Imine Surrogates Research Articles

Challenge N- versus O-six-membered annulation: FeCl3-catalyzed synthesis of heterocyclic N,O-aminals.

A new class of heterocyclic N,O-aminal and hemiaminal scaffolds was successfully obtained by means of a three-component reaction (3-CR) of 1,2-diaza-1,3-dienes (DDs), α-aminoacetals and iso(thio)cyanates. These stable imine surrogates are generated from key-substituted (thio)hydantoin intermediates through selective FeCl3-catalyzed intramolecular N-annulation.

Interrupted Polonovski Strategy for the Synthesis of Functionalized Amino Acids and Peptides.

The α-functionalization of carbamate-protected hydroxylamine glycine derivatives, acting as imine surrogates via an interrupted Polonovski reaction, is described to access functionalized amino acid derivatives. The addition of C, N, O, and S nucleophiles was achieved in a one-pot procedure in 37% to 92% yield. This method could be extended to dipeptide derivatives for the functionalization of both the C-terminus and N-terminus.

1,1-Carboamination of Terminal Alkenes via a Reaction of Azo-Ene Adducts with Grignard Reagents

Facile conversion of petrochemical feedstocks into valuable amine molecules remains a long-standing challenge in organic chemistry. Here, we report a modular and practical alkene 1,1-carboamination technology that relies on sequential azo-ene reactions and attendant base-promoted N-N bond cleavage of azo-ene adducts with Grignard reagents. By employing allylic urazoles as imine surrogates, this method bypasses the conventional retrosynthetic logic of imine synthesis, thereby allowing for rapid access to diverse α-branched allylic amine derivatives.

In the Pursuit of (Ald)Imine Surrogates for the Direct Asymmetric Synthesis of Non-Proteinogenic α-Amino Acids

AbstractNature remarkably employs posttranslational modifications of the 20 canonical α-amino acids to devise a far larger structural, conformational, and functional diversity found in non-proteinogenic amino acids (NPAAs), which ultimately translates into a plethora of complex biological functions. Synthetic chemists are continuously trying to reproduce and even extrapolate the repertoire of NPAA building blocks to build structural diversity into bioactive molecules and materials. The direct asymmetric functionalization of α-imino esters represents one of the most robust and attractive routes to NPAAs. This review summarizes the most prominent examples of bench-stable (ald)imine surrogates exploited for the synthesis of NPAAs, including our most recent results in the nucleophilic substitution of α-haloglycines and other α-halo­aminals. A synopsis of kinetic studies, reaction optimizations, and enantio­selective catalytic methods is also presented.1 Introduction2 Asymmetric Synthesis of Tertiary α-Substituted NPAAs2.1 From N,O-Acetals (α-Hydroxy/Alkyloxy/Acetoxyglycines)2.2 From α-Amido Sulfones2.3 From α-Haloglycine Esters2.4 From N,O-Bis(Boc) Hydroxyglycine3 Asymmetric Synthesis of Acyclic Quaternary α,α-Disubstituted NPAAs4 Concluding Remarks

Halogen‐Imparted Reactivity in Lithium Carbenoid Mediated Homologations of Imine Surrogates: Direct Assembly of bis‐Trifluoromethyl‐β‐Diketiminates and the Dual Role of LiCH2I

AbstractThe selective formal insertion (homologation) of a carbon unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is reported. The tactic is levered on a highly chemoselective homologation–metalation–acyl nucleophilic substitution sequence which precisely enables to assemble novel trifluoromethylated β‐diketiminates within a single synthetic operation. Unlike previous homologations conducted with LiCH2Cl furnishing aziridines, herein we exploit the unique capability of iodomethyllithium to act contemporaneously as a C1 source (homologating effect) and metalating agent. The mechanistic rationale grounded on experimental evidences supports the hypothesized proposal and, the structural analysis gathers key aspects of this class of valuable ligands in catalysis.

Halogen-Imparted Reactivity in Lithium Carbenoid Mediated Homologations of Imine Surrogates: Direct Assembly of bis-Trifluoromethyl-β-Diketiminates and the Dual Role of LiCH2I.

The selective formal insertion (homologation) of a carbon unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is reported. The tactic is levered on a highly chemoselective homologation-metalation-acyl nucleophilic substitution sequence which precisely enables to assemble novel trifluoromethylated β-diketiminates within a single synthetic operation. Unlike previous homologations conducted with LiCH2Cl furnishing aziridines, herein we exploit the unique capability of iodomethyllithium to act contemporaneously as a C1 source (homologating effect) and metalating agent. The mechanistic rationale grounded on experimental evidences supports the hypothesized proposal and, the structural analysis gathers key aspects of this class of valuable ligands in catalysis.

Bench-stable imine surrogates for the one-pot and catalytic asymmetric synthesis of α-amino esters/ketones.

N,O-Bis(tert-butoxycarbonyl)hydroxylamines are readily accessible as imine surrogates, which are bench stable and could quantitatively generate the corresponding imines for in situ applications. An unpresented catalytic asymmetric method for the synthesis of α-amino esters and ketones from novel imine surrogates, N,O-bis(tert-butoxycarbonyl)hydroxylamines, as well as its preliminary mechanistic studies are reported. A variety of optically enriched products were obtained in excellent yields and enantioselectivities (up to 99% yield and >99% ee).

Copper-Catalyzed Asymmetric Formal Hydroaminomethylation of Alkenes with N,O-Acetals to Access Chiral β-Stereogenic Amines: Dual Functions of the Copper Catalyst

Chiral amines are synthetically versatile intermediates used for the preparation of a wide range of biologically active compounds and drugs. Compared with the well-developed synthesis of α-stereoge...

Telescoped, Divergent, Chemoselective C1 and C1‐C1 Homologation of Imine Surrogates: Access to Quaternary Chloro‐ and Halomethyl‐Trifluoromethyl Aziridines

AbstractA conceptually novel, high‐yielding, mono‐ or bis‐homologation was realized with lithium halocarbenoids and enables the one‐step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the homologation event, carried out with two different carbenoids (LiCH2Cl and LiCH2F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.

Telescoped, Divergent, Chemoselective C1 and C1-C1 Homologation of Imine Surrogates: Access to Quaternary Chloro- and Halomethyl-Trifluoromethyl Aziridines.

A conceptually novel, high‐yielding, mono‐ or bis‐homologation was realized with lithium halocarbenoids and enables the one‐step, fully chemocontrolled assembly of a new class of quaternary trifluoromethyl aziridines. Trifluoroacetimidoyl chlorides (TFAICs) act as convenient electrophilic platforms, enabling the addition of either one or two homologating elements by simply controlling the stoichiometry of the process. Mechanistic studies highlighted that the homologation event, carried out with two different carbenoids (LiCH2Cl and LiCH2F), leads to fluoromethyl analogues in which the first nucleophile is employed for constructing the cycle and the second for decorating the resulting molecular architecture.

Iminium Ion and N-Hydroxyimide as the Surrogate Components in DEAD-Promoted Oxidative Ugi Variant.

A practical metal-free oxidative Ugi-type three-component assembly has been achieved efficiently, employing a tertiary-amine-derived iminium ion as an imine surrogate, N-hydroxyimide as an acid surrogate, and DEAD as an oxidant. This dual-surrogate Ugi variant proceeded with a broad substrate scope and desired functional group tolerance, leading to a wide range of N-alkyl- N-acyl aminophthalimide and N-alkyl- N-acylaminosuccinimide derivatives in good isolated yields.

Catalytic Asymmetric Mannich Reaction with N-Carbamoyl Imine Surrogates of Formaldehyde and Glyoxylate.

N,O-acetals (NOAcs) were developed as bench stable surrogates for N-carbamoyl, (Boc, Cbz and Fmoc) formaldehyde and glyoxylate imines in asymmetric Mannich reactions. The NOAcs can be directly utilized in the chiral primary amine catalyzed Mannich reactions of both acyclic and cyclic β-ketocarbonyls with high yields and excellent stereoselectivity. The current reaction offers a straightforward approach in the asymmetric synthesis of α- or β-amino carbonyls bearing chiral quaternary centers in a practical and highly stereocontrolled manner.

Catalytic Asymmetric Mannich Reaction with N‐Carbamoyl Imine Surrogates of Formaldehyde and Glyoxylate

AbstractN,O‐acetals (NOAcs) were developed as bench stable surrogates for N‐carbamoyl, (Boc, Cbz and Fmoc) formaldehyde and glyoxylate imines in asymmetric Mannich reactions. The NOAcs can be directly utilized in the chiral primary amine catalyzed Mannich reactions of both acyclic and cyclic β‐ketocarbonyls with high yields and excellent stereoselectivity. The current reaction offers a straightforward approach in the asymmetric synthesis of α‐ or β‐amino carbonyls bearing chiral quaternary centers in a practical and highly stereocontrolled manner.

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)‐Sitagliptin

AbstractIn this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona‐based‐squaramide‐catalyzed enantioselective Mannich reactions of diverse imines or α‐amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α‐amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling‐reagent‐free synthesis of the antidiabetic drug (−)‐(R)‐sitagliptin.

Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin.

In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin.

ChemInform Abstract: Cerium(IV) Ammonium Nitrate Mediated Three‐Component α‐Allylation of Imine Surrogates.

A general and practical CAN-mediated oxidative radical α-coupling reaction of various imine surrogates with allylsilanes has been described. This multicomponent process affords β-allylated α-carbamido ethers as stable imine precursors in respectable yields under mild conditions.

Cerium(IV) Ammonium Nitrate Mediated Three-Component α-Allylation of Imine Surrogates

A general and practical CAN-mediated oxidative radical α-coupling reaction of various imine surrogates with allylsilanes has been described. This multicomponent process affords β-allylated α-carbamido ethers as stable imine precursors in respectable yields under mild conditions.

ChemInform Abstract: Catalyst‐Free Synthesis of α‐Aminoacyl‐amides via N,N′‐Bis(phenylmethylidene)phenylmethanediamine as Imine Surrogate in Ugi Multicomponent Reaction.

AbstractAdvantages of the title procedure are the ready availability of the starting materials, the mild conditions and the easy work‐up.

Photoredox‐Initiated α‐Alkylation of Imines through a Three‐Component Radical/Cationic Reaction

Radical-polar crossover reaction: The photoredox-mediated alkylation of enamides with diethyl bromomalonate in the presence of alcohols has been developed. This multicomponent domino process affords β-alkylated α-carbamido ethers as stables imine surrogates in good to excellent yields under mild conditions (see scheme).

Catalyst-Free Synthesis of α-Aminoacyl-amides via N,N′-Bis(Phenylmethylidene)phenylmethanediamine as Imine Surrogate in Ugi Multicomponent Reaction

A novel one-pot, multicomponent, and catalyst-free reaction of N,N’-bis (phenylmethylidene)phenylmethane, carboxylic acids, and isocyanides yielding α-aminoacyl-amides is described. The reaction is based on the combination of an Ugi three-component reaction followed by hydrolysis.