Chloro[(1,2,5,6H)-1,5-cyclooctadiene] (H5-2,4-Cyclopentadiene-1-yl) Ruthenium

[97913-63-8]  · C13H17RuCl  · (310)

(catalyzes the coupling reaction between alkenes and alkynes to yield Alder ene-type products)

Physical Data: air- and light-sensitive golden orange solid, mp 230-235°C.

Solubility: soluble in water and various organic solvents including alcohols, DMF and acetone.

Form Supplied in: readily synthesized in high yield.1

Cycloadditions

Chloro[(1,2,5,6H)-1,5-cyclooctadiene] (H5-2,4-cyclopentadiene-1-yl) ruthenium [CpRu(COD)Cl] catalyzes the cycloaddition of cyclooctadiene with a variety of alkynes to give the corresponding cycloadducts (eq 1).2 Terminal alkynes also undergo this ruthenium-catalyzed cycloaddition process. The reaction is highly chemoselective. However, the presence of aromatic groups on the alkyne moiety greatly diminish the yield of the cycloadduct. Interestingly, hexa-1,5-diene and octa-2,6-diene do not undergo cycloaddition under similar conditions.

Sterically bulky alkynes undergo such cycloadditions, but at a much slower rate. This has been exploited in the cycloaddition of a diyne which cycloadds exclusively to the less sterically congested alkyne (eq 2).2

Alkene-Alkyne Coupling Reactions

The most important synthetic application of CpRu(COD)Cl is that it catalyzes the addition of terminal alkenes to terminal alkynes. Reacting oct-1-ene and oct-1-yne at elevated temperature in the presence of 5 mol% of CpRu(COD)Cl gave a 5:1 ratio of the branched and linear 1,4-diene (eq 3).3 Other simple unfunctionalized alkenes/alkynes yielded the branched isomer as the major product. In a comparative study with other ruthenium complexes, CpRu(COD)Cl was found to be the most effective in such transformations.4 Unlike arene ruthenium complexes, the use of CpRu(COD)Cl does not employ a promotor or phosphines to increase the effectiveness of the catalyst.

Remote functionality on the alkene tether (alcohols, esters, enoates and ketones) and on the alkyne tether (ester and silyl ethers) did not affect the process in terms of yield or selectivity.3,4 Interestingly, a normally reactive enoate does not interfere with the coupling (eq 4).

Internal alkynes also undergo coupling with terminal alkenes (eq 5). Only one regioisomer is possible.3,4

The ruthenium-catalyzed Alder ene-type reaction has been applied to the formal synthesis of alternaric acid.5 In model studies it was found that relatively acidic substrates, such as carboxylic acids, inhibit the reaction. Esters, however, underwent clean conversion (eq 6).

In the key ruthenium-catalyzed coupling step, high regioselectivity was obtained with the free diol (protection reduced regioselectivity) and the Fmoc-protected ester (eq 7). The ratio of products was 8.9:1 in favor of the branched isomer.

CpRu(COD)Cl catalyzes the coupling of g-amido-a,b-alkynoate esters with monosubstituted alkenes (eq 8).6 Carbon-carbon bond formation occurs at the a-carbon of the alkynoate (4.2:1 ratio of a/b-regioisomers). Interestingly the usually more reactive conjugated diene was a spectator in the reaction. No Diels-Alder-type products were observed. The reaction is tolerant of a range of functionality on the alkene moiety, including esters and propargyl alcohols. The integrity of stereogenic centers on the alkyne moiety was maintained throughout the reactions.

Propargyl Substituents

Substitution at the propargylic position of the alkyne moiety has a profound effect on the regioselectivity of the addition. A cyclohexane substituent at that center reduces selectivity.3,4 Remarkably oxygen substituents reversed selectivity in favor of the linear product.3,4 Placing an acetal at the propargylic position increased the linear to branched selectivity to 6:1 (eq 9). The acetal hydrolyzes under the reaction conditions.

In optimization studies, using aqueous DMF as the solvent gave the highest yields and regioselectivity for the reaction of methyl 10-undecenoate and but-2-yn-1-ol (eq 10).4 A methanol/Bu4NCl system was found to give comparable yields to aqueous DMF but the regioselectivity of the reaction was diminished.

The combination of having oxygen substituents and branching at the propargylic center results in the highest regioselectivity (up to 9.9:1 in favor of the linear isomer).

Internal propargyl alcohols react with terminal alkenes to yield Baylis-Hillman-type products.7 Baylis-Hillman reactions are usually quite limited to electrophilic partners that do not interfere with the nucleophile. Yields were good and the isomeric ratio high in favor of the branched isomer in many examples. Hydroxy- and cyano- groups on the propargyl alcohol moiety gave particularly high regioselectivities, yielding almost exclusively the branched product. The addition of indium triflate as a co-catalyst was found to improve regioselectivity towards the branched isomer. Alkyl substituents at the propargylic center had no significant effect on the outcome of the reaction. Remote functionality on the alkyne moiety (R1) was found to have a large effect on regioselectivity (eq 11). Placement of a hydroxyl group two or three carbons away from the alkyne (R1=-OH or -CH2OH) led to only one regioisomer, the branched product. Placing cyano- or cyano/hydroxyl groups in a similar manner [R1=-CN or -CH(CN)CH2OH] yields only the branched isomer.

Silyl-alkynes are effective in controlling the regioselectivity of the coupling reaction with terminal alkenes.8 Although terminal alkynes couplings proceed with high chemoselectivity, the reactions have previously produced mixtures of isomers. For example, propargyl alcohols react with oct-1-ene to yield a single product (eq 12). In comparison the same alkyne, without the silyl substituent, yields a 1:1.3 mixture of the branched and linear regioisomers. However, a more reactive ruthenium catalyst (with the absence of chloride ligands) has been shown to be more effective in such transformations.8

Allylic Alcohols

CpRu(COD)Cl promotes the coupling of internal and terminal alkynes with allylic alcohols to yield linear and branched g,d-unsaturated ketones (eq 13 and 14).9

In contrast to other ruthenium coupling reactions, both aliphatic and aromatic acetylenes are efficient partners. Aromatic alkynes frequently inhibit such reactions, a consequence of the ease in forming arene complexes. Aqueous DMF as the solvent gave the best rates of reaction and regioselectivity. Alkynes conjugated to esters gave similar yields and regioselectivity in comparison with terminal alkynes (eq 15).9

An application of this methodology has been achieved for the introduction of a steroid side chain (eq 16).9 Reacting the alkyne with an allylic alcohol yielded the linear product in moderate yield.

The reaction of propargyl alcohol derivatives with allylic alcohols was found to give the highest regioselectivity in favor of the linear products in 50-60% isolated yields (eq 17).9

Butenolide Formation

CpRu(COD)Cl coupling reactions of an alkene to an alkyne have been utilized in the synthesis of butenolides. Methyl 10-undecenoate reacted with 4-hydroxybutynoate and 5 mol% of CpRu(COD)Cl to yield a 2.9:1 ratio of the butenolide and hydroxy ester (eq 18).10,11 Butenolide formation proceeds via attack at the a-carbon of the acrylate followed by elimination of ethanol. Introducing alkyl substituents at the propargylic position increased regioselectivity towards the butenolide (eq 18; ratios given are for butenolide/ester).

Studies have shown that the remote functionality in the terminal alkene has some effect on regioselectivity.10 With an alcohol functionality on the alkene the corresponding butenolide was the only regioisomer obtained in 71% yield (eq 19).

Of particular interest is that the ruthenium-catalyzed coupling of an alkene to an alkyne yields the corresponding butenolide with stereochemical information at the propargylic position intact (eq 20).10

Pentenolides have been synthesized in much the same way (eq 21).11

This methodology has been successfully applied to an efficient synthesis of ancepsenolide.10,11 The key step involves the double addition of the alkyne to a diene with 10 mol% of CpRu(COD)Cl (eq 22).

This type of coupling has been applied to the synthesis of the hydroxybutenolide terminus of the acetegenins.

Noteworthy is that, in general, electron-deficient alkynes produce predominantly the b-alkylated product in Lewis acid-assisted and thermal Alder ene-type reactions (path a; eq 23). In contrast the ruthenium-catalyzed Alder ene-type reaction yields predominantly a-alkylation (path b; eq 23). In addition, the reaction is more general than standard Alder ene-type reactions. Alder ene reactions are rarely used synthetic transformations due to the lack of generality and extreme conditions (temperatures in excess of 400°C have been used) associated with the reaction.

Allene-Alkene Coupling

Allenes have been utilized in replace of the alkyne component in the ruthenium-catalyzed coupling with terminal alkenes to yield 1,3-dienes (eq 24).13 In such reactions, a dummy alkyne was added to activate the ruthenium catalyst. The reaction gave excellent chemoselectivity with a range of allene partners. Only the E-isomers of the dienes were obtained.

Three-Component Coupling Reactions

The ruthenium-catalyzed Alder ene-type reaction has been adapted to synthesize E-vinyl chlorides by the inclusion of chloride ions in the reaction mixture (eq 25).14

Once again excellent chemoselectivity is observed; phthalididimide, keto-, hydroxy- and ester groups are all tolerated. E/Z selectivities were generally high. Internal alkynes undergo a similar reaction to yield tetrasubstituted alkenes (eq 26). It should be noted that cis-vinyl chlorides are precursors to a-hydroxyesters upon dihydroxylation of the alkene.

Such three component coupling reactions have been extended to the synthesis of 1,5-diketones using water as the additive (eq 27).15 Indium salts were found to substantially increase the yield of the reaction. Chemoselectivity was high. Unfortunately the reaction conditions are quite harsh requiring the use of sealed tubes at 100°C.

Cycloisomerization

CpRu(COD)Cl catalyzes the cycloisomerization-oxidation of homopropargyl alcohols to yield g-butyrolactones (eq 28).16 In this particular use of CpRu(COD)Cl, two phosphine ligands replaces the COD ligand in the first instance which is then the active catalyst in the system. The reaction is highly chemoselective and a number of examples have been performed. N-Hydroxysuccinimide was used as the oxidant - more conventional oxidants failed under the reaction conditions.

This methodology has been applied to the total synthesis of the acetogenin (-)-miricatacin (eq 29).16 Stereochemical integrity was maintained throughout the reaction.


1. Albers, M. O.; Robinson, D. J.; Shaver, A.; Singleton, E., Organometallics 1986, 5, 2199.
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Andrew Hudson

Wayne State University, Detroit, MI, USA



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