Asymmetric alkynation

Like alkenes, asymmetrical alkynes follow Markovnikov s rule when an asymmetrical molecule, such as H2O or HBr, is added to the triple bond. An example is given below. 

Among the catalytic asymmetric alkyne additions to the sp carbon center, such as carbonyl, imines, and iminiums, truly metal-catalyzed alkyne addition to alkenes is rare. By using a PINAP derivative (Figure 5.4), Cu-catalyzed Michael addition... 

Scheme 5.11. Asymmetric alkyne addition to activated alkenes.

The application of immobilized heterobimetallic cobalt-rhodium in nanoparticles has also been reported. In the presence of water, CO, and amine, internal acetylenes 119 were converted to 3,4-disubstituted furan-2(5H)-ones 120 and 121 in high yields, in which an amine was necessary for the formation of furanone and a higher CO pressure was required for good yield (Equation (8)). It is important to notice that the catalyst has been easily recovered without loss of activity or formation of hydrogenated side-products. The reaction proceeded in good yield for the symmetric substrates (entries 1 and 2) while it always gave two regioisomers for asymmetric alkyne substrates (entries 3-8). The isomer ratio was dependent on the steric and electronic nature of the substituents. 

In the case of internal symmetric or terminal alkynes, reaction takes place according to Markovnikov selectivity, unlike the problem of regioselectivity that appears when internal asymmetric alkynes are used. Unfortunately, at that time only the gold(I) compound K[Au(CN)2] was tested, a compound that is now known not to be effective as a catalyst, unlike many other gold(I) compounds. 

An important and extensively investigated application of CpCo complex chemistry is the catalyzed synthesis of pyridines from alkynes and nitriles. Dissociation of the L ligands liberates the CpCo fragment to react with alkyne to form a cobaltacyclopentadiene complex. The nitrile coordinates to this intermediate and subsequently undergoes insertion to form a seven-membered cobaltacycle. Reductive coupling gives pyridine and reforms CpCo. Asymmetric alkynes add to the carbon with the bulkier substituent adjacent to the nitrile carbon. 

Templeton and co-workers used the alkylidyne-carbonyl coupling reaction shown in Eq. (156) for the synthesis of the asymmetric alkyne com-... 

R R = H/Pr", H/Bu", H/CHjNMej, H/Ph, H/COjEt, Me/Me, Me/COjMe, Ph/C02Et, Ph/CX OPh, C02Me/C02Me. In some cases of asymmetrical alkynes, the other isomer (8) also forms. The preference for position 3 increases in the order H < C02Et < Ph < alkyl (Equation (2)). The products are remarkably stable both to oxidation and hydrolysis. Compound (7), R = Me, R = H, R = Ph, taken as an example, does not react with elemental sulfur or methanol or both of them (typically a reactive combination towards other azaphospholes) <86CB4io>. 

Aryne-nickel complexes, which were carefully studied by Bennett [6, 7], show a different reactivity, since following the insertion of a first unsaturated species, the metallacycles so formed usually undergo a second insertion and subsequent reductive elimination (Scheme 9). Thus, complex 44 undergoes the insertion of two molecules of 3-hexyne to afford 43 in good yield, and double insertion of the asymmetric alkyne t-butylacetylene into complex 44 yields naphthalene 45 with a high regioselectivity attributed to steric factors. Interestingly, the reaction of 44 with the more electron-deficient alkyne hexafluoro-... 

Other efforts in asymmetric alkynation using sterically congested BINOL were reported independently by Pu et al. and Jiang et al. The structures of the ligands are shown in Scheme 21.19. Again the e.e. values of the chiral propargyl alcohols were moderate to excellent. 

In this chapter we have highlighted several practical approaches for the synthesis of chiral propargyl alcohols by various methods, the most practical ones being the asymmetric alkynation of carbonyl compounds in the presence of chiral auxiliaries and the p-eUmination of stereochemically well-defined a,p-dioxyhalides. These two approaches have been utilized efficiently in the synthesis of several bioactive natural products. 

As a typical intermolecular carbopalladation and termination, hydroarylation of alkynes are carried out extensively in the presence of HCO2H as a hydride source. Formation of regioisomers is observed in the reaction of asymmetric alkynes, and ratios depend on the nature of the substituents. High regioselectivity was observed in the reaction of the tertiary propargylic alcohol 14 to give 15 as a major product [5]. The (Z)-2-arylcinnamates 17, rather than 3-arylcinnamate 18, was obtained by the hydroarylation of methyl phenylpropiolate (16) [6]. 3-Substituled quinoline 21 was prepared by the regioselective hydroarylation of 19, followed by treatment of 20 with an acid without isolation [6]. 

Hydroesterification of alkynes proceeds smoothly using PdCl2(PPh3)2 as a standard catalyst, offering a convenient synthetic method of a, jS-unsaturated esters 1. Carbonylation of 1-alkynes and asymmetric alkynes yields a mixture of regioisomers. 

Scheme 7.31 Asymmetric alkyne addition to aldehydes using BINOL.

Scheme 7.32 Asymmetric alkyne addition to benzaldehyde using ligands 59a and 59b.

Isoquinohnes were prepared by a rhodium-catalyzed annulation of pic-ohnamides with alkynes. A number of aryl alkynes are tolerated in this reaction (Scheme 52).With an asymmetric alkyne, the larger group (phenyl) is found distal to the amide. When the alkynes have alkyl groups instead of aryl, the yield is lowered.While some variation is also tolerated on the pico-linamide, when groups are placed at C-5, the yield is lowered, presumably due to steric hindrance (14SL1036). 

W(PhCCPh)3 (CO)] are equivalent however, the two Ph —C= fragments are not equivalent and the complex possesses symmetry (Figure 6.23). Therefore, the ligands lie at the vertices of a deformed tetrahedron. As a result, for asymmetric alkynes, R CCR the existence of isomeric compounds such as [M(R CCR )3L] is possible. 

It is assumed that the reaction proceeds through a thermally excited, strongly 7r-basic complex containing parallel cyclopentadienyl ligands because this reaction should be very slow for weakly c-basic dicyclopentadienyldihydridomolybdenum(IV) in the ground state. An example is provided by cis migration to the asymmetric alkyne CF3 = CH. 

The inserticHi of asymmetrical alkynes of type into borane and carbabmane cages... 

Scheme 3 Addition of alcohols to symmetric and asymmetric alkynes...

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