Cyclooctyne Diels-Alder reactions

Scheme 35 Homo-Diels-Alder reactions of dimethyl oxanorbornadiene-2,3-dicarboxylate and related compounds 128 with cyclooctyne [81]...

Cyclooctyne, being considerably strained, shows a high reactivity to various reagents such as bromine " and butyllithium - and its Diels-Alder reactions occur under milder conditions than with unstrained acetylenes -... 

Studies on the mechanism and regioselectivity of the Diels-Alder reaction with inverse electron demand have been published by Sauer and co-workers 381 383,384 it was found that the cycloaddition rate of cyclooctyne to a number of 1,2,4-triazines can be correlated with the reduction potential of these dienes provided steric substitution effects are approximately equal. 

The accumulation of the cycloaddition product is related to its thermal stability in regard to nitrogen elimination. Here, elimination of nitrogen is even more pronounced because of two reasons the presence of the double C-C bond instead of a cyclopropane moiety (Scheme 11) and because it can produce corresponding furan derivatives. Furan is actually one of the rare aromatic heterocyclic compounds that easily participates in Diels-Alder reactions as a moderately active diene. Therefore, it is also reasonable to postulate that the furan derivative obtained after elimination of nitrogen is more reactive than 2,5-bis(trifluoromethyl)-l,3,4-oxadiazole. Additionally, the cycloadduct with a second molecule of cyclooctyne would be a final product of the cycloaddition reaction. To explore this possibility further, a semiempirical study of cycloadduct stability and activation barrier needed for cyclooctyne to react with furan was performed. 

The Diels-Alder reaction of pyridinones (Scheme 4) with substituted butadienes is quite effective for the synthesis of the reduced isoquinolinones 23. Ozonolysis of the olefin provides a method for the synthesis of cA-3,4-disubstituted piperidines <97TL2295>. The high pressure Diels-Alder reaction of the pyridinone 24 with the strained cyclooctyne provides the corresponding stable, bridged tricyclic cycloadduct 25 <97H(45)15>. 

A sequence of Diels-Alder and homo-Diels-Alder reaction occurs to furnish the cage compounds 81a -i when a solution of 11a -e in toluene is subjected to reaction with alkynes. Suitable alkynes are acetylene itself, phenylacetylene, methyl propynoate, and cyclooctyne [70]. 

It seems that the homo-Diels-Alder reactions proceed markedly more rapidly than the Diels-Alder reactions since the primary [4-1-2] adducts carmot be detected spectroscopically. Furthermore, it is noteworthy that all 1 -alkynes react regiospecifically in the initial [4-1-2]-cycloaddition process. This addition proceeds in such a way that, independent of the polarity situation of the acetylene, the carbon atom bearing the substituent is positioned in the immediate vicinity of the phosphorus atom of the phosphirane increment. This suggests that steric factors are responsible for the direction of the addition. This is further supported by the observation that 11a does not participate in cycloaddition reactions with any disubstituted triple bond system, except for cyclooctyne, which possesses the necessary reactivity for a cycloaddition on account for the cisoid-dis-... 

Fig. 1 Cycloaddition reactions employed in nucleic acid labeling with reporter groups (green star). A Cu -mediated azide-alkyne cycloaddition (CuAAC) of a terminal alkyne with an azide. B Strain-promoted azide-alkyne cycloaddition (SPAAC) of an azide with a cyclooctyne derivative. C Staudinger ligation of an azide with a phosphine derivative (not a cycloaddition reaction, see below). D Norbornene cycloaddition of a nitrile oxide as 1,3-dipole and a norbornene as dipolarophile. E Inverse electron-demand Diels- Alder cycloaddition reaction between a strained double bond (norbornene) and a tetrazine derivative. F Photo-cUck reaction of a push-pull-substituted diaiyltetrazole with an activated double bond (maleimide)...

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