A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes.

The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

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The growing impact of click chemistry on drug discovery.

The site-selective formation of carbon-carbon bonds through direct functionalizations of otherwise unreactive carbon-hydrogen bonds constitutes an economically attractive strategy for an overall streamlining of sustainable syntheses. In recent decades, intensive research efforts have led to the development of various reaction conditions for challenging C-H bond functionalizations, among which transition-metal-catalyzed transformations arguably constitute thus far the most valuable tool. For instance, the use of inter alia palladium, ruthenium, rhodium, copper, or iron complexes set the stage for chemo-, site-, diastereo-, and/or enantioselective C-H bond functionalizations. Key to success was generally a detailed mechanistic understanding of the elementary C-H bond metalation step, which depending on the nature of the metal fragment can proceed via several distinct reaction pathways. Traditionally, three different modes of action were primarily considered for CH bond metalations, namely, (i) oxidative addition with electronrich late transition metals, (ii) σ-bond metathesis with early transition metals, and (iii) electrophilic activation with electrondeficient late transition metals (Scheme 1). However, more recent mechanistic studies indicated the existence of a continuum of electrophilic, ambiphilic, and nucleophilic interactions. Within this continuum, detailed experimental and computational analysis provided strong evidence for novel C-H bond metalationmechanisms relying on the assistance of a bifunctional ligand bearing an additional Lewis-basic heteroatom, such as that found in (heteroatom-substituted) secondary phosphine oxides or most prominently carboxylates (Scheme 1, iv). This novel insight into the nature of stoichiometric metalations has served as stimulus for the development of novel transformations based on cocatalytic amounts of carboxylates, which significantly broadened the scope of C-H bond functionalizations in recent years, with most remarkable progress being made in palladiumor ruthenium-catalyzed direct arylations and direct alkylations. These carboxylate-assisted C-H bond transformations were mostly proposed to proceed via a mechanism in which metalation takes place via a concerted base-assisted deprotonation. To mechanistically differentiate these intramolecular metalations new acronyms have recently been introduced into the literature, such as CMD (concerted metalationdeprotonation), IES (internal electrophilic substitution), or AMLA (ambiphilic metal ligand activation), which describe related mechanisms and will be used below where appropriate. This review summarizes the development and scope of carboxylates as cocatalysts in transition-metal-catalyzed C-H functionalizations until autumn 2010. Moreover, experimental and computational studies on stoichiometric metalation reactions being of relevance to the mechanism of these catalytic processes are discussed as well. Mechanistically related C-H bond cleavage reactions with ruthenium or iridium complexes bearing monodentate ligands are, however, only covered with respect to their working mode, and transformations with stoichiometric amounts of simple acetate bases are solely included when their mechanism was suggested to proceed by acetate-assisted metalation.

Carboxylate-assisted transition-metal-catalyzed C-H bond functionalizations: mechanism and scope.

The study of biomolecules in their native environments is a challenging task because of the vast complexity of cellular systems. Technologies developed in the last few years for the selective modification of biological species in living systems have yielded new insights into cellular processes. Key to these new techniques are bioorthogonal chemical reactions, whose components must react rapidly and selectively with each other under physiological conditions in the presence of the plethora of functionality necessary to sustain life. Herein we describe the bioorthogonal chemical reactions developed to date and how they can be used to study biomolecules.

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Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality

The cycloaddition of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. Here a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides on solid-phase is reported. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddition producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the X-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides derived from Fmoc-amino alcohols were prepared by the Mitsunobu reaction.

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides.

A library consisting of about half of 800 000 possible peptidotriazoles on 450 000 beads was prepared by solid-phase peptide synthesis combined with a regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition between a resin-bound alkyne and a protected amino azide. The central [1,2,3]-triazole was flanked on each side by two randomized amino acids introduced in a combinatorial approach. Importantly, the formation of the triazole could be performed quantitatively in a randomized fashion. The library was screened on solid phase for inhibitory effect against a recombinant cysteine protease, Leishmania mexicana CPB2.8ΔCTE and sorted by a high-throughput instrument, COPAS beadsorter (up to 200 000 beads/h). Forty-eight hits were analyzed by MALDI-TOF MS providing structural information about the protease specificity, and 23 peptidotriazoles were resynthesized and evaluated in solution, with the best inhibitor displaying a Ki value of 76 nM. A one-pot procedure was used to convert Fmoc-amino azides into thei...

Combinatorial library of peptidotriazoles: identification of [1,2,3]-triazole inhibitors against a recombinant Leishmania mexicana cysteine protease.

The formation of aromatic carbon–heteroatom bonds has traditionally been achieved by nucleophilic aromatic substitution or by the copper-mediated Ullman reaction. The former type of chemistry is generally limited to activated substrates, whereas the latter often requires prolonged heating in the presence of excess copper salts. The palladium-catalyzed formation of aromatic C N bonds, extensively developed by the groups of Hartwig and Buchwald, has provided a powerful alternative. Whereas aryl amination has been optimized so that it is even applicable to aryl chlorides and activated phenols, the analogous formation of C O and C S bonds has attracted less attention. For a medicinal chemistry project, we have identified conditions that enable the formation of C S bonds from thiophenols and aryl iodides, and C N bonds from amines and aryl bromides using the same catalyst in a one-pot reaction. We now report the application of this discovery to the synthesis of the promazine class of antipsychotics. Our attention was drawn to the phenothiazine backbone of the promazine series 1a–e as a suitable model system for the controlled construction of three carbon–heteroatom bonds in a single synthetic operation (Scheme 1). This synthesis would require that either C S or C N bond formation occur initially with subsequent cyclization to the phenothiazine nucleus. This disconnection of the promazines leads to the precursors 2-bromothiophenol (2), primary amine 3, and an appropriately substituted 1-bromo-2-iodobenzene 4a–e. From reported literature and our experience with reactions involving dppf, binap, dpephos, and xantphos, the formation of the C S bond was expected to precede the amination steps. Indeed, clean formation of diaryl sulfide 6 was observed when a mixture of 2, 3, 4a, and NaOtBu was treated with [Pd2dba3] and dppf at 60 8C for 20 minutes, and 1a was formed in high yield after 2 hours at 160 8C under microwave (MW) irradiation. These conditions were mimicked in a ligand optimization study using oil-bath heating (Figure 1). Figure 1 summarizes results obtained with commercially available and easily handled ligands reported for C S and C N coupling reactions. Ferrocene ligands such as dppf gave mainly the desired product (1a) in addition to the noncyclized intermediate 7. Significant amounts of aniline 5 were observed with davephos, x-phos, and binap. Noncyclized promazine 7 was the major product with dpephos and xantphos. Trace amounts of the desired product were formed with PPh3, P(o-tol)3, P(tBu)3, [12,13] or the carbene ligand. Low conversion of 4a occurred with diaryl sulfide 6 as the only detectable product in the absence of palladium and ligand, whereas small amounts of 6 and bromobenzene were formed without the ligand. The reaction appears to proceed in a stepwise fashion from diaryl sulfide 6 (only product with one equivalent of NaOtBu), to aniline 7 (only product with two equivalents of NaOtBu), to 1a (74% yield; Table 1) under MW conditions. The three-component reaction worked well for the parent promazines 1a–e with yields of the isolated products ranging from 50% to 76%, and an average yield of greater than 75% for each of the three bonds formed (Table 1). The reaction with allyl amine gave a complex mixture of unidentified products. Benzyl amines were good substrates and the scope of the reaction was extended to include anilines; 2,6disubstituted anilines participated in the reaction, albeit with reduced yields as the steric hindrance around the nitrogen atom increased. Themicrowave method was relatively slow as the reagents had to be mixed immediately before starting the reactions to avoid catalyst deactivation. Conveniently, the reaction was performed with conventional heating, warming from room temperature to 160 8C over approximately 0.5 hours, with subsequent stirring at 160 8C overnight (reaction times have not been optimized). Scheme 1. Retrosynthetic analysis for the promazines.

Palladium-Catalyzed Three-Component Approach to Promazine with Formation of One Carbon–Sulfur and Two Carbon–Nitrogen Bonds

[1,2,3]-Triazoles are important pharmacophores in medicinal chemistry and it is therefore important to develop synthetic methods for triazoles that are both mild, high yielding and applicable to combinatorial synthesis. [1,2,3]-Triazoles are typically prepared by refluxing an alkyne and an azide in toluene (110 °C), but the 1,3-dipolar cycloaddition has also been performed at lower temperatures by using sodium acetylide [1], lithium and magnesium acetylide [2,3] with varying success. The present work describes the preparation of [1,2,3]-triazoles at 25 °C on solid-phase with high yields (80–95%), and is compatible with Fmoc chemistry.

Christian Wenzel Tornøe

Papers

Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides.

Cu-catalyzed azide-alkyne cycloaddition.

Combinatorial library of peptidotriazoles: identification of [1,2,3]-triazole inhibitors against a recombinant Leishmania mexicana cysteine protease.

Palladium-Catalyzed Three-Component Approach to Promazine with Formation of One Carbon–Sulfur and Two Carbon–Nitrogen Bonds

Peptidotriazoles: Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions on Solid-Phase