Aminomereuration X ‐ Synthese D'hétérocyeliques monospiranniques par aminomereuration intramoléculaire

Hodjat, H.; Lattes, Armand; Laval, J.Y.; Périé, Jacques; Moulines, J.

doi:10.1002/jhet.5570090522

Cited by 21 publications

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References 11 publications

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“…In view of the studies of Shilov et al (5)(6)(7)9 ) and Lattes and co-workers (23)(24)(25)(26)(27)(28), it is highly probable that the intramolecular bromoamination reactions described in this work occurred via bromonium ion intermediates. On this basis, the bromination product lob of 86, would have structure 14 (R' = H ; R2 = C6H5; X = Br), but this assignment cannot be considered to be established in the absence of supporting evidence.…”

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confidence: 64%

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Intramolecular Bromoamination. Part I

Horning¹,

Muchowski²

1974

Can. J. Chem.

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The addition of bromine to 2,2-diphenyl-4-pentenylan~ine ( 8 0 ) resulted in the formation of 2-bromomethyl-4,4-diphenylpyrrolidine hydrobromide (IOn), the structure of which was established by its mass spectrum and other properties. Analogous products were obtained from the corresponding methyl secondary amine and two methyl-substituted primary amines.The bromomethylpyrrolidines IOa and 10c gave the aziridines I l n a n d I l b on treatment with sodium hydride in DMF. D r y hydrogen bromide converted the unsubstituted aziridine l l a to 3,3-diphenyl-5-bromopiperidine hydrobromide ( 1 2 0 ) . Liberation of the methyl substituted bromomethylpyrrolidine l o b from the hydrobromide salt resulted in the spontaneous transformation to a single 2-methyl-3-bromopiperidine (12b) of unestablished stereochemistry.L'addition d u brome sur la diphinyl-2,2 penttnyl-4 nmine (80) conduit au bromhydrate de la brornomCthy1-2 diphenyl-4,4 pyrrolidine (Ion) dont la structtire a CtC dCterminCe par spectrometric de masse ainsi que par d'aulres propri6tCs. Des produits analogues ont ttC obtenus h partir d e la methylamine secondail'e correspondante ainsi que de deux amines primaires substituCes par des groupes mithyles.Les bromomCthylpyrrolidines Ion et 10c par traitement avec de I'hydrure de sodium dans le DMF conduisent aux aziridines l l a et l l b . L'acide bromhydrique sec transforme l'aziridine non-substitut 1 l a en brornhydrate de diphenyl-3,3 bromo-5 pipiridhe ( 1 2 a ) . L a neutralisation de l'acide bromhydrique libtre la bromom6thylpyrrolidine substituC p a r un groupe mCthyle ( l o b ) qui se transforme spontanement en une seule mCthyl-2 bromo-3 piphidine (120) de sttrCochin1ie non dCterminCe.[Traduit par le journal] Can. J. Chem., 52, 1321 (1974) The first intramolecular haloamination reactions were carried out almost a century ago by Ladenburg (1,2) and Merling (3) but the structures of the products were not assigned correctly until 1900. At that time Willstatter (4) demonstrated that the zinc and hydroiodic acid reduction of the products obtained from dimethylamino-4-pentene (1, R' = R2 = CH,) and bromine or iodine gave 1,1,2-trimethylpy~rolidinium iodide (3, R' = R' = CH3). The five-membered further until 1962. In connection with their interest in the kinetics of the iodocyclization of various unsaturated systems, Shilov and coworkers (5) reported that primary as well as tertiary 4-pentenyl amines underwent the cyclization reaction. Subsequent publications (6-8) from that laboratory were devoted t o a further elaboration of the mechanism and the generality of the r e a~t i o n .~ In all cases the products were assigned five-membered cyclic structures (2), presumably on the basis of Willstatter's observation and by mechanistic analogy to other halocyclization reactions (9).3In relation to studies (14,15) concerning 'The existence of this reaction has evidently not been generally recognized in the chemical literature of the western world. Recent standard (!) reference texts (10-13) state only that, depending o n the ...

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confidence: 64%

“…Both the intermolecular (23,24)" and intramolecular (25)(26)(27)(28) variants of this reaction were shown to occur, the former giving rise to 2-aminoethyl mercuric salts. G,E-Unsaturated amines cyclized predominantly" or exclusively to 2-substituted pyrrolidines, while E,Sunsaturated amines gave piperidine derivatives as the sole products.…”

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confidence: 98%

Intramolecular Bromoamination. Part I

Horning¹,

Muchowski²

1974

Can. J. Chem.

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“…Since the discovery of the interferon system in 1957,3 a number of polymeric substances have been reported which stimulate interferon production, but all of these have limitations in clinical utility.4 Impetus for the search for a monomeric low-molecular-weight inducer of interferon was provided by reports that 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one (tilorone) and congeners induce interferon activity in mice.5•6 A preliminary report from our laboratories disclosed the interferon-eliciting activity of an entirely different structural type, viz. the pyrazo-lo [3,[4][5][6] quinoline 1 (BL-20803).7 We now report results of a research program designed to (i) define structural features of 1 responsible for the interferon-eliciting activity and (ii) increase potency relative to 1 with a concomitant improvement in therapeutic ratio. Chemistry.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and pharmacology of 2,9.alpha.-dimethyl-2'-hydroxy-6,7-benzomorphan

Inoue¹,

May²

1976

J. Med. Chem.

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2,9alpha-Dimethyl-2'-hydroxy-6,7-benzomorphan (14) has been synthesized in six to seven steps from trans-3,4-dihydro-4-(2-dimethylaminoethyl)-6-methoxy-3-methyl-1(2H)-naphthalenone (1). The key reaction of the sequence was mercuric acetate cyclization of trans-1,2-dihydro-1-(2-methylaminoethyl)-7-methoxy-2-methylnaphthalene (8) which gave a mixture of 9alpha-methyl-8alpha-hydroxy-6,7-benzomorphan (9, 49%), the corresponding acetate (10, 13%), and the 9beta-methyl-8alpha-hydroxy-6,7-benzomorphan (11, 5%). In the presence of Et3N, the yields were 16, 37, and 0%, respectively. Structural assignments are based on ir, NMR, and mass spectral data and on chemical conversions.

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“…We have prepared the paracyclophane analogs, 3-aza- [9]paracyclophane (2) and 4-aza [9]paracyclophane (3), of phenylethylamine (4) and phenylpropylamine (5), respectively. The amine-containing bridge in 2 and 3 is restricted to conformations which place it above and in close proximity to the aromatic ring.…”

Section: Methodsmentioning

confidence: 99%

Analgesic agents. 3. New bridged aminotetralins

Freed¹,

Potoski²,

Freed³

et al. 1976

J. Med. Chem.

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A number of new bridged aminotetralins have been synthesized. Several modifications not previously examined have been tested for their effect on the analgesic properties. A number of the compounds prepared demonstrated analgesic activity on the order of morphine.In previous reports we described the synthesis and analgesic properties of a series of 1,3-bridged aminotetralins 1.2,s It was suggested that for optimum activity R k I I1 I11 of these compounds the amine function should be unsubstituted and oriented equatorially relative to the tetralin ring (@-epimer) and that the aromatic substituent (R3 = CH3 < H) should be located meta to the quaternary carbon. Steric crowding about the amine function, which is dependent on the sue of the alkyl group at the 5 position (Me < Et) and on bridge size ( n = 3 < 4 < 5), is an important feature of the molecular geometry.The goal of the present investigation was to develop analgesics having superior pharmacologic properties and to better defme the required features for analgesic activity.This led to the synthesis of molecular modifications in which the polarity of the compounds was altered by introduction of ester groups a t the 3 position or by conversion of the tertiary amine to its N-oxide. The conformational flexibility of the 1,3 bridge was restricted by unsaturation (11) and by increasing the bulk (Le., increasing the steric crowding about the amine function) by including an aromatic moiety (111). Compounds which exemplified each of these new structural variations were synthesized and pharmacologically evaluated. Although these modifications did not produce compounds with significantly enhanced analgesic properties, a number had potency in the range of morphine.Chemistry. The synthetic routes utilized for the preparation of the required compounds are described in Schemes 1-111.Treatment of a l-alkyl-7-methoxy-2-tetralone (I) with excess cis-1,4-dichlorobutene in the presence of potassium tert-butoxide yielded 2 (X = 0) (Scheme I). The oxime 2 (X = NOH) was obtained by refluxing 2 (X = 0) with methanolic NH20H-AcOH. Reduction of this oxime with lithium aluminum hydride (LiAlHd), a reagent which generally does not attack the isolated double bond, led to a somewhat surprising ring closure4 with formation of a tetracyclic amine (3 or 4). The absence of absorption in the area of 5 p in the ir of the hydrochloride indicated that the product was not a primary amine. In the NMR the base showed no vinylic protons and only one exchangeable proton. Mass spectral analysis was carried out and showed m/e a t 243 (mol wt for CitiH2iN0, 243). Addition of the amine function to the bridge double bond occurred a t the 7 or 8 position, but not both. This conclusion is supported by the fact that the product was obtained in 98% purity by GLC (hence is either 3 or 4). The structure of the tetracyclic system was not established unequivocally since from the available data we were unable to distinguish between these two isomers.Under Bouveault-Blanc conditions5 (Na-EtOH) the oxime 2 (X = NOH) w...

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Aminomereuration X ‐ Synthese D'hétérocyeliques monospiranniques par aminomereuration intramoléculaire

Abstract: Dans Ie cours général de recherches relatives à l'hétéroeyelisation de systèmes éthyléniques par aminomercuration, nous développons ici un exemple d'extension de cette réaction: la formation d'hétérocycles monospiranniques.

Cited by 21 publications

References 11 publications

Intramolecular Bromoamination. Part I

Intramolecular Bromoamination. Part I

Synthesis and pharmacology of 2,9.alpha.-dimethyl-2'-hydroxy-6,7-benzomorphan

Analgesic agents. 3. New bridged aminotetralins

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