Substrates, Pauson-Khand

Simple acyclic olefins are rather poor Pauson-Khand substrates under thermal conditions. Ethylene reacts moderately well with terminal but less well with internal acetylenes [98,107]. Usable reaction rates require forcing conditions which, fortunately, can be optimized for catalytic use of the metal [Eq. (46)] [108]. Substituted olefins give very variable results, but reveal interesting regiochemical aspects of the process. Cycloaddition of vinylcyclohexane with phenylacetylene proceeds to a mixture of 4- and 5-cyclohexyl-2-phenyl-2-cyclopentenones in 45% overall yield. Regioselectivity is total with respect to the acetylene, as expected. However, insertion of the alkene proceeds with little regiochemical preference. Evidently, in going from... 

SCHEME 7.10 Synthesis of Pauson-Khand substrates from glycal template. 

The Pauson-Khand reaction was originally developed using strained cyclic alkenes, and gives good yields with such substrates. Alkenes with sterically demanding substituents and acyclic as well as unstrained cyclic alkenes often are less suitable substrates. An exception to this is ethylene, which reacts well. Acetylene as well as simple terminal alkynes and aryl acetylenes can be used as triple-bond component. 

Alkynylallenes have proved to be viable substrates for Pauson-Khand reactions (PKR), providing a-methylenecyclopentenones (Scheme 16.44) [44, 45]. It has been found that a combination of Mo(CO)6 and dimethyl sulfoxide (DMSO) is an effective catalytic system. The most commonly used Co2(CO)g catalyst for PKR is not effective since it causes polymerization. 

Allenyne represents an interesting substrate for the intramolecular Pauson-Khand(-type) reaction, where an allene moiety acts as an ene component. Here, there are two possible reaction pathways (Scheme 11.21) (i) the reaction of an external tr-bond of allene moiety gives a bicyclic dienone (type A) or (ii) the reaction of an internal 7i-bond gives a bicyclic cyclopentenone with an alkylidene substituent (type B). 

The [2+2+1] cycloaddition of an alkene, an alkyne and carbon monoxide is commonly known as the Pauson-Khand reaction. This transformation has been adopted many times in the synthesis of complex natural products and related compounds, which contain a cyclopentenone moiety, for example, prostaglandins. Two independent reports of this reaction appeared almost simultaneously in late 2002 by Iqbal and co-workers25 and Fisher and co-workers26, respectively. They not only used very similar substrate systems in their studies, but they also reached very similar conclusions Toluene was found to be the preferred solvent in this reaction, even though it is a very poor microwave absorber. A reaction time between 5 and 10 min, using dicob alto ctacar-bonyl or dicobalthexacarbonyl as the carbon monoxide source, and a temperature of 100-120°C resulted in high yields of the products. Fisher and co-workers used 20 mol% Co2(CO)8 and cyclohexylamine as an additive (Scheme 5.12), since this system had been used previously in order to allow a catalytic reaction. Iqbal and co-workers did not use cyclohexylamine, but instead used 1 equiv. of the carbon monoxide (Co2(CO)6) source. In both reports, the products were formed in 40-70% yield. 

Electron-deficient acetylenes, silylformylation, 11, 483 Electron-deficient substrates, Pauson—Khand reaction, 11,353 Electron-deficient unsaturated bonds boron conjugate additions, 9, 214 cycloadditions to, 9, 314... 

Parasites, antimicrobials for, 12, 458 Pauson-Khand reaction allenic substrates, 11, 352 and allenynes, 10, 356-357 with aminocarbonylation, 11, 531 asymmetric catalysts, in desymmetrizations, 11, 357 catalytic... 

The Pauson-Khand reaction, promoted by (CO)3Mo(DMF)3, has been found to take place under very mild conditions in the absence of any promoter. High yields of the adducts were obtained in the cyclization of a wide variety of functionalized 1,6- and 1,7-enynes. Enynes bearing electron-withdrawing groups at the alkene terminus proved to be particularly good substrates.121 The exclusive formation of cyclopentenones was observed in the molybdenum hexacarbonyl (10 mol%)-catalysed Pauson-Khand reactions of 1,6-allenynes under 1 atm of CO (balloon) in excellent yields.122... 

The formal [2 + 2+1] cycloaddition between an alkyne, an alkene and carbon monoxide has become commonly known as the Pauson-Khand (PK) reaction and has undergone extensive investigation since its initial discovery.4 7 Recent improvements in the reaction conditions and an increase in substrate scope has led to the reaction becoming an important method for the preparation of cyclopentenones. 

Increasing reactivity in the Pauson-Khand reaction. The PK reaction originally suffered from a lack of substrate scope and low reaction yields which prevented it from being widely employed. The discovery of new reaction conditions (additives and modified methods) led to an improvement in yields and reaction times, allowing the scope of the reaction to be expanded. 

The idea that alkenes possessing electron-withdrawing groups are not adequate substrates for Pauson-Khand reactions has in recent years turned out not to be precise. Carretero has reported several examples involving electron-deficient alkenes 3), such as os/Tunsaturalcd ketones, esters, nitriles, sulfoxides and sulfones. In these reactions they reach good yields of PK products (4) and isolate small amounts of dienes 5, that come from a /J-climinalion competitive reaction (Scheme 5) [26,27]. 

In terms of functional group compatibility, ethers, alcohols, tertiary amines, acetals, esters, amides and heterocycles are compatible with the Pauson-Khand reaction. In the intramolecular version, relatively few carbon skeletons undergo the cyclization. Most intramolecular PKRs use systems derived from hept-l-en-6-yne (6) or propargyl allyl ethers (7) or amines (8). Other interesting and more recent substrates are enynes connected through aromatic rings like 9-11, which have allowed us and other groups to obtain aromatic polycycles (Fig. 1) [28-31]. 

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). 

Scheme 7. A diastereoselective Pauson-Khand reaction using a chiral-modified substrate according to M. A. Pericas.

The Pauson-Khand reaction was studied in a similar manner [102], A single intermediate was observed for the [2 + 2 + 1] intramolecular cycloaddition which corresponded to the charged piperidinium substrate coordinated to a hexacarbonyl dicobalt complex (Fig. 26). This observation along with large positive enthalpy and entropy of activation values (calculated from PSI-MS data) supported the theory that CO dissociation is the rate limiting... 

Similarly, intramolecular Pauson-Khand reactions can be utilized for tetrahydrofuran synthesis, when the tethers are oxa substituted. Ligand effects on stereoselectivity in Rh(i)-catalyzed asymmetric Pauson-Khand-type reactions have been investigated and ee s of up to 92% have been achieved with the 2,2-bis(diphenyl-phosphanyl)-l,l-binaphthyl (BINAP) ligand and a Rh(i) precatalyst (Equation 91). However, it has to be noted that the ee is highly substrate dependent, and considerably lower in most other cases <2006S4053>. 

Initially, the Pauson-Khand reaction involved heating the substrate in a hydrocarbon solution at elevated temperatures and, as such, was not applicable to labile polyfunctional substrates. Later it was discovered that this cycloaddition could be greatly accelerated under the action of mild oxidants (morpholine... 

Dihydrofiirans have seen considerable use as substrates in the Pauson-Khand reaction. The parent compound reacts in excellent yield with acetylene, terminal and internal alkynes. Yields in this system respond very well to the use of catalytic reaction conditions (equation 4). Another unusual experimental modification has also been found by Pauson to be useful in this system addition of tri-n-butylphosphine oxide nearly doubles the product yield in certain cases (equation 37). The role of the added substance is unclear. Addition of phosphine oxide does not always improve reaction efficiency at this time there are no guidelines to indicate when its use might be beneficial. Substituted dihydrofurans give somewhat lower but still acceptable yields the poor regioselectivity in unsymmetrical cases is the more significant difficulty with these substrates (equation 38). 

In a novel combination of Pauson-Khand cycloaddition with vinylcyclopropane chemistry, de Meijere has described an entry to linearly fused triquinanes beginning with cyclopropylalkynes. Cyclopentenone formation has been carried out with a variety of substitution patterns on the cyclopropane, and moderate yields achieved with both norbomene and cyclopentene as substrates. Thermal vinylcyclopropane-cy-clopentene rearrangement of the cycloaddition products leads to the final tricyclic system (Scheme... 

Serratosa has critically evaluated the various entries to the triquinacene system available via Pauson-Khand chemistry, concluding that a route involving cycloaddition of the dibenzylated enyne substrate (Schemes 17 and 23) is operationally the simplest for preparation of multigram quantities of tricy-clo[5.2.1.0 °]decane-2,5,8-trione. This in turn is a key intermediate for the study of synthetic entries to dodecahedrane and its derivatives. An optically active version of this synthesis has l n developed as... 

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