Tackling N-Alkyl Imines with 3d Metal Catalysis: Highly Enantioselective Iron-Catalyzed Synthesis of α-Chiral Amines

A readily activated iron alkyl precatalyst effectively catalyzes the highly enantioselective hydroboration of N-alkyl imines. Employing a chiral bis(oxazolinylmethylidene)isoindoline pincer ligand, the asymmetric reduction of various acyclic N-alkyl imines provided the corresponding α-chiral amines in excellent yields and with up to >99 % ee. The applicability of this base metal catalytic system was further demonstrated with the synthesis of the pharmaceuticals Fendiline and Tecalcet.     

Iron‐Catalyzed Reductive Ethylation of Imines with Ethanol

The borrowing hydrogen strategy has been applied to the ethylation of imines with an air‐stable iron complex as precatalyst. This approach opens new perspectives in this area as it enables the synthesis of unsymmetric tertiary amines from readily available substrates and ethanol as a C₂ building block. A variety of imines bearing electron‐rich aryl or alkyl groups at the nitrogen atom could be efficiently reductively alkylated without the need for molecular hydrogen. The mechanism of this reaction, which shows complete selectivity for ethanol over other alcohols, has been studied experimentally and by means of DFT computations.     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

Regio‐ and Enantioselective Synthesis of Trifluoromethyl‐Substituted Homoallylic α‐Tertiary NH2‐Amines by Reactions Facilitated by a Threonine‐Based Boron‐Containing Catalyst

A method for catalytic regio‐ and enantioselective synthesis of trifluoromethyl‐substituted and aryl‐, heteroaryl‐, alkenyl‐, and alkynyl‐substituted homoallylic α‐tertiary NH₂‐amines is introduced. Easy‐to‐synthesize and robust N‐silyl ketimines are converted to NH‐ketimines in situ, which then react with a Z‐allyl boronate. Transformations are promoted by a readily accessible l ‐threonine‐derived aminophenol‐based boryl catalyst, affording the desired products in up to 91 % yield, >98:2 α:γ selectivity, >98:2 Z:E selectivity, and >99:1 enantiomeric ratio. A commercially available aminophenol may be used, and allyl boronates, which may contain an alkyl‐, a chloro‐, or a bromo‐substituted Z‐alkene, can either be purchased or prepared by catalytic stereoretentive cross‐metathesis. What is more, Z‐trisubstituted allyl boronates may be used. Various chemo‐, regio‐, and diastereoselective transformations of the α‐tertiary homoallylic NH₂‐amine products highlight the utility of the approach; this includes diastereo‐ and regioselective epoxide formation/trichloroacetic acid cleavage to generate differentiated diol derivatives.     

Disulfonimide‐Catalyzed Asymmetric Reduction of N‐Alkyl Imines

A chiral disulfonimide (DSI)‐catalyzed asymmetric reduction of N‐alkyl imines with Hantzsch esters as a hydrogen source in the presence of Boc₂O has been developed. The reaction delivers Boc‐protected N‐alkyl amines with excellent yields and enantioselectivity. The method tolerates a large variety of alkyl amines, thus illustrating potential for a general reductive cross‐coupling of ketones with diverse amines, and it was applied in the synthesis of the pharmaceuticals (S)‐Rivastigmine, NPS R‐568 Hydrochloride, and (R)‐Fendiline.     

Ultrafast Iron‐Catalyzed Reduction of Functionalized Ketones: Highly Enantioselective Synthesis of Halohydrines,Oxaheterocycles, and Aminoalcohols

A molecularly defined chiral boxmi iron alkyl complex catalyzes the hydroboration of various functionalized ketones and provides the corresponding chiral halohydrines, oxaheterocycles (oxiranes, oxetanes, tetrahydrofurans, and dioxanes) and amino alcohols with excellent enantioselectivities (up to >99 %ee) and conversion efficiencies at low catalyst loadings (as low as 0.5 mol %). Turnover frequencies of greater than 40000 h^?1 at ?30 °C highlight the activity of this earth‐abundant metal catalyst which tolerates a large number of functional groups.     

Enantioselective N‐Heterocyclic Carbene Catalysis by the Umpolung of α,β‐Unsaturated Ketones

N‐Heterocyclic carbene‐catalyzed formation of β‐anionic intermediates from enones has been employed in the enantioselective synthesis of 2‐aryl propionates. The reaction was achievable using a homochiral 4‐MeOC₆H₄ morpholinone catalyst allowing the first example of enantioselective catalysis by umpolung of α,β‐unsaturated ketones. The reaction is high yielding, and shows robustness with reasonable generality. A mechanism is proposed in which the enantiodetermining protonation is achieved using either hexafluoroisopropanol or the formed naphthol product.     

Enantioselective Organocatalytic Reduction of β‐Trifluoromethyl Nitroalkenes: An Efficient Strategy for the Synthesis of Chiral β‐Trifluoromethyl Amines

An efficient organocatalytic stereoselective reduction of β‐trifluoromethyl‐substituted nitroalkenes, mediated by 3,5‐dicarboxylic ester‐dihydropyridines (Hantzsch ester type), has been successfully developed. A multifunctional thiourea‐based (S)‐valine derivative was found to be the catalyst of choice, promoting the reaction in up to 97 % ee. The methodology has been applied to a wide variety of substrates, leading to the formation of differently substituted precursors of enantiomerically enriched β‐trifluoromethyl amines. The mechanism of the reaction and the mode of action of the metal‐free catalytic species were computationally investigated; on the basis of DFT transition‐state (TS) analysis, a model of stereoselection was also proposed.     

Iron‐Catalyzed α‐Alkylation of Ketones with Alcohols

A general and benign iron‐catalyzed α‐alkylation reaction of ketones with primary alcohols has been developed. The key to success of the reaction is the use of a Knölker‐type complex as catalyst (2 mol %) in the presence of Cs₂CO₃ as base (10 mol %) under hydrogen‐borrowing conditions. Using 2‐aminobenzyl alcohol as alkylation reagent allows for the “green” synthesis of quinoline derivatives.     

Lewis Acid Catalyzed Borotropic Shifts in the Design of Diastereo‐ and Enantioselective γ‐Additions of Allylboron Moieties to Aldimines

Catalytic allylboron additions to aldimines are presented for which small amounts of Zn(OMe)₂ serve as the co‐catalyst to accelerate allyl exchange and 1,3‐borotropic shift processes. Low‐yielding and moderately α‐ and diastereoselective reactions are thus turned into highly efficient γ‐, diastereo‐, and enantioselective transformations that exhibit considerable scope.     

Highly Selective Iron‐Catalyzed Synthesis of Alkenes by the Reduction of Alkynes

Herein, the iron‐catalyzed reduction of a variety of alkynes with silanes as a reductant has been examined. With a straightforward catalyst system composed of diiron nonacarbonyl and tributyl phosphane, excellent yields and chemoselectivities (>99 %) were obtained for the formation of the corresponding alkenes. After studying the reaction conditions, and the scope and limitations of the reaction, several attempts were undertaken to shed light on the reaction mechanism.     

Iron‐Catalyzed Hydroboration: Unlocking Reactivity through Ligand Modulation

Iron‐catalyzed hydroboration (HB) of alkenes and alkynes is reported. A simple change in ligand structure leads to an extensive change in catalyst activity. Reactions proceed efficiently over a wide range of challenging substrates including activated, unactivated and sterically encumbered motifs. Conditions are mild and do not require the use of reducing agents or other additives. Large excesses of borating reagent are not required, allowing control of chemo‐ and regioselectivity in the presence of multiple double bonds. Mechanistic insight reveals that the reaction is likely to proceed via a highly reactive iron hydride intermediate.     

Chiral Brønsted Acid Directed Iron‐Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with β‐Aryl α′‐Hydroxy Enones

A cooperative catalytic system established by the combination of an iron salt and a chiral Brønsted acid has proven to be effective in the asymmetric Friedel–Crafts alkylation of indoles with β‐aryl α′‐hydroxy enones. Good to excellent yields and enatioselectivities were observed for a variety of α′‐hydroxy enones and indoles, particularly for the β‐aryl α′‐hydroxy enones bearing an electron‐withdrawing group at the para position of the phenyl ring (up to 90 % yield and 91 % ee). The proton of the chiral Brønsted acid, the Lewis acid activation site, as well as the inherent basic site for the hydrogen‐bonding interaction of the Brønsted acid are responsible for the high catalytic activities and enantioselectivities of the title reaction. A possible reaction mechanism was proposed. The key catalytic species in the catalytic system, the phosphate salt of Fe^III, which was thought to be responsible for the high activity and good enantioselectivity, was then confirmed by ESIMS studies.