Intermolecular Dehydrative Coupling Reaction of Arylketones with Cyclic Alkenes Catalyzed by a Well-Defined Cationic Ruthenium-Hydride Complex: A Novel Ketone Olefination Method via Vinyl C–H Bond Activation

Summary

The cationic ruthenium-hydride complex [(η⁶-C₆H₆)(PCy₃)(CO)RuH]⁺BF₄⁻ was found to be a highly effective catalyst for the intermolecular olefination reaction of arylketones with cycloalkenes. The preliminary mechanistic analysis revealed that electrophilic ruthenium-vinyl complex is the key species for mediating both vinyl C–H bond activation and the dehydrative olefination steps of the coupling reaction.

Wittig reaction constitutes one of the most versatile olefination methods whose synthetic prowess has been immensely demonstrated over the years in both laboratory-scale and industrial processes.¹ Despite its synthetic versatility, however, Wittig and related Peterson and Horner-Emmons olefination methods require stoichiometric amount of ylides (or carbanion equivalents), which pose debilitating problems of the formation and removal of byproducts especially for large-scale industrial applications. The Perkin and related Aldol-type condensation/dehydration reactions have also been commonly used as carbonyl olefination methods, but these also suffer from similar restricted functional group compatibility and the formation of copious amount of byproducts.² Considerable research progress has been achieved in the development of transition metal-based carbonyl olefination methods that are more functional group tolerant and environmentally compatible, including: Tebbe’s and Petasis Ti reagents,³ carbonyl-to-diazo coupling,⁴ decarbonylative coupling reaction of aldehydes and alkynes,⁵ and Pd-catalyzed coupling reactions.⁶ From both synthetic and environmental points of view, the development of catalytic version of the carbonyl olefination methods from the intermolecular coupling of carbonyl compounds with unactivated olefins would be highly desirable, but still largely remains an elusive goal. Inspired by the recent progress on electrophilic C–H activation methods,⁷ we have been exploring the coupling reactions of ketones and amines by using cationic ruthenium catalysts.⁸ This report delineates a catalytic ketone olefination method that is transpired from the intermolecular dehydrative coupling reaction of arylketones and cyclic alkenes involving vinyl C–H bond activation.

(1)

We devised a convenient method to synthesize a cationic ruthenium-hydride complex from the protonation reaction of {[(PCy₃)(CO)RuH]₄(μ₄-O)(μ₃-OH)(μ₂-OH)} (1) (Eq 1).⁹ Thus, the treatment of 1 (200 mg, 0.12 mmol) with HBF₄·OEt₂ (64 μL) in C₆H₆ at room temperature cleanly led to the formation of the cationic ruthenium-hydride complex 2, which was isolated as an ivory-colored solid in 95% yield. The ¹H NMR of 2 in CD₂Cl₂ showed the Ru–H signal at δ −10.39 (d, J_PH = 25.9 Hz), and a single phosphine peak was observed at δ 72.9 ppm by ³¹P{¹H} NMR. The molecular structure of 2 as established from X-ray crystallography showed a three-legged piano stool geometry, which is capped by a η⁶-benzene moiety.¹⁰

Having well-defined cationic ruthenium-hydride complex 2 in hand, we next explored its catalytic activity for the coupling reaction of arylketones and alkenes. We initially anticipated the formation of the ortho-C–H insertion product 3, in light of the reported results on the chelate-directed coupling reaction of arylketones and alkenes.¹¹ Instead, the treatment of acetophenone with excess cyclopentene in the presence of 2/HBF₄·OEt₂ (5 mol %) in C₆H₅Cl cleanly produced a ~1:1 ratio of double bond isomers of the olefination products 4a and 5a, without forming any ortho-C–H insertion product 3 (Scheme 1).

Scheme 1.

The preliminary survey of ruthenium catalysts showed that both in-situ formed 1/HBF₄·OEt₂ and the isolated catalyst 2/HBF₄·OEt₂ exhibited uniquely high activity for the coupling reaction (Table 1). The addition of HBF₄·OEt₂ was found to be critical for giving the olefination products since the catalyst 2 alone exhibited a modest activity for the ortho-C–H insertion products (entries 5, 6).¹² One of the most remarkable feature of the coupling reaction is that a direct ketone olefination has been achieved from the intermolecular dehydrative coupling reaction of arylketones and unactivated alkenes without employing any reactive reagents.

Table 1.

Catalyst Survey for the Coupling Reaction of Acetophenone and Cyclopentene.^a

entry	catalyst	additive	4a:5a	convn (%)b
1	1			0
2	1	HBF4·OEt2	1:1	50
3	RuHCl(CO)(PCy3)2			0
4	RuHCl(CO)(PCy3)2	HBF4·OEt2		6
5	2			12c
6	2	HBF4·OEt2	1:1	60
7	RuH2(CO)(PPh3)3	HBF4·OEt2		8
8	RuCl2(PPh3)3	HBF4·OEt2		<5
9	RuCl3·3H2O	HBF4·OEt2		0
10	Ru3(CO)12	NH4PF6		0
11d	[RuH(CO)(PCy3)2(S)2]+BF4−	HBF4·OEt2		0
12	Re(CO)3(THF)2Br	HBF4·OEt2		<5
13	Au(PPh3)3Cl	HBF4·OEt2		<5
14	HBF4·OEt2			0
15	Cy3PH+BF4−			0

^aReaction conditions: acetophenone (0.1 mmol), cyclopentene (2.0 mmol), catalyst (10 mg, 5 mol %), additive (2 equiv to catalyst), C₆H₅Cl (2 mL), 110 °C, 15 h.

^bConversion was determined by GC based on acetophenone.

^cThree different double bond isomers formed from dehydrogenation of 3.

^dS = CH₃CN.

The scope of the olefination reaction was explored by using 2/HBF₄·OEt₂ catalyst (Table 2). Arylketones with para-electron donating group was found to modestly promote the coupling reaction (entries 2, 3), while both terminal and internal olefins such as 1-hexene and 2-hexenes yielded the C–H insertion products 3 under the similar conditions. Both cyclopentene and cyclohexene were found to be suitable substrates, but sterically demanding cyclic alkenes such as cyclooctene and methylcyclopentene as well as trisubstituted olefins yielded <5% of the coupling products. A considerably higher conversion was achieved for naphthyl-substituted ketones (entries 8–11). In most cases, high selectivity for the olefination products of the type 4 and 5 was observed over the ortho-C–H insertion product of type 3, where the formation of a nearly 1:1 ratio of the double bond isomers of 4 and 5 was observed on the crude product mixture. To obtain combined isolated yields, the hydrogenation reaction was performed on the crude product mixture. Thus, the treatment of a product mixture of 4 and 5 with H₂ (2 atm) at 110 °C in the presence of 2/HBF₄·OEt₂ (5 mol %) in C₆H₅Cl cleanly led to the olefin-hydrogenated product 6, which was isolated by a column chromatography on silica gel. The isolated yield of 6 is listed in Table 1.

Table 2.

Coupling Reaction of Arylketones and Cyclic Alkenes.^a

entry	ketone	alkene	products		convn (%)b	yd (%)c
1				X = H (4a, 5a)	60	52
2				X = Me (4b, 5b)	65	55
3				X = OMe (4c, 5c)	70	65
4				X = Cl (4d, 5d)	36	30
5				R = Et (4e, 5e)	42	34
6d				R = CH2Ph (4f, 5f)	30	23
7					53	45
8				X = H (4h, 5h)	92	84
9				X = Me (4i, 5i)	84	75
10				X = OMe (4j, 5j)	97	86
11					92	84
12e,f					50	40g
13e					26	19

^aReaction conditions: ketone (0.7 mmol), alkene (14 mmol), 2 (20 mg, 5 mol %), HBF₄·OEt₂ (10 μL, 2 equiv), C₆H₅Cl (2 mL), 110 °C, 15 h.

^bDetermined by GC based on ketone.

^cCombined isolated yield of 4 and 5 determined from the hydrogenation product 6.

^dContained 28% of PhCH₂CH₂Ph.

^eA 4:1 ratio of 4l and 5l was formed in the crude product mixture.

^f10 mol % of 2 was used.

^gA ~10% of ortho-C–H insertion product type 3 was also formed.

The following experiments were performed to gain mechanistic insights on the olefination reaction. First, the deuterium-labeling pattern was examined from the treatment of acetophenone-d₈ (90 mg, 0.7 mmol) with excess cyclopentene (0.95 g, 14 mmol) and 2/HBF₄·OEt₂ (5 mol %). Extensive H/D exchange was found to occur on the methyl group of both 4a and 5a as well as on cyclopentene, without significant exchange on the ortho positions of the phenyl group as examined by ¹H and ²H NMR.¹² The coupling reaction of acetophenone with a 1:1 mixture of 1-hexene and cyclopentene under the competitive conditions yielded the olefination products 4a and 5a predominantly over the C–H insertion product type 3 (4a+5a:3 = 11:1). These results indicate that the vinyl C–H activation is rapid and reversible and that this step is favored over the arene ortho-C–H activation for cyclopentene case.

To discern the nature of catalytically relevant species, the reaction of 2 with cyclopentene was monitored by NMR. The treatment of 2 (20 mg, 35 μmol) with excess cyclopentene (24 mg, 10 equiv) in CD₂Cl₂ slowly formed a new cationic complex [CpRu(CO)(PCy₃)(c-C₅H₈)]⁺BF₄⁻ (7) within 3 h at 100 °C, along with Cy₃PH⁺BF₄⁻, free benzene and cyclopentane. The structure of 7 was tentatively assigned on the basis of NMR spectroscopic data. Trapping of 7 with PhCN resulted in a stable nitrile complex [CpRu(CO)(PCy₃)(NCPh)]⁺BF₄⁻ (8) (Scheme 2).¹² The formation of cyclopentadienyl complex 8 can be readily rationalized from the dehydrogenation of cyclopentene and the elimination of cyclopentane.

Scheme 2.

Though details of the coupling reaction still remain to be established, we propose a mechanistic rationale that invokes both olefinic C–H bond activation and the dehydrative carbonyl olefination steps (Scheme 3). We propose that the electrophilic Ru-vinyl complex 9, initially generated from the vinyl C–H activation of cycloalkene, is the key species for the coupling reaction. The dative coordination of ketone substrate followed by the alkenyl group migration to the electrophilic carbonyl carbon would yield the alcohol product after transfer of a hydrogen obtained from vinyl C–H activation of a coordinated alkene to the alkoxide ligand. While the formation of metal-vinyl species has been well documented in the C–H bond activation literature,¹³ its synthetic utility has not been fully exploited in catalytic coupling reactions. The detailed mechanistic steps for the formation of the olefin products 4 and 5 from the alcohol are not clear at the present time, but it can be envisaged from an acid catalyzed reductive dehydration of the alcohol, in light of the well-known alcohol dehydration reactions.

Scheme 3.

A Mechanistic Rationale for the Ketone Olefination.

In summary, a novel catalytic ketone olefination method has been developed from the intermolecular coupling reaction of arylketones with cyclic alkenes. Electrophilic nature of the ruthenium catalyst 2 seems to be an essential feature for mediating both vinyl C–H bond activation and the subsequent dehydrative coupling steps of the reaction. The scope and synthetic efficacy of the catalytic method are currently being investigated.