N-benzyl Imines Research Articles

Nickel-catalyzed Nucleophilic C-Borylation of Imines.

Application of bioisostere plays an important role in drug discovery. α-Aminoboronic acid is the familiar bioisostere of α-amino acid. Developing reactions for the synthesis of a wide variety of α-aminoboronic acid is one important task for synthetic chemistry. Herein, we report the development of nucleophilic C-borylation chemistry for N-arylimines catalyzed by nickel. The reaction proceeds through the insertion of a borylnickel species into the C=N bond to afford the corresponding α-aminoboronate, which was isolated as acetamide after trapping with acetic anhydride. N-Benzyl imine is also tolerated by the developed reaction.

Synergistic Palladium-Phosphoric Acid Catalysis in (3 + 2) Cycloaddition Reactions between Vinylcyclopropanes and Imines

The palladium-catalyzed (3 + 2) cycloaddition reaction between vinylcyclopropanes (VCPs) bearing geminal EWG’s and imines represents a straightforward and flexible entry to polysubstituted pyrrolidine derivatives. In this paper, we demonstrate that using a synergistic catalysis approach, based on the combination of phosphoric acid and palladium catalysts, it is possible to engage for the first time N-aryl and N-benzyl imines in this cycloaddition reaction. A range of polysubstituted pyrrolidines is obtained with moderate to good yields and diastereoselectivities, using a simple palladium species (Pd(PPh3)4) and an archetypical phosphoric acid as catalyst combination. A two-step scheme which exploits the same palladium catalyst for two consecutive and mechanistically distinct reactions (the cycloaddition and a Suzuki–Miyaura cross-coupling) is also presented. This synergistic catalysis approach is well posited for the development of the enantioselective version of this reaction. A screening of common BINOL-derived chiral phosphoric acids as catalyst component identified a species giving the product with moderate, yet promising, enantioselectivity (64% ee).

Transition-metal-free C(sp3)-H/C(sp3)-H dehydrogenative coupling of saturated heterocycles with N-benzyl imines.

A unique C(sp3)–H/C(sp3)–H dehydrocoupling of N-benzylimines with saturated heterocycles is described. Using super electron donor (SED) 2-azaallyl anions and aryl iodides as electron acceptors, single-electron-transfer (SET) generates an aryl radical. Hydrogen atom transfer (HAT) from saturated heterocycles or toluenes to the aryl radical generates alkyl radicals or benzylic radicals, respectively. The newly formed alkyl radicals and benzylic radicals couple with the 2-azaallyl radicals with formation of new C–C bonds. Experimental evidence supports the key hydrogen-abstraction by the aryl radical, which determines the chemoselectivity of the radical–radical coupling reaction. It is noteworthy that this procedure avoids the use of traditional strong oxidants and transition metals.

ChemInform Abstract: In situ Assembled Boronate Ester Assisted Chiral Carboxylic Acid Catalyzed Asymmetric trans‐Aziridinations.

We developed herein a new chiral Bronsted acid catalyst which is composed of two independent organic molecules, a chiral diol, and 2-boronobenzoic acid. In situ formation of a boronate ester was utilized as a key process to generate an active catalyst. This boronate ester assisted chiral carboxylic acid catalyst was successfully applied to the trans-aziridination of N-Boc and N-benzyl imines with N-phenyldiazoacetamide. This is the first catalyst to achieve high enantioselectivities using N-benzyl imines.

In Situ Assembled Boronate Ester Assisted Chiral Carboxylic Acid Catalyzed Asymmetric Trans-Aziridinations

We developed herein a new chiral Brønsted acid catalyst which is composed of two independent organic molecules, a chiral diol, and 2-boronobenzoic acid. In situ formation of a boronate ester was utilized as a key process to generate an active catalyst. This boronate ester assisted chiral carboxylic acid catalyst was successfully applied to the trans-aziridination of N-Boc and N-benzyl imines with N-phenyldiazoacetamide. This is the first catalyst to achieve high enantioselectivities using N-benzyl imines.

The synthesis of (1 S,8a S)-1-hydroxyindolizidine using a stereoselective Grignard addition to an N-benzyl-3-deoxy sugar imine derived from D-Glucose

A highly stereoselective approach to 1-hydroxyindolizidine is described using a Grignard reaction on N-benzyl imine derived from 3-deoxy-1,2- O-isopropylidine-α- d-xylo-pentodialdofuranose and reductive cyclization as key steps.

ChemInform Abstract: A New Stereoselective Access to N-Benzyl trans-Propargylic Aziridines.

Abstract The metallation of 3-trimethylsilyl-1-chloroprop-2-yne and the subsequent reaction with N-benzyl imines affords stereospecifically trans propargylic aziridines with good to excellent yields.

A short and common stereoselective approach to 5/6, 6/6, 6/7 bicyclic aza sugars

An efficient and highly stereoselective approach to bicyclic aza sugars is described using Grignard reaction on an N-benzyl imine derived from 3- O-benzyl-1,2- O-isopropylidine-α- d- xylo-pentodialdofuranose, ring closing metathesis, and reductive cyclization as key steps.

Mechanism of BINOL−Phosphoric Acid-Catalyzed Strecker Reaction of Benzyl Imines

The mechanism and the origin of the selectivity for the BINOL-phosphoric acid-catalyzed Strecker reaction on N-benzyl imines has been investigated by theoretical methods and compared with earlier studies of N-aryl imines. ONIOM calculations show that the reverse in selectivity which is observed experimentally is not due to differences in the steric bulk of aryl and benzyl groups, but rather because of a switch from a preference for a Z imine to an E imine in the transition state of benzaldehyde-derived imines. The calculations predict this change will not be present for imines formed from acetophenone.

Carbon–carbon bond formations at the benzylic positions of N-benzylxanthone imines and N-benzyldi-1-naphthyl ketone imine

Two N-benzyl imines are designed to allow for carbon–carbon bond formations at the aminated benzylic positions. Direct benzylic arylation reactions of N-benzylxanthone imine with aryl chlorides proceed under palladium catalysis in the presence of cesium hydroxide, yielding the corresponding benzhydrylamine derivatives. Alkylation reactions of N-benzyldi-1-naphthyl ketone imine with alkyl halides in the presence of potassium tert-butoxide afford the corresponding 1-phenylalkylamines in high yields. Conjugate addition of N-benzyldi-1-naphthyl ketone imine is also described.

Asymmetric transfer hydrogenation of imines catalyzed by a polymer-immobilized chiral catalyst

The asymmetric transfer hydrogenation of imines was performed with the use of a polymer-immobilized chiral catalyst. The chiral catalyst, prepared from crosslinked polystyrene-immobilized chiral 1,2-diamine monosulfonamide, was effective in the asymmetric transfer hydrogenation of N-benzyl imines in CH(2)Cl(2) to give a chiral amine in high yield and good enantioselectivity. Furthermore, an amphiphilic polymeric catalyst prepared from crosslinked polystyrene containing sulfonated groups successfully catalyzed the asymmetric transfer hydrogenation of cyclic imines in water. Enantioenriched secondary amines with up to 94% ee were obtained by using a polymeric catalyst.

Alkylation of α,β-Unsaturated Imines via C-H Bond Activation

Alkylation of α,β-unsaturated imines is achieved through C-H bond activation. The N-benzyl imines were alkylated with various terminal alkenes (one example with a terminal alkyne) and very high Z/E ratios were obtained (>95:5 Z/E) for the imine product. Hydrolysis to the aldehyde often resulted in isomerization of the olefin. A mild hydrolysis protocol using activity III neutral alumina was developed to provide the aldehyde with a high integrity of retention of stereochemistry.

Rhodium-Catalyzed Imine-Directed C-H Bond Functionalization

A stereocenter can be set with high enantioselectivity (90%) using a catalytic C-H bond activation. The aromatic aldimines are more difficult substrates than their corresponding ketimines in the Rh-chiral phosphoramidite-mediated enantioselective cyclization reactions. Thus, it was necessary to modify the N-benzyl imine moiety to increase the efficiency of the cyclization. Going from the unsubstituted benzylaldimine 1b to the electron-poor modified 1c, the yield significantly increased from 31% to 57%. Decreasing the reaction temperature to 90 °C also afforded better results (61% yield, 90% ee). Intriguingly, the methylene moiety of the benzyl group appears to be critical in the transfer of chirality from catalyst to product; although imine 1a, derived from aniline, gives a higher yield than N-benzyl imine 1b, the ee value drops precipitously.

Stereoselective alkylation of alpha,beta-unsaturated imines via C-H bond activation.

The stereoselective alkylation of alpha,beta-unsaturated imines via C-H activation followed by imine hydrolysis produces tri- and tetrasubstituted alpha,beta-unsaturated aldehydes. In the presence of a rhodium catalyst, alpha,beta-unsaturated N-benzyl imines derived from methacrolein, crotonaldehyde, and tiglic aldehyde undergo directed C-H activation at the beta-position and react with terminal alkenes and alkynes to form the tri- and tetrasubstituted alpha,beta-unsaturated imines with very high stereoselectivity. Hydrolysis to provide alpha,beta-unsaturated aldehydes can be performed under carefully controlled conditions that maintain the stereochemistry of the beta-alkylated imine products. Alternatively, for beta-alkylation products of the N-benzyl imine of methacrolein, hydrolysis can be performed under conditions that provide complete isomerization to the E isomer.

Experimental and DFT study of the aza-Diels–Alder reaction between cyclopentadiene and protonated benzylimine derivated from glyoxylates

The Diels–Alder reaction of protonated N-benzyl imine of methyl glyoxylate with cyclopentadiene in different solvents gave mixtures of exo/ endo adducts. The exo/ endo selectivity of the reaction was elucidated by NMR experiments. Theoretical calculations by means of density functional theory (DFT) at the B3LYP/6-31G(d) level have also been performed to elucidate the molecular mechanism of this reaction. The DFT results suggest a highly asynchronous concerted mechanism, which in turn can explain the preferred exo stereoselectivity of the reaction. Inclusion of solvent effects enhances the exo selectivity, and this effect increases with the polarity of the solvent, in good agreement with the experimental findings.

Thiourea‐Catalyzed Enantioselective Hydrophosphonylation of Imines: Practical Access to Enantiomerically Enriched α‐Amino Phosphonic Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Thiourea-catalyzed enantioselective hydrophosphonylation of imines: practical access to enantiomerically enriched alpha-amino phosphonic acids.

Chiral thiourea 1b catalyzes the highly enantioselective hydrophosphonylation of a wide range of N-benzyl imines. The hydrophosphonylation products are readily deprotected by hydrogenolysis, providing access to free alpha-amino phosphonic acids in highly enantioenriched form.

Variable strategy toward carbasugars and relatives. 6. Diastereoselective synthesis of 2-deoxy-2-amino-5a-carba-beta-L-mannopyranuronic acid and 2-deoxy-2-amino-5a-carba-beta-L-mannopyranose.

Efficient, total syntheses of novel 2-deoxy-2-amino-5a-carba-beta-L-mannopyranuronic acid (1) and 2-deoxy-2-amino-5a-carba-beta-L-mannopyranose (2), a positional stereoisomer of validamine, have been achieved in 28% and 24% overall yields and in 12 steps and 13 steps, respectively, from 2-[(tert-butyldimethylsilyl)oxy]furan (3) and (2S)-2,3-O-isopropylideneglyceraldehyde N-benzyl imine (4) via two highly diastereoselective Mukaiyama aldol-related chemical maneuvers. The strategy, which furnishes the targeted carbasugars in enantiopure forms, allows for complete control of the configuration at all five contiguous stereocenters of the targets by utilizing the sole element of chirality present in the aldimine progenitor 4.

Synthesis of highly 1,3-proton shift transferable N-benzyl imines of trifluoroacetophenone under the “low-basicity” reaction conditions

The standard reaction conditions commonly used for the condensation of carbonyl compounds with amines were found to be synthetically inefficient for preparation of the imines derived from trifluoroacetophenone and benzylamines owing to the susceptibility of these imines to 1,3-proton shift. Application of a “low-basicity” method, using instead of free benzylamines their salts formed from acetic acid (AA), allowed synthesis of the target compounds in chemically pure form and excellent chemical yields.

The exo-selectivity of the new non-natural chiral auxiliary (+)-(1 R, endo)-2-benzonorbornenol in an asymmetric aza-Diels–Alder reaction

The recently reported compound (+)-(1 R, endo)-2-benzonorbornenol ( 2 ) proved to be an efficient chiral auxiliary in the asymmetric aza-Diels–Alder reaction between cyclopentadiene and the N-benzyl imine of its glyoxylate, which afforded a virtually all- exo mixture of cycloaducts with a 1 S:1 R diastereomeric ratio of 63:37.