Alkynes internal, 6 + 2-cycloaddition with

The bicyclo[4.2.1]nonatriene 323 was prepared by the [6+2] cycloaddition of internal alkyne with the complex 322 under irradiation [79]. Ligand exchange of 323 with toluene liberated 324. The complex 325 underwent the [6+2] cycloaddition with two moles of terminal alkyne to give the tetracyclic compound 327 via 326. The [6+2] cycloaddition of the complex 322 and 1,7-octadiyne (328) afforded 329 as a primary product, which was converted further to 330 in 56% yield by further intramolecular [6+2] cycloaddition [80]. The tropone complex 331 underwent intramolecular [6+2] cycloaddition under irradiation to give the strained tricyclic compound 332 in moderate yield [81]. 

The metallocene complex 27 containing a M=X double bond undergoes overall [2 + 2] cycloaddition with an internal alkynes to give heterometallacyclobutenes (28) [77], A formal [2 + 2] cycloaddition of CpjZr (=N Bu)(thf) with imine affords a 2,4-diazametallacyclobutane, whose further reaction with imines results in an imine metathesis reaction [78] azametallacyclobutene is an intermediate in the Cp2Zr(NHR)2-assisted hydroamination of alkynes and allene [79],... 

The scope of the Diels-Alder cycloaddition in synthesis planning is extended by the fact that both terminal and internal alkynes (RC=CH, RC=CR) enter into [4 - - 2] cycloadditions with dienes in the presence of Co(0) catalysts. These cycloadditions result in cyclohexa-1,4-dienes arising from a formal Diels-Alder reaction [33, 34]. Finally, numerous synthetic equivalents for ketene to be used in [4 + 2] cycloadditions have been developed in the context of prostaglandin sjmtheses. Thus, a broad range of possibilities for achieving these cycloadditions is now available [35, 36, 37] (Scheme 6.13). 

Ru3(CO)i2 coordinated with 2-(diphenylphosphino)benzonitrile catalysed the regioselective 2 + 2 + 2-cyclotrimerization of trifluoromethyl-substituted aryl alkynes in high yields and with a high regio-selectivity4 The alkyne 2 + 2 + 2-cyclotrimerization reaction has been applied to the synthesis of the central 4,5,6-tricyclic core (94) of 4,5,6-trinems (Scheme 30)4 The NbC /DMI-catalysed intermolecular 2 + 2 + 2-cycloadditions of terminal alkynes, internal alkynes, and alkenes produced 1,3,4,5-tetrasubstituted 1,3-cyclohexadienes in excellent yields and with high chemo- and regio-selectivities. ... 

Reaction with Internal Alkynes to Give 4, 5- Disubstituted AtProtected Triazoles. The cycloaddition of TSE-N3 (2) with internal alkynes is facilitated by both the Cu(I) and Ru(I) catalytic systems. Treatment of symmetrical alkynes 8, 9 with azide 2 using Cu(I) catalysis affords 4,5-disubstituted triazoles 10, 11 respectively, in good yields (eq 4). Similarly, Ru(I) catalyzed cycloaddition of symmetrical alkyne 12 provides triazole 13 in moderate yield (eq 5). ... 

Recently, the [64-2] cycloaddition of CHT with internal alkynes was described with rhodium catalysts (Scheme 8.37) [58]. The optimal catalytic system consisted of a combination of [Rh(cod)Cl]2, Cul, and PPh3. A mechanism involving rhodacycles similar to the one reported with cobalt complexes [55] was proposed and supported by density functional theory (DFT) calculations. 

Other computational studies involving NHC-Cu species considered the formation of phenylisocyanates from nitrobenzene, and the development of [3-1-2] cycloaddition reactions for the formation of 1,2,3-triazoles. In the latter case the use of NHCs allowed the direct use of copper(I) catalysts, whereas copper(II) precursors were predominant before. With [(NHQCuBrj the reaction could be run in water and was successful even for internal alkynes, an unusual observation as the intermediacy of Cu-acetylides had previously been assumed. Calculations showed that the [(SIMes)Cu] fragment was ideally set up to bind internal alkynes in an p -fashion and hence activate them towards cycloaddition. With terminal alkynes the acetylide route may still be operative. 

An internal diyne bearing methyl terminal moieties, which impair selfcycloaddition, was coupled with 3-hexyne using 6 at 60 °C to furnish fully substituted benzene 38 in 66% yield (Scheme 3.7) [14], Complex 6 also effectively catalyzed the [2 -I- 2 -I- 2] cycloaddition of l,2-bis(propiolyl)benzene 39 with both terminal and internal alkynes (Table 3.6) [39]. The diyne without terminal substituents underwent cycloaddition with 3-hexyne with a low yield of 33% (entry 9), while the corresponding reaction using the diyne with methyl terminal moieties led to an improved yield of 66% (entry 11). Notably, coupling of the same internal diyne with tolan delivered highly substituted naphthoquinone 40 in 90% yield under mild conditions (entry 12). 

Notably, use of the diyne 139 having a terminal ynamide and an internal alkyne moiety led in a related ruthenium-catalyzed [2 + 2 + 2] cycloaddition with... 

The same rhodium(I) complex could catalyze the atrop-selective completely inter-molecular [2 + 2 + 2] cycloaddition. Electron-rich internal alkynes 38, possessing the ortho-substituted phenyl group at the alkyne terminus, reacted with two molecules of... 

Ag-catalyzed in situ generation of azomethine ylides from alkynyl A-benzylidene glycinates 35 and their reaction with electron-deficient alkynes 36 were demonstrated by Su and Porco (Scheme 16.17) [26]. This reaction is supposed to be initiated by cycloisomerization of alkynyl imines 35 to isoquinolinium species A with the assistance of AgOTf. Subsequent proton transfer would afford azomethine ylides B with regeneration of Ag(I). 1,3-Dipolar cycloaddition with alkynes 36 followed by aerobic oxidation may furnish pyrroloisoquinoline products 37. It is worth noting that various types of electron-deficient alkynes, irrespective of internal and terminal alkynes, are applicable to this reaction. 

The use of ruthenium (CpRuCl(PPh3)2) or palladium salts (Pd(OAc)2/PPh3, PdCl2(dppf) and Pd(PPh3)4) to catalyze cycloadditions with internal alkynes has been recently compared. 

Other computational studies involving NHC-Cu species considered the formation of phenylisocyanates from nitrobenzene, and the development of [3+2] cycloaddition reactions for the formation of 1,2,3-triazoles. In the latter case the use of NHCs allowed the direct use of copper(i) catalysts, whereas copper(ii) precursors were predominant before. With [(NHC)CuBr] the reaction could be run on water and was successful even for internal alkynes, an unusual observation because the intermediacy of Cu-acetylides had previously been assumed. Calculations showed that the [(SIMes)Cu] fragment was ideally set up to bind internal alkynes in an i] -fashion and hence activate them towards cycloaddition. With terminal alkynes the acetylide route may still be operative. Other computational studies on the catalytic activity of [(NHC)Cu] complexes in which the NHC has no particular role but to stabilize the metal by strong o-donation and offer steric protection have been reported, including the activation of CO2 by [(NHC)Cu(EPh3)] (E = Si, Ge, Sn) and the carboxylation of the C-H bond of heteroarenes. The barriers of the two steps of the catalytic cycle of the [(NHC)Cu ]-catalyzed hydrosilylation of ketones have been computed, yet it was shown that the nature of the NHC was not a controlling factor. While the barrier of the hydrocupration step is determined by the nature of the ketone, that of the o-bond metathesis step occurs mainly under electronic control. 

Intermolecular Rhodium-Caialyzed [5+2] Cycloadditions In 1998, Wender et al. reported the first examples of intermolecular metal-catalyzed [5+2] cycloadditions of VCPs with alkynes [32]. While several catalysts have been proved to be efficient in promoting intramolecular [5+2] cycloadditions of VCPs and alkynes, the intermolecular [5+2] process has been Umited until recently to the use of [RhCl(CO)2]2 [33]. The initial study revealed that internal, terminal, electron-rich, and electron-poor alkynes all participated in the [5+2] cycloaddition with VCPs, giving... 

Complex 93 was tested in a variety of [5+2] cycloaddition reactions and compared, where relevant, with some other effective catalysts (Tab. 13.6). Excellent results were obtained with VCPs tethered to terminal and internal alkynes, alkynoates, and aUcenes. 

In an analogous late-stage arylation approach, terminal alkyne 31 was envisioned as a versatile intermediate. Slow addition of 4-pentynoyl chloride to imine 3 and (n-Bu)3N at reflux (efficient condenser, 100°C, 12 h, 1 1 toluene heptane) afforded only trace amounts of 31. Reaction of 4-pentynoyl chloride with triethylamine in methylene chloride under preformed ketene conditions ( 78°C, 1 h), followed by addition of 3 and warming to — 10°C over 4 h, afforded a complex mixture of products. Since high-yield preparation of 31 remained elusive, access to internal alkynyl analogs (type 33) was accomplished by preassembly of the appropriate arylalkynyl acid substrate for the ketene-imine cycloaddition reaction (Scheme 13.9). 

In constrast with intermolecular nitrone cycloadditions to alkynes and allenes, very little work has been done on the corresponding intramolecular cycloadditions. The bicyclic isoxazolidines (65a-b) were reported as products from reaction of an alkynone with methylhydroxylamine in ethanol.26b Presumably the initial strained bridgehead C—C double bond of the AMsoxazoline added ethanol under the reaction conditions. Cyclization of an allenyl ketone with methylhydroxylamine in ethanol solution also led to isoxazolidines (65a-b) as the major products and isoxazolidine (66) as a minor product.266 Thus, preferential cyclization to the internal C—-C double bond of the allene occurred followed by addition of ethanol to the exocyclic C—C double bond of the methyleneisoxazolidine intermediate. 

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