Direct, Redox Neutral Prenylation and Geranylation of Secondary Carbinol C-H Bonds: C4 Regioselectivity in Ruthenium Catalyzed C-C Couplings of Dienes to α-Hydroxy Esters

Abstract

The ruthenium catalyst generated in situ from Ru₃(CO)₁₂ and tricyclohexylphosphine, PCy₃, promotes the redox-neutral C-C coupling of aryl substituted α-hydroxy esters to isoprene and myrcene at the diene C4-position, resulting in direct carbinol C-H prenylation and geranylation, respectively. This process enables direct conversion of secondary to tertiary alcohols in the absence of stoichiometric byproducts or premetallated reagents, and is the first example of C4-regioselectivity in catalytic C-C couplings of 2-substituted dienes to carbonyl partners. Mechanistic studies corroborate a catalytic cycle involving diene-carbonyl oxidative coupling.

The ability to transform abundant feedstocks to value-added products in the absence of stoichiometric byproducts is a principal characteristic of a “process-relevant” method.¹ This attribute is exemplified by catalytic hydrogenation, which is applied across all segments of the chemical industry including the manufacture of chiral pharmaceutical ingredients on scale,² and alkene hydroformylation,³ which may be viewed as the prototypical C-C bond forming hydrogenation. As part of an effort aimed at the development of C-C bond forming hydrogenations beyond hydroformylation, we have found that hydrogen transfer between primary alcohols and π-unsaturated reactants generates organometal-aldehyde pairs that combine to form products of carbonyl addition, representing a departure from stoichiometric organometallic reagents in a range of C=X (X = O, NR) addition processes.⁴

Although primary alcohols participate in transfer hydrogenative C-C couplings to dienes^5,6 and other π-unsaturated reactants (allenes, enynes, alkynes and allylic acetates),⁴ to date, secondary alcohols have proven uniformly unreactive, presumably due to the relatively low electrophilicity of the transient ketones that arise upon dehydrogenation. It was reasoned that the transfer hydrogenative coupling of related α-hydroxy esters and π-unsaturated reactants might be feasible, as the transient α-ketoester esters are highly susceptible to nucleophilic addition. However, dehydrogenation of α-hydroxy esters is challenging from both a thermodynamic and a kinetic standpoint. Here, we report that the ruthenium catalyst generated from Ru₃(CO)₁₂ and tricyclohexylphosphine promotes efficient redox-neutral C-C coupling of aryl substituted α-hydroxy esters 1a-1f to isoprene 2a and myrcene 2b with unique regioselectivity for coupling at the diene C4-position, enabling direct carbinol C-H prenylation and geranylation, respectively (Figure 1).^5-21

Figure 1.

Regioselectivity in intermolecular metal catalyzed C-C couplings of 2-substituted dienes to carbonyl partners.^a

^aFor catalytic intramolecular diene-aldehyde reductive couplings, see reference 10. For catalyzed and non-catalyzed stoichiometric generation of allylmetal species from dienes followed by carbonyl allylboration, see references 11-21.

In preliminary experiments, a range of ruthenium and iridium catalysts were assayed for their ability to promote the C-C coupling of racemic ethyl mandelate 1a to isoprene 2a. These attempts were either completely unsuccessful or provided only trace quantities C-C coupling product or the α-ketoester, oxo-1a. Recently, however, Beller demonstrated that the catalyst generated from Ru₃(CO)₁₂ and Cy₂P(CH₂)₂PCy₂ in t-amyl alcohol at 150 °C promote the direct conversion of α-hydroxy amides to α-amino amides through dehydrogenation of the former.²² While these conditions did not translate directly to the coupling of ethyl mandelate 1a and isoprene 2a (Table 1, entry 1), simply changing the solvent to THF and increasing the loading of ligand led to a 45% isolated yield of the n-prenylated hydroxy ester 3a (Table 1, entry 2). Other bidentate phosphine ligands such as ferrocene-derived ligands DPPF, DiPPF and BINAP-PCy₂ were assayed under these conditions, however, conversion to 3a was not observed (Table 1, entries 3-5). In contrast, use of the simple monodentate phosphine ligand PCy₃ (12 mol%) under these conditions led to a 59% isolated yield of 3a (Table 1, entry 6). A comparable isolated yield of 3a could be obtained at 130 °C by extending the reaction time (Table 1, entry 7). At this stage, different solvents were evaluated (Table 1, entries 8-10). By conducting the reaction in toluene, the n-prenylated product 3a was obtained in 68% isolated yield (Table 1, entry 10). Variation of ligand loading did not improve the isolated yield of 3a (Table 1, entry 11), nor did changes in concentration (Table 1, entries 12, 13). However, by decreasing reaction time and increasing the loading of isoprene (500 mol%), a 75% isolated yield of the n-prenylated product 3a was obtained (Table 1, entry 15).

Table 1.

Selected optimization experiments in the C-C coupling of α-hydroxy ester 1 to isoprene 2a.^a

Entry	2 (mol%)	Ligand	Solvent (M)	T(°C)	Time (hr)	Yield%
1	400	Cy2P(CH2)2PCy2	t-AmOH (2.0)	150	48	<10b
2	400	Cy2P(CH2)2PCy2	THF (2.0)	150	48	45
3	400	DPPF	THF (2.0)	150	48	NR
4	400	DiPPF	THF (2.0)	150	48	NR
5	400	BINAP-PCy2	THF (2.0)	150	48	NR
6	400	PCy3	THF (2.0)	150	48	59
7	400	PCy3	THF (2.0)	130	72	56
8	400	PCy3	Dioxane (2.0)	130	72	60
9	400	PCy3	DCE (2.0)	130	72	NR
10	400	PCy3	PhMe (2.0)	130	72	68
11	400	PCy3	PhMe (2.0)	130	72	68c
12	400	PCy3	PhMe (1.0)	130	72	59
13	400	PCy3	PhMe (0.5)	130	72	50
14	400	PCy3	PhMe (2.0)	130	48	42
⇨ 15	500	PCy3	PhMe (2.0)	130	48	75

^aYields are of material isolated by silica gel chromatography. See Supporting Information for further details.

^bCy₂P(CH₂)₂PCy₂ (6 mol%).

^cCy₃P (18 mol%).

Under these optimal conditions, the redox neutral C-C coupling of aryl substituted α-hydroxy esters 1a-1f and isoprene 2a was explored (Table 2). In each case, the corresponding n-prenylated products 3a-3f were isolated in good yield as single regioisomers. Alkyl substituted α-hydroxy esters such as ethyl lactate provide low isolated yields of C-C coupling product using this first generation catalyst. However, analogous coupling reactions of aryl substituted α-hydroxy esters 1a-1f with myrcene 2b were successful, delivering products of geranylation 4a-4f with complete control of olefin geometry (Table 3). Thus, direct secondary carbinol C-H prenylation and geranylation is achieved under redox neutral conditions in the absence of stoichiometric byproducts or premetallated reagents.²³ Reaction using 2,3-dimethylbutadiene, 1,3-pentadiene and 3-methyl-1,3-pentadiene were attempted under standard conditions, but only trace quantities of product were observed.

Table 2.

Prenylation of α-hydroxy esters 1a-1f via ruthenium catalyzed hydrohydroxyalkylation of isoprene 2a.^a

Table 3.

Geranylation of α-hydroxy esters 1a-1f via ruthenium catalyzed hydrohydroxyalkylation of myrcene 2b.^a

To probe the catalytic mechanism and gain insight into the origins of regioselectivity, deuterated rac-ethyl mandelate, deuterio-1a, was exposed to isoprene 2a under standard conditions for redox-neutral C-C coupling (eqn. 1). Notably, the nprenylated adduct deuterio-1a incorporates deuterium exclusively at the cis-methyl group of the n-prenyl moiety (²H 50%). Incomplete deuterium incorporation may be attributed to the reversible transfer of hydrogen between deuterio-1a and isoprene, as corroborated by deuterium loss in recovered deuterio-1a (²H 54%). The regioselectivity and extent of ²H incorporation were evaluated using ¹H and ²H NMR spectroscopy. Also, recovered from this reaction in 9% yield is the α-ketoester, oxo-1a. Indeed, for many of the reactions reported in Tables 2 and 3 small quantities of the corresponding the α-ketoesters can be observed by thin layer chromatography or isolated by flash silica gel chromatography (typically < 5% yield).

(eqn. 1)

The regioselectivity of C-C coupling and deuterium incorporation are each consistent with the indicated catalytic cycle, which involves diene-carbonyl oxidative coupling (Scheme 1). To further challenge this mechanistic hypothesis, the redox neutral coupling of rac-ethyl mandelate 1a and butadiene 2c was performed under standard conditions. The product of C-C coupling 5a is formed as (Z)-stereoisomer, which is consistent with the proposed oxidative coupling mechanism (eqn. 2).

(eqn. 2)

Scheme 1.

Plausible catalytic mechanism for the redox neutral C-C coupling of deuterio-1a to isoprene 2a.

In other hydrohydroxyalkylations we have developed, which employing ruthenium(II) catalysts, mechanisms involving diene hydrometallation to form π-allylruthenium intermediates appear operative.⁵ The present ruthenium(0) catalyst system is unique in its ability to promote both alcohol dehydrogenation and diene-carbonyl oxidative C-C coupling, as illustrated in the formation of oxametallacycle I (Scheme 1) and as found in related Pauson-Khand type reactions of 1,2-diones.²³ As suggested by Beller's work²² and our collective studies, the Ru₃(CO)₁₂/phosphine catalyst system also appears better at promoting alcohol dehydrogenations that require β-hydride elimination of electron deficient carbinol C-H bonds, in comparison to ruthenium(II) catalysts.

In summary, the redox neutral prenylations and geranylations reported herein represent the first examples of the transfer hydrogenative C-C coupling of secondary alcohols. Further, the C4-regioselectivity displayed by these processes is unique among catalytic diene-carbonyl C-C couplings. As corroborated by mechanistic studies (eqns. 1 and 2), this unique regioselectivity is a consequence of a novel catalytic mechanism that links alcohol dehydrogenation and dienecarbonyl oxidative coupling. Direct prenylations and geranylations of secondary carbinol C-H bonds employing isoprene and myrcene, respectively, should facilitate access to diverse terpenoid natural products.