Azomethine imines, asymmetric 1,3-dipolar

Asymmetric dipolar cycloaddition of azomethine imines derived from diazoal-kane-pyridazine cycloadducts 98JHC1187. 

High levels of asymmetric induction (97-74% ee) along with high diastereoselectivity (>99 1-64 36) were reported for asymmetric 1,3-dipolar cycloaddition reactions of fused azomethine imines 315 and 3-acryloyl-2-oxazolidinone 709 leading to 711 using a chiral BINIM-Ni(n) complex 710 as a chiral Lewis acid catalyst (Equation 100) <20070L97>. 

The use of chiral azomethine imines in asymmetric 1,3-dipolar cycloadditions with alkenes is limited. In the first example of this reaction, chiral azomethine imines were applied for the stereoselective synthesis of C-nucleosides (100-102). Recent work by Hus son and co-workers (103) showed the application of the chiral template 66 for the formation of a new enantiopure azomethine imine (Scheme 12.23). This template is very similar to the azomethine ylide precursor 52 described in Scheme 12.19. In the presence of benzaldehyde at elevated temperature, the azomethine imine 67 is formed. 1,3-Dipole 67 was subjected to reactions with a series of electron-deficient alkenes and alkynes and the reactions proceeded in several cases with very high selectivities. Most interestingly, it was also demonstrated that the azomethine imine underwent reaction with the electronically neutral 1-octene as shown in Scheme 12.23. Although a long reaction time was required, compound 68 was obtained as the only detectable regio- and diastereomer in 50% yield. This pioneering work demonstrates that there are several opportunities for the development of new highly selective reactions of azomethine imines (103). 

Stanovnik B, Jelen B, Turk C, Zlicar M, Svete J (1998) 1,3-dipolar cycloadditions of diazoalkanes to pyridazines. Asymmetric 1,3-dipolar cycloaddition of azomethine imines derived from diazoalkane-pyridazine cycloadducts. J Heterocycl Chem 35 1187-1204... 

Table 10.9 Asymmetric 1,3-dipolar cycloaddition of cyclic enones and azomethine imines.

In 2011 the same research group described another efficient application of dicarbo Q lic acids 63 in the asymmetric inverse-electron-demand 1,3-dipolar cycloaddition (lED 1,3-DC) of C//-cyclic azomethine imines with t-butyl vinyl ether or vinylogous aza-enamines (synthesized from enals) (Scheme 24.23). This latter reaction, carried out without exclusion of moisture and air, gave cycloadducts regioisomeric to the products observed in the normal-electron-demand 1,3-dipolar cycloaddition (NED 1,3-DC) catalysed by Ti/binolate starting from the enals and for this reason the authors introduced the concept of lED umpolung 1,3-DC. 

A year later, based on the same principle by using primary amine-catalyzed iminium ion activation in combination with external Brpnsted acid additives, Chen et al. [129] were able to achieve the asymmetric 1,3-dipolar cycloaddition of cyclic enones and a variety of azomethine imines in excellent yields and selectivities (Scheme 11.48). In this case, to scavenge the generated H2O during the formation of the enamine nucleophile intermediate, and to overcome the expected hydrogenbonding interaction, a stoichiometric amount of molecular sieves (4 A) was added. Interestingly, when the pseudoenantiomer catalyst 61 was employed, an opposite enantiomer of the product was formed in good yields and selectivities. 

Asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of C,A-cyclic azomethine imines with c-rich dipolarophiles was accomplished with a high stereo-selectivity by using an axially chiral dicarboxylic catalyst (40)." The metal-free silicon Lewis-acid-catalysed 3-1-2-cycloadditions of A-acylhydrazones with cyclopentadiene provides a mild access to pyrazolidine derivatives in excellent... 

The asymmetric 1,3-dipolar cycloaddition of C,A(-cyclic azomethine imines with unsaturated nitriles yielded chiral cyanopyrazolidines in good to excellent yields and... 

Kobayashi and co-workers successfully achieved the asymmetric 1,3-dipolar cycloaddition reaction of azomethine imines with terminal alkynes catalyzed by CuHMDS and DIP-BINAP ligand to provide N,N-bicyclic pyrazolidinone derivatives in high yields with exclusive regioselectivity and excellent enantioselectivity (Scheme 26) [46]. Mechanistic studies elucidated a stepwise reaction pathway and revealed that the steric character of the ligand determines the regioselectivity. Arai and co-workers applied chiral bis(imidazolidine)pyridine-CuOAc complex to the [3+2]cycloaddition of azomethine imines with propiolates for the construction of bicyclic pyrazolo[l,2-a]pyrazolone derivatives with up to 74% ee [47]. 

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. 

The use of 27f, with bis(2-naphthyl)methyl groups at the 3,3 -positions, as a catalyst enabled the employment of C,N-cyclic azomethine imines as a dipole for the asymmetric inverse-electron-demand 1,3-dipolar cycloaddition with vinyl ethers as exemplified in Scheme 7.52 [79],... 

Recently, Maruoka and coworkers reported the exploitation of C,iV-cyclic azomethine imines in highly enantiose-lective asymmetric 1,3-dipolar cycloadditions catalyzed by a titanium-binaphtholate (BINOLate) complex, which offers access to pharmaceutically attractive chiral tetrahydroisoqui-nolines and piperidines with a 1,3-diamine unit [13,14]. Not... 

TABLE 7.3 Asymmetric 1,3-Dipolar Cycloadditions of C -Cyclic Azomethine Imines"... 

SCHEME 7.4 Asymmetric 1,3-dipolar cycloadditions of A,A -cyclic azomethine imines with cyclic enones. 

Recently, Maruoka and coworkers have also developed an asymmetric inverse electron demand 1,3-dipolar cycloaddition of C,A -cyclic azomethine imines with fort-butyl vinyl ether catalyzed by a newly developed axially chiral dicarboxylic acid having diarylmethyl groups at the 3,3 -positions (Scheme 7.7) [18]. Based on this finding, the concept of the inverse electron demand umpolung 1,3-dipolar cycloaddition was introduced as a strategy for switching the regioselectivity of the cycloaddition from that of the titanium BINOLate-catalyzed normal electron demand 1,3-dipolar cycloaddition with enals (Table 7.3) by... 

SCHEME 7.7 Asymmetric inverse electron demand 1,3-dipolar cycloaddition of C.Al-cyclic azomethine imines with fert-butyl vinyl ether. 

SCHEME 7.9 Asymmetric 1,3-dipolar cycloadditions of AA -cyclized azomethine imines with aUyl alcohol by the use of only the Grignard reagent as a magnesium source. 

SCHEME 7.10 Catalytic asymmetric 1,3-dipolar cycloadditions of JV.iV -cyclized azomethine imines to allyl alcohol. 

First, the 1,3-dipolar cycloaddition of l-alkylidene-3-oxopyrazolidin-l-ium-2-ide 11 was examined. In this case, a magnesium-mediated system instead of the zinc-mediated system was found to be effective to realize the asymmetric 1,3-dipolar cycloaddition, that is, to a mixture of allyl alcohol (lA) and (R,R)-DIPT were added 3.0 equiv of alkylmagne-sium bromide and azomethine imines 11 successively. The corresponding pyrazolidines 12 were obtained in a good chemical yield with the excellent enantioselectivities as listed in Table 11.1, even in the case of pentyl- and cyclohexyl-substituted ones llg and llh (entries 7 and 8) [14]. 

TABLE 11.1 Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Imines 11... 

To synthesize optically active nitrogen-containing chemicals with oxygen functionalities, it would be ideal to employ various types of unsaturated alcohols as a 1,3-dipolarophile. We developed a stoichiometric and a catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines 11 to a one-carbon homologated homoallylic alcohol 16A as shown in Table 11.5. 

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