Reaction with azomethine imines

The [3+2] cycloaddition has also been shown to be effective in the reaction of azomethine imines 32 with a,P-unsaturated aldehydes by Chen and co-workers [70], A survey of seven catalysts revealed some interesting trends, with the diarylprolinol derivative 31 giving the highest yields and selectivities (40-95% yield endo. exo 1 4.3-1 49 77-96% ee for exo) with short reaction times (5-24 h) and low catalyst loading (10 mol%) (Scheme 11). The reaction was particularly sensitive to the amount of water present in the reaction medium and the choice of co-acid. This phenomenon is a reoccurring theme in many of the publications in the area of iminium ion catalysis and, as yet, no general explanation has been proposed to account for these observations. 

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). 

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. 

Stable triazolinedione ylides have been isolated from the reaction of TADs with appropriately substituted diazo derivatives, isobenzofurans, and acetylenes. Reaction of azomethine imines prepared by this way with ethyl-enic dipolarophiles, e.g, vinyl ethers or acetylene dicarboxylates, gives the... 

Reactions of azomethine imines with alkynes catalyzed by copper yielding fused nitrogen heterocycles have also been reported [131]. 

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]. 

In 2013, Wang and co-workers presented the first highly diastereo- and enantioselective [3-1-3] cycloaddition of azomethine ylides with azomethine imines employing Cu(l)/Bu-Phosferrox complex as the catalyst (Scheme 28) [49]. A wide range of azomethine ylides and azomethine imines, including those derived from aliphatic aldehydes, underwent this reaction to furnish the biologically active 1,2,4-... 

We decided to evaluate our new strategy with azomethine imines [111-116] as a possible reacting partner with homoenolates [117], Contrary to our findings with the p-protonation of homoenolates, the AfW-dimethyl substituted benzimidazole 4 was observed by NMR spectroscopy to interact irreversibly with the secondary electrophile, the starting azomethine imine [118], The more bulky A -mesityl-Ai-methylbenzimidazolium salt 5 was employed in order to sequester this nonproductive pathway (Scheme 11). The use of 20 mol% of this precatalyst in combination with DBU at 40°C catalyzed the reaction between enals and azomethine imines to afford tetrahydropyridazinones as a single diastereoisomer (all cis). A variety of substituents are tolerated on the azomethine imine. It was found that phenyl... 

The vinylidene complexes (CO)5W=C=CPh2 react with imines and triphenylketen-imines to give [2+2] cycloadducts AUenylidene complexes of chromium 56 also undergo [2+2] cycloaddition reactions with azomethines at the center C=C bond to give the cycloadducts 57 . 

TABLE 7.1 Asymmetric Cycloaddition Reactions of Azomethine Imines with 3-Acryloyl-2-oxazolidinone ... 

The thermal 3 + 2-cycloaddition reactions of azomethine imines with allenoates produced dinitrogen-fused heterocycles in moderate to excellent yields under mild... 

Dimethylamino-2-azabutadienes are readily accessible by the reaction of azomethines (imines) with DMF diethyl acetal (eq 13). 1-Dimethylamino-1,3-butadienes can be synthesized in the same manner. Reactions of 2-azavinamidinium salts with DMF diethyl acetal give rise to 2-aza- and 2,4-diazapentamethinium salts (eq 14). ... 

Azomethines add with great ease and stereospecificity to carbon-carbon double bonds affording pyrazolidines. They also add to carbon-carbon triple bonds with the formation of pyrazolines. Benzimidazolium iV-imines, e.g. (622), are a special case of azomethines. Its reaction with DMAD yields l-(2-methylaminophenyl)pyrazole (624), which is formed by cleavage of the initial adduct (623) (75JHC225). 

Huisgen et al. (1960, 1977 b) found that (i )-4-chlorobenzenediazocyanide reacts with 9-diazofluorene to give the azomethine imine 6.38 in 93 % yield (Scheme 6-28). Huisgen et al. interpret this reaction in terms of the electrophilicity of the diazocyanide at its a-nitrogen atom (not 0 ) and the nucleophilic character of 9-diazofluorene, as shown in the bipolar mesomeric structure 6.37. 

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-... 

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 thermal hydrazone-azomethine imine isomerization can be easily performed under microwave irradiation in the absence of solvent. The subsequent 1,3-dipolar cydoadditions with electron-defident dipolarophiles occur in only a few minutes to afford the corresponding cycloadducts. The use of pyrazolyl hydrazones 205 leads to valuable compounds, such as bipyrazoles 213, in good yields and this provides a new approach to the preparation of these heterocyclic derivatives [116] (Scheme 9.67). Reactions undertaken with dassical heating under comparable reaction conditions (time and temperature) lead to cydoadduct yields that are considerably lower and, indeed, several dipolarophiles do not react at all. 

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