Cycloaddition of 1,6-enynes

Further research on this subject was recently reported, in relation to the use of dienynes as substrates for intramolecular cycloaddition. While thermal intramolecular [4+2] cycloadditions of enynes with alkenes only took place at high temperatures, the gold(I) catalyzed transformations provided bi- or tri-cyclic ring systems under mild conditions [152]. 

Arenes from enynes and diynes. A novel synthesis of alkynylarenes by the intermolecular cycloaddition of enynes and diynes has been developed. With enynes alone the products are 2,6-disubstituted styrenes which are formed by cyclodimerization. Note that benzynes undergo trimerization to give triphenylenes in situ, e.g., by treatment of o-trimethylsilylphenyl triflate with CsF in the presence of (PhjPl.Pd. ... 

Zero-valent, nickel-mediated intramolecular enyne metathesis is also an effective method for the synthesis of functionalized ring structures. Oxidative cycloaddition of enynes having an electron-withdrawing group on the alkenyl group generates nickelacyclopentene intermediates that... 

Cycloaddition. In recent years, [2+2+2] cycloadditions are no longer limited to the synthesis of benzene derivatives. Many cycloadditions of various carbon and heteroatoms component combinations have achieved great success. In 2005, Evans and co-workers developed an asymmetric [2-I-2-I-2] cycloaddition of enynes 9 with symmetrical and unsymmetrical alkynes 10 to give 5-6 fused products 11 and 12 in good yields and excellent ees (Scheme 5) (14). Under the optimized conditions, highly regio- and enantioselective products were obtained from the reaction of enynes with unsymmetrical alkynes. 

Shibata and co-workers independently developed similar [2-I-2-I-2] cycloaddition of enynes 13 (Scheme 6) and alkynes 14, affording cyclohexadienes 15 (15). The significance of this work is the construction of quaternary carbon stereocenters, which remain a very challenging task in organic synthesis (16). The authors... 

Burrell, R.C., Daoust, K.J., Bradley, A.Z., DiRico, K.J. and Johnson, R.P. (1996) Strained cyclic cumulene intermediates in Diels-Alder cycloadditions of enynes and diynes. Journal of the American Chemical Society, 118(17), 4218-4219. 

Nakao, Y., Hirata, Y., Ishihara, S. et al. (2004) Stannylative cycloaddition of enynes catalyzed by palladium-iminophosphine. Journal of the American Chemical Society, 126(48), 15650-15651. 

Asymmetric versions of these reactions have been carried out by Tanaka [49] and Shibata [50] by using rhodium complexes of modified BlNAPs (Fig. 10.37). TolBinap and Hg-Binap were found to be appropriate chiral ligands for the cycloadditions of enynes with oxygen, carbon or nitrogen tethers. In the case of nitrogen-tethered substrates, the substituent of the alkyne unit has a crucial effect... 

Nieto-Oberhuber, C., Perez-Galan, P., Herrero-Gomez, E., Lauterbach, T, Rodriguez, C., Lopez, S., Bour, C., Rosellon, A., Cardenas, D.J. and Echavarren, A.M. (2008) Gold(I)-Catalyzed Intramolecular [4+ 2] Cycloadditions of Arylalkynes or 1,3-Enynes with Alkenes Scope and Mechanism. Journal of the American Chemical Society, 130, 269-279. 

A Dotz benzannulation reaction was utilized in the synthesis of the furo[2,3- >]furan core of aflatoxin B2 as illustrated below <06TL2299>. Synthesis of polynuclear aromatic compounds was achieved by using [5+5] cycloaddition of 2-alkynylarylcarbene complexes and enyne-aldehyde derivatives <06TL5303>. 

Palladocyclopentadiene reagent promotes [2 + 2]-cycloaddition of suitably positioned enynes to form cyclobutenes which undergo symmetry allowed ring opening to form 1,3-dienes with a bridgehead double bond (equation 149)264. 

Based on his previous work on the catalytic double addition of diazo compounds to alkynes173 using Cp RuCl(COD),174 Dixneuf has developed an efficient one-step synthesis of alkenyl bicyclo[3.1.0]-hexane derivatives of type 163 from enyne precursors 162 (Scheme 43). The catalytic cycle starts with the formation of an Ru=CHR species. It then adds to an alkyne to form ruthenacyclobutene 166, which evolves into vinylcarbene 167. [2 + 2]-Cycloaddition of 167 gives ruthenacyclobutane 168. The novelty in this transformation is the subsequent reductive elimination to give 170 without leading to the formation of diene 169. This can be attributed to the steric hindrance of the CsMes-Ru group. 

It should also be mentioned that very recently, a new cycloisomerization of enynes has been shown to proceed via a rhodium-vinylidene complex,187 which, after [2 + 2]-cycloaddition and ring opening of a rhodacyclobutane, furnishes versatile cyclic dienes (Scheme 47).188 Not only does this constitute a fifth mechanistic pathway, but it also opens new opportunites for C-C bond constructions. 

Enyne metathesis is unique and interesting in synthetic organic chemistry. Since it is difficult to control intermolecular enyne metathesis, this reaction is used as intramolecular enyne metathesis. There are two types of enyne metathesis one is caused by [2+2] cycloaddition of a multiple bond and transition metal carbene complex, and the other is an oxidative cyclization reaction caused by low-valent transition metals. In these cases, the alkyli-dene part migrates from alkene to alkyne carbon. Thus, this reaction is called an alkylidene migration reaction or a skeletal reorganization reaction. Many cyclized products having a diene moiety were obtained using intramolecular enyne metathesis. Very recently, intermolecular enyne metathesis has been developed between alkyne and ethylene as novel diene synthesis. 

The reaction course is shown in Scheme 4. Enyne 12 reacts with 2 to give vinyl carbene complex 17, which is in a state of equilibrium with vinyl ketene complex 21. [2+2] Cycloaddition of the ketene moiety and alkene part in 21 gives cyclob-utanone 22. On the other hand, the vinyl carbene complex 17 reacts with the alkene intramolecularly to produce metalacyclobutane 18. From metalacyclob-utane 18, reductive elimination occurs to give cyclopropane derivative 23. Ret-... 

Cycloaddition.2 In combination with a triarylphosphine, 1 catalyzes the cyclization of a 1,6-enyne (2) to a 1,3-diene (3), and it effects [2+2+2] cycloaddition of 2 with an alkyne to give 4, which is isomeric with the product (5) of Diels-Alder addition of 3 with an alkyne. 

A formal synthesis of y-lycorane was accomplished by Vollhardt and colleagues by employing a [2 + 2 + 2] cycloaddition between enyne 589 and 568h (equation 169)344. The reaction afforded a mixture of syn and anti adducts 590 and 591 in a 80 20 ratio when the reaction was conducted at room temperature. When the reaction was conducted in refluxing 568h/THF (1 1, v/v), a syn anti ratio of 60 40 was obtained. A small amount of [2 + 2] adduct 592 was also isolated. This product became the dominant product when the enamide double bond was substituted. The additional steric hindrance probably prevented the enamide double bond from participating in the cycloaddition reaction. 

Closely related to the ring-closing metathesis of enynes (Section 3.2.5.6), catalyzed by non-heteroatom-substituted carbene complexes, is the reaction of stoichiometric amounts of Fischer-type carbene complexes with enynes [266,308 -315] (for catalytic reactions, see [316]). In this reaction [2 + 2] cycloaddition of the carbene complex and the alkyne followed by [2 -t- 2] cycloreversion leads to the intermediate formation of a non-heteroatom-substituted, electrophilic carbene complex. This intermediate, unlike the corresponding nucleophilic carbene... 

The reaction of enynes with Fischer-type carbene complexes can also lead to the formation of cyclobutanones (Figure 2.23) [315]. The mechanism for this reaction is likely to be rearrangement of the intermediate, non-heteroatom-substituted vinylcarbene complex to a vinylketene, which undergoes intramolecular [2 -i- 2] cycloaddition to form the observed cyclobutanones. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

The enantioselective variants of the corresponding [2+2+2] cycloaddition were already achieved by chiral Rh catalyst however, the coupling partners of enynes were limited to monoalkynes with functionality, such as ester or alcohol [18]. 

Hydrogenated derivatives of this system have been prepared from acyclic enyne precursors (Scheme 75) by ringclosing metathesis, followed by [4-1-2] cycloaddition of the resulting diene with diethyl azodicarboxylate <2003S2017>. 

SCS-MP2 and the new perturbative B2-PLYP density functional methods provide accurate reaction barriers and outperform MP2 and B3-LYP methods when applied to the 1,3-dipolar cycloaddition reactions of ethylene and acetylene.39 Phosphepine has been shown to catalyse the asymmetric 3 + 2-cycloaddition of allenes with a variety of enones (e.g. chalcones) to produce highly functionalized cyclopentenes with good enantiomeric excess.40 The AuPPh3SbF6 complex catalysed the intramolecular 3 + 2- cycloaddition of unactivated arenyne- (or enyne)-yne functionalities under ambient conditions.41 A review of the use of Rh(I)-catalysed 3 + 2-cycloadditions of diaryl-and arylalkyl-cyclopropenones and aryl-, heteroaryl-, and dialkyl-substituted alkynes to synthesise cyclopentadienones for use in the synthesis of natural products, polymers, dendrimers, and antigen-presenting scaffolds has been presented.42... 

Scheme 22)87 The intramolecular 4 + 2-cycloaddition of ynamides with conjugated enynes produces substituted indolines that can be oxidized to indoles with o-chloranil.88 The double Diels-Alder cycloaddition of the linear conjugated tetraene... 

When the double bond of the enyne possesses a cyclopropyl substituent, an intramolecular [5+2] cycloaddition of alkyne and vinylcyclopropane takes place [75, 76]. The ruthenacycle does not undergo /l-hydride elimination but a rearrangement of the cyclopropane to produce a ruthenacyclooctadiene. Thus, a variety of bicyclic and tricyclic cycloheptadienes were obtained in good yields [75] (Eq. 55). 

The term intramolecular enyne metathesis describes two types of processes. One involves a [2+2] cycloaddition of a multiple bond and a transition-metal carbene complex and the other is an oxidative cyclization catalyzed by low-valent transition-metal complexes, for example, Pt, Pd and Ru. The latter reaction is also called a skeletal reorganization. Both processes lead to similar products (Eq. 84). 

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