Acid Catalyzed Transfer Hydrogenation Research Articles

Chiral phosphoric acid-catalyzed transfer hydrogenation of 3,3-difluoro-3H-indoles.

A convenient and efficient method for the synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with excellent yield and enantioselectivity.

Enantioselective Parallel Kinetic Resolution of Aziridine-Containing Quinoxalines via Chiral Phosphoric Acid-Catalyzed Transfer Hydrogenation.

This article describes the asymmetric synthesis of chiral aziridinoquinoxalines using (R)-TRIP-catalyzed parallel kinetic resolution under transfer hydrogenation conditions. This resolution was successfully accomplished for 16 different substrates and led to highly enantioenriched diastereomers with the (R)-configuration of the newly formed stereocenter (32-61% yield and 64-99% ee for the (R,R,R)-diastereomers and 7-46% yield and 97-99% ee for the (S,S,R)-diastereomers). This process could be coupled to ring-opening of the (S,S,R)-diastereomer with thiophenol to produce chiral tetrahydroquinoxalines with three contiguous stereocenters.

Tilting the Balance: London Dispersion Systematically Enhances Enantioselectivities in Brønsted Acid Catalyzed Transfer Hydrogenation of Imines.

London dispersion (LD) is attracting more and more attention in catalysis since LD is ubiquitously present and cumulative. Since dispersion is hard to grasp, recent research has concentrated mainly on the effect of LD in individual catalytic complexes or on the impact of dispersion energy donors (DEDs) on balance systems. The systematic transfer of LD effects onto confined and more complex systems in catalysis is still in its infancy, and no general approach for using DED residues in catalysis has emerged so far. Thus, on the example of asymmetric Brønsted acid catalyzed transfer hydrogenation of imines, we translated the findings of previously isolated balance systems onto confined catalytic intermediates, resulting in a systematic enhancement of stereoselectivity when employing DED-substituted substrates. As the imine substrate is present as Z- and E-isomers, which can, respectively, be converted to R- and S-product enantiomers, implementing tert-butyl groups as DED residues led to an additional stabilization of the Z-imine by up to 4.5 kJ/mol. NMR studies revealed that this effect is transferred onto catalyst/imine and catalyst/imine/nucleophile intermediates and that the underlying reaction mechanism is not affected. A clear correlation between ee and LD stabilization was demonstrated for 3 substrates and 10 catalysts, allowing to convert moderate-good to good-excellent enantioselectivities. Our findings conceptualize a general approach on how to beneficially employ DED residues in catalysis: they clearly showcase that bulky alkyl residues such as tert-butyl groups must be considered regarding not only their repulsive steric bulk but also their attractive properties even in catalytic complexes.

Visible-Light Induction/Brønsted Acid Catalysis in Relay for the Enantioselective Synthesis of Tetrahydroquinolines.

An efficient method merging Brønsted acid catalysis with visible-light induction for the highly enantioselective synthesis of tetrahydroquinolines has been developed. This mild process directly transforms 2-aminoenones into 2-substituted tetrahydroquinolines with excellent enantioselectivities through a relay visible-light-induced cyclization/chiral phosphoric acid-catalyzed transfer hydrogenation reaction.

Enantioselective Synthesis of 3,4-Dihydropyrimidin-2(1 H)-ones through Organocatalytic Transfer Hydrogenation of 2-Hydroxypyrimidines.

Chiral phosphoric acid-catalyzed transfer hydrogenation of 2-hydroxypyrimidines has been successfully realized using Hantzsch ester or dihydrophenanthridine as the hydrogen source, furnishing the chiral 3,4-dihydropyrimidin-2(1 H)-ones (DHPMs) with excellent yields and enantioselectivities of ≤99%. Notably, a novel kind of chiral DHPMs with an alkyl stereogenic center can be prepared through highly chemoselective transfer hydrogenation.

Brønsted Acid Catalyzed Transfer Hydrogenation of Imines and Alkenes

Key words transfer hydrogenation - cyclohexadienes - Brønsted acid - dihydrogen surrogate

Brønsted Acid-Catalyzed Transfer Hydrogenation of Imines and Alkenes Using Cyclohexa-1,4-dienes as Dihydrogen Surrogates.

Cyclohexa-1,4-dienes are introduced to Brønsted acid-catalyzed transfer hydrogenation as an alternative to the widely used Hantzsch dihydropyridines. While these hydrocarbon-based dihydrogen surrogates do offer little advantage over established protocols in imine reduction as well as reductive amination, their use enables the previously unprecedented transfer hydrogenation of structurally and electronically unbiased 1,1-di- and trisubstituted alkenes. The mild procedure requires 5.0 mol % of Tf2NH, but the less acidic sulfonic acids TfOH and TsOH work equally well.

ChemInform Abstract: Highly Enantioselective SPINOL‐Derived Phosphoric Acid Catalyzed Transfer Hydrogenation of Diverse C=N‐Containing Heterocycles.

AbstractHydrogenation of C=N‐containing heterocycles is carried out by using 1,1′‐spirobiindane‐7,7′‐diol‐derived chiral phosphoric acids as the catalyst.

Highly Enantioselective SPINOL‐Derived Phosphoric Acid Catalyzed Transfer Hydrogenation of Diverse C=N‐Containing Heterocycles

AbstractA highly efficient and enantioselective hydrogenation of diversely substituted C=N‐containing heterocyclic compounds such as 3‐aryl‐1,4‐benzoxazines and 2‐arylquinolines was experimentally explored by using 1,1′‐spirobiindane‐7,7′‐diol‐derived chiral phosphoric acids as the catalyst. This method provides straightforward access to the corresponding tetrahydroquinolines and dihydro‐2H‐1,4‐benzothiazines in high yields (85–99 %) with excellent enantioselectivities (91–99 %). The attractive features of this procedure, which include mild reaction conditions, operational simplicity, relatively low catalyst loading (1 mol‐%), and high levels of enantioselectivities, make it a useful approach for the practical synthesis of optically active nitrogen‐containing aromatic heterocycles.

ChemInform Abstract: Benzothiazoline: Versatile Hydrogen Donor for Organocatalytic Transfer Hydrogenation

AbstractReview: 62 refs.

Benzothiazoline: versatile hydrogen donor for organocatalytic transfer hydrogenation.

CONSPECTUS: The asymmetric reduction of ketimines is an important method for the preparation of amines in optically pure form. Inspired by the biological system using NAD(P)H, Hantzsch ester has been extensively employed as a hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation of ketimines to furnish amines with high to excellent enantioselectivities. We focused on 2-substituted benzothiazoline as a hydrogen donor in the phosphoric acid catalyzed transfer hydrogenation reaction of ketimines for the following reasons: (1) benzothiazoline is readily prepared just by mixing 2-aminobenzenethiol and aldehyde, (2) both reactivity (hydrogen donating ability) and enantioselectivity would be controlled by tuning the 2-substituent of benzothiazoline, and (3) benzothiazoline can be stored in a refrigerator under inert atmosphere without conceivable decomposition. Both the 2-position of benzothiazoline and the 3,3'-position of phosphoric acid are tunable in order to achieve excellent enantioselectivity. Benzothiazoline proved to be useful hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation reaction of ketimine derivatives to afford the corresponding amines with high to excellent enantioselectivities by tuning the 2-substituent of benzothiazoline. Ketimines derived from acetophenone, propiophenone, α-keto ester, trifluoromethyl ketone, and difluoromethyl ketone derivatives proved to be suitable substrates. Benzothiazoline could be generated in situ starting from 2-aminobenzenethiol and aromatic aldehyde in the presence of ketimine and chiral phosphoric acid and successfully worked in the sequential transfer hydrogenation reaction. The reductive amination of dialkyl ketones also proceeded with high enantioselectivities. Use of 2-deuterated benzothiazoline led to the formation of α-deuterated amines with excellent enantioselectivities. The kinetic isotope effect (kH/kC = 3.8) was observed in the competitive reaction between H- and D-benzothiazoline, which explicitly implies that the cleavage of the C-H (C-D) bond is the rate-determining step in the transfer hydrogenation reaction. Benzothiazoline yielded products with higher enantioselectivity in the transfer hydrogenation reaction of ketimines, particularly ketimines derived from propiophenone derivatives, than Hantzsch ester. DFT study elucidated the mechanism, as well as the difference in selectivity, between benzothiazoline and Hantzsch ester. The chiral phosphoric acid activates ketimines and benzothiazoline by means of the Brønsted acidic site (proton) and the Brønsted basic site (phosphoryl oxygen), respectively, to accelerate the hydride transfer reaction.

Phosphoric Acid Catalyzed Transfer Hydrogenation of Ethyl Ketimines

Phosphoric Acid Catalyzed Transfer Hydrogenation of Ethyl Ketimines

Chiral phosphoric-acid-catalyzed transfer hydrogenation of ethyl ketimine derivatives by using benzothiazoline.

Chiral phosphoric acid catalyzed transfer hydrogenation of ketimines derived from propiophenone derivatives and reductive amination of alkyl ethyl ketone derivatives were extensively examined in the presence of two representative hydrogen donors. The excellent enantioselective transfer hydrogenation was achieved by use of benzothiazoline as a hydrogen donor. The theoretical studies elucidated that the unsymmetrical structure of benzothiazoline plays an important role in high enantioselective hydrogenation.

ChemInform Abstract: Asymmetric Synthesis of Tetrahydro‐β‐carbolines via Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation Reaction.

AbstractAn efficient synthesis of enantioenriched tetrahydro‐β‐carbolines via chiral phosphoric acid catalyzed asymmetric transfer hydrogenation with a Hantzsch ester as organic hydride source is reported.

DFT Study of the Mechanism and Origin of Enantioselectivity in Chiral BINOL-Phosphoric Acid Catalyzed Transfer Hydrogenation of Ketimine and α-Imino Ester Using Benzothiazoline

Benzothiazoline is an efficient reducing agent for the chiral BINOL-phosphoric acid catalyzed enantioselective transfer hydrogenation of ketimines and α-imino esters to afford the corresponding amines with high enantioselectivities. DFT studies (M05-2X/6-31G*//ONIOM(B3LYP/6-31G*:HF/3-21G)) revealed the reaction mechanism and the origin of the high enantioselectivity in the present BINOL-phosphoric acid catalyzed transfer hydrogenation of ketimines and α-imino esters using benzothiazoline. The reaction mechanism is similar to that reported in the asymmetric transfer hydrogenation of ketimines using Hantzsch ester. Phosphoric acid simultaneously activates ketimine (α-imino ester) and benzothiazoline to form cyclic transition structures. The high enantioselectivity is attributed to the steric interaction between the substituents at the 3,3'-positions of BINOL-phosphoric acid and substrates. In contrast to the C2-symmetrical Hantzsch ester, the readily tunable 2-aryl substituent of unsymmetrical benzothiazoline plays a significant role in the steric interaction, influencing the asymmetric induction. This feature is responsible for the advantage of benzothiazoline over Hantzsch ester.

ChemInform Abstract: Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation: Facile Synthetic Access to Highly Optically Active Trifluoromethylated Amines.

AbstractThe desired products can be prepared from trifluoromethyl imines or trifluoromethyl ketones in the presence of organocatalyst BPA.

Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation of Ketimines

Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation of Ketimines

Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation: Facile Synthetic Access to Highly Optically Active Trifluoromethylated Amines

Optisch aktive α-CF3-funktionalisierte Amine wurden unter metallfreien Bedingungen erhalten. Die Methode umfasst die Transferhydrierung von CF3-substituierten Ketiminen mit 1 als Katalysator und die reduktive Aminierung von CF3-substituierten Ketonen. Der präparative Nutzen der Methode wird anhand der Synthese eines CF3-Analogons von NPS R-568 gezeigt. PMP=para-Methoxyphenyl. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation: Facile Synthetic Access to Highly Optically Active Trifluoromethylated Amines

Amines to an end: highly optically active α-CF(3)-functionalized amines can be obtained using metal-free reaction conditions. The method involves the transfer hydrogenation of CF(3)-substituted ketimines catalyzed by 1 and reductive amination of CF(3)-substituted ketones. The synthetic utility of this method was demonstrated by the synthesis of a CF(3) analogue of NPS R-568. PMP=para-methoxyphenyl.

Asymmetric Synthesis of Indolines by Catalytic Enantioselective Reduction of 3H-Indoles

A highly enantioselective metal-free reduction of 3H-indoles has been developed. This Brønsted acid catalyzed transfer hydrogenation of indole derivatives with Hantzsch dihydropyridine as the hydrogen source constitutes an efficient method for the synthesis of various optically active indolines with high enantioselectivities.