Nitrile-Alder-ene reaction

Diels-Alder reactions of 2-alkenyloxy-4,5-diphenyloxazoles 835 ( = 3,4) were not successful. There was no reaction up to 230°C, whereas FVP of 835 ( = 3,4) produced 4,5-diphenyl-2(3ff)-oxazolone 837 nearly quantitatively via an intramolecular ene reaction. Photolysis of 5-[(5-hexenyl)oxy]-2-phenyloxazole 838 (n = 3) afforded the azirine 840 in 54% yield as the sole photoproduct. This was postulated to arise via ring opening to the nitrile ylide 839 and recyclization. 

Some other highly efficient cycloaddition reactions have been used for polymer end-group modification and polymer-polymer conjugation. These include an additive-free version of the hetero Diels-Alder (HDA) reaction or the nitrile-imine-mediated tetrazole-ene cycloaddition (NITEC), the latter only requiring photoirradiation. Both techniques meet the criteria to be considered bioorthogonal reactions and can be performed under mild reaction conditions. As such, these reactions should also be applicable for the preparation of bioconjugates. 

Catalytic intermolecular coupling of alkene and alkyne is quite a challenging task. Nevertheless, cyclopentadienyl rutheniumcomplexes are able to catalyze alkyne-alkene coupling (an Alder-ene type reaction) to a mixture of the re-gioisomeric products 120 and 121 (Scheme 52). The most efficient catalysts are the complexes 78 or 53. The latter is more reactive. The scope of the reaction with respect to substituents attached to the both reactants is enormous ester, hydroxy, nitrile, ether, amino, and arylhalide groups are tolerated. Both terminal and internal alkynes and alkenes can be used. Some typical examples are summarized in Table 24 [67,69]. 

Hetero-Diels-Alder reactions performed with trifluoromethyl-substituled heterodienes or with trifluoromcthyl-substituted heterodienophiles have resulted in the synthesis of a large number of fluoro-heterocyclic compounds. Ketones, thioketones, imincs, nitriles, and their parent a,/3-unsaturated systems have been studied in cycloaddition reactions. Cycloadditions are regioselec-tive. An interesting aspect is the competition with ene-type reactions, aldol reactions and, depending on the partners, with [2 + 2]-cycloaddition reactions. 

As a rule, the initial hetero-DiELS-ALDER adduct 2 cannot be isolated. It eliminates N2 in a retro-DiELS-Alder reaction and is converted into a 4,5-dihydropyridazine 3. This can be stabilized as a 1,4-dihydropyridazine 7 (especially if X = H) by a 1,5 hydrogen shift or (if X = OR and NR2) as the pyridazines 5 and 6 by dehydrogenation or HX elimination. As a diazadiene, it can also engage in a further Diels-Alder reaction with excess of alkene 3delding the stable 2,3-diazabicyclo[2.2.2]oct-2-ene 4. The initial Diels-Alder product tetraazabicyclo[2.2.2]octatriene 8, which arises from the reaction between alkynes and 1,2,4,5-tetrazines, undergoes a cycloreversion with N2 elimination affording the pyridazine 6. With nitriles, 1,2,4-triazines 9 are obtained. 

Other metal-free dick reactions such as thiol-ene addi-tions, nitrile oxide/alkyne cycloadditions, " or ultrafast hetero-Dids-Alder tydoadditions have been reported and could be interesting options for polymer bioconjugation. For example, lones et al. described very recendy a thiol-ene route for the PEGylation of salmon caldtonin (Figure 8). 

There are many well-studied photochemical reactions that are clean, high yielding, relatively fast, and require no chemical catalysts. A number of these have been examined for SCNP formation, including the photochemically triggered Diels-Alder reaction between 2,5-dimethylbenzophenone and maleimide, the photo-dimerization of coumarin, the photodimerization of anthracene, and the photo-induced nitrile imine mediated tetrazole-ene cycloaddition. ... 

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