1.3- Dipolar cycloaddition reactions azomethine imines

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-... 

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. 

Asymmetric 1,3-dipolar cycloadditions of azomethine imines with terminal alkynes have been catalysed by 11 chiral ligand (8) coordinated metal amides to form N,N-bicyclic pyrazolidinone derivatives. Mechanistic studies have established the factors that determine the regioselectivity of the stepwise reaction. Novel phosphoramidite ligands (9) coordinated with palladium have been used to effect enantioselective synthesis of pyrrolidines by 3-P 2-cycloaddition of trimethylenemethane (from 2-trimethylsilylmethyl allyl acetate) to a wide range of imine acceptors (Scheme 11). ... 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utihzed to obtain highly substituted pyrroHdines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine yhdes 100,... 

Dipolar cycloaddition reaction of suitable dipolarophiles to azomethine imines is a well-known method leading to the pyrazolo[l,2-tf]pyrazole ring system and the methodology was duly reviewed in CHEC-II(1996) <1996CHEC-II(8)747>. During the covered period, some new applications have appeared. 

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>. 

Grigg and co-workers (383) found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloadditions of azomethine ylides derived from arylidene imines of glycine (Scheme 12.91). This work was published in 1991 and is the first example of a metal-catalyzed asymmetric 1,3-dipolar cycloaddition. The reaction of the azomethine yhde 284a with methyl acrylate 285 required a stoichiometric amount of cobalt and 2 equiv of the chiral ephedrine ligand. Up to 96% ee was obtained for the 1,3-dipolar cycloaddition product 286a. 

The formation and intramolecular dipolar cycloaddition of azomethine ylides formed by carbenoid reaction with C=N bonds has recently been studied by the authors group.84 Treatment of 2-(diazoace-tyl)benzaldehyde O-methyl oxime (176) with rhodium(II) octanoate in the presence of dimethyl acetylenedicarboxylate or N-phenylmaleimide produced cycloadducts 178 and 179, respectively. The cycloaddition was also carried out using p-quinone as the dipolarophile. The major product isolated corresponded to cycloadduct 180. The subsequent reaction of this material with excess acetic anhydride in pyridine afforded diacetate 181 in 67% overall yield from 176. The latter compound incorporates the basic dibenzofa, d -cyclohepten-5,10-imine skeleton found in MK-801,85 which is a selective ligand for brain cyclidine (PCP) receptors that has attracted considerable attention as a potent anticonvulsive and neuro-protective agent.86,87... 

Azine approach. Examples of this heterocyclic ring system have been prepared from 3,4-dihydroisoquinoline azomethine imines (706) and sulfenes by 1,3-dipolar cycloaddition reactions. The products are l,5,6,10b-tetrahydro-3H-[l,2,3]thiadiazolo[4,3-a]isoquinoline 2,2-dioxide derivatives (707) (75JOC2260). 

The concept of intramolecular 1,3-dipolar cycloaddition reaction has been extended to include azides, azomethine imines, nitrile oxides, nitrile imines and azomethine ylides. Such reactions are summarized in Table 1. 

Similarly small rate factors were obtained for 1,3-dipolar cycloadditions between diphenyl diazomethane and dimethyl fumarate [131], 2,4,6-trimethylbenzenecarbonitrile oxide and tetracyanoethene or acrylonitrile [811], phenyl azide and enamines [133], diazomethane and aromatic anils [134], azomethine imines and dimethyl acetylenedi-carboxylate [134a], diazo dimethyl malonate and diethylaminopropyne [544] or N-(l-cyclohexenyl)pyrrolidine [545], and A-methyl-C-phenylnitrone and thioketones [812]. Huisgen has written comprehensive reviews on solvent polarity and rates of 1,3-dipolar cycloaddition reactions [541, 542]. The observed small solvent effects can be easily explained by the fact that the concerted, but non-synchronous, bond formation in the activated complex may lead to the destruction or creation of partial charges, connected... 

Since Huisgen et al. first demonstrated the 1,3-dipolar character of pyridine N-imine in 1962,182 the 1,3-dipolar cycloaddition reactions of the heteroaromatic JV-imines have been explored extensively. The reactivity stems from the azomethine structure of the JV-imines.183 The cycloaddition of a variety of activated alkynes and alkenes to the JV-imines yields fused dihydro-pyrazoles and tetrahydropyrazoles, respectively. However, the aromaticity of the heteroaromatic ring is destroyed at this stage, so that such primary cycloadducts usually undergo further reaction to achieve stabilization in various ways as shown in Scheme 4 (i) aromatization, (ii) hydrogen transfer, (iii) rearomatization by rearrangement, and (iv) rearomatization by N—N... 

A number of stereospecific 1,3-dipolar cycloaddition reactions of the azomethine imine (385) with olefins have been reported. The dipole (386), generated as shown, has been trapped as the cyclo-adduct (387) to dimethyl fumarate. " The betaine (389) is formed in the reaction of 1,2-diphenyl-... 

The 1,3-dipolar cycloaddition reaction of azomethine ylides with thioketones has been used to prepare 1,3-thiazoIidines. The metallated azomethine ylides 67 were generated in situ by treating a-amino acid ester imines 66 with lithium bromide and DBU. The ylides were then treated with highly reactive thioketones such as thiobenzophenone or fluorene-9-thione, to afford 1,3-thiazolidine derivatives 68 (main isomer) and 69 (minor isomer) in good yield and in diastereoisomeric ratios of between 2 1 and 4 1 <01H(55)691>. 

Azomethine imines readily undergo 1,3-dipolar cycloaddition reactions with alkenes and alkynes to furnish pyrazoUdines and pyrazolines, respectively (Scheme 5.21). 

Dipolar cycloaddition reactions with stable and easily prepared azomethine imines, for the synthesis of a diverse array of heterocycles, have attracted considerable attention [125]. The complex RhjldS-MPPlM) (47) catalyzes the highly diastereoselective [3-l-2-l-l]-cycloaddition reaction between a diazo ketone and azomethine imines [126]. The final products are multi-functionalized bicyclic pyrazolidinone derivatives isolated in moderate to high yields (Scheme 9.12). 

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]. 

Suga, H., Funyu, A., Kakehi, A. (2007). Highly enantioselective and diastereoselective 1,3-dipolar cycloaddition reactions between azomethine imines and 3-acryloyl-2-oxazolidinone catalyzed by binaphthyldiimine-Ni(II) Complexes. Organic Letters, 9, 97-100. 

Scheme 10.73 Enantioselective 1,3-dipolar cycloaddition reactions of azomethine imines.

In contrast to the exo-selectivity of the cycloadditions catalyzed by a,a-bis[3,5-di(trifluoromethyl)phenyl]prolinol (10mol%) and trifluoroacetic acid (TFA, 10mol%) as an organocatalyst, only enrio-cycloadducts were obtained with high enantioselectivities in 1,3-dipolar cycloaddition reactions between N,N -cyc ic azomethine imines and cyclic enones employing the 6 -hydroxy derivative of 9-amino-9-... 

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