Bicyclic Amines Research Articles

Enzymatic resolution of bicyclic 1-heteroarylamines using Candida antarctica lipase B.

Candida antarctica lipase B has been used to kinetically resolve a structurally diverse series of bicyclic 1-heteroaryl primary amines by enantioselective acetylation. High yields of either enantiomer could be obtained with excellent enantioselectivity (90-99% ee), while the undesired enantiomer could, in some cases, be recycled by thermal racemization. The absolute stereochemistry of the products was confirmed by an X-ray crystal structure.

N-Heterocycles from Oxime and Oxime O-Benzyl Ethers via Electrophile Induced - Ring Formation. Route to Cyclic and Bicyclic Amine and Hydroxylamine

N-Heterocycles from Oxime and Oxime O-Benzyl Ethers via Electrophile Induced - Ring Formation. Route to Cyclic and Bicyclic Amine and Hydroxylamine

An Improved Preparation of 2‐Azabicyclo[2.2.2]octane.

ABSTRACT An improved preparative four-step synthesis to isoquinuclidine tosylate salt 4 has been demonstrated in 70% overall yield from p-aminobenzoic acid (PABA) 1. Hydrogenation of PABA 1 affords 4-aminocyclohexane carboxylic acid 2 as an 80 : 20 mixture of cis- and trans-isomers. Heating the mixture at 250°C effected epimerization and cyclization to provide the bicyclic lactam 3. Subsequent Red-Al reduction and treatment with tosic acid furnished the desired bicyclic amine, tosylate salt 4.

Nitrogen inversion in cyclic amines and the bicyclic effect.

The hitherto unsolved problem of the origin of the unusually high nitrogen inversion-rotation (NIR) barriers in 7-azabicyclo[2.2.1]heptanes (the bicyclic effect) was examined using the natural bond orbital (NBO) approach. Reinvestigating the NIR barrier for tropane by DNMR, we found that NIR barriers increase smoothly on going from nitrogen-bridged bicyclic systems of a larger ring size to the smaller ring homologous systems. The experimental NIR barriers are reproduced with good accuracy using the MP2/6-31G level of theory. The NBO analysis for these and other azabicycles led to the conclusion that the height of these barriers is mostly determined by the energy of the sigma-orbitals of the C(alpha)(-)C(beta) bonds as well as the nitrogen lone pair. Thus, the bicyclic effect is actually an extreme case of a common C(alpha-)N-C(alpha) tripyramid geometry-NIR barrier dependence for N-bridged bicyclic amines. By establishing the rate-determining role of the C(alpha-)N-C(alpha) tripyramid fragment for NIR, we have derived the first sufficiently accurate quantitative correlations amine geometry-NIR barrier for monocyclic as well as bicyclic N-H and N-Me amines (i.e., for an amine set which also includes the bicyclic effect systems).

3‐Azabicyclo[3.1.0]hex‐1‐ylamines by Ti‐Mediated Intramolecular Reductive Cyclopropanation of α‐(N‐Allylamino)‐Substituted N,N‐Dialkylcarboxamides and Carbonitriles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

3-Azabicyclo[3.1.0]hex-1-ylamines by Ti-Mediated Intramolecular Reductive Cyclopropanation of α-(N-Allylamino)-Substituted N,N-Dialkylcarboxamides and Carbonitriles

A variety of tris- and monoprotected derivatives with the 1-amino-3-azabicyclo[3.1.0]hexane and 1-amino-3-azabicyclo[4.1.0]heptane skeleton 10 have been synthesized by intramolecular reductive cyclopropanation of α-(N-allylamino)-substituted N,N-dialkylcarboxamides 6, 8, and 9. Starting from derivatives of the naturally occurring amino acid serine (4a, 4b), the enantiomerically pure compounds 10a and 10b were obtained with endo/exo ratios of 2.5:1 (a) and 2:1 (b), in 26 and 30% overall yields, respectively. The unprotected bicyclic amines 11aa, 11ab, 11ba, and 11ad have been prepared by palladium-catalyzed hydrogenative deprotection of 10aa, 10ab, 10ba and 10ad, respectively, under acidic conditions, in 91, 95, 96, and 99% yields, respectively. X-ray crystal structure analyses of 10aa and 10ad in each case found an equatorial position of the N-benzyl group on the heterocycle and a common boat conformation for the 3-azabicyclo[3.1.0]hexane and 3-azabicyclo[4.1.0]heptane skeletons as a whole. One-step preparations of the bicyclic diamines 11ac (41% yield) and 14a (48% yield) have been performed by application of the Kulinkovich−de Meijere procedure to the nitriles 12a and 12b. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Conformationally constrained ethylenediamines: synthesis and receptor binding of 6,8-Diazabicyclo[3.2.2]nonanes

The synthesis and receptor affinity of 6,8-diazabicyclo[3.2.2]nonanes representing conformationally constrained ethylenediamines are described. The Dieckmann analogous cyclization of the (piperazin-2-yl)propionate 9 provided the bicyclononane 10 only, when the first cyclization product was trapped with chlorotrimethylsilane. 10 was stereoselectively transformed into the bicyclic amines 19a,b and amides 22a,b, which were investigated in competition experiments with radioligands for their σ1-, σ2-, κ-, and μ-receptor affinities. The (2R)-configured dimethylamine 19a showed promising σ1-receptor affinity (Ki=23.8nM) and selectivity, whereas the (2S)-configured (dichlorophenyl)acetamide 22b displayed a σ-receptor binding profile (σ1: Ki=184nM; σ2: Ki=263nM) very similar to the binding profile of the atypical antipsychotic BMY-14802 (26).

ChemInform Abstract: Rearrangement of Ammonium Ylides Produced by Intramolecular Reaction of Catalytically Generated Metal Carbenoids. Part 2. Stereoselective Synthesis of Bicyclic Amines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Synthesis of Medium‐Sized Cyclic Amines by Selective Ring Cleavage of Sulfonylated Bicyclic Amines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AN IMPROVED PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE

ABSTRACT An improved preparative four-step synthesis to isoquinuclidine tosylate salt 4 has been demonstrated in 70% overall yield from p-aminobenzoic acid (PABA) 1. Hydrogenation of PABA 1 affords 4-aminocyclohexane carboxylic acid 2 as an 80 : 20 mixture of cis- and trans-isomers. Heating the mixture at 250°C effected epimerization and cyclization to provide the bicyclic lactam 3. Subsequent Red-Al reduction and treatment with tosic acid furnished the desired bicyclic amine, tosylate salt 4.

A novel stereoselective synthesis of N-heterocycles by intramolecular hydrovinylationElectronic supplementary information (ESI) available: 1H and 13C NMR spectra of compounds 1a–f, 2a–d, 3–5, 8–10. See http://www.rsc.org/suppdata/p1/b1/b108310d/

A novel method for the synthesis of bicyclic amines has been developed. Cyclisation of 1,6-dienes by intramolecular hydrovinylation in the presence of catalytic amounts of allylpalladium chloride dimer afforded bicyclic amines in one step. Added phosphines, silver salts, as well as the nature of the N-protecting group influenced the yield and selectivity of the reactions. Most strikingly, intramolecular hydrovinylation allowed the preparation of diastereomerically pure bicyclic amines as e.g. hexahydroindoles 2a–2d.

Studies of stereoselectivity in cycloaddition of cyclic dienes to 2-azabicyclo[2.2.2]octene derivatives; through-space effects on 15N NMR shifts of bicyclic amines and lactams

Only two of the four possible facial approaches of cyclohexa-1,3-diene to the double bond in 2-methyl-5,6-benzo-2-azabicyclo[2.2.2]oct-7-en-3-one 7 are observed, giving exo, endo- and endo, endo-Diels–Alder cycloadducts 10a and 11a at atmospheric pressure ( exo- and endo-defined here by reference to the benzo- and etheno-bridges, respectively). Hydride reduction of the carbonyl in 10a provides an indirect route to 9 , which is formally derived from 2-methyl-5,6-benzo-2-azabicyclo[2.2.2]oct-7-ene 6 but which is inaccessible directly owing to thermal retro-cycloaddition of 6 . X-Ray crystal structures confirm the stereochemical assignments. Cycloaddition of cyclopentadiene to 7 follows a similar path and the results are compared with corresponding studies on 7-azabicyclo[2.2.1]heptene analogues where only exo-facial attack is observed. Through-space interactions with proximate etheno- and ethano-bridges give rise to substantial upfield 15N NMR shifts of amino and lactam nitrogen.

Rearrangement of ammonium ylides produced by intramolecular reaction of catalytically generated metal carbenoids. Part 2. Stereoselective synthesis of bicyclic amines

Ammonium ylides produced by intramolecular reaction of copper carbenoids tethered to cyclic allylic amines undergo [2,3]-rearrangement to deliver bicyclic amines. The reaction can be performed using a cyclic N-allylamine in which the diazo group is tethered adjacent to nitrogen, or a vinyl-substituted cyclic amine in which the diazo group is N-tethered to the ring. In the former type of reaction, stereoselective ylide formation and rearrangement usually delivers high levels of diastereocontrol. In the latter case, efficient ‘chirality transfer’ can be accomplished when the reaction is performed using an enantiomerically pure substrate. The reactions have been used to construct pyrrolizidine, indolizidine and quinolizidine systems, and the CE sub-unit found in the manzamine and ircinal alkaloids.

8-Aminobicyclo[3.2.1]octanes: synthesis and anti-viral activity

A series of 8-chlorobicyclo[3.2.1]oct-6-enes has been prepared from cyclohexenyl chlorides and simple alkynes via a one-step [3+2] cycloaddition methodology, and then converted into the corresponding bicyclic amines. Against influenza-A virus a number of these showed in vitro activity, and amine ( 2 ) was comparable to amantadine in vivo. Good activity against influenza-B virus was less common, and none of the amines showed high potency against both viruses. Amines ( 20 ) and ( 23 ) showed significant activity versus respiratory syncytial virus.

Synthesis of medium-sized cyclic amines by selective ring cleavage of sulfonylated bicyclic amines.

An efficient method of synthesis of functionalized medium-sized cyclic amines (eight- to ten-membered rings) by selective ring opening of sulfonylated bicyclic pyrrolizidine, indolizidine, and quinolizidine compounds is described. The key step is the selective cleavage of the central C-N bond of the bicyclic amine by means of a Julia-like desulfonylation process. Reaction: see text.

Muscarinic Receptor Agonists and Antagonists

A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

A parallel preparation of a bicyclic N-chiral amine library and its use for chiral catalyst screening

A parallel library of optically active bicyclic tertiary amines bearing N-chiral bridgehead nitrogen atoms was readily prepared by condensation of primary amines, cyclic amino acids and aldehydes. The enantiocontrolling ability of each of the library members was examined for the asymmetric alkylation of benzaldehyde with diethylzinc, and (3 R,6 R,7a S)-(2,3-diphenyl-6-hydroxy)hexahydro-1 H-pyrrolo[1,2- c]imidazol-1-one, which contains a β-amino alcohol unit, showed high enantioselectivity.

Diastereoselective hydroboration of chiral enamines using an enantiomerically pure amine from an industrial waste material as the source of chirality

By a hydroboration/oxidation procedure trans-aminoalcohols with dr values from 74:26 to ≥95:5 were obtained. A bicyclic amine derived from the unnatural amino acid 2-azabicyclic[3.3.0]octane-3-carboxylic acid was used as the chiral precursor. The absolute configuration was clarified by X-ray structure of a descendant of the trans-aminoalcohols.

N + 1] Annulation Route to Highly Substituted Cyclic Ketones with Pendant Ketone, Nitrile, and Ester Functionality

Two carbon acids connected by a tether containing a ketone undergo two Michael reactions to 3-butyn-2-one to afford highly substituted and functionalized cyclic ketones with pendant ketone, nitrile, and ester functionality. The stereochemical courses of the double Michael reactions vary remarkably with the structure of the starting material. Double Michael adducts with equatorially disposed cyano groups can be hydrogenated to afford trans-fused bicyclic amines.

Novel reactions of cyclocarbaphosphazenes and cyclocarbathiazenes

The hybrid inorganic-organic heterocycles, pentachlorocyclocarba phosphazene, (ClCN)2(Cl2PN) and triachlorocyclocarbathiazene, (ClCN)2(ClSN) were synthesized and their reaction chemistry explored with emphasis on dealkylation reactions of the heterocycles with tertiary amines. Reactions of (ClCN)2(Cl2PN) were carried out with bicyclic, unsymmetric and sterically hindered tertiary amines as well as aminomethyl ferrocenes. In all cases, the C-Cl bonds of the carbaphosphazene were found to react with the tertiary amines resulting in the cleavage of an alkyl group and regiospecific substitution of the dialkylamino group on the ring carbon atoms of the heterocycle. While bicyclic amines were found to undergo ring opening, the preference of the cleaved group in the case of unsymmetrical amines were found to depend on the stability of the carbocations formed. Similar dealkylation was observed in the reactions of the carbathiazene (ClCN)2(ClCN) with tertiary amines.