[3 + 2] Cycloadditions of Azomethine Imines

Abstract

In spite of their late discovery in the middle of 20 th century, the importance of azomethine imines and their [3+2] cycloaddition reactions has grown constantly throughout the decades. Today, [3+2] cycloadditions of azomethine imines have become indispensable in the preparation of pyrazole derivatives with all degrees of saturation. The structural diversity of azomethine imines is wide and comprises acyclic, C , N ‐cyclic, N , N ‐cyclic, and C , N , N ‐cyclic 1,3‐dipoles. Although electron‐deficient dipolarophiles are preferred, electron‐rich dipolarophiles, such as enol ethers and enamines, are also commonly used in these reactions. Compared to cyclocondensation methods and [3+2] cycloadditions with diazoalkanes and nitrile imines, [3+2] cycloadditions with azomethine imines provide access to a greater diversity of pyrazole derivatives with all degrees of saturation. As with other 1,3‐dipolar cycloadditions, a concerted and nearly synchronous mechanism has been proposed for most [3+2] cycloadditions of azomethine imines, although a stepwise mechanism may be viable in some cases. Several examples of asymmetric [3+2] cycloadditions of azomethine imines that afford non‐racemic cycloadducts with high enantioselectivity have been reported. These asymmetric cycloadditions are performed with various types of transition metal catalysts and organocatalysts, and indicate their potential for the asymmetric synthesis of saturated pyrazole derivatives. Finally, many examples of copper‐catalyzed and thermal, strain‐promoted [3+2] cycloadditions of azomethine imines (in particular sydnones) clearly indicate wide applicability of these reactions in bioconjugation, fluorescent labelling, materials functionalization, and other applications outside the realm of pure organic synthesis.

Synthesis of 6,7-Dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles by Azomethine Imine-Alkyne Cycloadditions Using Immobilized Cu(II)-Catalysts

“…1,3-Dipolar cycloadditions of azomethine imines are important reactions to obtain pyrazoles with variable degree of saturation [ 1 , 2 ]. Since the end of the 20th century, this field has gained much attention; most azomethine imines have been recognized as stable compounds that are easy to prepare, store, and handle [ 1 , 2 ].…”

“…1,3-Dipolar cycloadditions of azomethine imines are important reactions to obtain pyrazoles with variable degree of saturation [ 1 , 2 ]. Since the end of the 20th century, this field has gained much attention; most azomethine imines have been recognized as stable compounds that are easy to prepare, store, and handle [ 1 , 2 ]. In this context, 1-alkylidene-3-oxopyrazolidin-1-ium-2-ides (3-oxopyrazolidin-1-azomethine imines), accessible by condensation of 1,2-unsubstituted pyrazolidin-3-ones with aldehydes or ketones, have been extensively used for regio- and stereoselective synthesis of pyrazolo[1,2- a ]pyrazoles (bicyclic pyrazolidinones).…”

“…The most prominent examples of bioactive bicyclic pyrazolidinones are Eli Lilly’s γ-lactam antibiotics, which exhibit antibiotic activity similar to that of penicillins and cephalosporins ( Figure 1 ) [ 3 , 4 , 5 ]. These antibiotics are based on 6,7-dihydro-1 H ,5 H -pyrazolo[1,2- a ]pyrazole scaffold, which is accessible by [3 + 2] cycloaddition of 3-oxopyrazolidin-1-ium-2-ides to acetylenes [ 1 , 2 ]. In this context, copper-catalyzed azomethine imine-alkyne cycloadditions (CuAIAC) [ 1 , 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ] provide easy access to 6,7-dihydro-1 H ,5 H -pyrazolo[1,2- a ]pyrazoles in a regio- and stereoselective manner under mild conditions that are compliant with requirements of “click” chemistry ( Figure 1 ) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…These antibiotics are based on 6,7-dihydro-1 H ,5 H -pyrazolo[1,2- a ]pyrazole scaffold, which is accessible by [3 + 2] cycloaddition of 3-oxopyrazolidin-1-ium-2-ides to acetylenes [ 1 , 2 ]. In this context, copper-catalyzed azomethine imine-alkyne cycloadditions (CuAIAC) [ 1 , 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ] provide easy access to 6,7-dihydro-1 H ,5 H -pyrazolo[1,2- a ]pyrazoles in a regio- and stereoselective manner under mild conditions that are compliant with requirements of “click” chemistry ( Figure 1 ) [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. In contrast to the CuAAC reaction, which is catalyzed only by Cu(I), the azomethine imine analogue (CuAIAC) is also catalyzed by Cu(II) [ 10 , 11 , 12 , 24 , 25 , 26 , 27 ].…”

(3 + 2) Cycloaddition Reaction of the Endocyclic N-Silyl Enamine and N,N′-Cyclic Azomethine Imine

“…Therefore, the efficient application of the MCI to drug candidates is an emerging topic in the pharmaceutical industry. The (3 + 2) cycloaddition reaction is a straightforward and atom-economic synthetic methodology for the preparation of novel five-membered heterocycles with the molecular complexity. − The azomethine imine is one of the recent 1,3-dipoles which was used for (3 + 2) cycloaddition reaction (Scheme a). − The reactivity of various types of azomethine imine has been investigated with conjugated alkene or enol ether. − However, the (3 + 2) cycloaddition reaction with azomethine imine and enamine is relatively unexplored. − …”