Ruthenium-Catalyzed Ortho-Selective C–H Alkenylation of Aromatic

Article pubs.acs.org/Organometallics

Ruthenium-Catalyzed Ortho-Selective C−H Alkenylation of Aromatic Compounds with Alkenyl Esters and Ethers Yohei Ogiwara,† Masaru Tamura,† Takuya Kochi,† Yusuke Matsuura,‡ Naoto Chatani,‡ and Fumitoshi Kakiuchi*,† †

Department of Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan ‡ Department of Applied Chemistry, Faculty of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan S Supporting Information *

ABSTRACT: A direct, regioselective alkenylation of aromatic C−H bonds of aryl- and heteroarylpyridines and related compounds with alkenyl esters was developed using Ru(cod)(cot) as a catalyst. Aromatic compounds bearing electronically diverse substituents and various heterocyclic directing groups are reacted with alkenyl acetates bearing mono- and disubstituted alkenyl groups with aliphatic and aromatic substituents to give ortho-alkenylation products in high yields. The results of deuterium-labeling experiments and competition reactions using different ratios of the E and Z isomers of βstyryl acetate suggested that the C−H alkenylation proceeded via a ruthenium−alkene intermediate and the C−O bond of the alkenyl acetate was cleaved by β-acetoxy elimination. Two types of catalytically relevant species were identified, and the reactivities of these species, combined with the results of the kinetic studies, suggest that the rate-limiting step is the exchange of the COD ligand with the alkenyl ester. On the basis of the elucidated mechanism, the first catalytic coupling reaction using aromatic C−H bonds with C−O bonds of ethers was also developed.

■

the first catalytic alkenylation of arenes with alkynes via C−H bond cleavage in 1979.4a Chelation-assisted control of regioselectivity in C−H functionalization has been applied to the coupling with alkynes to achieve predominantly orthoselective C−C bond formation.10−18 Oxidative arene C−H alkenylation with alkenes (type 2) can be performed catalytically using stoichiometric amounts of oxidants.19−24 The first oxidative coupling was reported by Moritani and co-workers using a Cu(II) or Ag(I) salt as an oxidizing agent,20a and similar oxidative C−H alkenylations with various oxidants including benzoquinone, oxygen, and internal oxidant, such as oxidizing directing groups, have been reported by several research groups.19−24 The dehydrogenative alkenylation of arenes (type 3) developed by several groups employed alkenes as both substrates and hydrogen acceptors, and hydrogenation of alkenes supervenes as an inevitable side reaction.25,26 The coupling of aromatic C−H bonds with alkenylmetal reagents (type 4) is another procedure for direct alkenylation.27,28 This reaction was considered to take place through transmetalation at the transition-metal center with alkenylmetal compounds, such as alkenylboron27 and alkenylsilicon reagents.28 Alkenyl halides and pseudohalides have also been used as alkenylating agents (type 5),29−34 and regioselective functionalizations have been achieved using several directing groups.32−34 These

INTRODUCTION Aromatic alkenes are a highly important class of organic compounds and have been used as versatile industrial and laboratory chemicals for the synthesis of various biologically active compounds and organic materials such as polymers. In recent years, extended π-conjugated systems such as polyarylenes and polyarylenevinylenes have attracted considerable attention, due to their potential applications as organic optical and electronic materials.1 The construction of aromatic alkene moieties by coupling of functionalized aromatic compounds with alkene derivatives is one of the areas where transitionmetal catalysis plays an invaluable role in modern organic synthesis.2 As the tremendous potential of catalytic functionalization of carbon−hydrogen bonds became widely recognized, considerable efforts have been devoted to the direct alkenylation of aromatic rings by transition-metal catalysts.3 To date, the following five alkenylation reactions via carbon− hydrogen bond cleavage by transition-metal catalysts have been developed: (1) addition of arene C−H bonds to alkynes,4−18 (2) oxidative coupling of arenes with alkenes using a stoichiometric oxidant,19−24 (3) dehydrogenative coupling using alkenes as both substrates and hydrogen acceptors,25,26 (4) coupling with alkenylmetal reagents,27,28 and (5) crosscoupling with alkenyl halides or pseudohalides.29−34 The catalytic addition of C−H bonds to C−C triple bonds (type 1) is a straightforward and well-studied direct alkenylation method.4−18 Yamazaki and co-workers reported © XXXX American Chemical Society

Received: December 15, 2013

A

dx.doi.org/10.1021/om401204h | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

Table 1. Generality of Alkenyl Acetatesa

alkenylation reactions produce acids as byproducts, and in general, addition of a base or use of a basic solvent such as DMF is necessary. We have published a preliminary communication on a new catalytic C−H alkenylation method employing alkenyl esters as alkenylating agents.35 This reaction is considered to be a new entry to the type 5 alkenylation, when carboxylate ions are regarded as pseudohalides. However, the acidity of the corresponding conjugate acids, carboxylic acids, is weak and the reaction mostly does not require the use of an additional base or a weakly basic solvent. The alkenylation proceeds in the presence of Ru(cod)(cot) as a catalyst and sp2-nitrogencontaining heterocycles as directing groups. Therefore, this alkenylation can be catalytically performed under both halogen-36 and oxidant-free conditions. This paper provides a detailed description of our research on C−H alkenylation using alkenyl esters, including the substrate scope and a proposed catalytic cycle. In particular, mechanistic investigations using styryl acetate suggested that the alkenyl C− O bond of the ester was not cleaved by oxidative addition, as typically described for catalytic functionalization of carbon− pseudohalide bonds, but rather by β-acetoxy elimination for this reaction. Two catalytically relevant ruthenium complexes were also characterized. In addition, on the basis of the mechanistic analysis, we extended the scope of the alkenylating agents to alkenyl aryl ethers, which give phenol derivatives, acids even weaker than acetic acid, as byproducts. This reaction represents the first catalytic coupling reaction using aromatic C−H bonds with C−O bonds of ethers.

■

RESULTS AND DISCUSSION Optimization and Scope of the C−H Alkenylation with Alkenyl Esters. Screening of Catalysts for Alkenylation of 2-(2-Methylphenyl)pyridine (1) with Vinyl Butylate (2). First, several transition-metal catalysts and additives were screened for the C−H alkenylation using 2-(2-methylphenyl)pyridine (1) and vinyl butylate (bp 115−116 °C)37 (2) as substrates.38 When the reaction was performed using Ru(cod)(cot) (4; COD = 1,5-cyclooctadiene, COT = 1,3,5-cyclooctatriene) as a catalyst, which exhibits interesting reactivities such as cleavage of ortho C−H bonds in 2-phenylpyridine39 and oxidative addition of the C−O bonds in vinyl acetate,40 the alkenylation product 3 was obtained in 34% GC yield (eq 1).

a

Reaction conditions: 1 (1 mmol), alkenyl acetate (3 mmol), Ru(cod)(cot) (4; 0.05 mmol), toluene (1.5 mL), 120 °C. bIsolated yield. cDetermined by 1H NMR spectroscopy. dPerformed in 1,4dioxane (1 mL) at 100 °C. e2-Phenylvinyl n-butylate (6d′) was used instead of 6d. f1 was recovered in 69% yield. gPerformed with 0.1 mmol of 4 and 0.1 mmol of P(2-furyl)3. h1 was recovered in 68% yield. i1 was recovered in 42% yield.

acetates 6a−d bearing an alkyl or phenyl substituent at the β carbon (abbreviated as Cβ) reacted with 1 to provide the corresponding alkenylation products in 82−99% isolated yields with E selectivity (entries 1−5). β-Alkyl -substituted vinyl acetates were used as a mixture of E and Z isomers (E:Z = 40:60 to 59:41), and as the steric bulk of the alkyl substituent increased, the E:Z ratio of the product was improved from 91:9 to 96:4 (entries 1−3). In the alkenylation with 1-hexenyl acetate (6c), use of 1,4-dioxane as a solvent improved the product yield to 99% but had apparently no effect on the E:Z ratio (entry 4). Exclusive formation of the E isomer was observed for the reaction using 2-phenylvinyl acetate (6d) (entry 5). In this case, 2-phenylvinyl n-butylate (6d′) was also tested as an alkenylating agent, but the yield was lower (84%) than that obtained with 2-phenylvinyl acetate (entry 6). The

On the other hand, the use of additives or other transitionmetal complexes was not effective for the alkenylation. On the basis of these results, Ru(cod)(cot) (4) was chosen as a catalyst for the following examinations. Generality of Alkenyl Acetates. Introduction of a variety of alkenyl groups to arylpyridine 1 was then investigated. Acetate was used as a leaving group because of its small size and easy accisibility to the corresponding alkenyl esters. 41 The alkenylation reactions of 1 with several alkenyl acetates 6 were carried out in toluene in an oil bath with its temperature adjusted to 120 °C (Table 1). In all cases, C−C bond formation took place between the ortho carbon of 1 and the α carbon (abbreviated as Cα) of the alkenyl acetates. Alkenyl B

dx.doi.org/10.1021/om401204h | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

Table 2. Generality of the Directing Groupsa

reaction can be applied to an alkenyl ester containing a trisubstituted olefin moiety (6e), and the product was obtained in 90% yield (entry 7). The reaction with β,β-disubstituted vinyl ester 6f under the standard conditions afforded only 21% of the corresponding alkenylation product 7f and a large amount (69% yield) of 1 was recovered (entry 8). Screening of additives was again examined for the reaction with 6f and revealed that the use of tri(2-furyl)phosphine (P(2-furyl)3)42 with higher catalyst loading (10 mol %) effectively increased the yield to 91% (entry 9). 1-Cycloalkenyl acetate (6g) was also applicable for this reaction (entry 10). It is noteworthy that 7f,g are the types of alkenylation products simple C−H/alkyne coupling (type 1) cannot provide mechanistically. The alkenylation of 1 with (E)-1,2-diphenylvinyl acetate ((E)-6h) for 24 h afforded only the E isomer of the corresponding product ((E)-7h) in 23% yield, and a 68% yield of 1 was recovered (entry 11). Interestingly, even in the case of (Z)-1,2-diphenylvinyl acetate ((Z)-6h), complete inversion of the geometry around the CC bond occurred and the E isomer (E)-7h was obtained as the sole product in 46% yield (entry 12). The stereoselectivity of the alkenylation is important for elucidation of the reaction mechanisms, and detailed analyses are presented in a later section. Due to the high reactivity of 2-phenylvinyl acetate (6d) among the alkenyl acetates screened, 6d was used for further examinations. Generality of Directing Groups. Several sp2-nitrogencontaining heterocycles function as directing groups for the C−H alkenylation (Table 2). The reaction of 2-phenylpyrimidine (8) with 6d in refluxing toluene for 30 h gave the 2,6-dialkenylphenylpyrimidine 9 in 90% isolated yield (entry 1). A variety of five-membered N-heterocyclic rings also served as directing groups (entries 2−6). When the reactions of 2phenyl- and 2-(2-tolyl)oxazolines (10 and 12, respectively) were carried out under base-free conditions, the corresponding alkenylation products decomposed during the reactions. For these reactions, the use of 2,6-lutidine as an additive effectively suppressed the decomposition to afford products 11 and 13 in 79% and 69% isolated yields, respectively (entries 2 and 3). The reaction of 1-methyl-5-phenyl-1H-tetrazole (14), which has two ortho C−H bonds, yielded the monoalkenylation product 15 in 52% yield as a sole product (entry 4). Steric repulsion between the methyl group on the tetrazole ring and the styryl group introduced is considered to disturb the second C−H alkenylation. Thiazole and pyrazole rings also functioned as directing groups for the alkenylation, and the corresponding products 17 and 19 were isolated in good yields (entries 5 and 6). In these cases, 1:2 coupling products 17b and 19b were also formed. Benzo[h]quinoline (20), a fused heteroaromatic compound, underwent alkenylation selectively at the 10position (entry 7). Scope of Arylpyridine Substrates. A variety of arylpyridines were examined as subtrates for the alkenylation with 6d to explore the scope and functional group compatibility of the reaction (Table 3). The reaction of 2-phenylpyridine (22) with 3 equiv of 6d in refluxing toluene for 32 h afforded a 3.3:1 mixture of 1:1 (23a) and 1:2 (23b) coupling products (entry 1). As the amount of 6d was increased to 5 equiv and the reaction time was extended to 72 h, the 1:2 coupling product 23b was formed exclusively and isolated in 93% yield (entry 2). The coupling of 3-methyl-2-phenylpyridine (24) with 6d provided only the monostyrylation product 25 in 93% yield due to steric repulsion of the methyl group and the styryl group (entry 3).43 Both electron-donating and -withdrawing func-

a Reaction conditions: aromatic compound (1 mmol), 6d (3 mmol), Ru(cod)(cot) (4; 0.05 mmol), toluene (1.5 mL), 120 °C. bIsolated yield. c2,6-Lutidine (2 equiv) was added. d14 was recoverd in 38% yield.

tional groups were tolerated, and the alkenylation products were mostly obtained in high yields (entries 4−9). An arylpyridine bearing a methoxy group at the 2-position (26a) (entry 4) was slightly more reactive than those arylpyridines bearing electron-withdrawing CF3 and Ac groups (26b,c) (entries 5 and 6). While acetyl3k and cyano44 groups have been reported as directing functionalities for a variety of rutheniumcatalyzed C−C bond formations via aromatic C−H bond cleavage, the alkenylation of 26c and 28 proceeded only at the ortho position of the pyridyl group. Alkenylation of Heteroaromatic Compounds. Introduction of heteroaromatic rings such as thiophenes and pyrroles into extended π systems is one of the methods to tune the optical and electronic properties of the materials.45 Therefore, the C

dx.doi.org/10.1021/om401204h | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

Table 3. Reactions of Arylpyridines with β-Styryl Acetate (6d)a

Table 4. Reactions of Heteroaromatic Compounds with Alkenyl Acetatesa

a

Reaction conditions: heteroaryl compound (0.5−1 mmol), alkenyl acetate (5 equiv), 4 (0.05 equiv), toluene (0.75−1.5 mL), 120 °C. b Isolated yield. c3 equiv of acetate were used. dE:Z = 59:41. eOnly the E isomer was observed. fYields were determined on the basis of the 1H NMR spectra of 31 isolated as a mixture with a,β-dialkenylated compound. g2,6-Lutidine (2 equiv) was added. hE:Z = 66:34.

described in Schemes 1 and 2. The ruthenium catalyst may first react with either an arylpyridine or an alkenyl acetate. The reaction may start with oxidative addition of an ortho C−H bond of an arylpyridine to the ruthenium catalyst (Scheme 1). Chaudret and co-workers reported cleavage of an ortho C−H bond of 2-phenylpyridine (22) by Ru(cod)(cot) (4) in the presence of H2 and PiPr3 to form a five-membered chelate.39 After the oxidative addition to form ruthenacycle 36 proceeds, alkenyl acetates may react in several ways. Insertion of an alkenyl acetate into the Ru−H bond of 36 may take place, and depending on the direction of the insertion, two types of intermediates are formed. If 1,2-insertion occurs (pathway A), β-acetoxy elimination, followed by a Heck reaction type sequence, gives the alkenylation product. β-Acetoxy elimination has been proposed in many transition-metal-mediated processes.46 2,1-Insertion of an alkenyl acetate to 36 (pathway B), followed by α-acetoxy elimination, may lead to the formation of a ruthenium carbene complex, in a way similar to a reaction reported by Caulton and co-workers,47 and this intermediate may also give the product by carbene C−H insertion48 and β-hydride elimination. If 6d is inserted into the Ru−C bond of 36, the product can be formed via β-acetoxy elimination (pathway C). As described earlier in this paper, oxidative addition of vinyl acetate was reported for Ru(cod)(cot) in the presence of PEt3,40 and catalytic cycles involving the oxidative addition of the alkenyl C−O bond of the ester are also reasonable. In pathway D (Scheme 1), oxidative addition of the C−O bond after the initial C−H bond cleavage is involved. Mechanisms starting with C−O bond cleavage to form intermediate 37 are also possible and are described in Scheme

a

Reaction conditions: arylpyridine (1 mmol), 6d (3 mmol), 4 (0.05 mmol), toluene (1.5 mL), 120 °C. bIsolated yield. cProducts were isolated as a mixture of 23a and 23b, and the yields were determined on the basis of the 1H NMR spectrum of the mixture. d5 mmol of 6d was used. e29 was obtained as a 94:6 mixture of E and Z isomers.

application of C−H alkenylation to heteroaromatic compounds was also investigated (Table 4). The reaction of 3-(2pyridiyl)thiophene (30) with 6d took place preferentially at the α C−H bond to give monoalkenylation product 31 and α,β-dialkenylated product in 89% and 6% yields, respectively (entry 1). Couplings of N-(2-pyridyl)pyrrole (32) with alkenyl acetates containing phenyl (6d) and 2-indolyl (6i) groups at Cβ gave the corresponding 2,5-dialkenylated compounds in excellent yields (entries 2 and 3). The oxazolyl group also functioned as a directing group, and C−H bonds at the 2- and 5-positions were both efficiently alkenylated (entry 4). Possible Intermediacy of Ruthenium−Alkene Complex Formed via β-Acetoxy Elimination. The mechanism of the ruthenium-catalyzed alkenylation has not been obvious, because alkenyl esters have not been utilized as alkenylating agents in C−H functionalization reactions except for our reaction. 35 There have been several reports on C−H alkenylation using alkenyl halides or pseudohalides, but different types of mechanisms have been proposed for these reactions.32,33 Several possible mechanisms speculated for the ruthenium-catalyzed alkenylation with alkenyl esters are D

dx.doi.org/10.1021/om401204h | Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

Scheme 1. Hypothetical Reaction Pathways Starting with Oxidative Addition of a C−H Bond

Scheme 2. Hypothetical Reaction Pathways Starting with Oxidative Addition of a C−O Bond

Table 5. Deuterium-Labeling Experimentsa

2. While pathway E, containing oxidative addition of the ortho C−H bond, leads to the same hydrido complex as that in pathway D, an electrophilic metalation or a concerted metalation−deprotonation mechanism (so-called CMD mechanism)49 provides the product without forming a ruthenium− hydride intermediate (pathway F). With these several pathways in mind, we carried out mechanistic studies of the catalytic alkenylation to determine which pathway is the most plausible. Deuterium-Labeling Experiments on the RutheniumCatalyzed Alkenylation of Arylpyridines with 6d. First, we conducted the alkenylation with the deuterium-labeled substrate 24-d5. The reaction of 24-d5 with 6d was carried out at 120 °C. After 1 h, 9% conversion of 24-d5 was observed, and the alkenylation product 25-dn was isolated in 6% yield (Table 5, entry 1). The 1H and 2H NMR spectra of the product revealed that the deuterium content at the alkenyl carbon next to the pyridylaryl moiety (Cα) was 81%, while less than 1% introduction of the deuterium was observed at the other alkenyl carbon (Cβ). However, as the reaction time became longer, the deuterium content at the Cα position of 25-dn was decreased and deuterium incorporation at the Cβ position increased instead (entries 2 and 3). The gradual change in the deuterium content at both alkenyl carbons is considered to be caused by

D incorp, % entry

time, h

conversion, %

yield, %

Cα

Cβ

1 2 3

1 3 20

9 38 100

6 24 98

81 68 45