Iminium Catalysis Research Articles

Synthesis of Polycyclic Amines through Mild Metal‐Free Tandem Cross‐Dehydrogenative Coupling/Intramolecular Hydroarylation of N‐Aryltetrahydroisoquinolines and Crotonaldehyde

AbstractA [4+2] cycloaddition reaction proceeding through tandem cross‐dehydrogenative coupling/intramolecular hydroarylation between N‐aryltetrahydroisoquinolines and crotonaldehyde was developed by virtue of enamine–iminium catalysis, which enabled the rapid construction of ring‐fused tetrahydroquinolines. The first metal‐free catalytic oxidative coupling of γ‐selective C(sp3)–H bonds of crotonaldehyde was realized by using a secondary amine catalyst and 2,3‐dichloro‐5,6‐dicyanoquinone.

Exploring the activation modes of a rotaxane-based switchable organocatalyst.

The reactivity of a rotaxane that acts as an aminocatalyst for the functionalization of carbonyl compounds through HOMO and LUMO activation pathways has been studied. Its catalytic activity is explored for C-C and C-S bond forming reactions through iminium catalysis, in nucleophilic substitutions and additions through enamine intermediates, in Diels-Alder reactions via trienamine catalysis, and in a tandem iminium-ion/enamine reaction. The catalyst can be switched "on" or "off", effectively controlling the rate of all of these chemical transformations, by the in situ change of the position of the macrocycle between two different binding sites on the rotaxane thread.

Rationally designed multifunctional supramolecular iminium catalysis: direct vinylogous Michael addition of unmodified linear dienol substrates.

The development of a direct vinylogous Michael addition of linear nucleophilic substrates is a long-standing challenge because of the poor reactivity and the considerable difficulty in controlling regioselectivity. By employing a rationally designed multifunctional supramolecular iminium catalysis strategy, the first direct vinylogous Michael addition of unmodified linear substrates to α,β-unsaturated aldehydes, to afford chiral 1,7-dioxo compounds with good yields and excellent regio- as well as enantioselectivity, has been developed.

Rationally Designed Multifunctional Supramolecular Iminium Catalysis: Direct Vinylogous Michael Addition of Unmodified Linear Dienol Substrates

AbstractThe development of a direct vinylogous Michael addition of linear nucleophilic substrates is a long‐standing challenge because of the poor reactivity and the considerable difficulty in controlling regioselectivity. By employing a rationally designed multifunctional supramolecular iminium catalysis strategy, the first direct vinylogous Michael addition of unmodified linear substrates to α,β‐unsaturated aldehydes, to afford chiral 1,7‐dioxo compounds with good yields and excellent regio‐ as well as enantioselectivity, has been developed.

ChemInform Abstract: Diastereo‐ and Enantioselective Synthesis of Hexasubstituted Cyclohexanes via a Metal—Organocatalytic Quadruple Cascade Sequence.

A quadruple cascade reaction, comprising iminium, enamine–copper, iminium, and enamine catalysis, was investigated. This reaction afforded highly optically active hexasubstituted cyclohexanes from α,β-unsaturated aldehydes, nitromethane, and 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO). To enhance the stereoselectivity of the organocatalytic cyclization, TEMPO was incorporated into the cyclohexane skeleton using copper catalysts.

Catalytic imine-imine cross-coupling reactions.

We report here efficient catalytic imine-imine cross-coupling reactions based on an umpolung strategy; an imine bearing a 9-fluorenyl moiety on its nitrogen atom, which acted as a nucleophile, reacted with another imine to afford an imine-imine cross-coupling adduct in high yield. Furthermore, a chiral guanidine acted as a chiral catalyst for these coupling reactions, and optically active 1,2-diamines were obtained in high yields with high enantioselectivities.

Direct remote asymmetric bisvinylogous 1,4-additions of cyclic 2,5-dienones to nitroalkenes.

Here we report that cyclic 2,5-dienones can act as bisvinylogous precursors through in situ generation of linear trienamine species with a cinchona-derived primary amine, and exclusively remote ε-regioselective 1,4-additions to nitroalkenes were accomplished in moderate to high enantioselectivity. Moreover, a diversity of complex spirocyclic frameworks could be efficiently constructed in an enantioenriched manner from these multifunctional 1,4-adducts via subsequent vinylogous iminium and even cascade iminium catalysis of the same amine.

Diastereo- and Enantioselective Synthesis of Hexasubstituted Cyclohexanes via a Metal–Organocatalytic Quadruple Cascade Sequence

A quadruple cascade reaction, comprising iminium, enamine–copper, iminium, and enamine catalysis, was investigated. This reaction afforded highly optically active hexasubstituted cyclohexanes from α,β-unsaturated aldehydes, nitromethane, and 2,2,6,6-tetramethylpiperidin-1-yloxy (TEMPO). To enhance the stereoselectivity of the organocatalytic cyclization, TEMPO was incorporated into the cyclohexane skeleton using copper catalysts.

A Practical and Stereoselective Organocatalytic Alkylation of Aldehydes with Benzodithiolylium Tetrafluoroborate

Recently, the direct substitution of allylic, benzylic, and tertiary alcohols has been achieved via SN 1-type reactions with catalytic amounts of Brønsted or Lewis acids. When a new stereogenic center is formed most of these transformations produce the desired product as a racemate, as these reactions proceed through carbenium ions. The arsenal of activation modes available in organocatalysis can be used to set up suitable reaction conditions in which chiral nucleophiles (enamine catalysis) or chiral electrophiles (iminium catalysis, chiral counterion catalysis) can easily be generated. Recently, we have used stabilized carbenium ions, directly available or obtained from the corresponding alcohols, in new organocatalytic stereoselective SN 1-type reactions. The commercially available carbenium ion benzodithiolylium tetrafluoroborate can be used for the straightforward organocatalytic stereoselective alkylation of aldehydes. In this account we will illustrate the application of this methodology in the total synthesis of natural products and the preparation of valuable starting materials.

ChemInform Abstract: Enantioselective Total Synthesis of (‐)‐Minovincine in Nine Chemical Steps: An Approach to Ketone Activation in Cascade Catalysis.

ChemInform Abstract: Enantioselective Total Synthesis of (‐)‐Minovincine in Nine Chemical Steps: An Approach to Ketone Activation in Cascade Catalysis.

A New Approach for Supramolecular Iminium Catalysis

An alternative modular strategy has been developed for hydrogen-bond-mediated supramolecular iminium catalysis (SIC). To improve the efficiency of traditional iminium ion catalysis and provide a new approach to asymmetric catalysis, we recently developed a new concept which aims to activate iminium ions. To expand the scope of SIC, we reported here a rationally designed strategy involving the dual activation of both iminium ions and the nucleophilic partner that provides new opportunities for improving the reactivity and designing new reactions. We analyzed the different reaction rates of the addition reaction of malonate to alpha,beta-unsaturated aldehyde catalyzed by traditional iminium ion catalysis and supramolecular iminium catalysis by the means of H-1 NMR monitoring of the reaction conversions and comparison of the isolated yields. Moreover, different carboxylic acids were employed in iminium catalytic Michael addition reaction of malonate to alpha,beta-unsaturated aldehyde to test our hypothesis. General speaking, by using this novel supramolecular iminium catalysis, the enantioselectivities of the Michael addition products are excellent (93%similar to 95%) with moderate to good yields (61%similar to 86%), meanwhile, all these reactions were rather slow and only 33%similar to 57% conversions were obtained even after 7 days in the presence of traditional iminium ion catalysis. Further reducing the catalyst loading to 5 mol%, the reaction proceeded smoothly to give a >90% conversion with 94% ee after 12 h. The results revealed that the use of less acidic acid which generates lower concentration of iminium ion associated with stronger anion-binding stabilized conjugate base gives faster reaction rate. The experimental results indicate a new approach for SIC which involves an anion-exchange process between anion-binding stabilized carboxylate ion and malonate. The self-assembled supramolecular system has higher reactivity, better efficiency and greater turnover numbers. This general strategy has the potential to be applied in many iminium catalytic nucleophilic addition reactions and might provide new opportunities for designing new asymmetric reactions. The further study is currently underway in our laboratory.

ChemInform Abstract: Asymmetric Mannich Reaction of α‐Keto Imines Catalyzed by Diarylprolinol Silyl Ether.

AbstractThe reaction proceeds via base‐promoted desulfonative generation of an intermediary electrophilic imine followed by organocatalytic asymmetric Mannich reaction yielding an β‐aminoaldehyde.

The organocatalytic enantioselective [3+2] cycloaddition reaction of α,β-unsaturated aldehydes with azomethine ylides applied to the asymmetric synthesis of densely substituted pyrroloisoquinolines

The synthesis of densely functionalized pyrrolo[2,1-a]isoquinolines was accomplished using the organocatalytic [3+2] cycloaddition between enals and azomethine ylides under iminium catalysis developed in our group some years ago as the key step. The cycloaddition proceeds smoothly yielding the corresponding pyrrolidine as a single endo diastereoisomer with enantiopurity in the range of 94–96% and further manipulations of the obtained cycloadducts using high yielding reaction protocols and a final mesylation/intramolecular N-alkylation sequence allowed the synthesis of target compounds in which the integrity of all stereocenters installed during the first step is maintained.

Asymmetric Organocatalytic Synthesis of Spiro-cyclopropaneoxindoles

Straightforward cascade reactions for the synthesis of spiro-cyclopropaneoxindoles are described. The target compounds are obtained in high yields and in good enantio- and diastereoselectivities via hydrogen bonding or iminium catalysis.

ChemInform Abstract: Using Conveniently Designed α‐Amino Ketones in Michael Reactions under Iminium Catalysis: Enantioselective Synthesis of γ‐Lactams and γ‐Amino‐δ‐keto Esters.

AbstractThe reaction of α,β‐unsaturated aldehydes with N‐tosylaminoacetophenone (II) proceeds with moderate cis‐selectivity but both diastereomers are obtained with high enantioselectivity.

Asymmetric Mannich Reaction of α‐Keto Imines Catalyzed by Diarylprolinol Silyl Ether

Synthetic methods: An asymmetric catalytic, desulfonylative Mannich reaction of α-keto imines with aldehydes, as catalyzed by diarylprolinol silyl ether 1, was developed. It gave the Mannich product in good yield with excellent anti and enantioselectivity (see scheme; Boc = tert-butoxycarbonyl, TMS = trimethylsilyl).

An investigation into the mechanism of the imidazolidinone catalyzed cascade reaction

The cascade reaction of α,β-unsaturated butyric aldehydes with 2-methyl furan and chlorinated quinone catalyzed by a (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one·TFA was investigated by using density functional theory (DFT) calculations at the PCM(EtOAc)/B3LYP/6-311++G(d,p)//B3LYP/6-31G(d) level to (a) confirm the detailed reaction mechanism and key factors controlling the enantioselectivity; and (b) check the models of the iminium ion formation and hydrolysis process that were carried out in another reaction. Two favorable reaction channels, corresponding to the enantioselectivity of the (2R,3S)-product and (2S,3S)-product, have been characterized. The enantioselectivity is controlled by the steps involved in the formation of the C–C bond and the C–Cl bond in the iminium catalysis and the enamine catalysis, respectively. The calculated results explain the reaction mechanism and the enantioselectivity, which are in agreement with experimental observations, and may be helpful for understanding the reaction mechanism of similar cascade reactions.

Asymmetric Protonation of Silyl Ketene Imines Catalyzed by Phosphoric Acids

Asymmetric Protonation of Silyl Ketene Imines Catalyzed by Phosphoric Acids

Modular Pyridine Synthesis from Oximes and Enals through Synergistic Copper/Iminium Catalysis

We describe here a [3+3]-type condensation reaction of O-acetyl ketoximes and α,β-unsaturated aldehydes that is synergistically catalyzed by a copper(I) salt and a secondary ammonium salt (or amine). This redox-neutral reaction allows modular synthesis of a variety of substituted pyridines under mild conditions with tolerance of a broad range of functional groups. The reaction is driven by a merger of iminium catalysis and redox activity of the copper catalyst, which would initially reduce the oxime N-O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediate to the pyridine product.

Cover Picture: Bio-Inspired Catalytic Imine Reduction by Rhodium Complexes with Tethered Hantzsch Pyridinium Groups: Evidence for Direct Hydride Transfer from Dihydropyridine to Metal-Activated Substrate (Angew. Chem. Int. Ed. 12/2013)

Cover Picture: Bio-Inspired Catalytic Imine Reduction by Rhodium Complexes with Tethered Hantzsch Pyridinium Groups: Evidence for Direct Hydride Transfer from Dihydropyridine to Metal-Activated Substrate (Angew. Chem. Int. Ed. 12/2013)