Pauson Khand reaction

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. 

As a very typical cyclopentenone synthesis the Pauson-Khand process has become very popular in natural products synthesis. 

Since cyclopentenone and its derivatives show very high synthetic flexibility and additionally are synthetic equivalents of S-lactones and lactams, a reliable route to this system raises common interest. If the cyclopentenone ring is to be embedded into a polycyclic framework, there may be stereoselectivity problems. 

As the transition states of cyclization reactions tend to show high product similarity, substrate manipulations could be quite helpful in this case. 

This was nicely shown to be true in the Pauson-Khand cyclization of diol 438. 

In an effort to synthesize the lycopodium alkaloid huperzine Q 437 the Pauson-Khand cyclization, leading to the very promising intermediate 436, was investigated in detail. 

Although the cobalt-mediated Pauson-Khand reaction was discovered more than 30 years ago, few asymmetric versions of this reaction have so far been developed. Up to now, the only direct method of controlling the enantioselectivity of intermo-lecular cobalt-mediated Pauson-Khand reactions involves the use of alkaloid N-oxides [59-62]. 

Catalyst for the first catalytic asymmetric Pauson-Khand reaction. 

More recent work on the asymmetric PKR has focused on reactions catalyzed by rhodium and iridium complexes. Jeong and co-workers reported reactions catalyzed by a combination of [Rh(CO)jCl]2, (S)-BINAP, and AgOTf. Good to excellent ee s were obtained for a small range of substrates (Equation 17.79). After the observation that phosphine ligands improve the yield of the Ir-catalyzed PKR, Shibata reported intramolecular PKRs catalyzed by the combination of Tol-BINAP and [Ir(COD)Cl]2 in excellent yields and enantioselec-tivities (Equation 17.80).  

Intermolecular PKRs have been less well studied, in part because of the difficulty in controlling regioselectivity. Several strategies have been followed to develop intermo-lecular PKRs, including the incorporation of ligating groups on the alkene, and the use of strained alkenes. 

Toluene or xylenes Slow addition (3 ii) Hydrolysis SiMea 100-140 °C, 10 min 100-140 C, 24 h 

The second strategy is illustrated in Equation 17.83. In this case, the LUMO of the olefin is lowered by using strained alkenes, such as cyclopropene and cyclobutene, and the binding constant of the olefin to the metal is higher because of relief of strain during coordination (see Chapter 3). These factors have been proposed to lead to faster reactions with these strained alkenes.  

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], 

Although the mechanistic details remain to be established, it is likely that the catalytic process is comprised of alkyne coordination and multiple insertions of alkene and CO followed by reductive elimination. 

Diradical species 4 is more stable than diradical 5, and the oxetane 6 is thus formed preferentially oxetane 7 is obtained as minor product only. Evidence for diradical intermediates came from trapping experiments, as well as spectroscopic investigations.  

In addition to the intermolecular Paterno-Buchi reaction, the intramolecular variant has also been studied the latter allows for the construction of bicyclic structures in one step. For example the diketone 8 reacts quantitatively to the bicyclic ketone 9  

Although the Paterno-Buchi reaction is of high synthetic potential, its use in organic synthesis is still not far developed. In recent years some promising applications in the synthesis of natural products have been reported. The scarce application in synthesis may be due to the non-selective formation of isomeric products that can be difficult to separate—e.g. 6 and 7—as well as to the formation of products by competitive side-reactions such as Norrish type-I- and type-II fragmentations. 

Ninomiya, T. Naito, Photochemical Synthesis, Academic Press, New York, 1989, p. 138-151. 

Iqbal and co-workers also used 1,2-dichloromethane as the solvent, which facilitated purification of the product and led to less of the corresponding emio-diastereomer being formed. 

substituted alkyl and aryl transition metal complex Co2(CO)8, Fe(CO)5, Ru2(CO)i2, Cp2TiR2, Ni(COD)2, W(CO)e, Mo(CO)e, [RhCI(CO)2]2 Promoter NMO, TMAO, RSCH3, high-intensIty llght/photolysis, hard Lewis base 

The mechanism of the Pauson-Khand reaction has not been fully elucidated. However, based on the regio- and stereochemical outcome in a large number of examples, a reasonable hypothesis has been inferred. 

The total synthesis of the sesquiterpene (+)-taylorione was achieved in the laboratory of J.G. Donkervoort who used the modified Pauson-Khand reaction to prepare the five-membered ring of the natural product. The preformed alkyne-cobalt complex was exposed to excess triethylamine-A/-oxide, which oxidized off two CO ligands to free up a coordination site for the ethylene. The optimum pressure of the ethylene gas had to be at 25 atm, and the reaction was conducted in an autoclave. 

During the synthetic studies toward the natural product kalmanol, L.A. Paquette and co-workers prepared the CD diquinane substructure by using an intramoiecuiar Pauson-Khand reaction. The use of an A/-oxide promoter for the cyclization resulted in very mild conditions and afforded the desired triquinane in good yieid and as a single diastereomer. 

In the laboratory of S.L. Schreiber, the total synthesis of (+)-epoxydictymene was accomplished by the tandem use of cobalt-mediated reactions as key steps. The eight-membered carbocycle was formed via a Nicholas reaction, while the five-membered ring was annulated by the Pauson-Khand reaction. Several P.-K. conditions were explored and the best diastereoselectivity was observed when NMO was used as a promoter. The annulated product was isolated as an 11 1 mixture of diastereomers. 

Formal [2 + 2+1] cycloaddition of an alkene, alkyne, and carbon monoxide mediated by octacarbonyl dicobalt to form cyclopentenones. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 193, Springer-Verlag Berlin Heidelberg 2009 

Schore, N. E. In Comprehensive Organic Synthesis Paquette, L. A. Fleming, I. Trost, B. M., Eds. Pergamon Oxford, 1991, Vol. 5, p.l037. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 206, Springer International Publishing Switzerland 2014 

Torres, R. R. The Pauson-Khand Reaction Scope, Variations and Applications, Wiley Hoboken, NJ, 2012. (Review). 

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Asymmetric Pauson-Khand reaction in syntheses of heterocycles fused with five-member carbocyclic fragment 980PP121. 

The reaction of an alkyne 1 and an alkene 2 in the presence of dicobaltoctacar-bonyl to yield a cyclopentenone 3 is referred to as the Pauson-Khand reaction Formally it is a [2 + 2 + 1 ]-cycloaddition reaction. The dicobaltoctacarbonyl acts as coordinating agent as well as a source of carbon monoxide. 

An example for the synthetic potential is the formation of a fenestrane skeleton 11 from the open-chain compound 10 by a cascade of two consecutive intramolecular Pauson-Khand reactions, the yield in this case is however only 9% J... 

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. 

RCM of 132 to the medium-sized enyne 135, for example, appears to be highly unlikely. This transformation was achieved by conversion of 132 to the cobalt complex 133, which is cyclized to the protected cycloenyne 134. Deprotection yields 135, and a subsequent Pauson-Khand reaction yields the interesting tricyclic structure 136 (Scheme 27) [125c]. 

The reaction of alkenes with alkenes or alkynes does not always produce an aromatic ring. An important variation of this reaction reacts dienes, diynes, or en-ynes with transition metals to form organometallic coordination complexes. In the presence of carbon monoxide, cyclopentenone derivatives are formed in what is known as the Pauson-Khand reaction The reaction involves (1) formation of a hexacarbonyldicobalt-alkyne complex and (2) decomposition of the complex in the presence of an alkene. A typical example Rhodium and tungsten ... 

Mukai, C., Yoshida, T., Sorimachi, M., Odani, A. (2006) Co2(CO)8-Catalyzed Intramolecular Hetero-Pauson-Khand Reaction of Alkynecarbodiimide Synthesis of ( )-Physostigmine. Organic Letters, 8, 83-86. 

Scheme 10.67 Intermolecular Pauson-Khand reactions with PuPHOS and CyPHOS.

Scheme 10.69 Intermolecular Pauson-Khand reactions of amido-alk5mes with PuPHOS and CamPHOS-derived ligands.

The Pauson-Khand reaction (PKR) is an efficient method to synthesize cyclopentenones.105 The reaction is usually carried out in organic solvent. The first aqueous Pauson-Khand reaction was reported by... 

Later, Chung et al. successfully developed an intramolecular Pauson-Khand reaction in water without any cosolvent by using aqueous colloidal cobalt nanoparticles as catalysts. The catalyst was prepared by reducing an aqueous solution of cobalt acetate containing sodium dode-cyl sulfate (SDS) surfactant. The cobalt nanoparticle could be reused eight times without any loss of catalytic activity (Eq. 4.57).107... 

Scheme 6/3.25. Domino metathesis/Pauson-Khand reaction.

A combination of a metathesis and a Pauson-Khand reaction, which leads to tricyclic compounds starting from diene-ynes, has been described by Perez-Castells and colleagues [262]. Treatment of the Co-complex 6/3-86, obtained from the corresponding alkyne in 75 % yield, with 5 mol% of the Ru-catalyst 6/3-13 for 18 h, followed by addition of an N-oxide as trimethylamine-N-oxide (TMANO) or NMO as copromoters, gave 6/3-87 in 81% yield. 

Co-catalyzed transformations are concerned mainly with the [2+2+2] cycloadditions of three alkyne groups to give arenes. Another important reaction is the [2+2+1] cycloaddition of alkynes, alkenes and CO to give cyclopentenones, which is the well-known as Pauson-Khand reaction [272]. 

The Pauson-Khand reaction is the Co-induced formation of cyclopentenones from ene-ynes and CO. One impressive example of a domino Pauson-Khand process is the synthesis of fenestrane 6/4-15, as reported by Keese and colleagues [278]. The transformation is initiated by a double Grignard reaction of 4-pentynoic acid 6/4-12, followed by protection of the formed tertiary hydroxyl group to give 6/4-13. The Co-induced polycyclization of 6/4-13 led directly to the fenestrane 6/4-15... 

It is not quite clear which step takes place first - the Co-catalyzed [2+2+1] cycloaddition of the outer alkyne moiety, or the Diels-Alder reaction of the diene with the inner alkyne to form a 1,4-cyclohexadiene, which then undergoes a Pauson-Khand reaction with the remaining alkyne. Recently, it has been shown that a domino reaction can also be performed using 1 mol of a 1,7-diphenyl-1,6-diyne 6/4-20 and a 1,3-diene 6/4-21 in the presence of Co/C at 150 °C under 30 atm CO, to give the polycyclic compounds 6/4-22 as sole product (Scheme 6/4.7) [282]. 

The Pauson-Khand reaction can be facilitated by preparing the necessary ene-yne in situ by an allylic substitution of an alkyne with allylic acetate using a Pd°- and Rh-catalyst The yield of the cydization product 6/4-24 ranges from 0 % with X = O (6/4-24a) to 92% with X=NTs, as well as X = C(C02Et)2 (6/4-24c) (Scheme 6/4.8) [283],... 

Scheme 6/4.8. Combination of a nucleophilic substitution and a Pauson-Khand reaction.

A combination of Co-mediated amino-carbonylation and a Pauson-Khand reaction was described by Pericas and colleagues [286], with the formation of five new bonds in a single operation. Reaction of l-chloro-2-phenylacetylene 6/4-34 and dicobalt octacarbonyl gave the two cobalt complexes 6/4-36 and 6/4-37 via 6/4-35, which were treated with an amine 6/4-38. The final products of this domino process are azadi- and azatriquinanes 6/4-40 with 6/4-39 as an intermediate, which can also be isolated and separately transformed into 6/4-40 (Scheme 6/4.11). 

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