Abstract:A series of homochiral 7‐substituted 1‐aminoindans was prepared by means of asymmetric reductive amination from racemic 7‐substituted 1‐indanones via E‐imines and E‐imine/ enamine mixtures, respectively, and subjected to 5‐hydroxytryptamine (5‐HT) receptor subtype binding studies. The ee’s of the title compounds were determined by HPLC of the corresponding Mosher’s amides and range from 96 to 99.9%. The absolute configuration was elucidated by means of correlation CD spectroscopy. On the basis of the pKI value… Show more
“…7-OHAI and its derivatives have been reported as neuroprotectives 4a,b and as 5-HT-1A receptor ligands …”
Section: Resultsmentioning
confidence: 99%
“…In fact, preparation of the few N -alkyl-7-OHAIs reported in the literature invariably involved reductive amination of indanones 4,13 and not reductive alkylation of aminoindans. Moreover, the authors specifically noted that 7-hydroxy- N , N -dipropyl-aminoindan was not “directly accessible from the amine”, in contrast to non-OH analogues …”
The chemical stability and reactivity of hydroxy-1-aminoindans and their N-propargyl derivatives are strongly affected by the position of the OH group and its orientation relative to that of the amino moiety. Thus, the 4- and 6-OH regioisomers were found to be stable, while the 5-OH analogues were found to be inherently unstable as the free bases. The latter, having a para orientation between the OH and the amino moieties, could be isolated only as their hydrochloride salts. 7-Hydroxy-1-aminoindans and 7-hydroxy-1-propargylaminoindans represent an intermediate case; while sufficiently stable even as free bases, they exhibit, under certain experimental conditions, unexpected reactivity. The instability of the 5- and 7-hydroxy-aminoindans is attributed to their facile conversion to the corresponding, reactive quinone methide (QM) intermediates. The o-QM obtained from 7-hydroxy-aminoindans was successfully trapped with ethyl vinyl ether via a Diels-Alder reaction to give tricyclic acetals 32a,b.
“…7-OHAI and its derivatives have been reported as neuroprotectives 4a,b and as 5-HT-1A receptor ligands …”
Section: Resultsmentioning
confidence: 99%
“…In fact, preparation of the few N -alkyl-7-OHAIs reported in the literature invariably involved reductive amination of indanones 4,13 and not reductive alkylation of aminoindans. Moreover, the authors specifically noted that 7-hydroxy- N , N -dipropyl-aminoindan was not “directly accessible from the amine”, in contrast to non-OH analogues …”
The chemical stability and reactivity of hydroxy-1-aminoindans and their N-propargyl derivatives are strongly affected by the position of the OH group and its orientation relative to that of the amino moiety. Thus, the 4- and 6-OH regioisomers were found to be stable, while the 5-OH analogues were found to be inherently unstable as the free bases. The latter, having a para orientation between the OH and the amino moieties, could be isolated only as their hydrochloride salts. 7-Hydroxy-1-aminoindans and 7-hydroxy-1-propargylaminoindans represent an intermediate case; while sufficiently stable even as free bases, they exhibit, under certain experimental conditions, unexpected reactivity. The instability of the 5- and 7-hydroxy-aminoindans is attributed to their facile conversion to the corresponding, reactive quinone methide (QM) intermediates. The o-QM obtained from 7-hydroxy-aminoindans was successfully trapped with ethyl vinyl ether via a Diels-Alder reaction to give tricyclic acetals 32a,b.
“…Amine Alkylation (Reductive Amination of Aldehydes and Ketones). Our initial N -alkylation of amines with NaBH 4 /RCO 2 H involved the generation of an aldehyde, RCHO (or an equivalent species), from the RCO 2 H solvent as the source of the alkyl group. , Although this method continues to find some use for the introduction of simple alkyl groups (Scheme ), − a superior variation was developed later by Abdel-Magid (vide infra). 2 Amine alkylation using NaBH 4 /RCO 2 H …”
Section: Chemistry Of Acyloxyborohydridesmentioning
confidence: 99%
“…alkyl groups (Scheme 2), [15][16][17][18] a superior variation was developed later by Abdel-Magid (vide infra).…”
Acyloxyborohydrides are unsurpassed in their versatility as reagents in organic synthesis. In addition to their superior ability in effecting reductive amination of aldehydes and ketones, acyloxyborohydrides can reduce nitrogen heterocycles (indoles, quinolines, isoquinolines), imines, enamines, oximes, amides, nitriles, benzylic alcohols, aryl ketones, aldehydes (but not ketones), acetals, -hydroxy ketones, and other substrates. The ability to control chemoselectivity, regioselectivity, and stereoselectivity by adjusting the carboxylic acid, borohydride reagent, stoichiometry, and temperature has no parallel in the repertoire of the organic chemist.
Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful.
This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.
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