Aromatic azomethine imines, cycloaddition

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. 

The enantioselective 3 + 3-cycloaddition reaction of aromatic azomethine imines with donor-acceptor cyclopropane diesters produced 6,6,6-tricyclic dihydroquinolines in high yields (99%) and up to 98% ee. The side-arm-modified In-TOX/Ni(II) complex was shown to be an effective stereoselective catalyst for this reaction. The formal 3 + 3-cycloaddition reaction of allylic phosphonium ylides (127) to a, -unsaturated carbonyls (128) formed multi-substituted benzenes (129) in high yields (36-93%) (Scheme 38). °... 

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. 

Mesoionic compounds have been known for many years and have been extensively utilized as substrates in 1,3-dipolar cycloadditions.158-160 Of the known mesoionic heterocycles, munchnones and sydnones have generated the most interest in recent years. These heterocyclic dipoles contain a mesoionic aromatic system i.e. 206) which can only be depicted with polar resonance structures.158 Although sydnones were extensively investigated after their initial discoveiy in 1935,160 their 1,3-dipolar character was not recognized until the azomethine imine system was spotted in the middle structure of (206). C-Methyl-N-phenylsydnone (206) combines with ethyl phenylpropiolate to give the tetrasub-... 

Aromatic-substituted imines, especially those having electron-donating groups in the /wzz-position, undergo a [2+2] cycloaddition reaction with aryl isocyanates <1969CB938, 1978T101>. In the presence of an excess of azomethine, the six-membered triazine derivative is the exclusive product <1970MI149>. 

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... 

It would not be imprudent to say that most imine cycloadditions have been discovered unexpectedly during investigations on the generation of azo-methine ylides. As already discussed (Section II,C), imines 60, formed by the condensations of diethyl aminomalonate with aromatic aldehydes, quickly isomerize into highly stabilized azomethine ylides 61, which are all trapped by the imine 60 to give imidazolidine derivatives 217 (80TL2197). It has also been described above (Section II,E) that the iminium salt 75 (R = OMe, EWG = CN), formed in the N-alkylation of 6,7-dimethoxy-3,4-dihydroiso-quinoline with chloroacetonitrile, quickly loses a proton generating stabilized... 

A convenient one-step transformation of primary and secondary amines into the corresponding unprotected guanidines using 4-benzyl-3,5-dimethyl-l/f-pyrazole-l-carboxamidine 90 and its polymer-bound variant were described <06S461>. 1,3-Dipolar cycloaddition of polymer-bound alkynes to azomethine imines generated in situ from N-aminopyridine iodides followed by aromatization of the cycloadducts gave polymer-bound pyrazolopyridines that were released from the resin as carboxylic acids with trifluoroacetic acid or as methyl esters with sodium methoxide <06JCO344>. 

Takahashi and co-workers [264] constructed two 48-member p-strand mimetic libraries on solid phase using a [2 -i- 3]-cycloaddition between two different Rink-amide resin-linked vinylsulfones (161) and azomethine imines. The latter were generated in situ from cyclic hydrazides (162) and various aliphatic and aromatic aldehydes (Scheme 34). The cycloaddition took place on refluxing 1,2-dichloro-ethane in a sealed tube for 48 h, followed by elimination of the p-toluenesulfonyl group with DBU. The reaction afforded a single regioisomer (164) in moderate to good yields. 

Selective synthesis and cycloaddition reactions of new azomethine imines 109 containing a 1,2,4-triazine ring have been reported. 4,5-Dihydro[l,2,4]triazolo[3,4-c]benzo[l,2,4]triazines 108 with aromatic aldehydes gave stable iminium salts which were deprotonated to give new mesomeric betaines 109. These underwent 1,3-dipolar cyclization reactions affording tetra- and pentacyclic heterocycles 110 <05EJO3553 05H1889>. 

As previously pointed out, heteroaromatic A-imines contain the structural element of an azomethine imine. A typical reaction of this class of compound is 1,3-dipolar cycloaddition.121139 In heteroaromatic A-imines, such reactions are difficult since they involve loss of the aromaticity of the heterocyclic ring. Factors essential to the success or failure of a 1,3-dipolar reaction are the aromatic character of the parent heterocycle, the electron effect of the substituent R, and the nature of the dipolarophile. 

Phenylperhydro-l,3,4-oxadiazin-2-ones 151 react with aliphatic or aromatic aldehydes or ethyl 2-oxoacetate to give the intermediates 152. The azomethine imine ylides 152 yield primary oxazolidines 153 <200081170, 2002S1885, 2004TL3127>. These compounds can be synthesized also by treatment of 151 with ethyl oxoacetate or aldehydes in the presence of magnesium bromide etherate. The tandem cycloreversion-cycloaddition of 153 with various electron-poor dipolarophiles then leads to pyrazolidines 154-156 (Scheme 22). 

Compounds of the general formula 69 are prepared by cycloaddition of N-methyl- or A(-arylmaleimides with arylidene imines of AAs and in the presence of an aromatic aldehyde. Stabilized azomethine ylides are formed as intermediates, which then afford the cycloadducts. Several isomers are formed, and the influence of various metal salts and solvents was investigated (87BCJ4067 88T557). Similar transformations have been performed with A-ailyl glycine esters (91TL1359). 

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... 

Murphy et al. [39] reported the synthesis of pyrrolidine 7 combinatorial libraries. Starting from polystyrene resin-bound amino acids, the a-amino ester was condensed with aromatic and heteroaromatic aldehydes in neat trimethylorthoformate to afford the resin-bound aryl imine. Pyrrolidine and pyrroline derivatives were obtained through cycloaddition of the 1,3-dipoles azomethine ylides to olefin and acetylene dipolarophiles. A library of 500 compounds was reported. The screening of this library for in vivo inhibition of angiotensin-converting enzyme (ACE) led to the identification of l-(3 -mercapto-2 -(S)-methyl-1 -oxopropyl)-5-phenyl-2,4-pyrrolidinedicarboxy-lic acid 4-methyl ester as a potent ACE inhibitor that incorporates the mer-captoisobutyryl side chain (Fig. 3e). 

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