Protonated acyclic imines

HNMR spectra of azirines which are unsubstituted at C-2 (69TL4073). The imine protons are commonly observed at ca. 10 p.p.m. whereas those of normal acyclic aldimines are observed in the vicinity of 8 p.p.m. imine (12), for example, displays a singlet at 7.63 p.p.m. (62CJC882). A similar but less pronounced shielding effect of ca. 0.4 p.p.m. hat been observed for the protons at C-3 compare, for example, the resonances assigned to the azirine (13)... 

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). 

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. 

Metalation of unsymmetrical mines. Pioneering studies on the metalation and subsequent alkylation of unsymmetrical imines indicated that the reaction occurs predominantly at the less substituted a-position.5 This pattern has since been observed generally with lithium diethylamide, LDA, and ethylmagnesium bromide. Recent studies6 indicate that the site of alkylation is independent of the alkylating group but is dependent on the substituent on the imine and particularly on the basicity of the base. Butyllithium ( -, sec-, and /-) can abstract a proton from the more substituted a-carbon of the acyclic imine 1 to some extent. In the case of the cyclic imine 2, alkylation at the more substituted position is actually the main reaction. However, only substitution at the less substituted position of the dimethylhydrazone of 2-methylcyclohexanone is observed with either LDA or jcc-butyllithium (7,126-128). 

Similar to thiol addition to imines, imidic esters,69,70 and cyano compounds possessing an a-proton (35), such as cyanic acid,71 cyanamide,71 monosubstituted cyanimides,72 and a-substituted acetonitriles,69,70,73,74 react smoothly with a-mercaptoacetic acids (26) to generate an unstable acyclic intermediate 36, which cyclizes to give 37 (Y = O, NH, NR, and CHR, respectively) [Eq. (10)]. 

Heterobimetallic catalysis mediated by LnMB complexes (Structures 2 and 22) represents the first highly efficient asymmetric catalytic approach to both a-hydro and c-amino phosphonates [112], The highly enantioselective hydrophosphonylation of aldehydes [170] and acyclic and cyclic imines [171] has been achieved. The proposed catalytic cycle for the hydrophosphonylation of acyclic imines is shown representatively in Scheme 10. Potassium dimethyl phosphite is initially generated by the deprotonation of dimethyl phosphite with LnPB and immediately coordinates to the rare earth metal center via the oxygen. This adduct then produces with the incoming imine an optically active potassium salt of the a-amino phosphonate, which leads via proton-exchange reaction to an a-amino phosphonate and LnPB. 

We indicated in the introduction that the trimerization of pyrrole involves, in the reaction of the third molecule of pyrrole, the interaction with a protonated enamine. Such an intermediate could also be generated by protonation of an imine. Although few examples of intermolecular reactions have been reported, it is clear that this is another method that is capable of further exploitation. Acyclic and cyclic im-ines have been shown to interact successfully with nucleophilic aromatic substrates such as indole. In the case of the cyclic imines they may be generated in situ from relatively stable trimers. 

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