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Early mechanistic studies of rhodium-catalysed cyclisation of enals from Miller22 and Bosnich23 suggest that there are two major pathways that can take place: hydroacylation (a) and isomerisation decarbonylation (b) via β-hydride elimination (Scheme 17). After insertion of the rhodium catalyst into the carbon-hydrogen bond in 34, insertion of the terminal olefin can occur in two ways leading to either 6-membered rhodacycle 34a or 5-membered rhodacycle 34b. Predominant carbon-carbon reductive elimination would be the result from the 6-membered rhodacycle formation, affording the cyclopentanone 35. Conversely, the 5-membered rhodacycle favours β-hydride elimination followed by carbonyl migration to the rhodium by which decarbonylation24 can occur, thereby resulting in products such as 36.

Sakai et al. discovered the first intramolecular hydroacylation of enals using Wilkinson’s catalyst in stoichiometric amount under mild conditions (Scheme 18).25 A moderately low yield of 30% was obtained for the hydroacylation product 40, in addition to 32% of cyclopropane 39 formed by decarbonylation of the substrate. This could arise from the formation of the five membered rhodacycle 38b, which can undergo decarbonylation via carbonyl migration to the rhodium, forming the four-membered rhodacycle 38c. Final reductive elimination of the rhodium metal would furnish the observed cyclopropane 39.

Scheme 18: Rhodium-catalysed intramolecular hydroacylation of enals

A computational study was conducted by Sargent and co-workers on the mechanism of intramolecular hydroacyclation of 4-pentenals postulated by Bosnich (Scheme 19).26 During oxidative addition step, four possible diastereoisomers of 41b can be formed. Interestingly, only two diastereoisomers are calculated with low enough energy barriers are ones that have the acyl group apical. Each diastereoisomer undergoes a different pathway. One undergoes 1,2-insertion of the alkene to form 41a, the other undergoes 2,1-insertion alkene to form 41c. The energy barriers for these insertion steps are low and are therefore readily reversible. 41a will undergo reductive

elimination of the rhodium to afford the cyclopentanone 42. However, 41a can also undergo a carbonyl deinsertion to give 41e. Further β-hydride elimination affords 41f which can undergo decarbonylation to give 43. However, contrasting to Bosnich’s theory, the energy barrier from 41f

to 43 is 29.9 kcal/mol which suggests decarbonylation does not occur via this pathway. Instead, decarbonylation must occur from intermediate 41c. Formation of the more stable 41d from the 5- membered rhodacycle 41c has a lower energy barrier than from 41g (20.7 vs 22.4 kcal/mol respectively). This would be the favoured decarbonylation pathway leading to the isomerisation products 43 and 44. Once the monocarbonyl rhodium catalyst 45 is formed, this can rapidly decarbonylate aldehydes further to generate the deactivated dicarbonyl rhodium catalyst 46.

Tanaka and Fu reported on a rhodium-catalysed [4 + 2] annulation into constructing functionalised cyclohexenones in an intermolecular fashion through the formation of a rhodacyclopentanone intermediate (Scheme 20).27 The reaction was initially focused on internal alkynes, reacting 47 with phenylacetylene afforded a 3:1 mixture of regioisomers with the major isomer having the phenyl group on the α-position next to the carbonyl. Remarkably, disubstituted alkynes were also well tolerated and in the presence of electron poor disubstituted alkynes, the yield significantly increased to 79% and regioselectivity to 6:1 of 48 and 49 respectively. A plausible mechanism would include oxidative insertion of the rhodium into the C‒H bond at the aldehyde position. Coordination followed by alkyne insertion would furnish the rhodacyclopentanone species 47b. Complexation to the second alkyne which would undergo migratory insertion to form the 7-membered rhodacycle 47c. Reductive elimination of the rhodium metal affords the desired tetrasubstituted cyclohexenone products. Deuterium labelling experiments were conducted with a deuterium labelled aldehyde, which led to quantitative incorporation of the deuterium into the terminal alkene in a highly stereospecific manner.

A few years later, Tanaka and co-workers developed the intermolecular rhodium-catalysed [4 + 2] annulation reaction with alkenes in a highly regio- and enantioselective fashion (Scheme 21).28 Initial results with dppb ligand afforded the cyclohexanone product albeit in low yields. After a short ligand screen, enabling the reaction with a chiral bidentate phosphine ligand (R,R)-52 the yield was significantly enhanced to 80% and excellent enantioselectivities were also obtained (97% ee).

Scheme 21: Rhodium-catalysed intermolecular [4 + 2] annulation with alkenes

The intermolecular rhodium-catalysed [4 + 2] annulation reaction was developed further with unfunctionalised 4-alkynals and isocyanates into preparing 4-alkylideneglutarimide motifs.29 The reaction afforded good to excellent yields when a non-chiral dppp was used as a ligand. Interestingly, a parallel kinetic resolution was observed furnishing both 54 and 55 when the ligand was switched to (S)-segphos under the same conditions (Eq. 3). Excellent enantioselectivities were observed albeit in modest yields.

Scheme 22 shows a plausible mechanism of how the two pathways are generated in the parallel kinetic resolution. The first step is oxidative addition of the rhodium into the C‒H bond to give the acyl hydride species 53a. Coordination to the alkyne can then lead to two different outcomes. Pathway (a) would follow a migratory insertion of the C1 of the alkyne, affording the 6- membered rhodacycle 53b. Reductive elimination of the rhodium furnished the hydroacylation product 55. Pathway (b) undergoes migratory insertion of the alkyne at the C2 position, which gives rise to rhodacyclopentanone 53c. Complexation of the isocyanate followed by insertion furnishes the 7-membered rhodacycle 53d. Final reductive elimination affords the glutarimide motif 54.