Azomethine imines cycloaddition

Finally, fully reduced heterocycles have been prepared either from a sequential azomethine imine cycloaddition-palladium-mediated cyclization process <2003T4451>, or from the reaction of A-( l-benzotriazolylalkyU-AyV-disubstitutcd hydrazine with methyl vinyl ether <1997JOC8210>. 

Azomethine imine cycloadditions provide access to pyrazolidines, pyrazolines and pyrazoles. Intramolecular cyclizations were first reported in 1970.78 The main method for generation of azomethine im-ines involves reaction of a 1,2-disubstituted hydrazine with an aldehyde or an aldehyde precursor. 

The answer to this dilemma was provided by Huisgen et al. (1962 a, 1962 b) by the cycloaddition reaction of C-methyl-A-phenylsydnone (6.10) with styrene, which yields, via the bicyclic intermediate 6.11 and elimination of CO2, 4,5-dihydro-5-methyl-l,3-diphenyl-li/-pyrazole (6.12). As mentioned briefly in Section 6.2 (Table 6-1, footnote a), sydnones are cyclic azomethine imines. As Huisgen (1968) demonstrated later, sydnone and azomethine imine cycloadditions are kinetically very similar with respect to solvent effects and in the sequence of reactivity with a series of 11 dipolarophiles. 

Fishwick, C.W.G., Grigg, R., Sridharan, V. and Virica, J. (2003) Sequential azomethine imine cycloaddition-palladium catalysed cyclisation processes. Tetrahedron, 59, 4451-68. 

Organocatalysts are also effective promoters of azomethine imine cycloadditions. 1,3-Dipolar cycloadditions of cycHc enones remain challenging... 

N. Fuchi, T. Doi, T. Takahashi, A library synthesis of pyrazoles by azomethine imine cycloaddition to the polymer-supported vinylsulfone. Chem. Lett. 200S, 34, 438-439. 

As the sp nitrogen atom in many heterocycles can be alkylated and aminated, the construction of an azomethine ylide or azomethine imine dipole is readily attainable as shown in Scheme 13. These ylides are very reactive and undergo cycloaddition with a... 

The above cycloaddition process consists of two separate [3-1-2] cycloaddition steps and represents a 1,3-2,4 addition of a multiple bond system to a hetero-1,3-diene [7S7]. The structure ot the azomethine imine intermediate has been proved unequivocally by X-ray analysis [195] Ethylene [194], acetylene [/iS2] . many alkyl- and aryl- as well sgemmal dialkyl- and diaryl-substituted alkenes [196,197, 198, 199], dienes [200], and alkynes [182, 201], certain cyclic alkenes [198, 199,... 

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. 

Pyrrolo annulated triazine 77 was prepared (88TL4415) by the [6 + 4]-cycloaddition of azoniafulvene ion 76 with azomethine imines generated from benzylidene phenylhydrazone (Scheme 19). 

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 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>. 

Combinatorial solution-phase cycloadditions of (1Z,4R, 5R )-4-benzoylamino-5-phenylpyrazolidin-3-on-l-azomethine imines 320 to 3-keto esters afforded a library of 26 highly pure bicyclic pyrazolidinones 713 in 6-89% yields and in 14-100% de. Most of the products were isolated as mixtures of the major (13, 23, 3/ , 5/ , 6/ )-epimers 713 and the minor (1R, 2A, 3R, 5R, 6R )-epimers 714 (Scheme 113). Epimerization of these cycloadducts at the anomeric position in solution was confirmed by H NMR spectroscopy <2007MI717>. 

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>. 

Other 1,3-dipoles, such are azides and azomethine imines, have also been employed in microwave-induced cycloadditions. The main results reported are reviewed in this section. 

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

The reaction of phenylazoalkenes 424 with an excess of potassium thiocyanate in acetic acid produces the cycloadducts 425 that undergo further [3+2]-cycloaddition reaction with thiocyanic acid at the azomethine imine function giving rise to the bicyclic product imidazo[l,5-3][triazole]-2,5-dithiones 41 (Equation 87) <1998SL786>. 

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. 

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