Cocycloaddition reactions

The cyclotrimerization of alkynes to give benzene derivatives is perhaps the most general reaction of these compounds in the presence of transition metal complexes. Practically any mono- or di-substituted alkyne, in addition to acetylene itself, may be cyclotrimerized. In addition, cocycloadditions involving more than one different alkyne are possible with some degree of selectivity, and intramolecular versions of the reaction have seen sophisticated development. 

Chemoselective cocycloaddition of two molecules of a terminal alkyne together with one molecule of an internal alkyne into a benzene product is possible due to the relative unreactivity of phosphine nickel carbonyls towards simple trimerization of the internal alkyne itself (equation 28). ° " Careful control of reaction conditions has also permitted selective intermolecular cocycloaddition in the presence of cobalt catalysts as well for example, diphenylacetylene and 3-hexyne give rise to a 57% yield of 1,2,3,4-tetra-pheny 1-5,6-diethylbenzene. ... 

Without question, the metal-promoted cycloaddition of three alkynes to produce benzenes is the most extensively studied organometallic cycloaddition in intramolecular versions. Early work indicated the utility of Ni° systems e.g. Ni(CO)2(PPh3)2), Ziegler catalysts and rhodacyclopentadienes in the partially intramolecular cocycloaddition of a,b>-diynes with additional alkynes. Ziegler catalysts were noteworthy in giving rise to products containing the benzocyclobutene moiety from reactions of 1,5-hex-adiyne, while the Rh systems showed considerable utility in the preparation of anthraquinone derivatives from appropriate diyne precursors (Scheme 29). 

Intramolecular cycloaddition does not occur with a,(o-dinitriles each cyano group instead undergoes independent cocycloaddition with two molecules of alkyne to afford high yields of di(2-pyridyl)alkanes. The reaction may also be controlled to give high yields of 2-((o-cyanoalkyl)pyridines. ... 

For the palladium-catalyzed cyclotrimerization of arynes, a mechanism similar to the accepted mechanism for [2+2+2] cycloaddition of alkynes may be proposed (Scheme 15). Though it has not been studied in depth, some experimental results support it. Firstly, aryne-forming conditions are necessary for the reaction to proceed (see Table 1, entry 8) no reaction of trifiate 55 takes place at room temperature in the presence of the catalyst if fluoride is absent, which rules out a mechanism initiated by the oxidative addition of the aryl trifiate to palladium. Data obtained in the closely related cocycloadditions of benzyne with alkynes, discussed below, hkewise point to benzyne as the reactive species. Secondly, the benzyne-palladium complex 67 is a plausible initial intermediate because the ability of group 10 metals to coordinate benzyne is well known (see Sect. 1.2.2), and although benzyne complexes of palladium have eluded isolation (apparently because of their instability) [7,26], they may well be able to exist as transient intermediates in a catalytic cycle such as that shown in Scheme 15. Thirdly, it is known that benzyne complex 34 can form metallacy-cles similar to 68, albeit with dcpe as hgand instead of PPhj [26]. 

The same chemoselectivity is observed in the reaction of substituted arynes with DMAD [63]. The cocycloaddition of 4,5-difluorobenzyne (62), when promoted by Pd(PPh3)4, affords phenanthrene 105 as major product (64%), accompanied by minor amounts of naphthalene 106 (8%) and hexafluorotriphenylene (63, 8%). However, using Pd2(dba)3 the selectivity is inverted, naphthalene 106 being obtained in 54% yield and phenanthrene 105 in 9% yield (Scheme 23). 

Curiously, the mixture of regioisomers obtained in the reaction of the ben-zyne precursor 64 under these conditions (Scheme 29) is not the same as is obtained under the conditions mentioned above for cocycloadditions of DMAD (Scheme 26). This result, together with the participation of electron-rich alkynes and the requirement of higher reaction temperatures, suggests that the... 

Palladium catalysts have been used for cycloaddition of dimethylacetylene di-carboxylate (DMAD) to polycyclic arynes 3, 77 and 79 (Schemes 34-36). All these reactions exhibit the same reactivity pattern as is observed in the [2+2+2] cycloaddition of benzyne to DMAD (see Sect. 3.1) Pd2(dba)3 leads selectively to the cocycloaddition of one molecule of aryne and two molecules of DMAD, while Pd(PPh3)4 induces the reaction of two molecules of aryne with one molecule of DMAD. Both reactions afford the corresponding polycyclic aromatic hydrocarbons in good yields and with high chemoselectivity, constituting a novel and versatile method for the synthesis of functionalized PAHs under mild reaction conditions [70-72] (Scheme 34). 

This cocycloaddition is also effective in the reaction of two molecules of cyclohexyne (96) with electron-poor alkynes, which afford octahydrophenan-threnes 139a and 139b (Scheme 38). In this case, however, it was not possible to direct the reaction to the construction of the corresponding tetrahydron-aphthalenes,by using Pd2(dba)3 as catalyst, even when a large excess of alkyne was employed [72]. 

Several polyarenes obtained by palladium-catalyzed cocycloaddition of arynes and DMAD are conformationally stable chiral helicenes. For example, cocycloaddition of aryne 141 and DMAD affords a mixture of polyarenes from which helicene 142 can be isolated in yields up to 30%. Furthermore, this reaction proceeds with good enantioselectivity when performed in the presence of chiral bidentate ligands such as BINAP, which leads to an ee of 67% when the solvent is THF (Table 5, entry 2) [73]. 

Intramolecular or partially intramolecular cycloaddition reactions are extremely useful tools in the synthesis of polycyclic molecules, since they can allow the construction of several rings in a single step. Preliminary studies indicate that this general principle also holds for partially intramolecular versions of the palladium-catalyzed cocycloaddition of arynes and alkynes. For example, benzo[fc]fluorenones 144a-d, which constitute the polycyclic skeleton of the kinamycin family of antitumour antibiotics, can be obtained by [2+2+2] cy-... 

Arylnaphthalene skeletons (146) can also be synthesized by partially intramolecular palladium-catalyzed [2-t-2+2] cocycloaddition of arynes and diynes. Indeed, this reaction is the key step in an elegant convergent total synthesis of taiwanins C and E (Scheme 39) [75]. 

Another family that can participate in metal-catalyzed cocyclotrimerization with arynes are the terminal allenes (e.g. 162). This cocycloaddition is best catalyzed by Ni(0), and leads in the case of 162 to 9-cyclohexyl-10-methylene-9,10-dihydrophenanthrene (163). For monosubstituted allenes the reaction appears to be highly selective, since only the internal C-C double bond of the allene participates in the cocyclotrimerization. With disubstituted allenes, mixtures of the two possible regioisomers are obtained as the result of the participation of both C-C double bonds in the cycloaddition reaction [79,80] (Scheme 46). 

In this chapter we outline advances in the ruthenium-mediated alkyne [2 + 2 + 2] cycloaddition reactions. These can be classified into two major categories in terms of the types of products (1) syntheses of benzene derivatives via alkyne [2 + 2 + 2] cycloadditions and (2) syntheses of heteroaromatics via [2 + 2 + 2] cocycloadditions of alkynes with nitriles or heterocumulenes. Benzene ring-forming reactions are essentially prototypes of the corresponding heteroaromatic annulations. Therefore, the first class of reactions is reviewed in the next section and followed by a discussion of the second class of reactions. The mechanistic aspects and synthetic applications of ruthenium-catalyzed [2 + 2 + 2] cycloadditions are also described to exemplify the scientific and practical significance of ruthenium catalysis. 

---