Dipolar cyclo addition

In 2000, it was proposed that the regioselectivity of the [3 + 2] cycloaddition of fullerenes could be modified under microwave irradiation. Under conventional heating, N-methylazomethine yhde and fullerene-(C7o) gave three different isomeric cycloadducts because of the low symmetry of C70 vs. Ceo. Using microwave irradiation and o-dichlorobenzene as a solvent, only two isomers were obtained, the major cycloadduct 114 being kinetically favored (Scheme 39) [75]. The same authors had previously reported the 1,3-dipolar cyclo addition of pyrazole nitrile oxides, generated in situ, to Geo under either conventional heating or microwave irradiation. The electrochemical characteristics of the cycloadduct obtained with this method made this product a candidate for photophysical apphcations [76]. 

Wagner and co-workers explored the different selectivity of 1,3-dipolar cyclo additions of nitrones 140 and cinnamonitrile 139 leading to oxadia-zolines 141 derived from an exclusive CN attack instead of a C = C attack (Scheme 50). This behavior was observed when cinnamonitrile was coordinated to a transition metal like Ft or Pd [89]. A similar approach to platimun-promoted nitrile-nitrone cyclo additions was reported using cychc nitrones. In this case, the authors reported a higher stereoselectivity of cychc nitrones with respect to the acyclic nitrones, due to a rigid E conformation adopted by cyclic nitrones [90]. 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

Another, slightly different method, is to use the resin to capture a molecule followed by release of a modified product. This is illustrated by the example shown in Scheme 13 where a nitrone undergoes a 1,3-dipolar cyclo-addition with an immobilized chiral auxiliary followed by a reductive cleavage to yield an isoxazoh-dine (Scheme 2.13) [32]. Here the polymer is acting as both an active reagent and as a purification technique [33]. 

Starting material which, upon oxidation with PSP, gave aldehydes. These were in turn condensed with primary hydroxylamines, promoted by polymer-bound acetate, to produce nitrones. The nitrones assembled using either method then underwent 1,3-dipolar cyclo-addition reactions with various alkenes to give the corresponding isoxazolidines (Scheme 2.46 and 2.47). 

Scheme 2.47 Preparation of isoxazolidines via 1,3-dipolar cyclo-addition.

Diorthohydroxazo, 153 1,3-Dipolar cyclo additions, with dimethyl acetylenodicarboxylate, 426, 427 with methyl fumarate, 425,426 with methyl maleate, 425, 426 of A-2-thiazoline-4-one, 425, 426 Dipole moment, 2-ammothiazole. 29 2-imino-4-thiazoline, 29 A-4-thiazoline-2-one, 389 in A-4-thiazoline-2-thione, in relation with protomery, 379 Disproportionation, 107 2-Disubstituted aminothiazoles, 259-267... 

Azine approach. 4,5-Dihydro-6//- 1,2-oxazine 2-oxides undergo 1,3-dipolar cyclo-addition reacting with appropriately substituted alkenes and alkynes to form isoxazolo-[2,3-Z>][l,2]oxazines. With styrene as the dipolarophile in the reaction with the oxazine (87), the product (88) with cis methyl and phenyl groups is formed. With acrylonitrile and methyl acrylate, some trans isomer is formed, but the cis isomer is predominant. The rings are always c/s-fused (77IZV211). 

Isoxazoles are made from hydroxylamine or by 1,3-dipolar cyclo additions... 

Another example features a Heck-type 5-exo-trig cyclization of the aryl iodide 139 occurring at room temperature in dichloromethane (Scheme 22) [82]. Azomethine ylides originating from imines 133 were used to trap the Heck product 140 in a subsequent 1,3-dipolar cyclo addition. The diastereomeric products 141 and 142 both derive from an endo attack of... 

The 1,3-dipolar cycloaddition of nitrile oxide to an unsaturated ester is a useful synthetic strategy for the synthesis of heterocycles such as A -isooxazolines and a-hydroxy-y-keto or y-imino carboxylic acids. Thus, the 1,3-dipolar cyclo-addition of the 4-0-acryloyl derivative 115 (R = f-butyldimethylsilyl) with two nitrile oxides (R = Ph or t-Bu) was explored by the Tadano group [95] (O Scheme 33). In the case of benzonitrile oxide (R =Ph), a functionalized A -isooxazoline 124 was obtained as a single isomer in excellent yield. Thus, the cycloaddition proceeded smoothly at room temperature with extreme stereoselectivity. 

A review of such additions reactions can be found in the recent very interesting publications of Huisgen and co-workers (see Centenary lecture on 1,3-dipolar cyclo-additions) (775),... 

Bixchler Napiralski, Dieckmann cyclization [15], Suzuki reaction [48], Wittig reaction, ozonolysis, condensation, esterification, nucleophilic substitution [49], Henry reaction, 1.3-dipolar cyclo-addition, electrophilic addition [50], oxidation chloride -> aldehyde [50], sulfide —> sulfone [51], alcohol —> ketone, Arbuzov reaction (phosphine-phosphorox-ide) [52], reduction hydration [45], ester -> alcohol [49, 53]... 

Cyclo-addition [76] (nitriloxide - isoxazole alkene —> isoxazoline), 1,3-dipolar cyclo-addition (pyrrole), Ugi 4-components reaction [75], Aza-Wittig reaction, N-alkylation [77], Stille reaction [78], Heck reaction [74], Pd-cata yzed amina-tion with primary and secondary alkyl- or aryl- ... 

Dipolar cyclo-addition, Diels Alder reaction [233], metalorganic alkylation (Pd, Mn) [234], Mitsunobu reaction (57[. 

The final option is to convert both functional groups in one reaction step. During the synthesis of isoxazolines [24] via a 1,3-dipolar cyclo-addition with nitrile oxides [25], the hydroxy function reacts with phenylisocyanate which is used to dehydrate the nitroalkane to form a carbamate. 

In the following section we focus our attention on library analysis, and especially on libraries which are not related to oligomers. To demonstrate the possibilities and limits of this analysis, two typical compound libraries were chosen. The first group of libraries contains an aromatic scaffold, pyrroles, which were synthesized by the Hantzsch pyrrole synthesis. The second class of compounds are heterocyclic isoxazolines synthesized via a 1,3-dipolar cyclo-addition. In both cases the reaction conditions were first established on single compounds. Supporting mass spectrometric data are presented in Section 17.7 (Appendix). 

Synthesis of the isoxazoline library [59] was performed on 2-chlorotritylchloride resin. The resin was loaded with diethylphosphonoacetic acid and the polymer-bound phospho-nate reacted with aldehydes to yield substituted E-cinnamic esters or substituted E-acrylic esters. This was followed by a 1,3-dipolar cyclo-addition with nitrileoxides, synthesized via the method of Mukaiyama and Floshinoc [60] (Fig. 17.18). In this reaction, two regioi-somers are formed, each of which exist in two enantiomeric forms. Table 17.4 shows the building blocks used in the library synthesis. 

By using the same type of 1,3-dipolar cyclo-addition of azomethine ylides it was possible to anchor ferrocene (Fc) onto the sidewalls of SWCNTs [96]. Accordingly, a nitrogen-functionalized glycine (R-NHCH2COOH, R= CH2CH2OCH2CH2OCH2CH2NHCO-FC) and paraformaldehyde were refluxed in dimethylformamide in the presence of SWCNTs. From differential scanning calorimetry the extent of functionalization was determined as approximately 1 Fc molecule per 100 carbon atoms of the SWNTs. 

Figure 4.4 Schematic presentation of covalent functionalisation of CNTs via 1,3-dipolar cyclo-addition for enhancing the ability to process CNTs and facilitating the preparation of hybrid composites, which is achieved solely by mixing. EtOH, ethanol. Reproduced with permission from Georgakilas et alf ...

Dipolar Cyclo addition of Various Reagents to the Enantiomeric ally Pure Euranones 170 and 227... 

Biodegradable polyamides have been reported together with the formation of ladder polymers by 1,3-dipolar cyclo-addition of a cyclic dinitrone. 

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