1,3-Dipolar cycloadditions azomethine imines

The azomethine imines exhibit the typical cycloaddition behavior expected of 1,3-dipolar species [fSJ] Numerous [3+2] cycloaddition reactions have been performed [201 204] Tetracyanoethylene adds to azomethine imines across the nitnle function instead of the C=C double bond This reaction is a rare example of this type of periselectivity [208] (equation 47)... 

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

The azomethine imine 6.39 reacts readily to give various 1,3-dipolar cycloaddition products (Huisgen and Eckell, 1977 for the naming of cycloadditions see Huisgen 1968). 

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,... 

It is well known that azomethine ylides, which are usually formed in situ, are very good substrates for 1,3-dipolar cycloadditions. The group of Novikov and Khlebnikov [328] generated such a 1,3-dipol by reaction of difluorocarbene formed from CBr2F2 (2-626) with the imine 2-627. Cycloaddition of the obtained 2-629 with an ac-... 

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. 

Thermolysis of 6-substituted l,5-diazabicyclo[3.1.0]hexanes 326, easily available from 325, leads to a diaziridine ring opening and to the intermediate formation of labile azomethine imines 327. These compounds can be stabilized by a proton shift to form 1-substituted 2-pyrazolines 328. However, when the thermolysis is carried out in the presence of a 1,3-dipolarophile, the corresponding products of dipolar cycloaddition can be obtained. For example, iV-arylmaleimides provide mixtures of the major trans- and minor air-products 329 and 330, respectively (Scheme 47) C1999RJO110, 2001RJ0841, 2003RJ01338, 2004RJ067>. 

Pyrazolo[l,2- ][l,2,4]triazolo[3,4-f][l,2,4]benzotriazines 485-487, containing the title substmcture, can be prepared by application of a well-known strategy using 1,3-dipolar cycloaddition to suitable azomethine imines... 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

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>. 

Synthetic work commenced with evaluation of an azomethine ylide dipole for the proposed intramolecular dipolar cycloaddition. A number of methods exist for the preparation of azomethine ylides, including, inter alia, transformations based on fluoride-mediated desilylation of a-silyliminium species, electrocyclic ring opening of aziridines, and tautomerization of a-amino acid ester imines [37]. In particular, the fluoride-mediated desilylation of a-silyliminium species, first reported by Vedejs in 1979 [38], is among the most widely used methods for the generation of non-stabilized azomethine ylides (Scheme 1.6). 

The benzocinnolinium azomethine imines 76 (R = Ph, OEt) react readily with DEAZD by 1,3-dipolar cycloaddition to give the corresponding tetra-zolidine derivatives (Eq. 10).124 The masked azomethine imine 77 is particularly unreactive as a 1,3-dipole, although PTAD reacts cleanly where other dipolarophiles either failed to react or gave complex mixtures (Eq. 11).125... 

Similarly, Yli-Kauhaluoma and co-workers have studied the 1,3-dipolar cycloaddition of polymer-bound alkynes to azomethine imines, generated in situ from A-ami nopyridine iodides, in the synthesis of pyrazolopyridines <06JCC344>. 

From the 1,3-dipolar cycloaddition of nitrile oxides to azomethines (imines) 291... 

The exact stmcture of a cycloadduct 39 obtained by dipolar cycloadditions of a [l,2,4]triazolo[3,4-c]benzo[l,2,4]triazine-based azomethine imine has been determined by X-ray investigation <2005EJO3553> (Scheme 4). The data supported the unambiguous connectivity of the particular atoms (i.e., attachment of the />-anisyl carbon atom to N-l) and, furthermore, the fact that the central triazine ring had a quasi-envelope stmcture with the N l atom at the top. 

The intermolecular reaction of imines with acceptor-substituted carbene complexes generally leads to the formation of azomethine ylides. These can undergo several types of transformation, such as ring closure to aziridines [1242-1245], 1,3-dipolar cycloadditions [1133,1243,1246-1248], or different types of rearrangement (Figure 4.9). 

Dipolar cycloaddition is another route to benzopyrrolo[l,2-a]azepines by pyrrole ring formation. The azomethine ylide derived from imine 88 and difluorocarbene adds to DMAD to produce dimethyl 3-fluoro-9H-dibenzo[c,/]-pyrrolo[l,2-fl]azepine-l,2-dicarboxylate 89 in 20% yield (Equation (12)... 

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). 

Garner et al. (90,320) used aziridines substituted with Oppolzer s sultam as azomethine ylide precursors. The azomethine ylide generated from 206 added to various electron-dehcient alkenes, such as dimethyl maleate, A-phenylmalei-mide, and methyl acrylate, giving the 1,3-dipolar cycloaddition product in good yields and up to 82% de (for A-phenylmaleimide). They also used familiar azomethine ylides formed by imine tautomerization (320). Aziridines such as 207 have also been used as precursors for the chiral azomethine ylides, but in reactions with vinylene carbonates, relatively low de values were obtained (Scheme 12.59) (92). 

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. 

Cyclobut[f]thiophene is a poor dipolarophile and requires prolonged reaction times to produce the 1,3-dipolar cycloaddition product 84 on reaction with diazomethane (Equation 44) <1999J(P1)605>. Reactions with nitrile imines or azomethine imines fail to provide cycloadducts. 

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