Chiral Allylic Amines Research Articles

A Rapid Synthesis of Chiral Allylic Amines via Microwave‐assisted Asymmetric Alkenylation of N‐Tosyl Aldimines Catalyzed by Rhodium/Chiral Diene Complexes

A method providing expeditious access to chiral allylic amines via a Rh(I)/bicyclo[2.2.1]heptadiene‐catalyzed enantioselective alkenylation of N‐tosyl aldimines with potassium alkenyltrifluoroborates under microwave irradiation is described. The rate of the asymmetric 1,2‐addition reaction, conducted in the presence of 1 mol % of the catalyst, was significantly enhanced as compared to when the standard heating method was applied while still providing the corresponding products without decrease in enantioselectivity.

Efficient synthesis of functionalized olefins by Wittig reaction using Amberlite resin as a mild base

ABSTRACTA convenient procedure for the synthesis of olefins by the reaction of stabilized, semistabilized, and nonstabilized phosphorous ylides with various aldehydes or ketone using Amberlite resin as a mild base is described. Our developed method offers facile and racemization-free synthesis of α,β-unsaturated amino esters and chiral allylic amine. The developed methodology offers mild reaction conditions, high efficiency, and facile isolation of the final products, a practical alternative to known procedures.

Rhodium-Catalyzed Hydrofunctionalization: Enantioselective Coupling of Indolines and 1,3-Dienes.

We communicate a strategy for the hydrofunctionalization of 1,3-dienes via Rh-hydride catalysis. Conjugated dienes are coupled to nucleophiles to demonstrate the feasibility of novel C-C, C-O, C-S, and C-N bond forming processes. In the presence of a chiral JoSPOphos ligand, hydroamination generates chiral allylic amines with high regio- and enantioselectivity. Tuning both the pKa and steric properties of an acid-additive is critical for enantiocontrol.

Rh-Catalyzed Chemo- and Enantioselective Hydrogenation of Allylic Hydrazones.

A highly efficient P-stereogenic diphosphine-rhodium complex was applied to the chemo- and enantioselective hydrogenation of allylic hydrazones for the synthesis of chiral allylic hydrazines in 89-96 % yields and with 82-99 % ee values. This methodology was successfully applied to the preparation of versatile chiral allylic amine derivatives.

The Aryne [2,3] Stevens Rearrangement.

Arynes are employed in the transition-metal-free and mild [2,3] Stevens rearrangement of tertiary allylic amines for the synthesis of functionalized homoallylic amines in moderate to good yield with a broad substrate scope. The key nitrogen ylide intermediate was generated by the N-arylation of allyl amines using arynes. Moreover, the reaction of chiral allyl amines with arynes resulted in the enantiospecific synthesis of homoallylic amines. In addition, preliminary studies on the [1,2] Stevens rearrangement is also presented.

ChemInform Abstract: Asymmetric Synthesis of Allylic Amines via Hydroamination of Allenes with Benzophenone Imine.

Abstractα‐Chiral allylic amines are prepared by highly regio‐ and enantioselective hydroamination of various allenes applying a rhodium(I)/Josiphos catalyst.

ChemInform Abstract: Chiral NHC Ligands Bearing a Pyridine Moiety in Copper‐Catalyzed 1,2‐Addition of Dialkylzinc Reagents to β‐Aryl‐α,β‐unsaturated N‐Tosylaldimines.

Asymmetric 1,2-addition of dialkylzinc reagents to α,β-unsaturated N-tosylaldimines was catalyzed by copper salt in the presence of chiral imidazolium salts having a pyridine ring, which were derived from amino acid, to afford the corresponding chiral allylic amines with up to 91% ee in reasonably high yields. The chiral N-heterocyclic carbene (NHC) ligand played an important role in controlling chemoselectivity.

Chiral NHC Ligands Bearing a Pyridine Moiety in Copper-Catalyzed 1,2-Addition of Dialkylzinc Reagents to β-Aryl-α,β-unsaturated N-Tosylaldimines.

Asymmetric 1,2-addition of dialkylzinc reagents to α,β-unsaturated N-tosylaldimines was catalyzed by copper salt in the presence of chiral imidazolium salts having a pyridine ring, which were derived from amino acid, to afford the corresponding chiral allylic amines with up to 91% ee in reasonably high yields. The chiral N-heterocyclic carbene (NHC) ligand played an important role in controlling chemoselectivity.

Enantioselective synthesis of β-substituted chiral allylic amines via Rh-catalyzed asymmetric hydrogenation.

An asymmetric mono-hydrogenation of 2-acetamido-1,3-dienes catalyzed by a Rh-DuanPhos complex has been developed. This approach provides easy access to chiral allylic amines with excellent enantioselectivities and high regioselectivities. The products are valuable chiral building blocks for pharmaceuticals.

Formaldehyde as Tethering Organocatalyst: Highly Diastereoselective Hydroaminations of Allylic Amines.

Catalysts possessing sufficient activity to achieve intermolecular alkene hydroaminations under mild conditions are rare, and this likely accounts for the scarcity of asymmetric variants of this reaction. Herein, highly diastereoselective hydroaminations of allylic amines utilizing hydroxylamines as reagents and formaldehyde as catalyst are reported. This catalyst induces temporary intramolecularity, which results in high rate accelerations, and high diastereocontrol with either chiral allylic amines or chiral hydroxylamines. The reaction scope includes internal alkenes. Overall this work provides a new, stereocontrolled route to form complex vicinal diamines.

ChemInform Abstract: Asymmetric Cascade Reaction to Allylic Sulfonamides from Allylic Alcohols by Palladium(II)/Base‐Catalyzed Rearrangement of Allylic Carbamates.

AbstractA catalytic asymmetric method for the transformation of allylic alcohols into sulfonyl‐protected chiral allylic amines is presented.

ChemInform Abstract: Practical Approach for Asymmetric Hydroxyamination of Aldehydes with in situ Generated Nitrosocarbonyl Compounds: Application to One‐Pot Synthesis of Chiral Allylamines.

The highly regio- and enantioselective hydroxyamination of aldehydes with in situ generated nitrosocarbonyl compounds from a hydroxamic acid derivative was realized by simple and readily available chiral amine catalysts. The resulting hydroxyamination products were readily converted to the corresponding chiral 1,2-aminoalcohol or allylamine derivatives in one pot.

ChemInform Abstract: Highly Enantioselective Rh‐Catalyzed Alkenylation of Imines: Synthesis of Chiral Allylic Amines via Asymmetric Addition of Potassium Alkenyltrifluoroborates to N‐Tosyl Imines.

AbstractFor the first time, simple N‐tosyl aryl aldimines are used as substrates in the rhodium catalyzed 1,2‐addition reaction with alkenylboron nucleophiles.

Practical Approach for Asymmetric Hydroxyamination of Aldehydes with in Situ Generated Nitrosocarbonyl Compounds: Application to One-Pot Synthesis of Chiral Allylamines

The highly regio- and enantioselective hydroxyamination of aldehydes with in situ generated nitrosocarbonyl compounds from a hydroxamic acid derivative was realized by simple and readily available chiral amine catalysts. The resulting hydroxyamination products were readily converted to the corresponding chiral 1,2-aminoalcohol or allylamine derivatives in one pot.

Highly Enantioselective Rh-Catalyzed Alkenylation of Imines: Synthesis of Chiral Allylic Amines via Asymmetric Addition of Potassium Alkenyltrifluoroborates to N-Tosyl Imines

For the first time, simple N-tosyl aryl aldimines, prepared from the condensation of tosyl amide and aromatic aldehydes, can be used as substrates in the rhodium catalyzed 1,2-addition reaction using alkenylboron nucleophiles. In the presence of 1.5 mol % of [RhCl(1e)]2, enantioselective addition of various potassium alkenyltrifluoroborates to aryl aldimines furnished the corresponding chiral allylic amines in 73-96% yield and 72->99.5% ee. Notably, this method efficiently provides the di-, tri-, and tetrasubstituted allylic N-tosyl amines with high asymmetric induction.

Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.

The presence of nitrogen atoms in most chiral pharmaceutical drugs has motivated the development of numerous strategies for the synthesis of enantioenriched amines. Current methods are based on the multi-step transformation of pre-functionalized allylic electrophiles into chiral allylic amines. The enantioselective allylic amination of unactivated olefins represents a more direct and attractive strategy. We report the enantioselective synthesis of ent-sitagliptin via an allylic amination of an unactivated terminal olefin.

A Stable Route to Selectivity

Chemistry In general, the purpose of catalysis is to speed up reactions that otherwise proceed too slowly. Asymmetric catalysis is something of a special case though: When the catalyst's role is to bias a reaction toward one particular product isomer, problems arise if the background reaction is too fast on its own. This circumstance limited a prospectively promising route to chiral allylic amines. Specifically, decades-old chemistry established that adducts of terminal olefins and imido-sulfur compounds quickly rearrange to form carbon-nitrogen bonds. Bao and Tambar realized that stabilization of such adducts could slow down the bond-forming event sufficiently for a catalyst to dictate stereoselectivity. Benzenesulfonyl sulfurdiimide proved the optimal reagent, affording an adduct so slow to rearrange that it persisted for days below 0°C. The authors could then introduce a palladium catalyst coordinated by a chiral ligand to coax the adducts toward allylic amine products with enantioselectivities exceeding 90%. The reaction tolerated electrophilic substituents on the olefin framework, such as aldehydes, nitriles, and halides. J. Am. Chem. Soc. 134 , 10.1021/ja307851b (2012).

Access to Enantiomerically Enriched cis-2,3-Disubstituted Azetidines via Diastereoselective Hydrozirconation

An asymmetric variant of the hydrozirconation reaction has been established starting from Boc-protected chiral allylic amines. The resulting diastereoselectively formed N-functionalized organozirconiums can be considered as promising chirons. In this case, they have been transformed into enantiomerically enriched cis-2,3-disubstituted azetidines through a iodination/cyclization sequence.

Convenient Method for Synthesis of N-Protected α-Amino Epoxides: Key Intermediates for HIV Protease Inhibitors

A convenient method for synthesis of 2R,3S and 2S,3S N-Boc phenylalanine epoxides using readily available allylamine is described. Previous methods employed multistep synthetic routes from l-phenyl alanine that include use of m-chloroperbenzoic acid (m-CPBA) and a chromatographic method for purification of the desired diastereomers. Column purification could be eliminated by bringing in much improvement in the existing process. The process was further enhanced by replacing m-CPBA with oxone, an ecofriendly reagent advantageous for commercial application. The overall green process discussed involves the recovery and recycling of enantiomers of chiral allyl amines and judicial separation of diastereomers of the epoxides using simple economical methods.

Enantioselective Formal Alkenylations of Imines Catalyzed by Axially Chiral Dicarboxylic Acid Using Vinylogous Aza‐Enamines

In the zone: The use of vinylogous aza-enamaines (hydrazones) as a source of an alkenyl group has been achieved (see scheme). Unmasking of the aza-enamine moiety opens up a novel approach for the preparation of chiral allylic amines bearing an electron-withdrawing alkene moiety functionalized at the electron-deficient β position.