Enantioselective aza-Henry Reaction Research Articles

Secondary Orbital Effect Involving Fluorine is Responsible for Substrate-Controlled Diastereodivergence in the Catalyzed syn-aza-Henry Reaction of α-Fluoronitroalkanes.

The fluorine atom is a powerful, yet enigmatic influence on chemical reactions. True to form, fluorine was recently discovered to effect diastereodivergence in an enantioselective aza-Henry reaction, resulting in a very rare case of syn-β-amino nitroalkane products. More bewildering was the observation of an apparent hierarchy of substituents within this substrate-controlled behavior: Ph>F>alkyl. These cases have now been examined comprehensively by computational methods, including both non-fluorinated and α-fluoro nitronate additions to aldimines catalyzed by a chiral bis(amidine) [BAM] proton complex. This study revealed the network of non-covalent interactions that dictate anti- (α-aryl) versus syn-selectivity (α-alkyl) using α-fluoronitronate nucleophiles, and an underlying secondary orbital interaction between fluorine and the activated azomethine.

Enantioselective Synthesis of cis- and trans-Cycloheptyl β-Fluoro Amines by Sequential aza-Henry Addition/Ring-Closing Metathesis.

The synthesis of 7-membered carbocyclic β-fluoroamines is accomplished by a combination of the enantioselective aza-Henry reaction of aliphatic N-Boc imines and ring-closing metathesis. Use of reductive denitration gives both diastereomers of the β-fluoro amine carbocycle, each with high enantiomeric excess.

Fluorine-induced diastereodivergence discovered in an equally rare enantioselective syn-aza-Henry reaction.

Attention to the aza-Henry reaction, particularly over the past two decades, has resulted in a wide range of effective catalysts for the enantio- and diastereoselective versions, driven by the versatility of the β-amino nitroalkane products as precursors to secondary amines and vic-diamines. Despite this broad effort, syn-diastereoselective variants are exceedingly rare. We have discovered a subset of α-fluoro nitroalkane additions that are characterized by an unusual crossover in diastereoselection, often delivering the products with high selectivities. We report here a rigorous comparative analysis of non-fluorinated and α-fluoro nitroalkanes in their additions to azomethines. Both homogeneous and heterogeneous catalysis were applied to probe the possibility that this phenomenon might be more widely operative in the enantioselective additions of fluorine-substituted carbon nucleophiles. A complete correlation within four categories is described that uncovered a clear trend, while revealing a dramatic and distinct reversal of diastereoselection that would normally go undetected.

Asymmetric synthesis of tetrasubstituted cyclic amines via aza-Henry reaction using cinchona alkaloid sulfonamide/zinc(II) catalysts.

The first enantioselective aza-Henry reaction of non-activated cyclic iminoesters, derived from cyclic amino acids, has been developed. Good yields and enantioselectivities were observed for the reaction using our original cinchona alkaloid sulfonamide/zinc(II) catalyst. The transition state was proposed to explain the stereoselectivity based on experiments and DFT calculations.

L-tert-Leucine derived urea-ammonium salts: Efficient bifunctional phase transfer catalysts for highly diastereo- and enantioselective aza-Henry reaction of isatin-derived N-Boc ketimines with α-aryl nitromethanes

An efficient way of aza-Henry reaction between isatin-derived N-Boc ketimines and α-aryl nitromethanes catalyzed by bifunctional phase transfer catalysts with a quaternary ammonium center derived from L-tert-Leucine has been developed. A series of 3-substituted 3-amino-oxindoles were constructed by this catalytic protocol in excellent yields (90–99%), with high enantioselectivities (83–95%) and diastereoselectivities (79:21–97:3). The asymmetric aza-Henry reaction of N-Boc amidosulfones and α-aryl nitromethanes were also investigated and gave the corresponding products in high to excellent yields (72–97%) with high enantioselectivities (up to 99%) and diastereoselectivities (up to >99:1).

An enantioselective aza-Henry reaction of trifluoromethyl ketimines catalyzed by phase-transfer catalysts

An enantioselective aza-Henry reaction of acyclic trifluoromethyl ketimines was performed using a bifunctional catalyst. The products were converted to diamines and imidazolidine-2-ones.

Highly enantioselective aza-henry reaction of ketimines catalyzed by a chiral bifunctional thiourea-tertiary amine derived from quinine

We have developed a highly enantioselective aza-Henry reaction of aryl α-ketoester-derived N-Ts ketimines with a wide range of substrate scope by a simpler bifunctional thiourea-tertiary amine catalyst derived from quinine. A variety of ketimines were investigated and corresponding products were obtained in excellent yields (up to 99% yield) with excellent enatioselectivities (up to 99% ee).

Bifunctional Thiourea-Ammonium Salt Catalysts Derived from Cinchona Alkaloids: Cooperative Phase-Transfer Catalysts in the Enantioselective Aza-Henry Reaction of Ketimines.

An efficient enantioselective aza-Henry reaction of aryl α-ketoester-derived ketimines has been realized by using bifunctional thiourea-ammonium salt phase-transfer catalysts, which were derived from quinine. A variety of aryl α-ketoester-derived N-Ts ketimines were investigated, and the corresponding products were obtained in high to excellent yields (up to 99%) with good to high enantioselectivities (up to >99% ee).

Enantioselective aza-Henry reaction of t-Boc protected imines and nitroalkanes with bifunctional squaramide organocatalysts

A quinine-derived sterically encumbered squaramide organocatalyst afforded high enantioselectivity and excellent conversion in an aza-Henry reaction performed with imines and nitroalkanes.

Recyclable chiral Cu(II) macrocyclic salen complex catalyzed enantioselective aza-Henry reaction of isatin derived N-Boc ketimines and its application for the synthesis of β-diamine

Recyclable chiral Cu(II) macrocyclic salen complex Cu(II)-7 generated in situ efficiently catalyzed asymmetric aza-Henry reaction of various isatin derived N-Boc ketimines with nitromethane as nucleophile at RT to give a high yield (88%) of β-nitro amines with excellent chiral induction (ee, up to 99%) with the added advantage of six times catalyst recyclability. This catalytic system also worked well with nitroethane and nitropentane to furnish the corresponding products in moderate yields with high enantioselectivities for major diastereomers. This protocol is also used for the synthesis of enantiomerically pure (S)-β-diamines via asymmetric aza-Henry reaction of N-Boc ketimine (1b) in two steps in good yield with high enantioselectivity.

Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid-Base Catalyst with Recycle.

A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid-base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage.

Enantioselective aza-Henry reaction for the synthesis of (S)-levamisole using efficient recyclable chiral Cu(II)–amino alcohol derived complexes

Chiral Cu(II) complexes were generated in situ by the interaction of aminoalcohol based ligands L1–L6 derived from (1R,2S)-(−)-2-aminodiphenylethanol, (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol, (R or S)-valinol and (S)-2-amino-1,1-diphenylpropan-1-ol with 4-tert-butyl-2,6-diformylphenol and screened for aza-Henry reaction of a variety of aromatic, aliphatic N-tosylaldimine and aromatic N-benzenesulfonamide aldimine in toluene at RT. Excellent enantioselectivity, diastereoselectivity (99%) of β-nitro-N-tosylaldamine with good yield (80%) was achieved in case of complex L2–Cu(II) with low catalyst loading. The enantio-pure aza-Henry product obtained was straightforwardly transformed into the enantioenriched chiral vicinal diamine (ee; 96%) with good yield in successive two steps and was further used for the synthesis of (S)-levamisole (an anthelminthic agent). The catalytic system worked well up to five cycles with retention of enantioselectivity.

Chiral bifunctional guanidine-catalyzed enantioselective Aza-Henry reaction of isatin-derived ketimines.

An efficient asymmetric aza-Henry reaction of isatin-derived ketimines has been achieved by using a chiral guanidine-amide organocatalyst. A series of 3-substituted 3-amino-2-oxindoles was obtained with excellent results (up to 99% yield, 94% ee). Other functionalized derivatives were also conveniently transformed. This metal-free system was convenient, practical, and insensitive to air and moisture. On the basis of the crystal structure of the catalyst and NMR spectra analysis, a bifunctional catalytic model was suggested to explain the origin of the asymmetric process.

Vinylogy in nitronates: utilization of α-aryl conjugated nitroolefins as a nucleophile for a highly stereoselective aza-Henry reaction.

The vinylogous reactivity of α,β-disubstituted nitroolefins was uncovered through the facile generation of the corresponding α-substituted vinylogous nitronates and their use in the development of a highly diastereo- and enantioselective aza-Henry reaction with N-Boc aldimines under the catalysis of chiral ammonium betaines. The novel vinylogous nitronates undergo stereoselective bond formation at the sterically encumbered α-position exclusively, allowing the construction of contiguous tertiary-quaternary stereogenic carbon centers.

Chiral ureas and thioureas supported on polystyrene for enantioselective aza-Henry reactions under solvent-free conditions

Chiral recoverable supported bifunctional ureas or thioureas promote highly enantioselective aza-Henry reactions under solvent-free conditions.

ChemInform Abstract: Construction of Chiral Quaternary Carbon Center via Catalytic Asymmetric Aza‐Henry Reaction with α‐Substituted Nitroacetates.

The catalytic enantioselective aza-Henry reaction of N-Boc aldimines 2 and 2-nitropropionic acid ethyl ester 3 in the mixed solvents of toluene–saturated brine (10 : 1) was catalyzed by cinchona quaternary ammonium salts to form a new quaternary carbon center. High yields (up to 90%), and excellent enantioselectivities (up to 99% ee) and diastereoselectivity ratio (up to 22 : 1) were successfully obtained with mild conditions.

Enantioselective Synthesis of D-α-Amino Amides from Aliphatic Aldehydes.

Peptides consisting of D-amino amides are highly represented among both biologically active natural products and non-natural small molecules used in therapeutic development. Chemical synthesis of D-amino amides most often involves approaches based on enzymatic resolution or fractional recrystallization of their diastereomeric amine salts, techniques that produce an equal amount of the L-amino acid. Enantioselective synthesis, however, promises selective and general access to a specific α-amino amide, and may enable efficient peptide synthesis regardless of the availability of the corresponding α-amino acid. This report describes the use of a cinchona alkaloid-catalyzed aza-Henry reaction using bromonitromethane, and the integration of its product with Umpolung Amide Synthesis. The result is a straightforward 3-step protocol beginning from aliphatic aldehydes that provides homologated peptides bearing an aliphatic side chain at the resulting D-α-amino amide.

Asymmetric Synthesis of Functionalized Tetrasubstituted α-Aminophosphonates through Enantioselective Aza-Henry Reaction of Phosphorylated Ketimines.

Bifunctional Cinchona alkaloid thioureas efficiently catalyze asymmetric nucleophilic addition of nitromethane to ketimines derived from α-aminophosphonic acids to afford tetrasubstituted α-amino-β-nitro-phosphonates. Catalytic hydrogenation of (S)-α-amino-β-nitro-phosphonate 2d gives enantiopure (S)-α,β-diaminophosphonate 3.

Organocatalytic enantioselective aza-Henry reaction of ketimines derived from isatins: access to optically active 3-amino-2-oxindoles

An organocatalytic asymmetric aza-Henry reaction of ketimines derived from isatins with nitroalkanes has been achieved using Cinchona alkaloid organocatalysts.

Construction of chiral quaternary carbon center via catalytic asymmetric aza-Henry reaction with α-substituted nitroacetates

The catalytic enantioselective aza-Henry reaction of N-Boc aldimines 2 and 2-nitropropionic acid ethyl ester 3 in mixed solvents were catalyzed by cinchona quaternary ammonium salts to form a new quaternary carbon center. High yields (up to 90%), excellent enantioselectivities (up to 99% ee) and diastereoselectivities ratio (up to 22 : 1) were successfully obtained with mild conditions.