Enantioselective N-heterocyclic carbene-catalyzed nucleophilic dearomatization of alkyl pyridiniums.
ABSTRACT: NHC-catalyzed nucleophilic dearomatization of alkyl pyridiniums has been achieved to generate 1,4-dihydropyridines with high enantioselectivity. This is a rare example of catalytic, asymmetric addition of a nucleophile to the activated pyridinium that prefers C-4 functionalization leading to the 1,4-dihydropyridine with high selectivity.
Project description:In this study, the first example of the carbene-catalyzed tandem dearomatization/rearomatization reaction of azonaphthalenes with α-chloroaldehydes is described. This protocol enables the efficient assembly of chiral dihydrocinnolinone derivatives in good yields with excellent enantioselectivities (up to 99% ee). Moreover, this strategy enables not only the highly enantioselective NHC-catalyzed nucleophilic aromatic substitution, but also a formal Csp2-Csp3 bond formation.
Project description:4-Aza-6-nitrobenzofuroxan (ANBF) reacts with 1,3-dicarbonyl compounds and other CH acids to give carbon-bonded 1,4-adducts - 1,4-dihydropyridines fused with furoxan ring. In the case of most acidic ?-diketones, which exist mainly in the enol form in polar solvents, the reactions proceed in the absence of any added base emphasizing the highly electrophilic character of ANBF. The resulting compounds combine in one molecule NO-donor furoxan ring along with a pharmacologically important 1,4-dihydropyridine fragment and therefore can be considered as prospective platforms for the design of pharmacology-oriented heterocyclic systems.
Project description:Dearomatization is an effective method to transform readily available N-heterocycles into partially saturated motifs. Manipulation of dihydro-derivatives holds great potential and provides access to a variety of semi-saturated N-heterocyclic building blocks. However, current strategies are limited in scope and the use of sensitive reagents restricts the applicability in synthetic laboratories. Herein, we report the synthesis of a broad variety of N-substituted 1,4- and 1,2-dihydropyridines by very mild and selective reduction with amine borane for the first time.
Project description:This data file describes the synthetic protocol for preparation of the original 2,6-di(bromomethyl)-3,5-bis(alkoxycarbonyl)-4-aryl-1,4-dihydropyridines. In total, 6 unpublished compounds were obtained and characterised. The 2,6-di(bromomethyl)-1,4-dihydropyridines are mainly used as intermediates for synthesis of various lipid-like compounds based on 1,4-dihydropyridine cycle. All the structures of 2,6-di(bromomethyl)-1,4-dihydropyridines were confirmed by Nuclear Magnetic Resonance (NMR, including <sup>1</sup>H NMR and <sup>13</sup>C NMR) data. The data provided herein are directly related to the previously published research article - "Novel cationic amphiphilic 1,4-dihydropyridine derivatives for DNA delivery"  where three derivatives (2,6-di(bromomethyl)-4-phenyl-1,4-dihydropyridines <b>2a-c</b>) from six presented in this data file were used as starting materials in synthesis of amphiphilic 1,4-dihydropyridines without any purification and characterisation. Synthesis of other three 2,6-di(bromomethyl)-3,5-bis(alkoxycarbonyl)-4-aryl-1,4-dihydropyridines <b>2d-f</b> and their characterisation are reported herein at the first time. Information provided in this data file can be used in organic synthesis by other chemists to develop synthetic strategies for the construction of various cationic 1,4-dihydropyridine derivatives and related heterocycles.
Project description:Bis(phosphine) copper hydride complexes are uniquely able to catalyze direct dearomatization of unactivated pyridines with carbon nucleophiles, but the mechanistic basis for this result has been unclear. Here we show that, contrary to our initial hypotheses, the catalytic mechanism is monometallic and proceeds via dearomative rearrangement of the phenethylcopper nucleophile to a C<i>para</i>-metalated form prior to reaction at heterocycle C4. Our studies support an unexpected heterocycle-promoted pathway for this net 1,5-Cu-migration beginning with a doubly dearomative imidoyl-Cu-ene reaction. Kinetics, substituent effects, computational modeling, and spectroscopic studies support the involvement of this unusual process. In this pathway, the CuL<sub>2</sub> fragment subsequently mediates a stepwise Cope rearrangement of the doubly dearomatized intermediate to the give the C4-functionalized 1,4-dihydropyridine, lowering a second barrier that would otherwise prohibit efficient asymmetric catalysis.
Project description:An efficient three component reaction with enaminones, primary amines and aldehydes resulted in easy access to 1,4-dihydropyridines with different substituents at the 1-, 3-, 4- and 5-positions. Microwaves improved the reaction yield, reducing also considerably the reaction time and the amount of solvent used. Chiral primary amines gave chiral 1-substituted-1,4-dihydropyridines. The 4-(1-naphthyl) and 4-(phenanthren-9-yl)dihydropyridine derivatives exhibited an interesting photoluminescence behavior, which suggests their potential application as suitable photoinduced intramolecular electron-transfer systems.
Project description:The stoichiometric reduction of N-carbophenoxypyridinium tetraphenylborate (6) by CpRu(P-P)H (Cp = eta(5)-cyclopentadienyl; P-P = dppe, 1,2-bis(diphenylphosphino)ethane, or dppf, 1,1'-bis(diphenylphosphino)ferrocene), and Cp*Ru(P-P)H (Cp* = eta(5)-pentamethylcyclopentadienyl; P-P = dppe) gives mixtures of 1,2- and 1,4-dihydropyridines. The stoichiometric reduction of 6 by Cp*Ru(dppf)H (5) gives only the 1,4-dihydropyridine, and 5 catalyzes the exclusive formation of the 1,4-dihydropyridine from 6, H(2), and 2,2,6,6-tetramethylpiperidine. In the stoichiometric reductions, the ratio of 1,4 to 1,2 product increases as the Ru hydrides become better one-electron reductants, suggesting that the 1,4 product arises from a two-step (e(-)/H(*)) hydride transfer. Calculations at the UB3LYP/6-311++G(3df,3pd)//UB3LYP/6-31G* level support this hypothesis, indicating that the spin density in the N-carbophenoxypyridinium radical (13) resides primarily at C4, while the positive charge in 6 resides primarily at C2 and C6. The isomeric dihydropyridines thus result from the operation of different mechanisms: the 1,2 product from a single-step H(-) transfer and the 1,4 product from a two-step (e(-)/H(*)) transfer.
Project description:Preliminary results concerning the first asymmetric synthesis of highly functionalized 1-benzamido-1,4-dihydropyridine derivatives via the reaction of hydrazones with alkylidenemalononitriles in the presence of ?-isocupreidine catalyst are reported. The moderate, but promising, enantioselectivity observed (40?54% ee), opens the door to a new area of research for the asymmetric construction of new chiral 1,4-dihydropyridine derivatives, whose enantioselective catalytic preparation are still very limited. Moreover, the use of hydrazones for the enantioselective construction of chiral 1,4-dihydropyridines has been overlooked in the literature so far. Therefore, our research represents a pivotal example in this field which remains still unexplored.
Project description:The 1,3-diaryl-imidazolium chlorides IPr.HCl (aryl = 2,6-diisopropylphenyl), IMes.HCl (aryl = 2,4,6-trimethylphenyl) and IXy.HCl (aryl = 2,6-dimethylphenyl), precursors to widely used N-heterocyclic carbene (NHC) ligands and catalysts, were prepared in high yields (81%, 69% and 89%, respectively) by the reaction of 1,4-diaryl-1, 4-diazabutadienes, paraformaldehyde and chlorotrimethylsilane in dilute ethyl acetate solution. A reaction mechanism involving a 1,5-dipolar electrocyclization is proposed.
Project description:A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved.