Stoichiometric reactions Pauson-Khand reaction

Another approach to the stoichiometric enantioselective Pauson-Khand reaction involves the use of chiral auxiliaries. Extensive investigations on this subject have been carried out by Periods, Moyano, Greene, and coworkers. Initial reports detailed the use of frans-2-phenylcyclohexanol as a chiral auxiliary for the... 

Development and Variations in Stoichiometric Pauson-Khand Reactions... 

Development and Variations in Stoichiometric Pauson-Khand Reactions 11.10.2.1 Problems in Association with the Proposed Mechanism... 

Development of the catalytic Pauson-Khand reaction. One disadvantage of the PK reaction, as first reported, was its need for stoichiometric amounts of dicobalt octacarbonyl. In order to make the reaction more attractive, both synthetically and environmentally, efforts were made to reduce the quantities of the transition metal species, although this often led to the requirement for high pressures of CO in order to obtain respectable yields. 

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. 

Only catalytic Pauson-Khand reactions fulfill the criterion of atom economy [6], and the use of stoichiometrical amounts of the transition metal is not acceptable commercially. It is not surprising, therefore, that several research groups have focused more recently on the development of catalytic variants. 

Scheme 2. Stoichiometric Pauson-Khand reactions according to T. Sugihara. a) 3.5 equiv. cyclohexylamine, 1,2-dichloromethane, 83°C b) 1,4-dioxan/2N NHj(aq) (1 3), lOO C.

Although a whole series of carbonyl complexes of other transition metals (Fe, Mo, W, Ni) could only be used in stoichiometric Pauson-Khand reactions [11], two Japanese laboratories have since independently reported efficient ruthenium-catalyzed (intramolecular) reactions. The desired cy-clopentenones are formed in good to excellent yields in dimethylacetamide [12] or dioxane [13] in the presence of 2 mol% of [Ru3(CO),2] at 140-160 °C and 10-13 atm CO pressure. 

Pauson and Khand discovered the very important class of alkyne/alkene/CO cyclization catalytic reactions catalyzed, once again, by Co2(CO)g see Pauson-Khand Reaction). This reaction produces a, /3-unsaturated cyclopentanones (equation 23). With unstrained alkenes the reaction works best in a stoichiometric setting, but with strained alkenes like norbomadiene the reaction can be made catalytic. These reactions have been fairly extensively studied, and the reaction proceeds through an alkyne-bridged Co2(CO)6 dimer species. Unsymmetrical alkynes lead to mixtures of the various substituted a, /3-unsaturated cyclopentanone products. 

The Pauson-Khand reaction is a well-known method for preparing cydopente-nones by the [2 + 2 + 1] cycloaddition reaction of alkyne, alkene and CO. While reactions using stoichiometric amounts of Co2(CO)g were initially examined, catalytic versions with cobalt, titanium, rhodium, iridium, and ruthenium complexes have recently been developed. Whilst the intramolecular version is rather easy, the inter-molecular version is a very difficult problem that has not yet been solved [76]. 

Enantioselectivities up to 44 % were reached in intermolecular PKRs when chiral aminoxides R 3N—>0 were used [19]. Although the mechanism is not known, it seems likely that the chiral A-oxide discriminates between the prochiral carbonyl cobalt units, either oxidizing one carbon monoxide selectively to produce a vacant site for the alkene insertion, or stabilizing a vacant site on one of the cobalts preferentially. This approach was modified by application of chiral precursor substrates [20]. Albeit the synthesis of the latter is cumbersome, the concept was successfully applied in several total syntheses, for example of hirsutene [21], brefeldine A [22], /9-cuparenone [23], and (+)-15-norpentalenene [24] (eq. (10)). Stoichiometric amounts of the mediator compound Co2(CO)8 are still necessary in this useful version of the Pauson-Khand reaction. 

Other metal complexes have been found to promote the Pauson-Khand reaction, including Mo(CO)6, Fe(CO)5, W(CO)6, and Cp2Ti(CO)2, and variants of the Pauson-Khand reaction that use catalytic amounts of the metal have also been developed, but stoichiometric Co2(CO)8 remains the most widely used method for effecting this transformation. 

The Pauson-Khand reaction is a powerful tool for the synthesis of cyclopentanones, 246, from a>-alkenylacetylenes, 245, and carbon monoxide.176 Enyne cyclization has been catalyzed with nitriles using catalytic (77S-CsH5)2Ti(PMe3)2 95177-179 and other variants have since been discovered where the desired cyclopentenones can be directly prepared from the enyne and CO using (77S-CsHs)2Ti(CO)2 68 (Scheme 33) 176,180-184 Addition of PMe3 to the latter reaction mixture has proved to be beneficial. Stoichiometric reactions established that the initial step in the catalytic cycle is reductive coupling of the alkyne and the olefin to form the titanacycle. Carbon monoxide insertion followed by reductive elimination generates the observed product. 

Enynes in which three or four atoms separate the double and triple bonds cyclize upon complexation to Co2(CO)g and subsequent heating to give bicyclic enones (equation 52). With the exception of slightly elevated temperatures the conditions required are no different than those of the stoichiometric procedure described earlier for reactive substrates in intermolecular Pauson-Khand reactions. The intramolecular cycloaddition cannot in general be carried out under catalytic conditions. Hex-l-en-5-yne, which would give a four-membered ring upon intramolecular cycloaddition, instead undergoes alkyne trimerization exclusively.3 The most extensively studied systems are those derived from hept-l-en-6-yne, as the products, bicyclo[3.3.0]oct-l-en-3-ones, are useful in the synthesis of numerous cyclopentane-based polycy-clics. 

Besides [m + n] cycloadditions and [m 4- m + m +. ..] cyclo- and cocyclooligomerizations of alkenes, dienes or alkynes (see Sections 1.5.8.3.5, and 1.5.8.3.6.), transition metal complexes can also catalyze the cycloaddition of more than two different components. Most important is carbonylative ring synthesis with carbon monoxide as the C, unit. Several methods of this type use transition metals stoichiometrically, others catalytically. For some of the stoichiometric methods, developments towards catalytic versions are under way (e g., the Pauson-Khand reaction, see below). 

Numerous applications of the latter methods to stereoselective20 25- 94 105 and asymmet-ric26-33,io6-r is organic ancj natural product synthesis have been described however, those methods which use a stoichiometric amount of the metal are not the subject of this section. Few examples of transition metal catalyzed cyclopentenone and cyclopentadienone syntheses starting from alkenes and alkynes have been reported 34. It should be noted, however, that considerable efforts (and the first positive results) towards the catalytic use of zirconium13 and cobalt (in the Pauson-Khand reaction)35 36- U6l 117 have been reported. 

Although this reaction usually requires stoichiometric amounts of the metal carbonyl, Kraft has shown that substoichiometric amounts can be used.3 3 jjer work, 35-50% of Co2(CO)8 was used under a nitrogen atmosphere, in dimethoxyethane with 3 equivalents of cyclohexylamine. Kraft and Bonaga also developed dodecacarbonyltetracobalt as a viable catalyst.3 4 j e use of amines to promote the reaction was mentioned above. Molecular sieves have also been used to promote the Pauson-Khand reaction,3 5 d high intensity ultrasound is also effective.3 6 Polymer-supported promoters of this reaction are also known. " ... 

Although tremendous advances in the catalytic Pauson-Khand reaction have been made, the development of an asymmetric version did not share the same degree of success. Several asymmetric Pauson-Khand reactions were reported using chiral auxiliaries. However, those systems required stoichiometric amounts of cobalt as well as the chiral source. Attempts at using a catalytic amount of cobalt did not give satisfactory results. By contrast, the use of titanium chiral catalyst S,Sy (EBTHI)Ti(CO)2 (EBTHI = ethylene-l,2-bis(tiM,5,6,7-tetrahydro-l-indenyl)... 

Chapter 17 closes with a brief presentation of the Pauson-Khand reaction. The Pauson-Khand reaction (PKR) is a formal [2+2+1] cycloaddition reaction involving an alkyne, an alkene, and carbon monoxide to form a cyclopentanone shown generically in Equation 17.71. The Pauson-Khand reaction was initially reported as a stoichiometric reaction mediated by cobalt carbonyl, but it has been translated into a catalytic process in recent years. Most recently, it has developed into an enantioselective catalytic process. Complexes of Ti, Mo, W, Fe, Co, Ni, Ru, Rh, Ir, and Pd have all been shown to catalyze this reaction. 

The Pauson-Khand reaction forms cyclopentenones from three groups, a C=C, a C=C, and a CO molecule (Eq. 14.28). Originally, stoichiometric and based on Co, the Rh-catalyzed version is now widely adopted. Equation 14.29 shows the formation of the carbon skeleton of guanacastepene A, a novel antibiotic candidate." ... 

In an analogy to the well-known octacarbonyldicobalt-mediated Pauson-Khand reaction, the formal [2+2+1] cycloaddition of alkyne, alkene, and carbon monoxide can be promoted by pentacarbonyliron. However, the iron-mediated [2+2+1] cycloaddition of two alkynes with carbon monoxide has attracted much more attention. When heated in glyme at 140 °C in the presence of stoichiometric amounts of penta-carbonyliron, substituted trimethylsilylacetylenes afford tricarbonyliron complexed cyclopentadienones in moderate to good yields (Scheme 4-3). ... 

Nadal and colleagues recently reported a Ni-catalyzed carbonylative Pauson-Khand-like [2+2+1] cycloaddition of allyl halides and alkynes in the presence of carbon monoxide and iron as the stoichiometric reducing agent [148]. The reaction was proposed to occur via reductively generated Ni(I)-radical like species free radicals were, however, considered unlikely. 

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. 

Pauson-Khand Cycloaddition. Pauson Khand cycloaddition (see Pauson-Khand Reaction) is a cobalt-mediated method to prepare cyclopentenone from the cyclization of an alkyne with an alkene and CO (equation 14). This method is widely used to produce cychc ketones. Originally, stoichiometric amounts of Co2(CO)g were used in these reactions with the cobalt carbonyl being the CO source. However, it was shown that a strict temperature profile and high-purity reagents allowed the use of catalytic amounts of Co2(CO)g for reactions with 1 atm of CO. Currently, there is intense interest in developing catalytic cobalt starting materials for use in Pauson-Khand reactions. 

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