Cobalt-catalyzed -cycloaddition

A key intermediate, 163, which possesses all but one chiral center of (+ )-brefeldin, has been prepared by the enantiocontrolled cycloaddition of the chiral fi,/3-unsaturated ester 162 to 154[107], Synthesis of phyllocladane skeleton 165 has been carried out by the Pd-catalyzed cycloaddition of the unsaturated diester 164 and cobalt-catalyzed cycloaddition of alkynes as key reactions[108]. Intramolecular cycloaddition to the vinylsulfone in 166 proceeds smoothly to give a mixture of the trans and cis isomers in a ratio of 2.4 1[109], Diastereocontrolled cycloaddition of the hindered vinylsulfone 167 affords a single stereoisomeric adduct, 168, which is used for the synthesis of the spirocarbocyclic ring of ginkgolide[l 10],... 

The annelated pyridines QJ) and (M) are also obtained with cpCo(CO)2 as catalyst [77AG758, 77AG(E)708]. Using this variant of the cobalt-catalyzed cycloaddition, Schleich et al. opened up a new route to pyridox-ine (Vitamin 65) as its hydrochloride [Eq.(25)] (84HCA1274). 

Alkyl thiocyanates can also be used as the cyano component for the cobalt-catalyzed cycloaddition (80MI1) [Eq.(28)] (experimental details in 84MI8). 

The cobalt catalyzed cycloaddition reaction of diphenylcarbodiimide with disubstituted acetylenes 255 affords the isomeric 2-imino-l,2-dihydropyridines 256 and 251 ... 

Okamoto and coworkers reported a cobalt-catalyzed cycloaddition reaction of nitriles and a,cobalt chloride hexahydrate (C0CI2 6H2O)/ zinc-catalyzed [2 -I- 2 + 2] cycloaddition reaction from the corresponding substrates with excellent regioselectivity (Scheme 3.10). More specifically, symmetrical and unsymmetrical 1,6-diynes and 2-cyanopyridine reacted in the presence of 5 mol% of dppe, 5 mol% of... 

Cobalt-catalyzed cycloaddition reactions of symmetrical alkynes usually generate Cg-symmetric hexaphenylbenzenes (Pisula et al., 2004 Chebny et al., 2006). Synthesis of the star-shaped compound 14, which contains six ort/io-carborane clusters surrounding a hexaphenylbenzene core (Figure 26.3) was synthesized in a like manner. Heximer 14 was then decapitated in a methanolic sodium hydroxide solution to convert the neutral cZoio-carboranes into their corresponding [nido-C2B9H,o] cages, as shown for 15, imparting water solubility (Dash et al., 2009). 

Touge et al. [15], The cobalt-catalyzed cycloaddition was used to generate several functionalized dihydroaromatic intermediates such as 26 on a scale of up to 1 mol, and the oxidation of these intermediates was achieved by ruthenium(III) (Scheme 13.14). Thereby, the corresponding arene-ruthenium complexes 27 were obtained, which were further converted into ruthenium catalysts 28 for the asymmetric transfer-hydrogenation reaction of ketones. 

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. 

The reaction can be carried out intramolecularly to produce, in one step, three new rings in moderate yield (Equation (36)).149 It is noteworthy that up to six stereogenic centers could be formed. Additionally, cobalt-catalyzed [4 + 2 + 2]-cycloadditions of bicyclo[2.2.2]octadienes have been reported (Equations (37) and (38)).150... 

Cobalt, as its CpCo(CO)2 complex, has proven to be especially suited to catalyze [2 + 2 + 2] cycloadditions of two alkyne units with an alkyne or alkene. These cobalt-mediated [2 + 2 + 2] cycloaddition reactions have been studied in great detail by Vollhardt337. The generally accepted mechanism for these cobalt mediated cycloadditions, and similar transition metal mediated cycloadditions in general, has been depicted in equation 166. Consecutive co-ordination of two triple bonds to CpCo(CO)2 with concomitant extrusion of two molecules of carbon monoxide leads to intermediates 578 and 579 via monoalkyne complex 577. These react with another multiple bond to form intermediate 580. The conversion of 578 to 580 is said to be kinetically favored over that of 579 to 580. Because intermediates like 580 have never been isolated, it is still unclear whether the next step is a Diels-Alder reaction to form the final product or an insertion to form 581. The exact circumstances might determine which pathway is followed. 

The cobalt catalyzed cocyclization of alkynes with heterofunctional substrates is not limited to nitriles. cpCo-core complexes are capable of co-oligomerizing alkynes with a number of C,C, C,N or C,0 double bonds in a Diels-Alder-type reaction. Chen, in our laboratories, has observed that these cycloadditions are best performed with the help of stabilizers such as ketones or acetic esters that are weakly coordinated to the cobalt and prevent the alkynes from being cyclotrimerized at the metal center... 

Related co-cyclotrimerizations of two alkyne molecules with limited isocyanates have also been achieved using cobalt and nickel catalysts. With respect to intramolecular versions, two examples of the cobalt(I)-catalyzed cycloaddition of a,m-diynes with isocyanates have been reported to afford bicyclic pyri-dones only in low yields, although 2,3-dihydro-5(lff)-indolizinones were successfully obtained from isocyanatoalkynes and several silylalkynes with the same cobalt catalysis [19]. On the other hand, the ruthenium catalysis using Cp RuCl(cod) as a precatalyst effectively catalyzed the cycloaddition of 1,6-diynes 21 with 4 equiv. of isocyanates in refluxing 1,2-dichloroethane to afford bicyclic pyridones 25 in 58-93% yield (Eq. 12) [20]. In this case,both aryl and aliphatic isocyanates can be widely employed. 

Cobalt catalyzed double [2 + 2 + 1] cycloaddition reactions of branched triynes 169 have led to novel [5.5.5.6] tetracyclic dienone systems 172, instead of the expected [S.5.5.5] systems 173. These substrates underwent first... 

It is also worthy of note that the construction of tetracyclic compounds 44 by cobalt-catalyzed tandem Pauson-Khand/[2 + 2 + 2] cycloaddition reactions of 1,6-diynes 43 was also reported by Chung et al. [45,46]. It was experimentally shown that the [2 + 2 + 2] cycloaddition reaction occurs after the [2 + 2 + 1] cycloaddition between CO and the substrate (Scheme 22). 

Estrones. An A —> BCD approach to estrones involves a cobalt catalyzed intramolecular 2 + 2 -y 2] cycloaddition of the enediyne 1 to form the B, C. and D rings in one step. The high stereoselectivity suggests that the cyclization involves a Dicls-Alder-type reaction of the vinyl group with a cobaltacyclopentadiene formed by coupling of the two alkyne units. The homoannular diene obtained on demetalation is isomcrized easily to the diene 3. 

Review. Vollhardt6 has reviewed the use of cobalt-catalyzed [2 + 2 + 2] cycloadditions for synthesis of annelated benzenes, pyridines, and other heterocycles, as well as of complex natural products. 

A major initial limitation of the benzocyclobutene approach to o-quinodimethanes was the lack of efficient, large-scale syntheses for many specifically substituted derivatives. Fortunately, recent developments have lemov much of this impediment. Q>nceptually, the synthesis of benzocyclobutenes from aromatic precursors can be envisaged in only a limited number of ways. These include [2 -i- 2] cycloadditions involving benzynes and alkenes, intramolecular cyclization on to a benzyne, cyclizations involving arene anions, and electrocyclic closure of o-quinodimethanes. Benzocyclobutene derivatives can also be prepared by aromatization of bicyclo[4.2.0]octanes. Detailed discussion of variations to these approaches can be found in the cited reviews. The cobalt catalyzed co-oligomerization of 1,5-hexadiynes with al-kynes, especially bis(trimethylsilyl)acetylene, has also been employed for the preparation of specifically substituted benzocyclobutenes. In the latter case the cyclobutenes are often not isolated but converted directly to o-quinodimethanes and subsequent products. ... 

The cobalt-mediated cycloaddition of an alkyne, an alkene, and CO leading to a cyclopentenone has been known as the Pauson-Khand (PK) reaction [78], Due to its synthetic importance, numerous variants - especially catalytic reactions - have been developed to date [79]. The first ruthenium-catalyzed PK reaction of enynes has been achieved using Ru3(CO)i2 by two research groups independently (Scheme... 

This behaviour correponds to the observation that other unsaturated hydrocarbons, e.g. alkynes, allenes or 1,3-butadienes, which readily undergo transition metal catalyzed cyclooligomerizations, do also incorporate CX multiple bonds in such cycloadditions only with difficulty in most cases 207 208). Besides the well known cobalt-catalyzed pyridin synthesis from alkynes and nitriles98 cocyclooligomerizations have been achieved with alkynes on one side and isocyanates 209), carbodiimides210) and carbondioxide 211) on the other side as well as with 1,3-butadienes and aldehydes 212), carbondioxide213 and 2-aza- or 2,3-diaza- 1,3-butadiene214. ... 

Son et al. reported that the cobalt-catalyzed [2 + 2 + 1]-cycloaddition of the diyne 102 with CO, followed by Diels—Alder reaction of the resulting product with 2,3-dimethyl-1,3-butadiene, gave the tricyclic heterocycle 107 in a good yield (Scheme 37).115 The Pauson-Khand reaction of 69, followed by the [2 + 2 + 2]-cycloaddition of the resulting bi-cyclopentadienone with the cobaltacyclopentadiene... 

Moretto et al. reported the synthesis of the pyridine-containing macrocycles 411 and 412 by the cobalt-catalyzed hetero-[2 + 2 + 2]-cycloaddition of the diyne 409 with the nitrile 410 (Scheme 130).190c A high para-selectivity was obtained and 411 was produced as the major product. 

M 10. Krafft, M.E. Regiocontrol in the Intermolecular Cobalt-Catalyzed Olefin-Acetylene Cycloaddition J. Am. Chem. Soc. 1988,110, 968-970... 

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