Amine 1b Research Articles

Preparation of 2-azabicyclo[3.3.1]nonan-3-ones by a Radical C-Carbonylation of Methylcyclo-Hexylamines

The search for a rational method for the synthesis of 2-azabicyclo[3.3.1]nonane, needed for pharmaceutical studies, has led us to the idea that the -C-carbonylation of tertiary alkylamines and the synthesis of lactams can be effected similarly to the radical C-carboxylation of branched alkanes [1, 2]. Remote -carbonylation of alkanols is associated with a 1,5-H transfer on a generated alkoxyl radical [3-6]. As a result, a -hydroxylalkyl radical is formed which reacts with carbon monoxide to give the corresponding acyl radical. This stage is reversible hence a high pressure of the carbon monoxide is needed to ensure the cyclization. The only limitation of such -CH-functionalization reactions of alkanols in a singleelectron oxidation process (e.g., by the action of Pb(OAc)4) is that tertiary alcohols can not be used [7]. Under the conditions given above a -CH-functionalization of the tert-alkylamines can be accomplished, however further oxidation of the substrate occurs [8]. In a modified method for generating -aminoand -amidoalkyl radicals it was necessary to use not only an oxidant but also iodine [4]. However, this variation is inapplicable to amines 1a,b since it can lead to -C-iodination and the subsequent formation of a pyrrolidine ring [4]. Azacyclization using NBS also proceeds via formation of an aminoalkyl bromide intermediate [9] and is not applicable to carbonylation. Hence, despite the expected oxidative side reactions, we had to use Pb(OAc)4 in the presence of K2CO3 by analogy with the study [1]. The amine 1b has a fixed axial amino group and presumably can ensure the 1,5-H transfer on an aminyl radical. Analysis of the reaction mixture of amines 1a,b has shown that, in fact, the corresponding 2-azabicyclo[3.3.1]nonanes 4a,b are formed, but in the case of amine 1a the yield of bicycle 4a relative to the other reaction products is 19% (68% conversion) while the yield of bicycle 4b in the reaction of amine 1b is only 6% (52% conversion). Such result can only be explained by a more rapid azacyclization of radical B due to stabilized conformation that is optimal for formation of bicycle 2b. This is confirmed by the domination of the products of in situ oxidation of amine 2b (imine 3b in 11% and lactam 7b in 22% yields) when an excess of

Solid-phase Parallel Synthesis of a Novel N-[Alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted Amide and Amine Drug-like Libraries

Center for Drug Discovery Platform Technology, Korea Research Institute of Chemical Technology, Daejeon 305-600, Korea Received November 1, 2011, Accepted November 11, 2011We report the solid-phase library construction of 222 number of a novel N-[alkyl sulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 1A and amine 1B derivatives. The polymer-bound N-[alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 9 and amine 10 derivativeswere obtained by first diversity generation with various acid chlorides and alkyl halides. Further reactions onthe resins 9 and 10 with substituted sulfonyl chlorides produced the desired N-[alkylsulfonamido-spiro(2H-1-benzopyran-2,4-piperidine)-6-yl] substituted amide 1A and amine 1B analogues.Key Words : Spiro(2H-1-benzopyran-2,4-piperidine)-6-yl derivatives, Solid-phase parallel synthesis, Drug-like benzopyran core skeleton IntroductionHeterocyclic compounds provide scaffolds on whichpharmacophores can be arranged to yield potent andselective drugs, and a variety of heterocycles have beensynthesized on solid support.

Enantioselective Iridium-Catalyzed Imine Vinylation: Optically Enriched Allylic Amines via Alkyne−Imine Reductive Coupling Mediated by Hydrogen

The first asymmetric iridium-catalyzed C−C bond forming hydrogenation is described. By simply hydrogenating alkynes in the presence of N-arylsulfonyl imines using an iridium catalyst modified by (R)-Cl,MeO-BIPHEP, one may obtain the corresponding allylic amines 1b−21b in highly optically enriched form (92−99% ee). This protocol circumvents the use of preformed vinyl metal reagents and is applicable to aromatic, heteroaromatic, and aliphatic N-arylsulfonyl aldimines 1a−16a. The reductive coupling products, allylic amines 1b−21b, are produced as single geometrical isomers (≥99:1, E:Z). Nonsymmetric alkynes couple to imines 8a and 12a under standard conditions with excellent levels of regioselection. Absolute stereochemical assignment of allylic amines 1b−21b is based upon single-crystal X-ray diffraction analysis of 22b, the p-bromophenylsulfonyl analogue of adduct 1b, using the anomalous dispersion method. A stereochemical model accounting for the observed sense of absolute stereoinduction and regioselectivity is provided.

Allylic Amines via Iridium-Catalyzed C−C Bond Forming Hydrogenation: Imine Vinylation in the Absence of Stoichiometric Byproducts or Metallic Reagents

Exposure of aromatic, heteroaromatic, and aliphatic N-arylsulfonyl aldimines 1a−12a in toluene solution at 60 °C to 2-butyne and hydrogen at ambient pressure in the presence of a cationic iridium(I) catalyst modified by BIPHEP enables formation of reductive coupling products, allylic amines 1b−12b, in good isolated yields as single geometrical isomers (>95:5, E:Z). The nonsymmetric alkynes 4-methyl-2-pentyne couple to imines 6a, 12a, and 13a under standard conditions with complete levels of regioselection. Hydrogenative coupling of 2-hexyne to imines 6a, 12a, and 13a delivers allylic amines 15b, 16b, and 18b in 10:1 regioisomeric ratios in each case. As revealed by 2H NMR analysis, reductive coupling of 2-butyne to imine 2a under an atmosphere of elemental deuterium provides deuterio-2b, which incorporates deuterium at the vinylic position (83% 2H) and at the allylic methyl groups (5% 2H). An equal distribution of deuterium at the allylic methyl groups suggests H−D exchange at the propargylic positions of...

Enantioselective Reductive Coupling of Acetylene to N-Arylsulfonyl Imines via Rhodium Catalyzed C−C Bond-Forming Hydrogenation: (Z)-Dienyl Allylic Amines

The first highly enantioselective catalytic vinylation of aldimines to furnish allylic amines is reported. Exposure of aromatic and aliphatic N-arylsulfonyl aldimines 1a−12a to equal volumes of acetylene and hydrogen gas at 45 °C and ambient pressure in the presence of chirally modified cationic rhodium catalysts provides the (Z)-dienyl allylic amines 1b−12b in highly optically enriched form (93−98% ee) and as single geometrical isomers (>95:5, Z/E). The coupling products 1b−12b arise via multicomponent coupling of four molecules: two molecules of acetylene, a molecule of aldimine, and elemental hydrogen. Unlike other imine additions involving nonstabilized carbanions, the present protocol circumvents use of preformed organometallic reagents.

Azulene-Substituted Aromatic Amines. Synthesis and Amphoteric Redox Behavior of N,N-Di(6-azulenyl)-p-toluidine and N,N,N‘,N‘-Tetra(6-azulenyl)-p-phenylenediamine and Their Derivatives

[reaction: see text] N,N-Di(6-azulenyl)-p-toluidine (1a) and N,N,N',N'-tetra(6-azulenyl)-p-phenylenediamine (2a) and their derivatives with 1,3-bis(ethoxycarbonyl) substituents on each 6-azulenyl group (1b and 2b) were prepared by Pd-catalyzed amine azulenylation and characterized as a study into new aromatic amines for multistage amphoteric redox materials. The redox behavior of each compound was characterized by cyclic voltammetry. These compounds undergo facile reduction to stable anion radicals and dianion diradicals owing to the resonance stabilization between the 6-azulenyl groups and exhibit electrochemical oxidation depending on the amine subunits. The ESR measurement of anion radicals and a dianion diradical generated by the electrochemical reduction of amine 1b and diamine 2b revealed that the unpaired electron of these radicals delocalizes over the entire azulene ring including the central nitrogen atoms. UV-vis spectral analysis of amines 1a,b and diamines 2a,b, taken during the electrochemical reduction, exhibited a gradual decrease of the absorption bands of the neutral species along with an increase of the new absorption maxima at 625, 605, 640, and 610 nm, respectively, with the development of well-defined isosbestic points at 502, 562, 478, and 545 nm, respectively. As indicated by a combined ESR and UV-vis spectral study, the species giving rise to the new absorption maxima are concluded to be the generation of anion radicals and dianion diradicals of aromatic amines and diamines with high thermodynamic stability.

Zirconium complexes having a chiral phosphanylamide in the co-ordination sphere

The chiral phosphanylamido ligand, (N(CHMePh)(PPh2))-, has been introduced into co-ordination chemistry. As starting material the oily amines HN(R-*CHMePh)(PPh2)(1a) and HN(S-*CHMePh)(PPh2)(1b) were used. To reconfirm their absolute structure, 1b was oxidized with H2O2 in air to obtain HN(S-*CHMePh)(P(O)Ph2)(2) as a solid compound. The solid-state structure of 2 was established by single-crystal X-ray diffraction. The lithium salts of both enantiomers Li(N(R-*CHMePh)(PPh2))(3a) and Li(N(S-*CHMePh)(PPh2))(3b) were prepared by deprotonation reaction of 1a,b. Compounds 3a,b were further reacted with zirconocen dichloride to give the chiral metallocenes [(eta5-C5H5)2Zr(Cl)(eta2-N(R-*CHMePh)(PPh2))](4a) and [(eta5-C5H5)2Zr(Cl)(eta2-N(S-*CHMePh)(PPh2))](4b). In an alternative approach to give chiral zirconium compounds, the neutral amine 1b was reacted with [(PhCH2)4Zr] to give the enantiomeric pure complex [(PhCH2)3Zr(eta2-N(S-*CHMePh)(PPh2))](5). The solid-state structures of all zirconium complexes were determined by single-crystal X-ray diffraction.

Utilization of industrial waste materials. Part 14.† Synthesis of β-amino alcohols and thiols with a 2-azabicyclo[3.3.0]octane backbone and their application in enantioselective catalysis

New, chiral β-tert-amino tert-alcohols have been synthesized from the enantiomerically pure sec-amine (all-R)-1b via the new glycine, alanine and phenylglycine derivatives 2–6. Grignard additions to these esters provided the new rigid amino alcohols 7–11 in fair yields. The absolute configurations of the stereogenic centers, which arose during the alkylation step, were assigned by an independent route leading to some of the optical antipodes of 7–10. Condensation of enantiomerically pure β-amino alcohols 13a–g, 16 and 17 with γ-ketoester rac-12 afforded the N,O-acetals 14a–g, 18 and 19, which were subsequently reduced to the β-tert-amino alcohols 10a,c and 15a–g. X-Ray analysis of compound 19 was performed to verify the stereochemistry observed by chemical correlation. The nucleophilic ring opening of enantiomerically pure styrene oxide by amine 1b resulted in the formation of regioisomeric amino alcohols 9a, 21a, and 10a, 21b. Amino thiol derivatives 22 and 25a,b were prepared by treatment of 10a and 15a,b, respectively, with methanesulfonyl chloride followed by regio- and stereoselective cleavage of the in situ formed aziridinium ions with potassium thioacetate. Reduction of these compounds to thiols 23 and 26a,b and subsequent oxidation afforded amino disulfides 24 and 27a,b. Finally, the bicyclic β-amino alcohols and thiols were used as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde and ee values up to 96% were found.

Chiral acetylenic sulfoxides in organic synthesis: Secondary amine cyclization and total synthesis of (S)-(−)-carnegine

Michael addition of secondary amines 1b–1g onto chiral acetylenic sulfoxides 2 followed by acid induced cyclization afforded structures of tetrahydroisoquinoline skeleton in high to moderate diastereoselectivity. Optical pure (S)-(−)-carnegine has been synthesized.

Novel inhibitors of rat lens aldose reductase: N-[[(substituted amino)phenyl]sulfonyl]glycines.

A number of N-[[(substituted amino)phenyl]sulfonyl]glycines 3a-n were synthesized as analogues of the simple (phenylsulfonyl)glycines 1a-c with increased lipophilic character and therefore greater aldose reductase inhibitory potential. The 2-benzoylamino derivative 3c was found to be less potent than the corresponding amine 1c as an inhibitor of rat lens aldose reductase, but both the 3- and 4-benzoylamino analogues, 3b and 3a, are substantially more potent than their amines 1b and 1a; compound 3a is the most effective inhibitor of this series, with an IC50 of 0.41 microM. The 4-benzoylamino derivative 3a is also significantly more active than the 4-acetylamino analogue 3d and the 4-benzylamino (3e) and 4-dimethylamino (3f) derivatives, suggesting that both the additional carbonyl moiety and aromatic ring present in this compound may bind to complementary sites present on the enzyme. Furthermore, structure-activity studies reveal that increasing the number of atoms between the carbonyl and aromatic moieties of 3a results in a decrease in inhibitory activity. Kinetic studies demonstrate that 3a, like other known inhibitors of aldose reductase, functions as an uncompetitive inhibitor with respect to the substrate and therefore may interact at the proposed common inhibitor binding site of this enzyme.

Pyridiniums as potential synthetic substitutes for nitrogen mustards

AbstractDialkylamino‐alkyl primary amines 1b and 2b are converted by pyrylium salts into the corresponding pyridinium derivatives. The pyridinium salts act as aminoalkylating agents for representative O‐, S‐, N‐, and C‐nucleophiles and are potentially safe substitutes for nitrogen mustards in the reactions.