Alkynes functionalization

A valuable feature of the Nin/Crn-mediated Nozaki-Takai-Hiyama-Kishi coupling of vinyl iodides and aldehydes is that the stereochemistry of the vinyl iodide partner is reflected in the allylic alcohol coupling product, at least when disubstituted or trans tri-substituted vinyl iodides are employed.68 It is, therefore, imperative that the trans vinyl iodide stereochemistry in 159 be rigorously defined. Of the various ways in which this objective could be achieved, a regioselective syn addition of the Zr-H bond of Schwartz s reagent (Cp2ZrHCl) to the alkyne function in 165, followed by exposure of the resulting vinylzirconium species to iodine, seemed to constitute a distinctly direct solution to this important problem. Alkyne 165 could conceivably be derived in short order from compound 166, the projected product of an asymmetric crotylboration of achiral aldehyde 168. 

The fact that pentacarbonyl carbene complexes react with enynes in a chemo-selective and regiospecific way at the alkyne functionality was successfully applied in the total synthesis of vitamins of the Kj and K2 series [58]. Oxidation of the intermediate tricarbonyl(dihydrovitamin K) chromium complexes with silver oxide afforded the desired naphthoquinone-based vitamin K compounds 65. Compared to customary strategies, the benzannulation reaction proved to be superior as it avoids conditions favouring (E)/(Z)-isomerisation within the allylic side chain. The basic representative vitamin K3 (menadione) 66 was synthesised in a straightforward manner from pentacarbonyl carbene complex 1 and propyne (Scheme 38). 

Hexacarbonyldicobalt complexes of alkynes have served as substrates in a variety of olefin metathesis reactions. There are several reasons for complex-ing an alkyne functionality prior to the metathesis step [ 125] (a) the alkyne may chelate the ruthenium center, leading to inhibition of the catalytically active species [125d] (b) the alkyne may participate in the metathesis reaction, giving undesired enyne metathesis products [125f] (c) the linear structure of the alkyne may prevent cyclization reactions due to steric reasons [125a-d] and (d) the hexacarbonylcobalt moiety can be used for further transformations [125c,f]. 

As predicted from the comparative rates for C=C over C=C hydrozirconation cited earlier, a (poly)enyne is selectively hydrozirconated at the alkyne moiety, whatever the position of the alkene function [138, 210] in the molecule. It can be exempUfied by the chemoselective hydrozirconation of 1,3-butenyne. One exception to this chemoselectivity has been reported, which showed the terminal alkene to react with 1 but leaving the TMS-substituted alkyne function intact (Scheme 8-25). 

The synthesized CPMV-alkyne 42 was subjected to the CuAAC reaction with 38. Due to the strong fluorescence of the cycloaddition product 43 as low as 0.5 nM, it could be detected without the interference of starting materials. TMV was initially subjected to an electrophilic substitution reaction at the ortho-position of the phenol ring of tyrosine-139 residues with diazonium salts to insert the alkyne functionality, giving derivative 44 [100]. The sequential CuAAC reaction was achieved with greatest efficiency yielding compound 45, and it was found that the TMV remained intact and stable throughout the reaction. 

Lactam antibiotics, such as cephalosporins, and penicillins, such as ampicillin (11) and aztreonam, covalently modify their protein targets. Alkyne-functionalized versions of these antibiotics, for example, AmpN (12), were used to probe various penicillin-binding proteins in vitro and in vivo using CC-ABPP [36,37],... 

Hiki S, Kataoka K (2010) Versatile and selective synthesis of click chemistry compatible heterobifunctional poly(ethylene glycol)s possessing azide and alkyne functionalities. Bioconjug Chem 21 248-254... 

In another application of coupling proteins to surfaces using click chemistry, Duckworth et al. (2006) carried out prenylation of a protein using a farnesyl azide derivative and the enzyme farnesyl transferase for subsequent chemoselective ligation to alkyne-functionalized agarose beads. The result is a highly discrete, site-specific attachment of the protein to the solid phase at a single location. 

The reaction of (TPP)Rh with terminal alkenes or alkynes is of special interest due to the cleavage of the carbon-carbon bond adjacent to either the alkene or the alkyne functionality and results in the ultimate formation of (TPP)Rh(R). This overall reaction implies activation of a relatively inert carbon-carbon bond, especially for the case of the terminal alkene. However, the ultimate formation of (P)Rh(R) is not surprising if one considers the relative stability of the rhodium carbon bond in this species(17). 

The single best piece of evidence for the intermediacy of vinylketene complexes is however the isolation and characterization by Wulff22 of amine-stabilized T74-vinylketenechromium(0) complexes (42) from the thermolysis of the chromium carbene complexes 43, containing a tethered alkyne functionality. This was the first time that a d6-rf-vinylketene complex of any group 6 metal had been isolated. 

However, a crucial difference was seen in analogous reactions with the (tert-butyl)alkynylcarbene complex 184.a, carried out under a pressure of carbon monoxide. A [4 + 2] cycloaddition takes place, but in this case the ene fragment is not the alkyne functionality, but the carbene-alkyne bond. The mechanism presented by Park implies that this is due to the preliminary... 

Diazonium salts are another useful source of free radicals, and the formation of the reactive species can be achieved by reductive electrolysis or direct treatment with diazonium tetrafluoroborate salts [39]. By this route, several aryl derivatives could be introduced onto the nanotube sidewalls [40]. Aryl groups bearing halogen or alkyne functionalities are particularly interesting as they can be further reacted in Pd-catalyzed coupling reactions (Suzuki, Heck) or in click chemistry reactions to create products with great potential in materials science [41]. 

Campidelli et al. have synthesized interesting linear and hyperbranched porphyrin polymers from CNTs via copper-catalyzed alkyne-azide cycloaddition (CuAAC) [122], Zinc porphyrin monomers containing an azide group and one or three alkyne groups were synthesized and chemically bound to alkyne functionalized SWCNTs via CuAAC. Depending upon the number of alkyne functionalities either linear (single alkyne) or dendrimer-like (triple alkyne) porphyrin polymers were produced (Fig. 5.9) [122],... 

Fig. 5.9 Covalent grafting of (a) linear polymer and (b) dendrimer-like hyperbranched polymer of azo-functional porphyrin groups from alkyne functionalized CNTs. Redrawn from [122].

Figure 16 (a) Structures of adenylation domain intermediates and inhibitors aminoacyl-sulfamoyl adenosine (AMS) and cisoid -like macrocyclic inhibitor, (b) Alkyne-functionalized chemical probe for NRPS A and PCP domains, (c) Structure of aminoacyl PCP, SNAC substrate analogue, and hydrolytically stable phosphopantetheinyl analogue, (d) Structure of vinylsulfonamide probe. R represents a peptide component and R an amino acid side chain. 

Finally, Lecomte and coworkers reported the synthesis of mikto-arm star-shaped aliphatic polyesters by implementing a strategy based on click chemistry (Fig. 36) [162]. Firstly, the polymerization of sCL was initiated by a diol bearing an alkyne function. The chain-ends were protected from any further undesired reaction by the esterification reaction with acetyl chloride. The alkyne was then reacted with 3-azidopropan-l-ol. The hydroxyl function located at the middle of the chain was then used to initiate the ROP of sCL and y-bromo-s-caprolactone. Finally, pendant bromides were reacted successfully with sodium azide and then with N, N-dimethylprop-2-yn-l-amine to obtain pendant amines. Under acidic conditions, pendant amines were protonated and the polymer turned out to exhibit amphiphilic properties. 

We also studied the catalytic cyclization of such epoxide/alkyne functionalities via the selective formation of ruthenium-2-iodovinylidene 77 or it-iodoalkyne 78 intermediate in suitable solvents [26]. The former was preferentially generated in DMF whereas the latter was the dominant species in benzene, as depicted in Scheme 6.27. 

The versatility of these [4+2] heterocyclization reactions is a consequence of the wide range of ene and diene components which can be used. In addition to alkenes and alkynes functioning as ene components, a variety of heterodienophiles is available such as electron-deficient imines (e.g. equation 89), nitriles e.g. equation 90), electrophilic carbonyl compounds (e.g. equation 91), thiocarbonyl compounds (e.g. equation 92), singlet oxygen (e.g. equation 93), nitroso compounds (e.g. equation 94), sulfenylsulfonamides (e.g. equation 95) and azo compounds (e.g. equation 96). Many of these reactions proceed with excellent regioselectivity and stereoselectivity, probably because in many instances they involve... 

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