Successive C-C Coupling of Dienes to Vicinally Dioxygenated Hydrocarbons: Ruthenium Catalyzed [4+2] Cycloaddition across the Diol, Hydroxycarbonyl or Dione Oxidation Levels

Abstract

The ruthenium(0) catalyst generated from Ru₃(CO)₁₂ and tricyclohexylphosphine or BIPHEP promotes successive C-C coupling of dienes to vicinally dioxygenated hydrocarbons across the diol, hydroxyketone and dione oxidation levels to form products of [4+2] cycloaddition. A mechanism involving diene-carbonyl oxidative coupling followed by intramolecular carbonyl addition from the resulting allylruthenium intermediate is postulated.

Vicinal diols are ubiquitous in Nature and are of interest vis-à-vis biomass conversion,^1,2 yet there exist no examples of their direct catalytic C-C coupling. We have developed a broad family of transformations wherein hydrogen transfer between alcohols and π-unsaturated reactants produces organ-ometal-carbonyl pairs that combine to form products of addition.³ In the course of these studies, a ruthenium(0) catalyst recently was identified that promotes alcohol C-C coupling through an alternate mechanism, wherein alcohol dehydrogenation drives carbonyldiene oxidative coupling to form metallacyclic intermediates, as illustrated in couplings of α-hydroxy esters to isoprene or myrcene to form products of prenylation or geranylation, respectively.⁴ It was posited that the allylruthenium species arising transiently upon diene-carbonyl oxidative coupling might be intercepted via allylruthenation onto a tethered carbonyl moiety to form products of cycloaddition, suggesting the feasibility of utilizing diols as partners for C-C coupling. Here, we report that vicinal diols and their more highly oxidized forms (hydroxyketones and diones) engage in [4+2] cycloaddition with a diverse range of conjugated dienes – a powerful, new cycloaddition that may be conducted in reductive, redox-neutral or oxidative modes (Figure 1).^5,6

Figure 1.

Cycloaddition of vicinally dioxygenated hydrocarbons through interception of an allylruthenium intermediate.

Following the mechanism postulated above, the phenethyl diol 1a was exposed to isoprene 4b in the presence of sub-stoichiometric quantities of Ru₃(CO)₁₂ and tricyclohexylphosphine, PCy₃, at 130 °C in toluene solvent. Remarkably, the product of cycloaddition 5a was obtained in 78% isolated yield as a 6:1 mixture of regioisomers. Whereas PCy₃ was the preferred ligand for terminal 1,2-diols 1a-1b, a screen of phosphine ligands revealed that the chelating phosphine ligand BIPHEP, 2,2′-bis(diphenylphosphino)-1,1′-biphenyl, was the better for internal 1,2-diols 1c-1h. For internal diols 1c-1h, cis- or trans-diastereomers react with equal facility (Table 1).

Table 1.

Oxidative ruthenium catalyzed [4+2] cycloaddition of isoprene 4b with diols 1a-1h.^a

^aYields are of material isolated by silica gel chromatography.

^bPCy₃ (12 mol%).

^c150 °C. See Supporting Information for further details and structural assignments.

The scope of the diene partner is illustrated in cycloadditions of rac-cyclohexanediol 1f. Butadiene 4a and a range of substituted dienes 4b-4h participate in the ruthenium catalyzed cycloaddition to furnish decalins 5f, 5i-5o in excellent yield. A single substituent is tolerated at any position of the diene. For the dimethyl substituted butadienes 4e-4g, good to excellent yields of cycloadducts 5l-5o, respectively, are obtained. For the terminally disubstituted diene 4h, 2,4-hexadiene, substantial olefin isomerization in advance of cycloaddition is observed (Table 2). Indeed, Ru₃(CO)₁₂ catalyzed olefin isomerization has been documented.⁷ This phenomena is advantageous in terms of recruiting non-conjugated dienes as partners for cycloaddition. For example, rac-cyclohexanediol 1f was reacted with the non-conjugated diene iso-4g (eqn. 1). Remarkably, iso-4g and 4g produce cycloadduct 5n with roughly equal facility.

Table 2.

Ruthenium catalyzed [4+2] cycloaddition of rac-cyclohexanediol 1f with dienes 4a-4h.^a

^aYields are of material isolated by silica gel chromatography.

^b300 mol% diene.

^c150 °C.

^dThe same products are generated in the same distribution using 1,5-hexadiene. See Supporting Information for further details and structural assignments.

(1)

The cycloadditions of diols 1a-1h are oxidative processes wherein excess diene presumably serves as the hydrogen acceptor (Tables 1 and 2). The feasibility of cycloaddition from more highly oxidized congeners of diols 1a-1d and 1f were evaluated in reactions with isoprene 4b (Table 3). In the event, exposure of the α-hydroxycarbonyl compounds 2a-2d and 2f to standard conditions employing substoichiometric quantities of Ru₃(CO)₁₂ and either PCy₃ or BIPHEP as ligand provided the cycloadducts 5a-5d and 5f in good to excellent yield. Whereas reactions of α-hydroxycarbonyl compounds 2a-2d and 2f are redox-neutral processes, cycloadditions of the corresponding dicarbonyl compounds 3a-3d and 3f are reductive processes requiring a stoichiometric hydrogen donor. For such dicarbonyl reactants, formic acid proved to be most effective reductant, and use RuH₂CO(PPh₃)₃ as precatalyst was advantageous in certain cases.⁸ While glyoxals 3a and 3b failed to deliver any cycloadduct, the vicinal diketones 3c, 3d and 3f provided the anticipated products 5c, 5d and 5f in modest yields. Thus, ruthenium catalyzed [4+2] cycloaddition is achieved from the diol, hydroxycarbonyl and dicarbonyl oxidation levels.

Table 3.

Ruthenium catalyzed [4+2] cycloaddition of isoprene 4b with vicinally dioxygenated hydrocarbons 1a-1d, 1f, 2a-2d, 2f, and 3a-3d, 3f.^a

Entry	Cycloadduct	Reactant	Yield %
1		Diol 1a	78b
		Hydroxyketone 2a	75b
		Dicarbonyl 3a	Trace
2		Diol 1b	60b,e
		Hydroxyketone 2b	72b
		Dicarbonyl 3b	Trace
3		Diol 1c	90c
		Hydroxyketone 2c	98c
		Dicarbonyl 3c	70d
4		Diol 1d	84b
		Hydroxyketone 2d	61b
		Dicarbonyl 3d	35d,f
5		Diol 1f	90b
		Hydroxyketone 2f	68b
		Dicarbonyl 3f	54d,f

^aYields are of material isolated by silica gel chromatography.

^bPCy₃ (12 mol%).

^cBIPHEP (6 mol%).

^dRuH₂CO(PPh₃)₃ (6 mol%), BIPHEP (6 mol%).

^e150 °C.

^fHCO₂H (300 mol%). See Supporting Information for further details and structural assignments.

A general catalytic mechanism has been proposed, as illustrated in the cycloaddition of rac-cyclohexanediol 1f and isoprene 4b (Scheme 1). It is well established that exposure of Ru₃(CO)₁₂ to chelating phosphine ligands provides complexes of the type Ru(CO)₃(diphosphine).⁹ Hence, intervention of a discrete, mono-metallic catalyst is anticipated. The Ru₃(CO)₁₂ catalyzed oxidation of alcohols employing olefins and alkynes as hydrogen acceptors has been described.^10,11 Further, mechanistically related Ru₃(CO)₁₂ catalyzed secondary alcohol aminations involving dehydrogenation of 1,2-diols^12a and α-hydroxy esters^12c are known. These data suggest the present Ru₃(CO)₁₂-phosphine catalyst system is capable of converting 1,2-diol 1f to the hydroxyketone 2f and, ultimately, the corresponding 1,2-dione 3f using diene 4b as the hydrogen acceptor.¹⁰ The diol rac-1f, which is introduced as the isomerically pure trans-stereoisomer, appears as a mixture of cis- and trans-diastereomers when recovered from the reaction mixture, suggesting dehydrogenation of 1f is reversible. Small quantities of hydroxyketone 2f also can be recovered from reaction mixtures. Oxidative coupling of 1,2-dione 3f and diene 4b to form oxametallacycle I finds precedent in the work of Chatani and Murai on Pauson-Khand type reactions of 1,2-diones,¹³ and our own work on the prenylation of substituted mandelic esters.⁴ Protonolytic cleavage of oxametallacycle I by 1f or 2f to form the allylruthenium complex II triggers intramolecular allylruthenation to form the ruthenium(II) alkoxide III. Finally, β-hydride elimination forms ruthenium hydride IV and OH reductive elimination delivers the product 5f and returns ruthenium to its zero-valent form to close the cycle.¹⁴

Scheme 1.

Proposed mechanism and stereochemical model for the cycloaddition of rac-cyclohexanediol 1f and isoprene 4b.

The assignment of regio- and stereochemistry merit discussion. Single crystal X-ray diffraction analysis of cycloadduct 5j revealed the cis-diastereomer. Additionally, the ¹H NMR spectral characteristics of cycloadducts 5i and 5l are consistent with the indicated meso-stereoisomers, not the corresponding C₂-symmetric stereoisomers. The stereochemical assignment of other cycloadducts was made in analogy to compounds 5j, 5i and 5l. A model accounting for the observed syn-diastereoselectivity is presented has been postulated, which involves intramolecular allylruthenation through a boat-like transition structure. Finally, aromatization of cycloadduct 5a via acid catalyzed double dehydration enabled the regiochemical assignment of this cycloadduct (see supporting information). Indeed, a systematic investigation of diol cycloaddition-aromatization is now underway in our laboratory.

In summary, since the advent of the photocycloaddition in 1908^15a and the Diels-Alder reaction in 1928,^15b several distinct and powerful classes of cycloaddition reactions have been developed, including diverse metal catalyzed processes.¹⁶ However, despite decades of intensive investigation, reductive and oxidative variants of cycloaddition reactions remain highly uncommon.^5,6 Here, we report a powerful and conceptually novel strategy for the [4+2] cycloaddition of dienes with 1,2-diols and their higher vicinally dioxygenated congeners. This work demonstrates that merged redox-construction events¹⁷ can be exploited in succession to form multiple C-C bonds, enabling generation of complex polycyclic frameworks in the absence of premetallated reagents. The development of related transformations and application of this methodology to the direct modification of abundant renewable polyols is ongoing.