1.3- Dipolar cycloaddition maleimides

Scheme 10.10 1,3-Dipolar cycloadditions of azomethine ylides with maleimides in the...

By far the majority of reports of pyrrolindolizines involve their synthesis via dipolar cycloaddition reactions. Thus, almost exclusively, such compounds are derived from maleimides. 

Differently substituted pyrrolopyrroles can be constructed from a 1,3-dipolar cycloaddition, between the adduct from glycines and aldehydes and maleimides. Then, for example, the initially formed iV-allyl-o-bromophenyl-substituted pyrrolopyrrole mixture, 223, + 224, can then undergo an intramolecular cyclization in the presence of catalytic palladium(O) to give the pyrroloindolizine 225 <1991TL1359> (Scheme 61). 

N-Arylmaleimides are useful reagents for trapping and characterization of nitrile oxides (see, e.g., Ref. 165). However, their cycloadducts can also be target products. Thus, a series of 3,5-diaryl-4,6-dioxo-3a,4,6,6a-tetrahydropyrrolo- 3.4-r/]isoxazoles 95 was obtained by 1,3-dipolar cycloaddition of substituted benzonitrile oxides with N-(2,6-dialkylphenyl)maleimides. Certain compounds 95 showed bactericidal and fungicidal activity (264). 

PM3 calculations of the 2 + 3-cycloaddition of t-butylphosphaacetylene with 2,4,6-triazidopyridine are consistent with the dipole-LUMO-controlled reaction type. An FTIR spectroscopic study of the 1,3-dipolar cycloaddition of aryl azides with acetylenes shows that the rate of reaction increases logarithmically with pressure (below 1 GPa). The 3 -I- 2-cycloaddition between an azide (69) and a maleimide (70) has been greatly accelerated by utilizing molecular recognition between an amidopyridine and a carboxylic acid [see (71)] (Scheme 24). ... 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive amination of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with Al-methyl maleimide or styrene (301). 

Pyrrolo[3,4- -1,2,3-triazoles are often synthesized by 1,3-dipolar cycloaddition of maleimides with azides. At-Methylmaleimide and azide 179 heated at reflux in dry toluene for 24-48h led to triazole 180 as a 1 1 mixture of diastereomers <2002JA2134>. Benzotriazol-l-ylmethyl azide 181 formed the cycloadduct 182 with At-methyl-maleimide after refluxing in toluene for 3h (Equations 34 and 35) <1996JHC335>. 

The role of the zwitterion intermediate 164 and its rearrangement in the photocyclization of aromatic thioethers 163 to arene dihydro thiophene derivatives 165 is supported [81] by its independent trapping (via 1,3-dipolar cycloaddition) with biphenyl maleimide to obtain 166 in high yields (Scheme 8.47). 

These results indicate that the sulfinyl group seems to be much more efficient in the control of the stereoselectivity of 1,3-dipolar cycloadditions (endo or exo adducts are exclusively obtained in de> 80%) than in Diels-Alder processes (mixtures of all four possible adducts were formed). Additionally, complete control of the regioselectivity of the reaction was observed. Despite these clearly excellent results, the following paper concerning asymmetric cycloaddition of cyclic nitrones and optically pure vinyl sulfoxides was reported nine years later [154]. (Meanwhile, only one paper [155], related to the synthesis of /1-nicotyri-nes, described the use of reaction of nitrones with racemic vinyl sulfoxides, but these substrates were merely used as a masked equivalent of acetylene dipolaro-phile). In 1991, Koizumi et al. described the reaction of one of the best dipolarophiles, the sulfinyl maleimide 109, with 3,4,5,6-tetrahydropyridine 1-oxide 194 [154]. It proceeded in CH2C12 at -78 °C to afford a 60 20 10 6 mixture of four products in ca. 90 % yield (Scheme 92). 

The first example of this nature was published by Sadownik and Philp [45], who reported an efficient synthetic replicator based on 1,3-dipolar cycloaddition between a nitrone and a maleimide. They constructed their library from two aldehydes, with only one having an amidopyridine recognition site (Fig. 5). 

Dipolarophiles most frequently employed in trapping of azomethine ylides are acetylenedicarboxylates and maleimides because they are much more reactive than most other dipolarophiles. Maleic anhydride is almost equal to maleimides in reactivity toward azomethine ylides, and furmarates and maleates rank next. These dipolarophiles are so highly reactive in 1,3-dipolar cycloadditions that most of the azomethine ylides cited in this article can be smoothly trapped as the corresponding cycloadducts. Accordingly, less reactive dipolarophiles are selected in this section in order to evaluate the reactivity of azomethine ylide 1,3-dipoles. 

Maleimides and maleic anhydride have been most frequently employed as cyclic cis-olefin dipolarophiles in the stereochemical investigation of 1,3-dipolar cycloadditions, especially on the endo and exo selection of the reaction. They are one of the most reactive dipolarophiles toward many kinds of azomethine ylide 1,3-dipoles. Because of their structural simplicity, the only stereochemical variation possible in cycloadditions is an endo and exo selection. If a strong attractive interaction exists between the extended conjugation of these dipolarophiles and azomethine ylides, an endo-selective cycloaddition results. 

Hoveyda et al. [262] prepared different N-aryhnaleimidobenzoic acids linked to SASRIN resin, whose double bond present in the maleimido moiety could act as a convenient dipolarophile in cycloaddition reactions. Thus, solution-generated a-iminoesters (from different aromatic aldehydes and aminoesters) were reacted vdth the supported maleimides (158) under Tsuge [263] conditions. Formation of the expected syn-endo cycloadduct (160) was observed after only 1 h at room temperature (Scheme 33). From structure-reactivity analysis, the authors concluded that the cycloaddition reaction is more sensitive to steric then to electronic factors on the azomethine yhde counterpart. The advantage of this procedure stems essentially from the fact that the iminoesters (159) are formed in situ. Aldehydes containing a-hydrogens could also be employed. Moreover, the resin in this case also plays the role of a protective group, because, in contrast with N-alkyl and N-aryl (see above) maleimides, N-unsubstituted maleimide is not suitable for 1,3 dipolar cycloadditions. 

Azizian et al. [103] described a novel four-component reaction for the diastereo-selective synthesis of spiro-pyrrolizidines 170 using a 1,3-dipolar cycloaddition of azomethine ylides to N-aryl maleimides. Reaction of ninhydrin 166 with 1,2-phenylenediamine 167 in DMSO, and addition of L-proline 168 and N-aryl maleimides 169 in a one-pot four-component reaction (Scheme 11.41) usually required extended reaction times of up to 3 h at 100 °C to obtain the desired spiro-pyrrolizidines 170 in 76-86% yield as single diastereoisomers. This process can be accelerated substantially (3-5 min) with good yields (87-95%) by performing the reaction under microwave irradiation conditions. 

An interesting variation of the classical multicomponent reaction was recently described starting from a glyoxale and a tetrahydroisoquinoline generating in the first step an immonium species which underwent 1,3-dipolar cycloaddition with A-methyl maleimide as shown in Scheme 1.8.5.10.i ... 

As shown in Scheme 4.3.4, several substituted hydroxybenzaldehydes 226 were attached to Wang resin 84 via an alkylaryl ether linkage through a Mitsunobu reaction to give 227. These polymer-supported aldehydes were allowed to react with an a-amino ester 228 and maleimide 229 in DMF to give immobilised proline analogues 230 that were liberated from the resin by treatment with 50% TFA to afford 231. The dipolar cycloaddition provided mixtures of diastereoisomers, which could be separated by HPLC. 

The thiocarbonyl ylide intermediate (378), generated by thermal extrusion of trimethylsilyl bromide from (377), undergoes 1,3-dipolar cycloaddition with iV-phenyl- and JV-methyl-maleimides... 

PEO-PSt-PtBA arms, PEO-fi-PSt, and PEO-b-PMMA was synthesized via Diels-Alder reaction of maleimide and anthracene end-functionalized polymers using ATRP or NMP. Durmaz et elegantly combined 1,3-dipolar cycloaddition with... 

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