Cyclooctyne acidity

Cycloadditions with other symmetrical acetylenes were carried out by using thiocarbonyl (5)-methylide (69) (159). Interestingly, no reaction was observed when acetylene dicarboxamide was used. The reaction of 69 with cyclooctyne resulted in the formation of cycloadduct 103 (Scheme 5.38). Interestingly, the spirocyclic 2,5-dihydrothiophenes of type 103 or 104 undergo acid-catalyzed ring opening upon treatment with silica gel or trifluoroacetic acid to give thiophenes 105 and 106, respectively. 

Coordination to alkynes distorts the triple bond character nearer to that of a double bond, decreasing the linearity. Utilization of the coordination effect makes it feasible to prepare cyclic alkynes whose synthesis is difficult to achieve. Highly strained cyclooctyne can be prepared by coordination. As an example, starting from (R)-pulegone, three of the four rings of the epoxydictymene skeleton 152 were constructed by the consecutive Lewis acid-promoted Nicholas reaction of allylic silane 149 to form 150, and the intramolecular Pauson-Khand reaction of 151. The total synthesis of (+)-epoxydictymene 153 from 152 has been achieved [38]. 

Upon reaction with the Simmons-Smith reagent104) or m-chloroperbenzoic acid,105 cyclooctyne is transformed at least in part to products of the bicyclo-[3.3.0]octane type. 

Thiiranium ions were proposed as intermediates in acid-catalyzed sulfur-atom transfer from sultene 29 to cyclic olefins under thermal conditions (Scheme 45). A high degree of diastereospecificity was observed during the sulfur atom transfer reaction to /ra r-cyclooctene. S-Dealkylation is facilitated by the formation of a stablilized carbocation, which may further cyclize or rearrange <1998JA4861>. Similar sulfur-atom transfer to cyclooctyne afforded a relatively stable thiirenium salt that did not undergo S-dealkylation (Section 1.06.5.2) <2002JA8316>. 

FIGURE 3.29 Commercial strained cyclooctynes (dibenzylcyclooctyne (DBCO)-NHS, difluorinated cyclooctyne (DIFO) acid, bicyclenonyne (BCN) carbonate) for introduction into (bio)macromolecules. 

The mechanism of CO substitution with phosphines in the 19-e complex Cp Mn(CO)2NO is dissociative, followed by spontaneous oxidation of the product. Trinuclear clusters containing CpRe(CO)-fiagments in combination with iron carbonyl sulfido dimers have been reported. The synthesis of CpMn(CO)2(n -cyclooctyne) and the ligand rearrangement to an allene complex within the metal coordination sphere has been investigated by NMR spectroscopy. Tc labelled esters of cytectrene carboxylic acid have been prepared by exchange with ferrocenylcarboxylic acids in the presence of carbonyl donors. ... 

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)...

Looked upon as a Cu-free click reaction with no apparent toxicity issues, the SPAAC reaction would appear to have a rich future. Still, the CuAAC reaction has the advantage of synthetic convenience due to the fact that terminal alkynes can be installed in biomolecules using simple building blocks, suh as commercially available alkynoic acids, while, in contrast, the synthesis of di uorinated cyclooctyne (DIFO) requires 12 steps and the overall yield is only about 1%. Synthetically tractable cyclooctynes having the reactivities of DIFO are therefore much needed in order to expand the use of this Cu free cUck reaction as an ef cient and biocompatible tool (Codelli et al., 2008). 

Iridium dimer complexes catalyse the 3 + 2-cycloaddition reactions of organic azides with bromoalkynes to furnish 1,5-disubstituted 4-bromo-1,2,3-triazoles in excellent yields under mild conditions. Ruthenium(II)-azido complexes undergo 3 + 2-cycloaddition reactions with strained cyclooctynes under ambient temperatures. No reaction was observed with non-activated terminal or internal alkynes under the same conditions. Dithioic acid copper catalysts (60) catalyse the 3 + 2-cycloaddition reaction of azides with alkynes to form 1,4-disubstituted-1,2,3-triazoles in various solvents and under various temperatures. Thermal Huisgen 3 + 2-cycloaddition reactions of azides and bis(trimethylsilyl)acetylene formed 4,5-bis(trimethylsilyl)-l/f-l,2,3-triazoles in low to high yields (15-95%). The Cu(I)-catalysed 3 + 2-cycloaddition... 

When cyclooctyne is treated with dilute, aqueous sulfuric acid and HgS04, a new compound results. It is best represented as... 

Fig. 14 Multistep conjugation strategy Salmonella O-antigen was first reacted with adipic acid dihydrazide and successively functionalized with a strained cyclooctyne the final conjugation step was achieved by SPAAC with different azido-CRMigy. ...

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