Pauson-Khand conditions

Two remarkable intramolecular reorganizations of the Diels-Alder adducts of methyl 2-chloro-2-cyclopropylideneacetate (1-Me) onto furans should be mentioned here. In a reaction of 1-Me with 2,5-bis(trimethylsilyl)furan (263) the unstable adduct 264 underwent a spontaneous deprotection followed by ring opening to give the dioxospiro[2.5]octene derivative 265 (Scheme 76) [7 m]. The Pauson-Khand reaction of the transformed Diels-Alder adducts 70, 71 of 1-Me have been discussed above (Scheme 18), however, when the compounds endo,-exo-62 e were treated under Pauson-Khand conditions, but at higher temperature, the interesting Co2(CO)8-promoted stereoselective rearrangement, in the presence as well as in the absence of an alkyne component, has been observed. The cis- and frans-substituted 6-methylenespiro[2.4]hexanes 266 were isolated as main products in these reactions (Scheme 76) [19b]. 

We next addressed the introduction of the I -hydroxyethyl group as an acetyl precursor at the triple bond terminus of the 2-oxazolone derivative. Treatment of 94 with acetaldehyde in the presence of NaHMDS afforded 99 in 83% yield as a mixture of two diastereoisomers, which were exposed to Co2(CO)s under the Pauson-Khand conditions to produce the corresponding tricyclic compound 100 in 51% yield (Scheme 23). 

An interesting family of polycyclic pyrroles was described in 2005 using again the synthetic sequence of a Stetter reaction for the preparation of the starting 1,4 diketones followed by a microwave-assisted Paal-Knorr condensation [35]. For example, cyclopentenone 23 (obtained in a Pauson-Khand cyclization) reacted imder Stetter reaction conditions to give the amino ketone 25 (Scheme 8). The microwave-assisted Paal-Knorr cyclization of 25 with different amines gave a small collection of tricychc pyrrole 2-carbox-amides. 

The intermolecular Pauson-Khand reaction of the resulting S/P-cobalt complexes with norbornadiene was studied under thermal and A -oxide activation conditions. Thus, heating the diastereomerically pure complex (R = Ph, R = Cy) with ten equivalents of norbornadiene at 50 °C in toluene afforded the corresponding exo-cyclopentenone in a quantitative yield and with an enantio-selectivity of 99% ee. Under similar conditions, the analogous trimethylsilyl complex (R = TMS, R = Cy) afforded the expected product in a high yield but with a lower enantioselectivity of 57% ee. In order to increase this enantio-selectivity, these authors performed this reaction at room temperature in dichloromethane as the solvent and in the presence of NMO, which allowed an enantioselectivity of 97% ee to be reached. These authors assumed that the thermal activation promoted the isomerisation of the S/P ligand leading to a nonstereoselective process. 

Under the conditions of the cobalt-mediated carbonylative A-oxide-promoted cocyclization (Pauson-Khand reaction) at room temperature, compound 547 provides exocyclic 1,3-diene 548 as the major product (>98%) together with only traces of the corresponding carbonylative product 549. Owing to the relative instability of the diene, it is more efficient to perform a one-pot cobalt cyclization/Diels-Alder process after A-oxide-promoted cyclization of the cobalt complexes. Compound 550 is obtained as a single diastereomer in 39% overall yield if MTAD is used as a dienophile (Scheme 90) <2003JOC2975>. 

The [2+2+1] cycloaddition of an alkene, an alkyne, and carbon monoxide is known as the Pauson-Khand reaction and is often the method of choice for the preparation of complex cyclopentenones [155]. Groth and coworkers have demonstrated that Pauson-Khand reactions can be carried out very efficiently under microwave heating conditions (Scheme 6.75 a) [156]. Taking advantage of sealed-vessel technology, 20 mol% of dicobalt octacarbonyl was found to be sufficient to drive all of the studied Pauson-Khand reactions to completion, without the need for additional carbon monoxide. The carefully optimized reaction conditions utilized 1.2 equivalents of... 

Currently, these reactions are typically conducted with Rh(l) or Ir catalysts. The Pauson-Khand-type reaction of allenynes has also witnessed important developments, especially in its applications to natural products synthesis.388 Brummond s group has been very productive in both areas. Duality in the reaction of allenynes is shown below. In the context of diversity-oriented synthesis, simply changing the reaction conditions gives versatile heterocycles in high yields (Scheme 116).389... 

Abstract The transition metal mediated conversion of alkynes, alkenes, and carbon monoxide in a formal [2 + 2+1] cycloaddition process, commonly known as the Pauson-Khand reaction (PKR), is an elegant method for the construction of cyclopentenone scaffolds. During the last decade, significant improvements have been achieved in this area. For instance, catalytic PKR variants are nowadays possible with different metal sources. In addition, new asymmetric approaches were established and the reaction has been applied as a key step in various total syntheses. Recent work has also focused on the development of CO-free conditions, incorporating transfer carbonylation reactions. This review attempts to cover the most important developments in this area. 

Hetero Pauson-Khand reactions with an aldehyde or ketone component have been shown to afford synthetically versatile y-butyrolactones. Buchwald [50] and Crowe [51] independently showed that aliphatic enones and enals react with CO under Cp2Ti(PMe3)2 mediation (Scheme 11). CO insertion and thermal (or oxidative) decomposition gave diastereomerically pure bicyclic y-butyrolactones and stable Cp2Ti(CO)2. Imines did not react under the reaction conditions. 

Co complexes, Buchwald reported the Ti-catalyzed carbonylative coupling of enynes-the so-called Pauson-Khand-type reaction [28]-and realized the first such catalytic and enantioselective reaction using a chiral Ti complex [29]. Here, a variety of enynes were transformed into bicyclic cyclopentenones with good to high ee-values however, several steps were required to prepare the chiral Ti catalyst, while the low-valent complex proved to be so unstable that it had to be treated under oxygen-free conditions in a glove box. 

In sharp contrast to the unique pattern for the incorporation of carbon monoxide into the 1,6-diyne 63, aldehyde 77 was obtained as the sole product in the rhodium-catalyzed reaction of 1,6-enyne 76 with a molar equivalent of Me2PhSiH under CO (Scheme 6.15, mode 1) [22]. This result can be explained by the stepwise insertion of the acetylenic and vinylic moieties into the Rh-Si bond, the formyl group being generated by the reductive elimination to afford 77. The fact that a formyl group can be introduced to the ole-finic moiety of 76 under mild conditions should be stressed, since enoxysilanes are isolated in the rhodium-catalyzed silylformylation of simple alkenes under forcing conditions. The 1,6-enyne 76 is used as a typical model for Pauson-Khand reactions (Scheme 6.15, mode 2) [23], whereas formation of the corresponding product was completely suppressed in the presence of a hydrosilane. The selective formation of 79 in the absence of CO (Scheme 6.15, mode 3) supports the stepwise insertion of the acetylenic and olefmic moieties in the same molecules into the Rh-Si bond. 

When this reaction is carried out under 1 atm of nitrogen or GO atmosphere, a cyclopentane 276 is formed selectively in a minute at 25 °G (Scheme 13, mode 2). Although the Pauson-Khand reaction of 1,6-enyne 273 (Scheme 13, mode 3) gives 21H, this transformation is completely suppressed under the conditions of mode 1. Even simple alkyne silylformylation product 277 is not detected at all. This contrasts sharply to the silylformylation of l-penten-4-yne 48 carried out under similar conditions (Equation (12)). These results can be explained by a pathway similar to the reaction of 1,6-diynes (i) stepwise insertion of the acetylenic and olefmic moieties into the Rh-Si bond in this order, and (ii) subsequent interaction of GO and Mc2PhSiH with the resultant intermediate to give 275. The... 

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... 

Among the carbonylative cycloaddition reactions, the Pauson-Khand (P-K) reaction, in which an alkyne, an alkene, and carbon monoxide are condensed in a formal [2+2+1] cycloaddition to form cyclopentenones, has attracted considerable attention [3]. Significant progress in this reaction has been made in this decade. In the past, a stoichiometric amount of Co2(CO)8 was used as the source of CO. Various additive promoters, such as amines, amine N-oxides, phosphanes, ethers, and sulfides, have been developed thus far for a stoichiometric P-K reaction to proceed under milder reaction conditions. Other transition-metal carbonyl complexes, such as Fe(CO)4(acetone), W(CO)5(tetrahydrofuran), W(CO)5F, Cp2Mo2(CO)4, where Cp is cyclopentadienyl, and Mo(CO)6, are also used as the source of CO in place of Co2(CO)8. There has been significant interest in developing catalytic variants of the P-K reaction. Rautenstrauch et al. [4] reported the first catalytic P-K reaction in which alkenes are limited to reactive alkenes, such as ethylene and norbornene. Since 1994 when Jeong et al. [5] reported the first catalytic intramolecular P-K reaction, most attention has been focused on the modification of the cobalt catalytic system [3]. Recently, other transition-metal complexes, such as Ti [6], Rh [7], and Ir complexes [8], have been found to be active for intramolecular P-K reactions. 

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. 

There is only one example of a catalytic Pauson-Khand reaction in an ionic liquid1471 although the reaction has also been conducted in ionic liquids using stoichiometric amounts of Co2(CO)8/481 In the catalysed reaction 10 mol% of Co2(CO)8 was used in [C4Ciim][PF6] under 10 bar of CO. Under these conditions, diethylallyl malonates could be obtained in 90-99% yield within 90 minutes at 80°C, as shown in Scheme 9.14. However, with hetero-bridged enynes, as well as in the reaction between norbomene and phenylacetylene, only poor to moderate yields were achieved. A slight increase in activity was observed with the analogous tetrafluoroborate ionic liquid. 

Their retro synthetic study was based around the Pauson-Khand cyclization (6), which couples an alkene, an alkyne, and a carbon monoxide source (typically dicobalt octacarbonyl) to give a cyclopentenone ring (Fig. 3.5, top). This reaction has been widely used for synthetic purposes, and some excellent reviews (7,8) have covered its principal features and the recent improvements to its experimental conditions. This reaction, in its intramolecular version, is ideal for the assembly of the l//-[2]pyrindi-none scaffold in two distinct versions, differing in the stereochemistry of the ring junction (Fig. 3.5, bottom). Hence, the readily available unsaturated amino acid derivatives 3.1a,b undergo intramolecular Pauson-Khand reaction to produce the two unsamrated scaffolds 3.2a,b. 

Scheme 2. Phenylselenyl groups are stable to many classical reaction conditions (organo-lithium, etherification, Pauson-Khand reaction)...

Application of the Pauson-Khand reaction to simple acylic alkenes has been limited by both low reactivity and lack of regiocontrol in incorporation of the alkene. Among simple alkenes, ethylene provides the most consistently useful results. Yields with terminal alkynes range from 30-60% (equations 9,15 and 16) internal alkynes have also been used with some success (equation 10). Forcing conditions (toluene, 130-160 C, 6()-80 atm, autoclave) are usually required for best results, although it has been recently demonstrated that the reaction proceeds, albeit slowly, at reduced pressures and temperatures (equation 17). ... 

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). 

Rhodium, " titanium,and tungsten " complexes have also been used for this reaction. The reaction can be promoted photochemically and the rate is enhanced by the presence of primary amines.Coordinating ligands also accelerate the reaction,polymer-supported promoters have been developed " and there are many possible variations in reaction conditions.The Pauson-Khand reaction has been done under heterogeneous reaction conditions, and with... 

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