Dipolar with maleimides

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

Triphenylthieno[3,4-c]pyrazole (414) can be presented as a hybrid of dipolar-contributing azomethine imine ylide (415) or thiocarbonyl ylide canonical forms 416. Upon reacting this ylide with electron-poor olefins, it behaved like a thiocarbonyl ylide. Thus, with maleimide, a mixture of endo (419) and exo adducts (420) were obtained (74JA4276), which resulted from addition at the thiocarbonyl moiety. The reaction of 414 with dimethyl acetylenedicarboxylate gives the desulfurized indazole 418 in addition to the adduct 417 (Scheme 41). 

The four building blocks can combine through reversible imine and nitrone formation to produce a small DCL containing imines 10 and 11 and nitrones 12 and 13. The two nitrones can undergo an irreversible 1,3-dipolar cycloaddition with maleimide derivative 14. The trans product of the cycloaddition of nitrone 12 (but not of 13) is a good catalyst for its own formation as it preorganizes 12 and... 

Nine substituted hydroxybenzaldehydes were coupled to a Wang resin with a Mitsu-nobu coupling (Scheme 11.4). Treatment of the aldehydes with amino acid methyl esters produced resin-bound azomethine ylides that reacted with maleimide in a 1,3-dipolar cycloaddition. Ether-linked cycloadducts were cleaved from the resin as phenols with 50% trifluoroacetic acid. The compounds were retained as a mixture and were not isolated. 

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>. 

Bradshaw [74] reported in 1966 that maleimide undergoes sensitized photochemical addition to benzene, producing the imide analog of the corresponding maleic anhydride photoadduct. The author observed that the reaction probably proceeds by the addition of electronically excited maleimide to benzene. The photoaddition proved successful also with toluene, /-butylbenzene, and ethylbenzene. Simultaneously, Bryce-Smith and Hems [75] reported that 2 1 photoadducts are formed from maleimide, iV-n-butyl-,. V-benzyl-, iV-o-tolyl-, and iV-2,6-xylylmaleimide with benzene.. V-Phenyl, N-p-tolyl-, and A-p-methoxyphenylmaleimide did not form photoadducts. Trifluoroacetic acid was found to be virtually without effect on the photoaddition of N-n - bulyI maleimide No phenyl-A- -butylsuccinimide was detected [36], It was concluded that a dipolar intermediate is not involved. When N-n-bulylmalcimide and benzene were irradiated in the presence of tetra-cyanoethylene, a 1 1 1 adduct was formed [37],... 

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). 

Reaction with a dipolarophile is the proving ground for azide reactivity. As such, many azide-containing molecules are reacted in a 1,3-dipolar fashion to yield triazine derivatives. Of interest here is the reaction of azides with a heterocyclic dipolarophile, such as an /V-substituted maleimide. 

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). 

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 ... 

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