Cycloaddition of azomethine imines

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

Scheme 11 [3+2] Cycloaddition of azomethine imines with a,P-unsaturated aldehydes...

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... 

Copper-catalyzed 1,3-dipolar cycloaddition of azomethine imine 264 with ethyl propiolate 265 with a chiral ferrocenyl bidentate ligand efficiently generated dihydropyrazol[l,2- 7]pyrazolones 266 in very good yields and ee... 

M. Keller, A. Sani Souna Sido, P. Pale, J. Sommer, Copper(I)-zeolites as new heterogeneous and ligand-free catalysts [3+2]-cycloaddition of azomethine imines, Eur. J. Org. Chem., 2009, 15, in press. 

Asymmetric [3 + 2] cycloaddition of azomethine imines with aliphatic traws-enals catalysed by prolinols. 

The Chi group recently achieved the first NHC-eatalyzed diastereo- and enantioselective [3 + 4] cycloaddition of azomethine imines and enals via 1,4-dipolarophile intermediates generated by oxidative catalytic remote y-car-bon aetivation of enals. Dinitrogen fused seven-membered heterocyclic products were produced with high enantiomerie purity (up to 81% yield and 99% ee). Racemic azomethine imines ean be used as 1,3-dipolar substrates to afford dinitrogen-fused seven-membered heterocyclic compounds with high enantiomeric purity (s-factor up to 339). The key vinyl enolate intermediate is generated by oxidative y-carbon activation of enal via NHC catalysis as the reactive 1,4-dipolarophile (Scheme 7.116). 

Following the same concept, a three-component stereoselective entry to pyrazolidinones, involving a 1,3-dipolar cycloaddition of azomethine imines and a-oxo-ketenes, was also reported. Thus, the microwave irradiation of a 1 1 1 mixture of a 2-diazo-1,3-diketone, an aldehyde or a ketone, and a substituted hydrazine in toluene led to the expected spiropyrazolidin-3-ones 38 [Scheme 3.301. The success of this reaction demonstrates that a-... 

SCHEME 11.47. Organocatalytic [3-1-2] cycloadditions of azomethine imines with... 

In 2006 Chen et al. [128] reported the first organocatalyzed stereoselective [3 + 2] dipolar cycloaddition of azomethine imines with aliphatic a,p-unsaturated aldehydes using chiral secondary amine catalyst 59. The desired cycloaddition products were obtained with good yields, good diastereoselectivities and good enantioselectivities for both electron-rich and electron-poor aromatic azomethine imines. In contrast, aliphatic azomethine imines (R = -Pr) led to poorer results (40% yield and 77% ee). Investigation of a variety of solvents and additives revealed that tetrahydrofurane/HaO mixture and 10 mol% of trifluoroacetic acid were preferred. No reaction was observed when aromatic a,p-unsaturated aldehydes were used. The authors proposed an iminium ion mechanism that could proceed via the transition states shown in Scheme 11.47. 

SCHEME 5.21 1,3-Dipolar cycloaddition of azomethine imines to alkenes and alkynes. 

Sommer et al. found that Cu(I)-exchanged zeolites (Cu(l)-USY) could be utilized as heterogeneous catalysts for [3 + 2] cycloaddition of azomethine imines with terminal alkynes (Scheme 4.20). This method provides an efficient, versatile, and highly regi-oselective approach to Af,Af-bicyclic pyrazolidinone derivatives, which might exhibit useful bioactivities. The catalysts were readily available, convenient to remove, and reusable (Keller et al., 2009). 

The 1,3-dipolar cycloaddition of azomethine imines with alkynes could also be well facilitated by an Al203-supported copper hydroxide [Cu(0H) /Al203] (Scheme 4.21). Generally, the desired pyrazolidinones were obtained in good to excellent yields (Yoshimura et al., 2011). 

Scheme 1.12 Cycloaddition of azomethine imines with 3-acryloyloxazolidin-2-ones.

Dipolar cycloaddition of azomethine imine or nitrile imine-type dipoles with alkenes or alkynes yields nitrogen heterocycles containing two nitrogen atoms in the ring. MeOPEG resin was applied in the solid-phase synthesis of pyrazolines (Scheme 11.13). Resin-bound... 

Intramolecular cycloaddition of azomethine imines and olefins has been used to synthesize various diazabicyclic systems (Scheme 29). A double Diels-Alder addition of coumalic acid with butadienes has been used to prepare tricyclo[3,2,l,0 ]oct-3-enes (475). ... 

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]. 

The 1,3-DC of azomethine imines and alkenes provides a straightforward access to dihydropyrazoles. In 2005, Sibi and coworkers developed the first catalytic enan-tioselective [3 -l- 2] cycloadditions of hydrazonyl bromide or chloride 31 to olefins 30 [19]. The corresponding dihydropyrazoles 32 were obtained in highly enantioen-riched form with 82-98% yields (Scheme 2.10). A concerted reaction mechanism was proposed considering the fact that only anti diastereomers of the cycloaddition products were observed by NMR analysis. Besides, other alkenes such as vinyl ether [20] and methallyl alcohol ether [21 ] were also good partners in the chiral Lewis acid-catalyzed cycloadditions of azomethine imines. 

Although considerable improvements have been made for endo-selective cycloadditions of azomethine imines, methods for exo and enantioselective cycloaddition of azomethine imines were relatively scarce. By employing novel, multifunctional primary amine catalysts 145 derived from cinchona alkaloids in the presence of triisopropylbenzene sulfonic acid (TIPBA) 146 as cocatalyst, Chen and coworkers developed the first organocatalytic, highly exo-selective, and enantioselective 1,3-DC reaction of cyclic enones 142 and azomethine imines 143 in 2007 [53]. The additional and synergistic hydrogen-bonding interaction of catalyst and 1,3-dipole is essential for enantiocontrol, and excellent stereoselectivities were achieved for a broad scope of substrates (dr > 99 1, up to 95% ee) (Scheme 2.37). 

Sibi, M. R, Rane, D., Stanley, L. M., Soeta, T. (2008). Copper(II)-catalyzed exo and enantioselective cycloadditions of azomethine imines. Organic Letters, 10, 2971-2974. 

A stereoselective [3+2] dipolar cycloaddition of azomethine imines 141 with ot,P-unsaturated aldehydes catalyzed by ot,a-diarylprolinol salts was also reported by Chen et al. [88]. More important, they extended the strategy to cyclic enones by employing a Cinchona alkaloid-derived bifunctional primary amine catalyst 142 (Scheme 1.52) [89]. The synergistic hydrogen-bonding interaction of the catalyst and 1,3-dipoles 141 plays a critical role in high enantiocontrol (dr >99 1, up to 95% ee). 

In contrast to tran -selectivity (cndo-selectivity) of the Ni (n)-catalyzed reactions, Sibi et al. reported ciiy-selective (exo-selective) and highly enantioselective cycloadditions between -cyclic azomethine imines and 2-acryloyl-l-benzyl-5,5-dimethyl-3-pyrazohdinone catalyzed by the bisoxazoline-Cu(II) complex (10mol%) consisting of Cu (OTf>2 and (15,2I )-l-amino-2-indanol-deiived bisoxazoline (INDABOX) (Table 7.2) [12]. Interestingly, the use of additional chiral Lewis acid complexes prepared from INDABOX and Mg(II), Zn(II), or Ni(II) salts led to tmns-selective (emio-selective) cycloadditions of azomethine imine. The INDABOX-Mg(OTf)2- and INDABOX-Zn... 

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