Imine Substrates Research Articles

Use of α,ω-Dichloroketimine Building Blocks for the Construction of 1-Azabicyclo[3.1.0]hexanes, Piperidines, Pyridines, Pyrroles, and Tetrahydroindoles

A variety of different N-[2-chloro-4-(chloromethyl)pent-4-enylidene]amines and N-(2,6-dichlorohex-4-enylidene)amines was prepared for the first time, and their reactivity as eligible building blocks for the synthesis of biologically relevant nitrogen-containing heterocyclic compounds was studied. In this way, a convenient entry into functionalized 1-azabicyclo[3.1.0]hexanes, piperidines, pyridines, pyrroles, and tetrahydroindoles was developed, pointing to the broad synthetic flexibility of these dichlorinated imine substrates.

Cobalt-catalyzed redox-neutral synthesis of isoquinolines: C–H activation assisted by an oxidizing N–S bond

A redox-neutral avenue to access isoquinolines has been realized by a Co(III)-catalyzed C–H activation process. Starting from readily available N-sulfinyl imine substrates and alkynes, the reaction occurred via N–S cleavage with broad substrate scope and functional group compatibility in the presence of cost-effective cobalt catalysts.

The biochemical characterization of three imine-reducing enzymes from Streptosporangium roseum DSM43021, Streptomyces turgidiscabies and Paenibacillus elgii.

Recently imine reductases (IREDs) have emerged as promising biocatalysts for the synthesis of a wide variety of chiral amines. To promote their application, many novel enzymes were reported, but only a few of them were biochemically characterized. To expand the available knowledge about IREDs, we report the characterization of two recently identified (R)-selective IREDs from Streptosporangium roseum DSM43021 and Streptomyces turgidiscabies and one (S)-selective IRED from Paenibacillus elgii. The biochemical properties including pH profiles, temperature stabilities, and activities of the enzymes in the presence of organic solvents were investigated. All three enzymes showed relatively broad pH spectra with maximum activities in the neutral range. While the (R)-selective IREDs displayed only limited thermostabilities, the (S)-selective enzyme was found to be the most thermostable IRED known to date. The activity of this IRED proved also to be most tolerant towards the investigated co-solvents DMSO and methanol. We further studied activities and selectivities towards a panel of cyclic imine model substrates to compare these enzymes with other IREDs. In biotransformations, IREDs showed high conversions and the amine products were obtained with up to 99% ee. By recording the kinetic constants for these compounds, substrate preferences of the IREDs were investigated and it was shown that the (S)-IRED favors the transformation of bulky imines contrary to the (R)-selective IREDs. Finally, novel exocyclic imine substrates were tested and also high activities and selectivities detected.

Indoline‐Based Constrained Peptidomimetic Motifs Obtained via the Joullié–Ugi Reaction of Indolenines

Sterically demanding indolenines were employed as cyclic imine substrates in the Joullié–Ugi reaction with diverse isocyanides and carboxylic acids resulting in a new type of conformationally constrained indoline‐based peptidomimetic compounds.

Hydrogenation and Transfer Hydrogenation Promoted by Tethered Ru−S Complexes: From Cooperative Dihydrogen Activation to Hydride Abstraction/Proton Release from Dihydrogen Surrogates

Hydrogenation and transfer hydrogenation of imines with cyclohexa-1,4-dienes, as well as with a representative Hantzsch ester dihydrogen surrogate, are reported. Both processes are catalyzed by tethered Ru-S complexes but differ in the activation mode of the dihydrogen source: cooperative activation of the H-H bond at the Ru-S bond leads to the corresponding Ru-H complex and protonation of the sulfur atom, whereas the same cationic Ru-S catalyst abstracts a hydride from a donor-substituted cyclohexa-1,4-diene to form the neutral Ru-H complex and a low-energy Wheland intermediate. A sequence of proton and hydride transfers on the imine substrate then yields an amine. The reaction pathways are analyzed computationally, and the established mechanistic pictures are in agreement with the experimental observations.

Zirconium-Catalyzed Imine Hydrogenation via a Frustrated Lewis Pair Mechanism

Zirconium-based frustrated Lewis pairs (FLPs) are active imine hydrogenation catalysts under mild conditions. Complexes of the type [CpR2ZrOMes][B(C6F5)4] utilize the imine substrate itself as the Lewis base component of the FLP. Catalyst performance is a function of ligand structure; in general more bulky, more electron rich cyclopentadienyl derivatives give the best results. However, Cp* derivatives are not catalytically active, being stable after initial heterolytic cleavage of H2; this allows experimental verification of the competence of the zirconocene–imine pair in FLP-type heterolytic H2 cleavage. Enamines and protected nitriles are also hydrogenated if an additional internal phosphine base is used.

Rapid Access to New Thiazepinyl and Oxazepinyl Phosphonates through a Green Pudovik Reaction

AbstractA simple, facile, and efficient microwave‐assisted synthetic protocol for the preparation of novel dibenzothiazepinyl and dibenzoxazepinyl phosphonates has been reported. The present Pudovik approach works without a catalyst or solvent to furnish cyclic α‐amino phosphonates by using dibenzothia‐ and dibenzoxazepines as imine substrates. This method has a greener edge and is amenable to large‐scale production.

Highly Stereoselective Synthesis of Terminal Chloro-Substituted Propargylamines and Further Functionalization.

The highly stereoselective addition of lithiated chloroacetylene, derived in situ from cis-1,2-dichloroethene and methyl lithium, to Ellman chiral N-tert-butanesulfinyl imines is reported. The reaction proceeds in high yield (up to 98%) and with excellent diastereoselectivity (up to >20:1) for a variety of aryl, heteroaromatic, alkyl, and α,β-unsaturated imine substrates. Transformations of the terminal chloro-substituted propargylamine products are described in which lithium-halogen exchange yields nucleophilic acetylides that can be quenched to yield terminal alkynes or intercepted by carbon electrophiles.

The Nature of meso- and pyro-Borate Precatalysts to the VANOL and VAPOL BOROX Catalysts

The structures of the meso- and pyro-borate esters generated by treatment of the VANOL and VAPOL ligands with triphenylborate have been revisited. These species were previously identified as precatalysts that could be in situ converted into VANOL and VAPOL BOROX catalysts by an imine substrate. The complete assignment of all protons for both the meso- and pyro-borate esters of both ligands was aided by the 1H NMR spectrum of each generated from pentadeuterophenol. There were significant differences between the chemical shifts for certain protons in the meso- and pyro-borate species in both the VANOL and VAPOL derivatives. Optimized structures for the meso-borates and two different isomers of the pyro-borates were determined by DFT calculations for each ligand. For each ligand the cyclic pyro-borate was found to be lower in energy than the corresponding linear pyro-borate at the B3LYP/6-311+G(d,p) level of theory. The structures of the cyclic pyro-borate esters were more consistent with the observed 1H NMR chemical shifts than the linear pyro-borates for each ligand and thus the structures of the pyro-borates esters of VANOL and VAPOL have been re-assigned as the cyclic isomers.

Asymmetric Transfer Hydrogenation of Imines in Water by Varying the Ratio of Formic Acid to Triethylamine.

Asymmetric transfer hydrogenation (ATH) of imines has been performed with variation in formic acid (F) and triethylamine (T) molar ratios in water. The F/T ratio is shown to affect both the reduction rate and enantioselectivity, with the optimum ratio being 1.1 in the ATH of imines with the Rh-(1S,2S)-TsDPEN catalyst. Use of methanol as a cosolvent enhanced reduction activity. A variety of imine substrates have been reduced, affording high yields (94-98%) and good to excellent enantioselectivities (89-98%). In comparison with the common azeotropic F-T system, the reduction with 1.1/1 F/T is faster.

Rhodium-catalyzed tandem addition–cyclization of alkynylimines

A rhodium-catalyzed tandem addition–cyclization of alkynylimines is described. In this process employing a single rhodium catalyst, alkyne-tethered N-sulfinyl and sulfonylimines react with aryl/alkenylboronic acids and aryl/alkyl zinc reagents to give 2-alkylidene-substituted cyclobutyl and cyclopentyl amine products. The reaction occurs through a tandem sequence involving 1,2-carbometalation of the alkyne and 4- and 5-exo-cyclization of the resulting alkenyl rhodium with the imine. This method allows for the catalytic alkyne addition/cyclization process to include imine substrates, providing expeditious access to complex cyclobutyl and cyclopentyl amines with potential stereocontrol.

Palladium catalysed sequential imine arylation/Suzuki–Miyaura coupling: synthesis of α-(biarylyl)benzylamines

We report an innovative, high yielding one-pot sequential catalytic imine arylation/Suzuki–Miyaura cross-coupling reaction, which converts suitably activated imine substrates to various biarylarylmethyl amine products using several commercial Pd catalysts. Many biarylarylmethyl amine molecules are biologically active. Insightful computational studies detail the mechanism of the imine arylation process. The sequence of reactions is likely to be dependent on the reaction conditions.

ChemInform Abstract: Experimental and Theoretical Perspectives of the Noyori‐Ikariya Asymmetric Transfer Hydrogenation of Imines

AbstractReview: 87 refs.

Structure, Activity and Stereoselectivity of NADPH-Dependent Oxidoreductases Catalysing the S-Selective Reduction of the Imine Substrate 2-Methylpyrroline.

Oxidoreductases from Streptomyces sp. GF3546 [3546-IRED], Bacillus cereus BAG3X2 (BcIRED) and Nocardiopsis halophila (NhIRED) each reduce prochiral 2-methylpyrroline (2MPN) to (S)-2-methylpyrrolidine with >95 % ee and also a number of other imine substrates with good selectivity. Structures of BcIRED and NhIRED have helped to identify conserved active site residues within this subgroup of imine reductases that have S selectivity towards 2MPN, including a tyrosine residue that has a possible role in catalysis and superimposes with an aspartate in related enzymes that display R selectivity towards the same substrate. Mutation of this tyrosine residue-Tyr169-in 3546-IRED to Phe resulted in a mutant of negligible activity. The data together provide structural evidence for the location and significance of the Tyr residue in this group of imine reductases, and permit a comparison of the active sites of enzymes that reduce 2MPN with either R or S selectivity.

Bio-inspired transition metal-organic hydride conjugates for catalysis of transfer hydrogenation: experiment and theory.

Taking inspiration from yeast alcohol dehydrogenase (yADH), a benzimidazolium (BI(+) ) organic hydride-acceptor domain has been coupled with a 1,10-phenanthroline (phen) metal-binding domain to afford a novel multifunctional ligand (L(BI+) ) with hydride-carrier capacity (L(BI+) +H(-) ⇌L(BI) H). Complexes of the type [Cp*M(L(BI) )Cl][PF6 ]2 (M=Rh, Ir) have been made and fully characterised by cyclic voltammetry, UV/Vis spectroelectrochemistry, and, for the Ir(III) congener, X-ray crystallography. [Cp*Rh(L(BI) )Cl][PF6 ]2 catalyses the transfer hydrogenation of imines by formate ion in very goods yield under conditions where the corresponding [Cp*Ir(L(BI) )Cl][PF6 ] and [Cp*M(phen)Cl][PF6 ] (M=Rh, Ir) complexes are almost inert as catalysts. Possible alternatives for the catalysis pathway are canvassed, and the free energies of intermediates and transition states determined by DFT calculations. The DFT study supports a mechanism involving formate-driven RhH formation (90 kJ mol(-1) free-energy barrier), transfer of hydride between the Rh and BI(+) centres to generate a tethered benzimidazoline (BIH) hydride donor, binding of imine substrate at Rh, back-transfer of hydride from the BIH organic hydride donor to the Rh-activated imine substrate (89 kJ mol(-1) barrier), and exergonic protonation of the metal-bound amide by formic acid with release of amine product to close the catalytic cycle. Parallels with the mechanism of biological hydride transfer in yADH are discussed.

ChemInform Abstract: Stereoselective Allylboration of Imines and Indoles under Mild Conditions. An in situ E/Z Isomerization of Imines by Allylboroxines.

Direct allylboration of various acyclic and cyclic aldimine, ketimine and indole substrates was performed using allylboronic acids. The reaction proceeds with very high anti-stereoselectivity for both E and Z imines. The allylboroxines formed by dehydration of allylboronic acids have a dual effect: promoting E/Z isomerization of aldimines and triggering the allylation by efficient electron withdrawal from the imine substrate.

ChemInform Abstract: Asymmetric Synthesis of β′‐Amino‐α,β‐enones via Addition of α,β‐Unsaturated Ketone‐Derived Enolates to Chiral N‐Phosphonyl Imines.

Abstract Efficient asymmetric Mannich addition reactions between α,β-unsaturated ketone derived enolates and N -phosphonyl imines were reported. These reactions could proceed smoothly for a variety of imine substrates with good (up to 96%) chemical yields and excellent diastereoselectivities (up to 98:2 dr). The method reported in this work provides an easy access to chiral β′-amino-α,β-enones.

Chiral sulfinamidourea and strong Brønsted acid-cocatalyzed enantioselective Povarov reaction to access tetrahydroquinolines.

This protocol describes a method for the laboratory synthesis of enantiomerically enriched, chiral tetrahydroisoquinolines through the application of a chiral sulfinamido urea catalyst for the Povarov reaction. Tetrahydroisoquinolines are bicyclic organic frameworks present in a wide assortment of natural and synthetic biologically important compounds including martinelline, scoulerine and tubocurarine. The methodology involves the [4+2] cycloaddition of a N-arylimines with electron-rich olefins such as vinyl lactams and dihydropyrroles in the presence of a two-catalyst system consisting of an achiral strong Brønsted acid (o-nitrobenzenesulfonic acid), together with the chiral sulfinamido urea derivative 1. The anion-binding properties of the urea lead to the association of the ion pair that results from protonation of the imine substrate. Cycloaddition is followed by spontaneous proton loss with re-aromatization to provide the tetrahydroisoquinoline products in highly enantio-enriched form.

Experimental and theoretical perspectives of the Noyori-Ikariya asymmetric transfer hydrogenation of imines.

The asymmetric transfer hydrogenation (ATH) of imines catalyzed by the Noyori-Ikariya [RuCl(η6-arene)(N-arylsulfonyl-DPEN)] (DPEN = 1,2-diphenylethylene-1,2-diamine) half-sandwich complexes is a research topic that is still being intensively developed. This article focuses on selected aspects of this catalytic system. First, a great deal of attention is devoted to the N-arylsulfonyl moiety of the catalysts in terms of its interaction with protonated imines (substrates) and amines (components of the hydrogen-donor mixture). The second part is oriented toward the role of the η6-coordinated arene. The final part concerns the imine substrate structural modifications and their importance in connection with ATH. Throughout the text, the summary of known findings is complemented with newly-presented ones, which have been approached both experimentally and computationally.

Phosphoric acid mediated tautomerism of imines: addition of a secondary enamine intermediate to aldehydes

A phosphoric acid derivative has been shown to promote the addition between an imine and several aldehyde substrates through an enamine intermediate to give cross-aldol condensation products. The reaction scope and preliminary mechanistic investigations will be presented.