Azide Substrates Research Articles

Synthesis of glycoconjugate carbonic anhydrase inhibitors by ruthenium-catalysed azide-alkyne 1,3-dipolar cycloaddition

Carbonic anhydrase IX (CA IX) is a recently validated target for the development of new cancer therapies. In this Letter we describe the synthesis and CA inhibition of a novel series of carbohydrate-based 1,5-disubstituted-1,2,3-triazole benzenesulfonamides. The key step of our synthesis is the regioselective Huisgen's 1,3-dipolar cycloaddition reaction (1,3-DCR) from carbohydrate azide substrates and 4-ethynylbenzenesulfonamide using a ruthenium-catalysed azide-alkyne cycloaddition (RuAAC). Our findings identified a number of triazole inhibitors (compounds 18, 19, 21-23, and 26) that block CA IX activity with inhibition constants less than 10 nM. One inhibitor (compound 17) possessed very good selectivity for CA IX over off-target CAs. These CA inhibitors have developmental potential to selectively target cancer cells, leading to cell death.

Chelation-Assisted, Copper(II)-Acetate-Accelerated Azide−Alkyne Cycloaddition

We described in a previous communication a variant of the popular Cu(I)-catalyzed azide-alkyne cycloaddition (AAC) process where 5 mol % of Cu(OAc)(2) in the absence of any added reducing agent is sufficient to enable the reaction. 2-Picolylazide (1) and 2-azidomethylquinoline (2) were found to be by far the most reactive carbon azide substrates that convert to 1,2,3-triazoles in as short as a few minutes under the discovered conditions. We hypothesized that the abilities of 1 and 2 to chelate Cu(II) contribute significantly to the observed high reaction rates. The current work examines the effect of auxiliary ligands near the azido group other than pyridyl for Cu(II) on the efficiency of the Cu(OAc)(2)-accelerated AAC reaction. The carbon azides capable of binding to the catalytic copper center at the alkylated azido nitrogen in a chelatable fashion were indeed shown to be superior substrates under the reported conditions. The chelation between carbon azide 11 and Cu(II) was demonstrated in an X-ray single-crystal structure. In a limited set of examples, the ligand tris(benzyltriazolylmethyl)amine (TBTA), developed by Fokin et al. for assisting the original Cu(I)-catalyzed AAC reactions, also dramatically enhances the Cu(OAc)(2)-accelerated AAC reactions involving nonchelating azides. This observation leads to the hypothesis of an additional effect of chelating azides on the efficiencies of Cu(OAc)(2)-accelerated AAC reactions, which is to facilitate the rapid reduction of Cu(II) to highly catalytic Cu(I) species. Mechanistic studies on the AAC reactions with particular emphasis on the role of carbon azide/copper interactions will be conducted based on the observations reported in this work. Finally, the immediate utility of the product 1,2,3-triazole molecules derived from chelating azides as multidentate metal coordination ligands is demonstrated. The resulting triazolyl-containing ligands are expected to bind with transition metal ions via the N(2) nitrogen of the 1,2,3-triazolyl group to form nonplanar coordination rings. The Cu(II) complexes of bidentate T1 and tetradentate T6 and the Zn(II) complex of T6 were characterized by X-ray crystallography. The structure of [Cu(T1)(2)(H(2)O)(2)](ClO(4))(2) reveals the interesting synergistic effect of hydrogen bonding, π-π stacking interactions, and metal coordination in forming a one-dimensional supramolecular construct in the solid state. The tetradentate coordination mode of T6 may be incorporated into designs of new molecule sensors and organometallic catalysts.

Synthesis of Cyclophosphoramidates by Intramolecular C-H Amination

Reported is a synthesis of six- and seven-membered cyclophosphoramidates by ­cobalt(II)-catalyzed intramolecular C-H amination effected by phosphoryl azides. A previously ­reported method for intramolecular amination of carbonyl azides catalyzed by commercially available [Co(TPP)] (TPP: tetraphenylporphyrin) (J. V. Ruppel, R. M. Kamble, X. P. Zhang Org. Lett. 2007, 9, 4889) was found to be ineffective for phosphoryl azide substrates. The success of [Co(II)(Por)] A may be the result of hydrogen-bond interaction between P=O and NH which activates the catalysis.

A Click Approach to Structurally Diverse Conjugates Containing a Central Di‐1,2,3‐triazole Metal Chelate

The selective and efficient synthesis of novel tridentate metal chelating systems containing two 1,4-disubstituted 1,2,3-triazole heterocycles obtained via the copper(I)-catalyzed cycloaddition of alkynes and azides (click reaction) is described. The constructs are shown to be efficient ligand systems for the chelation of fac-[M(CO)(3)(H(2)O)(3)](+) (M=(99m)Tc, Re) yielding well- defined and stable complexes. The organometallic (99m)Tc conjugates are suitable for application as diagnostic radiotracers for single photon emission computed tomography (SPECT) as demonstrated in vivo with a fragment of the tumor-targeting bombesin peptide functionalized with a di-1,2,3-triazole chelator and radiolabeled with [(99m)Tc(CO)(3)](+). Starting from readily available dialkyne precursors, the central chelating systems are formed as the conjugates are assembled by click reaction with azide-functionalized entities. Depending on the nature of the azide substrates employed (e.g. lipophilic or hydrophilic residues) pharmacologically relevant characteristics of the final metal conjugate such as hydrophilicity or overall charge can be readily modulated. The procedures described also enable the facile introduction of other probes into the metal conjugate, providing access to potential multimodal imaging agents.

Allenyl Azide Cycloaddition Chemistry. Photochemical Initiation and CuI Mediation Leads to Improved Regioselectivity

Irradiation of 2-(3-alkenyl)allenylphenyl azides in the presence of excess CuI furnished functionalized 2,3-cyclopentenylindoles in good yield with only trace amounts of competitive C-N-bonded regioisomeric products. These results represent a significant departure from the modest-to-nonexistent regioselectivity that attended thermal cyclization of these allenyl azide substrates.

Copper-Catalyzed Three-Component Reaction to Imino-pyrrolines

An efficient and general 3-component synthesis of 5-arylidene-2-imino-3-pyrrolines via a copper-catalyzed [2+3] cycloaddition of sulfonyl azides 1 with alkynes 2 followed by a reaction of the resulting ketenimines with aziridines 3 is described. Experiments using deuterated aziridine support the suggested mechanism involving tri­azolyl copper species and ketenimine as intermediates. The starting aziridines are conveniently available from chalcones (Y.-M. Shen et al. Angew. Chem. Int. Ed. 2006, 45, 8005; A. Armstrong et al. Org. Lett. 2007, 9, 351). Best yields and highest selectivity were obtained using acetonitrile as solvent and aromatic sulfonyl azide substrates.

Allenyl Azide Cycloaddition Chemistry. Synthesis of Anellated Indoles from 2‐(Allenyl)phenyl Azide Substrates.

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Allenyl Azide Cycloaddition Chemistry. Synthesis of Annelated Indoles from 2-(Allenyl)phenyl Azide Substrates

[reaction: see text] Thermolysis of 2-(allenyl)phenyl azides leads to a cascade cyclization sequence furnishing both C(2)-C(3) and N-C(2) cyclopentannelated indoles.

Photochemical Transformations, 75. The Azo/Nitrene Route to cis,cis‐Trialkyltriaziridines, 21b) Photolysis of syn‐Azo Azides of Defined Proximity – Attempts for N3 → N3X Ring Enlargement

AbstractThe as yet unknown route to triaziridines by the addition of nitrenes to the π side of the NN bond is achieved intramolecularly by the photolysis (thermolysis) of syn‐azo azide substrates with high proximity; the yields reflect the sterical (and possibly inductive) influences of the skeleton. The product composition is rather independent of the exciting light; intramolecular azo → azide energy transfer is assumed. The kinetic skeleton stabilization of the triaziridines permits the synthesis of 17 (18) by the thermolysis of 7 (8) at 200°C with the product composition deviating only marginally from that of the photolysis. Attempts towards enlargement of the triaziridines to N3X rings (XCHR, O, NR) lead exclusively to products of intramolecular fragmentation.

The Azo/Nitrene Route to cis,cis‐Trialkyltriaziridines, 1 Synthesis of syn‐Azo Azides of Defined Proximity

AbstractBi‐ and polycyclic syn‐azo azide substrates H, 5, 14 and I, 15–18, 36, 41d, respectively, of varying rigidity and proximity (with the potential nitrene nitrogen atom in the π plane of the azo function) are prepared in order to synthesize kinetically stabilized cis,cis‐trialkyltriaziridines.