Alkynes, activation cycloaddition

The platinum-catalysed intramolecular domino annulation reaction of o-alkynylben-zaldehydes has been described as a versatile approach to naphthalenes with annulated carbocycles or heterocycles of various sizes (Scheme 32).94 A plausible mechanism for the platinum(II)-catalysed annulation reaction shows that the double annulation process most probably proceeds through the benzopyrylium cation (117), which results from the nucleophilic attack of the carbonyl oxygen at the alkyne, activated by the Lewis-acidic platinum salt. A subsequent intramolecular Huisgen-type 3 + 2-cycloaddition of the second alkyne is assumed to generate intermediate (118). Rearrangement to (119) and the formal 4 + 2-cycloaddition product (118) leads to the aromatized final (116), liberating the active catalyst. In the case of FeCl3 as the Lewis acid, we assume that intermediate (118) is oxidatively transformed to (121). 

Recently, cyclopropane derivatives were produced by a ruthenium-catalyzed cyclopropanation of alkenes using propargylic carboxylates as precursors of vinylcarbenoids [51] (Eq. 38). The key intermediate of this reaction is a vinylcarbene complex generated by nucleophilic attack of the carboxylate to an internal carbon of alkyne activated by the ruthenium complex. Then, a [2+1] cycloaddition between alkenes and carbenoid species affords vinylcyclo-propanes. 

The Pauson-Khand Reaction and Silylformylation. Perhaps one of the earhest and most widely studied bimetallic alkyne activation processes is the Pauson-Khand Reaction (PKR), which involves the [2-1-2-1-1] cycloaddition of an alkyne, alkene and CO to yield a cyclopentenone product. The key intermediate in both the PKR and the related silylformylation reaction is a (p—r r )-bonded intermediate of structure E (Fig. 2). Extensive DFT modelling of the catalytic cycles has provided an excellent insight into the electronic changes that occur within the bimetallic unit during the reaction. 

Yamamoto reported the Cu(I)-catalyzed synthesis of 2,4-di- and 2,3,4-tri-substi-tuted pyrroles 317 (Scheme 8.111) [309]. Target products were obtained in modest to good yields via a 3 + 2 cycloaddition reaction between isonitriles 315 and activated alkynes 316. Steric congestion around the triple bond of 316 decreases the reaction efficiency. It was also demonstrated that alkynes activated with electron-withdrawing groups other than carbalkoxy were somewhat inefficient in this cascade transformation. However, much better compatibility of electron-withdrawing substituents on isocyanide 315 was observed. The reaction mechanism is outlined in Scheme 8.112. 

The gold-catalyzed formal cycloaddition reactions of 2-ethynylbenzyl ethers with 8-methylquinoline oxide and ethyl diazoacetate led to a skeletal rearrangement of the benzo[c]furan motif through an attack of the diazo compound on the initial oxonium species in the alkyne activation route, followed by a Roskamp-type rearrangement and ring closure (13AGE7559). 

Dendritic nanoreactor 1 was also employed as a recyclable micellar nanoreactor, stabilizer, and activator of Cu -catalyzed alkyne—azide cycloaddition click reaction, CuAAC reaction, in the presence of a very low amount (only 0.1%) of Cu (hexabenzyltren) Br (tren = triaminoethylantine) catalyst, 4, in aqueous media (Fig. 6.24) [60]. 

Catalyst-free Huisgen cycloadditions of alkynes activated by electron-withdrawing substituents have been reported to occur at room temperatures (Li et al., 2004) however, these compounds can undergo Michael reaction (see Section 14.2.2) with biological nucleophiles, thus effectively deleting the bioorthogonality of the system. 

Alkenes and alkynes undergo cycloaddition reactions with cyclobutadiene produced via decomposition of [Fe(CO)s(cyclobutadiene)]. Further studies on the oxidative decomposition of the optically active complexes (17) and (18) in the presence of dienophiles show that racemic adducts are formed. It would therefore appear that during the addition of the dienophile the iron is not sufficiently close to the cyclobutadiene to maintain the original chiral surroundings of the complex. ... 

The Raines group published an elegant paper on the replacement of an amide bond with a 1,5-substituted [l,2,3]-triazole 22 and incorporation of this dipeptide into bovine pancreatic ribonuclease (RNase A) by semisynthetic methods and showed that the melting temperature (T ) and catalytic activity of the resulting RNase A variants were retained. The triazolyl dipeptide was prepared by a Ru(ll)-catalyzed alkyne-azide cycloaddition which afforded 1,5-substituted triazoles, selectively (see Scheme 10.6). 

In recent years, activated esters have become increasingly important in polymer chemistry therefore, it is not surprising that they are also represented in the field of surface modification. In one example, Lin et al. used silica oxide-coated Fc304, where amine functionalities could be attached simply by adding 3-aminopropyltrimethoxysilane (Scheme 23) [44]. The amine was introduced by a disuccinimide, whereby one succinimide reacted with the surface-bonded amine and the other remained accessible for subsequent reaction with 3-azidopropane amine. As described before, the introduced azide could then be used for copper-catalyzed azide-alkyne Huisgen cycloaddition to obtain sugar-coated iron nanoparticles. 

Lu, Wang et al. developed an efficient preparation of dihydropyrimidin-4-ones from readily available AT-(prop-2-yn-l-yl)amides and sulfonyl azides using Cul as catalyst (Scheme 8.108). This cascade reaction includes copper-catalyzed alkyne-azide cycloaddition, formation and intramolecular nucleophilic addition of ketenimine, and subsequent rearrangement. The C(sp)-H bond was activated through copper-catalyzed alkyne-azide cycloaddition process in this reaction [182]. 

The behavior of strained,/Zuorimiret/ methylenecyelopropanes depends upon the position and level of fluorination [34], l-(Difluoromethylene)cyclopropane is much like tetrafluoroethylene in its preference for [2+2] cycloaddition (equation 37), but Its 2,2-difluoro isomer favors [4+2] cycloadditions (equation 38). Perfluoromethylenecyclopropane is an exceptionally reactive dienophile but does not undergo [2+2] cycloadditions, possibly because of stenc reasons [34, 45] Cycloadditions involving most possible combinations of simple fluoroalkenes and alkenes or alkynes have been tried [85], but kinetic activation enthalpies (A/f j for only the dimerizations of tetrafluoroethylene (22 6-23 5 kcal/mol), chlorotri-fluoroethylene (23 6 kcal/mol), and perfluoropropene (31.6 kcal/mol) and the cycloaddition between chlorotnfluoroethylene and perfluoropropene (25.5 kcal/mol) have been determined accurately [97, 98] Some cycloadditions involving more functionalized alkenes are listed in Table 5 [99. 100, 101, 102, 103]... 

The regio- and stereoselectivities of cycloadditions of trifluoroacetonitrile oxide, which is generated m situ by treatment of the tnfluoroacetohydroxamyl bromide etherate with tnethylamine in toluene (equation 31), have been determined in a senes of studies by Tanaka [55, 36, 37, 5 ]. The highly reactive nitnle oxide reacts regioselectively with a variety of activated terminal alkenes and alkynes (equations 32 and 33)... 

Recently, Burger devised an improved method of carrying out mild, regiospecific cyclizations that involve an intermediate that acts as a synthon for a nitrile ylide of HCN [47 (equation 48). With this methodology, cycloadditions with activated alkenes, alkynes, and azo compounds were earned out [47] (equation 49). All such reported reactions were regiospecific and had the same orientational preference... 

The strong o-donor property of NHC ligands enhances the catalytic activity in [3+2] cycloaddition by promoting the activation of internal alkynes (i.e. 26), which proceeds by the formation of a ti-alkyne complex 25 (Scheme 5.7). 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

The mechanism of [3 + 2] reductive cycloadditions clearly is more complex than other aldehyde/alkyne couplings since additional bonds are formed in the process. The catalytic reductive [3 + 2] cycloaddition process likely proceeds via the intermediacy of metallacycle 29, followed by enolate protonation to afford vinyl nickel species 30, alkenyl addition to the aldehyde to afford nickel alkoxide 31, and reduction of the Ni(II) alkoxide 31 back to the catalytically active Ni(0) species by Et3B (Scheme 23). In an intramolecular case, metallacycle 29 was isolated, fully characterized, and illustrated to undergo [3 + 2] reductive cycloaddition upon exposure to methanol [45]. Related pathways have recently been described involving cobalt-catalyzed reductive cyclo additions of enones and allenes [46], suggesting that this novel mechanism may be general for a variety of metals and substrate combinations. 

Interaction of a carbonyl group with an electrophilic metal carbene would be expected to lead to a carbonyl ylide. In fact, such compounds have been isolated in recent years 14) the strategy comprises intramolecular generation of a carbonyl ylide whose substituent pattern guarantees efficient stabilization of the dipolar electronic structure. The highly reactive 1,3-dipolar species are usually characterized by [3 + 2] cycloaddition to alkynes and activated alkenes. Furthermore, cycloaddition to ketones and aldehydes has been reported for l-methoxy-2-benzopyrylium-4-olate 286, which was generated by Cu(acac)2-catalyzed decomposition of o-methoxycarbonyl-m-diazoacetophenone 285 2681... 

Click chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various /weiido-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed... 

Bipyridinium ylides 133, generated in situ from 4,4-bipyridinium diquaternary salts 133, undergo 1,3-dipolar cycloaddition with activated alkynes under micro-waves, on KF-alumina in the absence of solvent, to give 7,7-bis-indolizines 134 in 81-93% yield (Scheme 9.40) [91]. The same reactions, when performed using benzene as a solvent under classical heating, yielded 7,7-bis-indolizine derivatives in yields of only 50-60% [92],... 

The cycloaddition-isomerization procedure can be accomplished in the presence of a catalytic amount of a transition metal salt. The reactions proceed at room temperature, neither air nor water needed to be excluded. The presence of an electron-withdrawing group is not necessary to activate the dienophile as the example below shows that gold coordination increases the electrophilicity of the triple bond. The presence of a terminal alkyne should also be important. In the case of a disubstituted alkyne no reaction can be observed <00JA11553>. 

A novel class of activators for chloride conductance in the cystic fibrosis transmembrane conductance regulator protein has been identified. These 3-(2-benzy-loxyphenyl)isoxazoles and 3-(2-benzyloxyphenyl)isoxazolines have been synthesized employing the 1,3-dipolar cycloaddition of nitrile oxides with various alkene and alkyne dipolarophiles (490). 

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