Ruthenium(0) Catalyzed C-C Coupling of Alkynes and 3-Hydroxy-2-oxindoles: Direct C-H Vinylation of Alcohols

Abstract

Upon exposure to a ruthenium(0) catalyst, N-benzyl 3-hydroxy-2-oxindoles react with diverse alkynes to form products of C-H vinylation with complete control of regioselectivity and olefin geometry. This method contributes to a growing body of catalytic processes that enable direct conversion of lower alcohols to higher alcohols in the absence of stoichiometric organometallic reagents.

Graphical abstract

We have developed a broad, new class of catalytic C-C bond formations that merge the characteristics of carbonyl addition and transfer hydrogenation.¹ The majority of these processes enable direct conversion of primary to secondary alcohols through mechanisms wherein alcohol oxidation is balanced by (a) reductive C-X bond cleavage² or (b) π-bond hydrometalation³ to form transient aldehyde-organometal pairs that engage in carbonyl addition. Recently, we found that ruthenium(0) catalysts promote the conversion of activated secondary alcohols to tertiary alcohols.⁴ These processes proceed through a distinctly different mechanism wherein C=O/C=C oxidative coupling forms oxaruthenacycles,^{4, 5} which undergo transfer hydrogenolysis mediated by the secondary alcohol reactant to release product and regenerate the ketone required for oxidative coupling.

In the course of exploring ruthenium(0) catalyzed C-C couplings of secondary alcohols, it was found that 1,2-diols and other vicinally dioxygenated hydrocarbons (α-ketols, 1,2-diones) will react with alkynes to form products of carbinol C-H vinylation, that is, tertiary allylic alcohols in the form of α-hydroxy-β,γ-unsaturated ketones (Scheme 1).^4e Although a variety of different diol partners could be employed, preparatively useful isolated yields were only achieved using aryl-substituted alkynes. Given the highly electrophilic nature of isatins, it was postulated that 3-hydroxy-2-oxindoles might serve as efficient partners for ruthenium(0) catalyzed C-C couplings with alkynes, potentially enabling broader scope with respect to the alkyne partner. Our interest was further motivated by the ubiquity of 3-substituted-3-hydroxy-2-oxindoles in naturally occurring compounds and as scaffolds in human medicine.⁶

Scheme 1.

Ruthenium(0) catalyzed couplings of activated secondary alcohols with alkynes.

In a series of initial experiments (Table 1), N-benzyl 3-hydroxy-2-oxindole 1a (100 mol %) was exposed to 1-phenyl-1-butyne 2a (300 mol %) in the presence of Ru₃(CO)₁₂ (2 mol %) in toluene (2.0 M) at 140 °C. While in the absence of ligand no reaction occurred (Table 1, entry 1), in the presence of 1,3-bis(diphenylphosphino)propane (dppp), the product of C-C coupling 3a was formed in 54% yield as a single regioisomer (Table 1, entry 2). Carboxylic acid additives have been shown to enhance yield dramatically by co-catalyzing the transfer hydrogenolysis of oxaruthenacycles.⁷ Upon evaluation of a series of carboxylic acids (Table 1, entries 3–6), adamantane carboxylic acid was most effective, allowing adduct 3a to be obtained in 90% yield (Table 1, entry 6). Further variation of ligand (Table 1, entries 7–13) and temperature (Table 1, entries 14–16) did not enhance the isolated yield of 3a. Finally, an attempt was made to decrease the loading of the catalyst, ligand and alkyne 2a (Table 1, entries 17–20). Although reduced loadings of alkyne 2a were not possible, a 90% yield of 3a could be obtained using only Ru₃(CO)₁₂ (1 mol %) and dppp (3 mol %) (Table 1, entry 19).

Table 1.

Selected optimization experiments in the ruthenium(0) catalyzed coupling of 3-hydroxy-2-oxindole 1a with alkyne 2a to form adduct 3a.^a

entry	ligand	t °c	RCO2H	3a yield (%)
1	---	140	---	trace
2	dppp	140	---	54
3	dppp	140	PhCO2H	60
4	dppp	140	p-NO2C6H4CO2H	26
5	dppp	140	C6F5CO2H	71
6	dppp	140	C10H15CO2H	90
7	dppe	140	C10H15CO2H	63
8	dCype	140	C10H15CO2H	39
9	dppb	140	C10H15CO2H	59
10	dppf	140	C10H15CO2H	45
11	rac-BINAP	140	C10H15CO2H	49
12	BIPHEP	140	C10H15CO2H	59
13	PCy3	140	C10H15CO2H	53
14	dppp	120	C10H15CO2H	34
15	dppp	130	C10H15CO2H	54
16	dppp	150	C10H15CO2H	60
17b	dppp	140	C10H15CO2H	47
18c	dppp	140	C10H15CO2H	56
19d	dppp	140	C10H15CO2H	90
20d,e	dppp	140	C10H15CO2H	65

^aCited yields are of material isolated by silica gel chromatography. C₁₀H₁₅CO₂H refers to adamantane carboxylic acid. See Supporting Information for further experimental details.

^b2a (150 mol %).

^cRu₃(CO)₁₂ (1 mol %), dppp (3 mol %), C₁₀H₁₅CO₂H (6 mol %).

^dRu₃(CO)₁₂ (1 mol %), dppp (3 mol %), C₁₀H₁₅CO₂H (12 mol %).

^e2a (200 mol %).

To assess reaction scope, optimal conditions determined for the coupling of oxindole 1a with alkyne 2a were applied to alkynes 2b–2i (Table 2). Aryl-substituted alkynes 2a–2c delivered adducts 3a–3c in excellent yield. Heteroatoms are not tolerated at the propargylic position of the alkyne, however, as demonstrated by the formation of adduct 2d, the presence of heteroatoms at the homopropargylic position is not problematic. Encouraged by these results, the coupling of oxindole 1a with terminal alkynes 2e–2f was explored. Adducts 3e–3f were obtained in good yield as single regioisomers. The coupling of oxindole 1a with acetylene 2i (1 atm) also was attempted. Remarkably, the product of carbinol C-H vinylation 3i was obtained in 69% yield.

Table 2.

Ruthenium(0) catalyzed coupling of 3-hydroxy-2-oxindole 1a with alkynes 2a–2i to form adducts 3a–3i.^a

^aCited yields are of material isolated by silica gel chromatography. C₁₀H₁₅CO₂H refers to adamantane carboxylic acid. See Supporting Information for further experimental details.

To probe reaction scope further, a set of substituted N-benzyl 3-hydroxy-2-oxindoles 1a–1f (100 mol %) were exposed to phenyl-1-propyne 2b (300 mol %) under optimal conditions determined for the coupling of oxindole 1a with alkyne 2a (Table 3). Uniformly high isolated yields of the respective coupling products 3b, 3j–3n were obtained, and in each case, a single geometrical isomer of the trisubstituted olefin was observed by ¹H NMR. Finally, reductive coupling of N-benzyl isatin dehydro-1a (100 mol %) with 1-phenyl-1-butyne 2a (300 mol %) mediated by 2-propanol (200 mol %) was attempted under otherwise standard conditions (eq 1). The adduct 3a was obtained in 65% yield as a single regioisomer with complete control of olefin geometry.

(1)

Table 3.

Ruthenium(0) catalyzed coupling of 3-hydroxy-2-oxindole 1a–1f with alkyne 2b to form adducts 3b, 3j–3n.^a

^aCited yields are of material isolated by silica gel chromatography. C₁₀H₁₅CO₂H refers to adamantane carboxylic acid. See Supporting Information for further experimental details.

^b2-PrOH (200 mol %)

To illustrate how the coupling products may be used as building blocks in chemical synthesis, adduct 3i was converted to the corresponding acrylic ester, which was subjected to ring-closing metathesis⁸ to deliver the spirooxindole 4a (eq 2). Alternatively, conversion of adduct 3i to the corresponding α-diazo ester using p-acetamidobenzenesulfonyl azide (p-ABSA)⁹ followed by exposure to rhodium acetate results in diastereoselective intramolecular cyclopropanation to form the spirooxindole 4b (eq 3).¹⁰ The stereochemistry of 4b was assigned on the basis of nOe studies, as described in the Supporting Information.

(2)

(3)

In summary, by harnessing the reducing power of alcohols, one may avoid the use of premetalated reagents in carbonyl addition.¹ Here, under the conditions of ruthenium(0) catalyzed C-C bond-forming transfer hydrogenation, N-benzyl 3-hydroxy-2-oxindole reacts with internal or terminal alkynes – even acetylene – to form products of hydrohydroxyalkylation. Alternatively, as demonstrated by the coupling of isatin dehydro-1a with 1-phenyl-1-butyne 2a, 2-propanol-mediated alkyne-carbonyl reductive coupling also is possible. Future studies will focus on the use of α-olefins¹¹ and related chemical feedstocks as pronucleophiles in redox-triggered carbonyl addition via alcohol-mediated hydrogen transfer.