Strain‐Promoted Azide–Alkyne Cycloaddition with Ruthenium(II)–Azido Complexes

Abstract

The reactivity of an exemplary ruthenium(II)-azido complex towards non-activated, electron-deficient, and towards strain-activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non-activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron-deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non-4-yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X-ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3-triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second-order rate constant for the ADIBO cycloaddition with the azido complex (k2=6.9 × 10(-2) M(-1) s(-1)) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k2=4.0 × 10(-1) M(-1) s(-1)). Our results demonstrate that it is possible to transfer the concept of strain-promoted azide-alkyne cycloaddition (SPAAC) from purely organic azides to metal-coordinated azido ligands. The favorable reaction kinetics for the ADIBO-azido-ligand cycloaddition and the well-proven bioorthogonality of strain-activated alkynes should pave the way for applications in living biological systems.

Au-iClick mirrors the mechanism of copper catalyzed azide–alkyne cycloaddition (CuAAC)

“…[2][3][4] Others [5][6][7] extended iClick to include the already prevalent [8][9] cycloaddition of an organic substrate to either a metal-azide or metal-acetylide. 7,[10][11][12][13][14][15][16][17][18][19][20][21] Important to this work, Gray et al 22 demonstrated that gold-acetylides and gold-azides will undergo cycloaddition to their organic counterparts. Despite the fact that several transition metals other than Cu(I) catalyze the azide-alkyne cycloaddition, including ruthenium, silver, and iridium, [23][24][25][26] it became apparent that not all metal-acetylide/azide species will participate in the iClick cycloaddition.…”

Organogold oligomers: exploiting iClick and aurophilic cluster formation to prepare solution stable Au4 repeating units

“…6 Critical in the pursuit of building complexity is the precise control of bond forming events and is particularly exemplified by the Cu I catalyzed azide-alkyne cycloaddition reaction (CuAAC). Others [11][12][13] have broadened the iClick concept to include the cycloaddition of organic substrates to either a metal-azide or metal-acetylide (M; Scheme 1), which are already rather prevalent reactions, [13][14][15][16][17][18][19][20][21][22][23][24][25] and the subject of reviews. The metal-azide/metal-acetylide cycloaddition (M-M′) was given the term inorganic click (iClick) as a distinguishing feature that calls attention to chemistry occurring within the coordination sphere of a metal ion.…”

Strain‐Promoted Reaction of 1,2,4‐Triazines with Bicyclononynes

“…We generated benzoyl-protected bicyclononyne 19 (Scheme 3ii) by adaptation of the synthetic route of Dommerholt et al; [33] following rhodium-catalysed cyclopropanation of 1,5-cyclooctadiene to yield am ixture of the anti-and syn-bicyclononene ethyl esters 17 and 17 b, anti-bicyclononene ethyl ester 17 was converted to bicyclononylol 18 (Scheme 3ii) by sequential reduction, dibrominationa nd double elimination, followed by protection using benzoyl chloridetogive alkyne 19. [34] We initially assessed the reaction of the protected bicyclononyne 19 with 12 at high concentration (65 mm in dichloromethane). Incubation of an equimolar mixture of the two reaction components yieldeda1 :1 mixture of the bicyclononapyr-idyl derivatives 20 a and b in 38 %y ield after 12 ha t3 78Ct ogetherw ith unreactedt riazine 12 (Scheme 3iii).…”