Imines acyclic azomethine

In the same year, chiral dicarboxylic acids 63 were applied to the asymmetric addition of weak nucleophiles to acyclic azomethine imines in this case the protonated acyclic azomethine imine I was generated in situ from aldehyde and N-benzylbenzoylhydrazide thanks to the presence of the chiral Bronsted acid 63f the following addition of a mild nucleophile such as allq l diazoacetate gave 77 with good yields and ee values that ranged from 93% to 99% (Scheme 24.24). 

Scheme 24.25 Catatytic as54iunetric Ugi-type reaction with acyclic azomethine imines.

Finally, a direct Mannich-type approach has been developed for the enantioselective synthesis of hydrazines and amines (Scheme 16.40). Thus, by trapping with alkyl diazoacetates some in s/iw-generated acyclic azomethine imines, in the presence of axially chiral dicarboxylic acids, a series of a-diazo-(3-hydrazino esters were obtained with excellent enantioselectivities [86]. 

In 2012, Maruoka and coworkers developed a new catalytic asymmetric Ugi-3CR through the use of an axially chiral dicarboxylic acid 27 [28], In the approach, a variety of aldehydes, 2-benzoyloxyphenyl isocyanide (26), and an acyclic azomethine imine 25 were initially reacted, yielding heterocyclic compounds 28 in excellent yields and good enantiomeric excesses (Scheme 7.11). Upon acid hydrolysis of the heterocyclic compound 28a, the corresponding a-hydrazino amide 29 was obtained without loss of enantioselectivity (bottom-left. Scheme 7.11). 

T. Hashimoto, H. Kimura, Y. Kawamata, K. Marnoka, Angew. Chem. Int. Ed. 2012, 51, 7279-7281. A catalytic asymmetric Ugi-type reaction with acyclic azomethine imines. 

Maruoka and co-workers reported the first catalytic asymmetric three-component 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides, which was realized using CuOAc/Ph-pybox and axially chiral dicarboxylic acid cocatalysts (Scheme 27) [48]. This transformation has abroad tolerance with regard to the substrates, affording diverse chiral 3,4-disubstituted pyrazolines with high enantioselectivities. The role of the axially chiral dicarboxylic acid is to generate the protonated acyclic azomethine imine, which then reacts with chiral Cu-acetylide. 

An additional salient feature of 27 as a chiral Br0nsted acid catalyst was its abihty both to generate in situ a protonated acyclic azomethine imine from an aldehyde and N -benzylbenzoylhydrazide and to control the absolute stereochemistry in the subsequent reaction with a mild nucleophile such as diazoacetates (Scheme 7.51) [78]. A key for inducing a high level of enantiocontrol in this previously elusive yet synthetically valuable catalytic system was the employment of 3,3 -diphenylmethylsilyl-substituted 27e as a catalyst. 

Scheme 7.51 Generation and utilization of acyclic azomethine imines.

Further appUcations of this catalyst class as Br0nsted acids were shown by Maruoka and coworkers in various enantioselective reactions, such as addition of aza-enamines and vinylogous aza-enamines to imines (178,179), addition of diazo compounds to in situ generated acyclic azomethine imines (Scheme 10.72) [180], and 1,3-dipolar cydoaddition reactions of cyclic azomethine imines with enol ethers and vinylogous aza-enamines (Scheme 10.73) (181). 

Scheme 10.72 Addition of diazo compounds to in situ generated acyclic azomethine imines.

A three-component Ugi-type reaction using A/ -alkylbenzohydrazide (instead of amine) has been catalysed by an axially chiral binaphthyl dicarboxylic acid and found to proceed with up to 93% ee with an acyclic azomethine imine. Stereoselectivity of a Ugi reaction starting from an oxanorbornenone / -amino acid, R CHO, and RNC has been improved through solvent selection. ... 

Aryne Annulation. Treatment of o-(trimethylsilyl)aryl triflates with TBAT results in the formation of ben-zyne intermediates. Fluoride-induced 1,2-eliminations of o-(trimethylsilyl)aryl triflates, which are readily prepared from phenols, have been shown to provide the respective aryne products, which, at room temperature, precipitously undergo cycloaddition in the presence of Diels-Alder adducts, including, but not limited to, tethered acyclic dienes, tethered enynes (eq 15), azomethine imines (eq 16),ene carbamates, and acetamidoacry-lates (eq 17). ... 

The first evidence for the existence of acyclic N-unsubstituted azomethine ylides as tautomers of imines was reported by Grigg (77CC125 78CC109). When the imines of a-amino esters are heated in benzene or toluene in the presence of a variety of dipolarophiles, pyrrolidine- or 3-pyrroline-2-carboxylates are isolated in high yields. These heterocycles correspond to the products produced by the 1,3-dipolar cycloadditions of N-unsubstituted azomethine ylides, indicating the thermal equilibrium between the imine esters... 

Synthetic and biological interest in highly functionalized acyclic and cyclic amines has contributed to the wealth of experimental methodology developed for the addition of carbanions to the caibon-mtrogen double bond of imines/imine derivatives (azomethines). While a variety of practical methods exist for the enantio- and stereo-selective syntheses of substituted alcohols from aldehyde and ketone precursors, related imine additions have inherent structural limitations. Nonetheless imines, by virtue of nitrogen substitution, add a synthetic dimension not available to ketones. In addition, improved procedures for the preparation and activation of imines/imine derivatives have increased the scope of the imine addition reaction. 

Generally speaking, piperideines and pyrrolines exist predominantly in the imine form and not in the tautomeric enamine form A -alkyl analogues have no alternative but to exist as enamines. These cyclic imines are resistant to hydrolytic fission of the C = N bond, in strong contrast with acyclic imines, but nonetheless they are very susceptible to nucleophilic addition at the azomethine carbon. An example of this is that both piperideine and pyrroline exist as trimers formed by the nucleophilic addition of nitrogen of one molecule to the azomethine carbon of a second molecule, etc. 

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