The Alkyne Cobalt Carbonyl Complexes

A large amount of the work on these complexes is inspired by the interest of this type of probe in assays and biological characterizations, and in particular on their appUcation in the carbonyl metallo immunoassay (CM I A), based on the 

A series of alkyne cobalt hexacarbonyl complexes was synthesized by Jung et al. [116] and Gust et al. [117-119], These include, for example, Co2(CO)g complexes derived from aspirin 40, from diphenyl acetylene 41 and from 2-propyn-l-ol 42. 

The antiproliferative effect of these compounds has been studied on various cell lines, including melanomas and lung cancers [116], leukemias and lymphomas [118], and also recently on hormone-dependent (MCF7) and hormone-independent (MDA-MB231) breast cancer cell lines [119]. The most active of these compounds is still the aspirin derivative 40 with IC5Q values between 1.4 and 10 pM. Its activity however remains lower than that of cisplatin, except in the case of breast cancer cells, which in any case are known not to respond optimally to cisplatin. The cytotoxic effect of these complexes does not appear to be linked to the accumulation of cobalt in the cells, nor to its bond to DNA. On the other hand, 40, the most effective compound, is a powerful cyclooxygenase (COX-1 and COX-2) inhibitor, which could explain its mode of action, although this has not yet been confirmed [119]. 

Doubtless these preliminary results will encourage complementary studies with this type of cobalt complex or with others in order to better elucidate and understand their behavior. 

Ferroquine, a New Weapon in the Fight T inst Malaria the Archetypical Bioorganometallic Approach 

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The alkyne-cobalt carbonyl complex 3 formed from the alkyne 1 and dicobalt octacarbonyl 2 should lose at least one of the GOs on the metal to provide the vacancy for the incoming olefins. Subsequently, an olefin-bound complex 5 rearranged oxidatively to yield a metallacyclic intermediate 6. Migratory insertion of GO of 6 would provide the homologated ring intermediate 7, and the following two successive reductive eliminations afford the cyclopentenone... 

Although the oxidative promoters have been quite effective, the reaction with less reactive olefins is still troublesome. Under the conditions with the oxidative promoter, the PKR is inevitably competing with the demetallation of the alkyne-cobalt carbonyl complex to give the metal-free alkynes. This competition is insignificant when the reactive olefins are employed, but it is prone to give more demetallated alkynes when the less reactive olefins are used (Scheme 3). This is reasoned by the fact that it is hard to expect from those promoters to oxidize only one of the COs on metal, and, in other words, the decarbonylation is not discriminative. As a result, the finding of the optimum condition is critical to favor the desired PKR product. 

Pauson-Khand cyclization of vic-enyne derivatives of /3-lactams gave good yields of fused tricyclic compounds. The 1,4-disubstituted 2-azetidinone 391 and cobalt octacarbonyl gave the alkyne-cobalt carbonyl complex, which on thermolysis gave the tricycle 392 in 95% yield (Equation 54). When the complexes of 393 with cobalt octacarbonyl were treated with TMANO, a lower yield (65%) of 394 was obtained (Equation 55). A single diastereoisomer was formed in each case <1996TL6901>. 

The cobalt(O) complex shown in Entry 2 (Table 3.49) could be prepared either by heating a mixture of an alkyne cobalt carbonyl complex with polystyrene-bound tri-phenylphosphine, or by pretreating resin-bound triphenylphosphine with dicobalt octacarbonyl and then treating the resulting support with the alkyne. 

In the steroid series, the alkyne cobalt carbonyl estrogen derivatives 19 and 20, substituted in position 17a and 11/3, have proved to be the most interesting. These complexes are both well recognized by ER alpha (RBA =12% and... 

Figure 10 Alkyne cobalt carbonyl complexes of the steroid RU 486 16, zearalenone 17, methotrexate 18, 17a-propynyl ethynylestradlol 19, 11/3-ethynylestradlol 20, aspirin 21, diphenyl aoetylene 22, and 2-propyn-1-ol 23.

Scheme 3.1 S Alkyne cobalt carbonyl complexes of the steroid RU 486 35, zearalenone 36, methotrexate 37.

The reaction using 11a as a substrate in the presence of several oxides as additives revealed that addition of tributylphosphine oxide, hexamethylphos-phoric triamide, and dimethyl sulfoxide all accelerate the reaction considerably. Furthermore, when about 10 molar amounts of N-methylmorpholine M-oxide (NMO) is added to the alkyne-cobalt complex 12b in THF,the reaction proceeds even at room temperature and cyclopentenone 13 b is obtained in 37% yield accompanied by another rearranged product, the methylenecyclobutanone 35, obtained in 23% yield as a mixture of ( )-and (Z)-isomers (Scheme 14). These facts indicate that dissociation of the carbonyl ligand of the alkyne-cobalt complex 12 is the rate-determining step in this rearrangement. This is also supported by the fact that under a CO atmosphere in refluxing THF the reaction is completely suppressed. 

Use of Co2(CO)8 in reactions involving 1,2-propadienes remains for the most part unexplored. It has been reported that terminal 1,2-propadienes react with Co2(CO)8 to form unidentified complexes, and that excess 1,2-propadiene is polymerized concurrently [30]. It has also been reported by Nakamura that a novel dimeric complex 54, in which a carbonyl ligand is connected to the central carbon of 1,2-propadiene, is produced by the reaction of 1,2-propadiene itself with Co2(CO)8 (Scheme 23) [31]. However, unlike the well-known chemistry of alkyne-Co2(CO)6 complexes, these 1,2-propadiene-cobalt carbonyl complexes have rarely been applied in synthetic reactions, probably due to their high activity in catalyzing the polymerization of 1,2-propadienes [32]. 

The third compound was made by a Pauson-Khand reaction using the same starting material = the first. The only difference between these two target molecules is the position of the double bor. In the Nazarov reaction, it goes into the thermodynamically most favourable position but in 1-Pauson-Khand reaction it goes where the alkyne was. So we simply react the cyclic ether wci acetylene cobalt carbonyl complex. The cis stereochemistry is inevitable. 

In chapter 6 we described the use of the remarkable Pauson-Khand reaction for the synthesis of cyclopentenones. If the components (CO, alkene and alkyne) are tethered by a nitrogen atom, a heterocycle will also be formed. The first stage in this process is to couple the cobalt carbonyl complex, e.g. 236, of ahalo-alkyne with an amine containing the alkene in the side chain. The best way to do this is to react 234 with Co2(CO)9 to give 235 and then 236 and to capture this complex with the amine without isolation of intermediates.34... 

Combination of three unsaturated compounds, i.e., alkyne, alkene, and CO provides a convenient means of catalytically synthesizing useful products such as cyclic unsaturated ketones in a one-pot process. On the basis of fundamental studies of the reactions of alkyne-coordinated cobalt carbonyl complex with olefins, a catalytic process to synthesize cyclic ketones has been developed (Eq. 1.20) [134],... 

The [CpFe(CO)2(K -2-pyrone)]+ complex behaved as a nonreleaser in the Mb assay but the Mo analog behaved as the a very rapid CO releaser, with tolerable cytotoxicity and a strong vasodilatory activity. However, the difference of CO release rates between both compounds remained unexplained [95]. The cobalt alkyne-bridged carbonyl complexes [1x2-(RC=CR )Co2(CO)6] are too lipophilic to enable extracting safe conclusions as to their real value as CORMs [96], and spurred the mechanistic studies conducted with several M(CO)5(amino ester) and Mo(CO)5(=CRR ) (examples in Fig. 41.3) in aqueous PBS solutions [97] and [M(CO)5X] (M = Cr, Mo, W X = Cl, Br, I) [98], which brought forward some specificities of the behavior of MCCs in water. 

A cobalt carbonyl complex can be available for the synthesis of pyridinophanes, 2-oxopyridinophanes and cyclophanes in the reaction of diynes with nitriles, isocyanates, alkynes, respectively. Meta/para selectivity was varied by the tether length of diynes and the substituents of alkynes. 

A new type of catalyst, a cobalt carbonyl complex, has been found for low-temperature (viz. 50 °C) homogeneous hydroformylation of alkenes. Nafion-H (a superacidic perfluorinated resin sulphonic acid) impregnated with mercury is recommended as a catalyst for the hydration of alkynes R C=CR (R = H or aryl, R = H, alkyl, or aryl) to form ketones R CH2C0R. Two mild methods for the hydrolysis of vinyl halides to ketones have been described one utilizes Bp3,Et20 and mercury(ii) acetate in acetic acid and the second mercury(ii) acetate in trifluoroacetic acid/ ... 

Several reports have appeared on the effect of additives on the Pauson-Khand reaction employing an alkyne-Co2(CO)6 complex. For example, addition of phosphine oxide improves the yields of cyclopentenones 119], while addition of dimethyl sulfoxide accelerates the reaction considerably [20]. Furthermore, it has been reported that the Pauson-Khand reaction proceeds even at room temperature when a tertiary amine M-oxide, such as trimethylamine M-oxide or N-methylmorpholine M-oxide, is added to the alkyne-Co2(CO)6 complex in the presence of alkenes [21]. These results suggest that in the Pauson-Khand reaction generation of coordinatively unsaturated cobalt species by the attack of oxides on the carbonyl ligand of the alkyne-Co2(CO)6 complex [22] is the key step. With this knowledge in mind, we examined further the effect of various other additives on the reaction to obtain information on the mechanism of this rearrangement. 

Strained cycloalkynes can be stabilized by coordination to one or more transition metal centers (198). The unusual vicinal defluorination reaction of perfluoro-l,3-cyclohexadiene with [Co2(CO)8] to give the /i-alkyne complex 45 (see Section III,E) prompted a study of the reactions of OFCOT with cobalt carbonyl precursors. 

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