4-benzyloxy)-propiophenone in 25 mI xylene was added slowly 10 a boiling mixture of 120 mmol (15.00 g) of m-anisidine and 35 mI of N,N-dimethylaniline with stirring. The mixture was kept at 1700C bath temp.…”

Section: -(4-acetoxyphenyj)-i-ethyl-jmethoxy-3-methylindoje(s)mentioning

confidence: 99%

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6,7‐Dihydro‐4H‐indolones: Synthesis and biological properties

Schiller

Angerer

Schneider

1991

Archiv der Pharmazie

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767Synthesesof 6.7-dihydr0-4H-indolones 6 and 10 by a selective Birch reduction of the benzene ring of the indole system are described.1be antiestrogen zindoxifene and the 2-phenylindole Z as well as 6 and 10 were tested for their relative bindingaffmitiesat the androgen receptoras well as for antiandrogenicand estrogenicproperties,Both compounds6 and 10 showed potent indirect antiandrogenic activity which were similar to those of the 2-phenylindoleszindoxifeneand 2.The main structural difference between estradiol and testosterone lies in ring A of the steroid system. For binding to the estrogen receptor (ER). a functional group with proton donor characteristics (phenolic OH-group) is essential ll • Many steroidal and nonsteroidal estrogens like estradiol. diethylstilbestrol (DES) or hexestrol (HES) as well as many nonsteroidal antiestrogens like hydroxytamoxifenor zindoxifene thus possess a hydroxylated phenyl ring.In contrast to estrogens a functional group with proton acceptor characteristics (keto group) is necessary for compounds with the ability to bind to the androgen receptor (AR)ll. Endogenous androgens like testosterone (1) and dihydrotestosterone(DHT) as well as the steroidal antiandrogen cyproterone acetate (CPA) contain a keto-group in position 3 of ring A.We have shown 2 ) that hydrogenation of one of the phenyl rings of hexestrol to a cyclohexenone system led to compounds with increased AR binding affinity and interesting biological propenies. 6,7.Dihydro-4H-lndolone: Synthese und blologJscheElgenscharten Die Synthese der 6.7-Dihydr0-4H-indolone 6 und 10 durch selektive BirchReduktion des Benzolringesdes Indolsysterns werden beschrieben,Das Antillstrogen Zindoxifen und das 2-Phenylindol 2 sowie 6 und 10 wurden auf ihre relative Bindungsaffinitlit zurn Androgenrezeptor sowie antiandrogene und llstrogene Aktivitllt untersucht, Beide Velbindungen 6 und 10 zeigten ausgeprligte indirekte antiandrogene Eigenschaften. die im Bereich der der 2-Phenylindole Zindoxifenund 2 lagen, ChemistryPowerful reduction systems such as alkali metals in liquid ammonia are capable of reducing indoles. Ring selectivity can be controlled by the presence or absence of a proton source like methanol. The presence of excess methanol leads to the preferential reduction of the benzene ring. If methanol is omitted, usually the heterocyclic pyrrole ring is reduced6,7).In the class of the antiestrogenic 2-phenylindoles selectivity of reduction is complicated by the presence of a second aromatic system. Aromatic carbocycles like fluorene containing both a methoxy and a hydroxy group are only reduced in the methoxy substituted moiety'", In the same way, treatment of compound 5 (with an acetoxy group in the 2-phenyl moiety and a 5-methoxy group in the indole moiety) with lithium in liquid ammonia in the presence of methanol yieldedAs the antiestrogen zindoxifene, a 2-phenylindole derivative, showed very promising tumor inhibitory effects against a variety of prostatic carcinoma tumor models 3 ,4l, we investigated the effect of the r...

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Section: Chemistrymentioning

confidence: 74%

Section: -(4-acetoxyphenyj)-i-ethyl-jmethoxy-3-methylindoje(s)mentioning

confidence: 99%

6,7‐Dihydro‐4H‐indolones: Synthesis and biological properties

Schiller

Angerer

Schneider

1991

Archiv der Pharmazie

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“…To synthesize the 2-vinylindole derivatives 14 and 15 , our synthetic approach is based on the dipole change of indole toward electrophilic substitution. Therefore, we reduced the indole with Li−MeOH in liquid NH 3 to give 4,7-dihydroindole ( 8 ) and 4,5,6,7-tetrahydroindole ( 9 ). , We investigated the reaction of the pyrrole derivatives 8 and 9 with DMAD ( 10 ). The reaction of 8 gave addition products 12 and 13 (in 73% yield) in a 1:2.5 ratio by 1 H NMR, which was separated by silica gel column chromatography eluted with ethyl acetate−hexane.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of New 2-Vinylation Products of Indole via a Michael-Type Addition Reaction with Dimethyl Acetylenedicarboxylate and Their Diels−Alder Reactivity as Precursors of New Carbazoles

Cavdar

Saraçoğlu

2006

J. Org. Chem.

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Reaction of 4,7-dihydroindole and dimethyl acetylenedicarboxylate provided a convenient route to functionalized 2-vinylindoles. Diels-Alder reactions of the 2-vinylindoles with naphthoquinone, p-benzoquinone, 1,2-dicyano-4,5-dichloroquinone, N-phenyltriazolinedione, and tetracyanoethylene were investigated to give [c]annelated 1,2-dihydro, 1,2,3,4-tetrahydro, and fully aromatized carbazoles. The structure and formation mechanism of both 2-vinylindoles and their cycloadduct are discussed.

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“…Similarity in Dissolving Metal Reductions (Table ). Remers et al reported that lithium in ammonia can reduce the indole nucleus to give a mixture of dihyro- and tetrahydroindoles. We found that reduction of indole-3-carboxaldehyde ( 15 ) (Chart ) by calcium gave the corresponding alcohol 16 as the major product in 80% yield.…”

Section: Resultsmentioning

confidence: 99%

Calcium Metal in Liquid Ammonia for Selective Reduction of Organic Compounds

1996

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Selective reduction of functional groups by use of dissolving calcium metal was performed, and the results are in comparison with those by lithium and sodium metals. Reduction with 2.0−2.2 equiv of calcium led chromone (1) to 4-chromanone (2, 75% yield), coumarin (4) to dihydrocoumarin (5, 76% yield) and 3-(2-hydroxyphenyl)-1-propanol (6, 6% yield), α-tetralone (7) to 1,2,3,4-tetrahydro-1-naphthol (8, 81% yield), and β-methoxystyrene (12) to methyl phenethyl ether (13, 85% yield). Performance of reductions on the same substrates by use of 4.0 equiv of lithium or sodium metal gave over-reduced products. Reduction of indole-3-carboxaldehyde (15) to 3-indolemethanol (16), 1-acetylnaphthalene (17) to 1-acetyl-3,4-dihydronaphthalene (18), and trans-4-phenyl-3-buten-2-one (19) to 4-phenyl-2-butanone (20) were accomplished by use of calcium, lithium, and sodium metals, among which calcium gave the highest yields (80−90%). Being a milder reducing agent than lithium and sodium, calcium metal in liquid ammonia offered a better selectivity.

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Reduction of nitrogen heterocycles by lithium in liquid ammonia. III. Indoles and quinolines

Cited by 42 publications

References 0 publications

6,7‐Dihydro‐4H‐indolones: Synthesis and biological properties

6,7‐Dihydro‐4H‐indolones: Synthesis and biological properties

Synthesis of New 2-Vinylation Products of Indole via a Michael-Type Addition Reaction with Dimethyl Acetylenedicarboxylate and Their Diels−Alder Reactivity as Precursors of New Carbazoles

Calcium Metal in Liquid Ammonia for Selective Reduction of Organic Compounds

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