DOI: 10.1002/chem.201300100

Aerobic Oxidative Coupling of Arenes and Olefins through a BiomimeticApproach

Beneesh P. Babu, Xu Meng, and Jan-E. B�ckvall*[a]

An important challenge in synthetic organic chemistry isthe design and development of new environmentally friend-ly synthetic methods that are efficient, selective, and cost ef-fective. As the demand for green chemical approaches is in-creasing, simple and short synthetic routes that produce aminimal amount of waste are called for.[1] Biomimeticmetal-catalyzed aerobic oxidation reactions are of interestin this respect because they are simple to carry out and theygive essentially no side products.[2] In these aerobic oxida-tion reactions, catalytically active, oxidized forms of themetal are maintained in the catalytic cycle through reoxida-tion of the reduced metal by using air (O2) as the terminaloxidant. In the biomimetic approach,[2] the high activationenergy of direct oxidation by O2 is circumvented by the useof electron-transfer mediators (ETMs), which ultimatelydivide the overall oxidation reaction into several intercon-nected redox cycles. This leads to low-energy electron trans-fer, which significantly reduces the activation energy. Anoxygen-activating metal-containing macrocycle and a p-ben-zoquinone derivative have been used as ETMs in combina-tion with an active metal catalyst and air (O2). During thepast two decades, our laboratory has explored this approachin detail and we have developed a range of biomimetic sys-tems[2b, 3–5] for the aerobic oxidation of dienes,[3] alkenes,[3b]

enallenes,[4a] azaenallenes,4b dieneallenes,[4c] alcohols,[5a] ami-nes,[5b,c,d] diols,[5e] and amino alcohols.[5f]

Encouraged by our previous results, we considered thepossibility of expanding the scope of the biomimetic ap-proach towards intermolecular C�C bond-forming reactions.Palladium-catalyzed arylation of olefins (Heck reaction) isone of the fundamental reactions for C�C bond formation.[6]

However, a limiting factor in these reactions is the requiredprefunctionalization of the arene partner, a requirementthat increases the synthetic steps and produces extra saltwaste. The dehydrogenative Heck reaction (DHR), in whicharylation of an olefin proceeds through direct C�H/C�Hcoupling, circumvents this problem.[7] Ever since, Fujiwaraand Moritani first reported the coupling of benzene and

styrene to yield stilbene,[8] the DHR has become the focusof intensive research and has found widespread applicationin organic synthesis.[9] Even though the inherent stability ofthe C�H bond and the lack of selectivity are often challeng-ing, attempts to increase the selectivity and productivity ofthis reaction has attracted much interest. These protocols re-quire stoichiometric amounts of an oxidant to reoxidize thepalladium(0) species back into the active palladium(II) spe-cies, the most commonly used oxidants being copper(II), sil-ver(I), benzoquinone, polyoxometalates, peroxides, and air/O2.

[9,10] By using substrates with a directing group, highlevels of site selectivity can be obtained in these olefinationreactions.[11]

Among the different oxidants mentioned above, molecu-lar oxygen is the ideal oxidant for oxidative couplings(Scheme 1). However, the aerobic DHR suffers from severelimitations such as the need for relatively high catalyst load-

ing, high pressure of oxygen, high concentration of arene(often used as the solvent), and stoichiometric amounts ofvarious additives.[7,8,9b] We considered the possibility of usinga biomimetic approach for this oxidative coupling in whichthe aerobic reoxidation of the metal is facilitated by catalyt-ic ETMs (Scheme 2). Herein, we report a direct C�H/C�Hcoupling of arenes and electron-deficient olefins through abiomimetic approach that employs relatively low catalyst

[a] Dr. B. P. Babu, X. Meng, Prof. J.-E. B�ckvallDepartment of Organic Chemistry, Arrhenius LaboratoryStockholm University, 106 91 Stockholm (Sweden)Fax: (+46) 8-154-908E-mail : jeb@organ.su.se

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/chem.201300100.

Scheme 1. General scheme for aerobic oxidative coupling.

Scheme 2. Biomimetic aerobic dehydrogenative coupling.

� 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 4140 – 41454140

loading and can be conducted under oxygen at atmosphericpressure.

The dehydrogenative coupling between n-butyl acrylate(1 a) and 1,4-dimethoxybenzene (2) was chosen as the testreaction, and after some initial trials we found that heatinga mixture of 1 a (1 mmol) and 2 (5 mmol) in the presence ofcatalytic amounts of Pd ACHTUNGTRENNUNG(OAc)2 (2.5 mol %), p-benzoquinone(BQ; 20 mol %) and iron phthalocyanine ([Fe(Pc)], Pc=

phthalocyanine; 2 mol %) in acetic acid (0.5 mL) at 90 8Cunder molecular oxygen (1 atm) for 24 h afforded couplingproduct 3 a in 69 % yield as a pale brown viscous liquid. n-Butyl 3-acetoxyacrylate (4) was the major side product withtrace amount of b,b-diarylated acrylate [Eq. (1)].

Encouraged by this result, we repeated the reaction usingvarious palladium salts, ETMs, and acids to find the best re-action conditions for this coupling and the results are sum-marized in Table S1 (see the Supporting Information).[12] Pd-ACHTUNGTRENNUNG(OAc)2 was the best catalyst for this oxidative coupling andit�s use gave the coupling product in 69 % yield; the use ofPd ACHTUNGTRENNUNG(OOCCF3)2 and [Pd ACHTUNGTRENNUNG(acac)2] (acac= acetylacetonate) af-forded the product in lower yields, 45 and 51 %, respectively.On the other hand, PdCl2 was not effective at all. 2,6-Dime-thoxy-1,4-benzoquinone and chloranil were also tested inplace of p-benzoquinone (BQ). However, both of these qui-nones were less effective than BQ and only gave the prod-ucts in yields ranging from 20 to 24 %. Interestingly, the roleof [Fe(Pc)] was quite unique in the coupling as attempts tosubstitute it with either cobalt(phthalocyanine), [Co(Pc)], orcobalt ACHTUNGTRENNUNG(salophen) were less successful and afforded couplingproduct 3 a in low yield (12 and 28 %, respectively). Thepresence and identity of acid was also crucial: the couplingwas inefficient in the absence of acetic acid and although tri-fluoroacetic acid promoted the reaction to some extent(31 % yield), the use of methane sulfonic acid was not effec-tive at all. The reaction completely failed in the absence ofPd ACHTUNGTRENNUNG(OAc)2, and the absence of an ETM in the coupled cata-lytic system resulted in less than 10 % yield. Decreasing theloading of BQ and [Fe(Pc)] to 5 mol % and 1 mol%, respec-tively, afforded the cinnamate derivative in only 38 % yield.

With optimized reaction conditions established, we nextexamined the scope of the oxidative coupling reaction byusing various olefins in conjunction with 2. As summarizedin Table 1, a wide range of electron-deficient olefins couldbe employed as the coupling partners. Thus, other acrylatessuch as methyl acrylate (1 b) and tert-butyl acrylate (1 c) alsocoupled smoothly with 2 to afford the corresponding cinna-

mate derivatives, 3 b and 3 c, in 66 and 61 % yield, respec-tively (Table 1, entries 2 and 3). Both a- and b-substitutedacrylates were effective in this aerobic coupling. Thus,whereas the use of methyl cinnamate (1 d) afforded the cou-pled product as a mixture of E/Z isomers in 65 % yield(Table 1, entry 4), the use of ethyl crotonate (1 e) gave asingle isomer in a moderate yield of 35 % (Table 1, entry 5).When n-butyl a-methacrylate (1 f) was used, two differentarylated products were obtained, namely the normal prod-uct, 3 f1, and its double bond isomer, 3 f2, which were ob-tained in a combined yield of 56 % (Table 1, entry 6). Nota-bly, in addition to acrylates, conjugated aldehydes and ke-tones are also suitable olefins to couple with 2 in this reac-tion. Thus, cinnamaldehyde (1 g) and chalcone (1 h) weresuccessfully coupled with 2 and the corresponding products,3 g and 3 h, were isolated in 67 and 63 % yield, respectively,as a 7:1 mixture of E/Z isomers in each case (Table 1, en-tries 7 and 8). In addition, the reaction of phenyl vinyl sul-fone (1 i) with 2 also gave the desired product in 55 % yield(Table 1, entry 9). Even though the stereochemistry of the

Table 1. Biomimetic aerobic C�H olefination of 1,4-dimethoxy-benzene.[a]

Entry Olefin Product Yield [%][b,c]

1 R= nBu, 1a R=nBu, 3 a 692 R= CH3, 1b R=CH3, 3 b 663 R= tBu, 1c R= tBu, 3c 61

465[d]ACHTUNGTRENNUNG(E/Z=3:1)

5 35

6 56[d] (1:1)

767[d]ACHTUNGTRENNUNG(E/Z=7:1)

863ACHTUNGTRENNUNG(E/Z=7:1)

9 55[e]

[a] Olefin (1 mmol), 2 (5 mmol), Pd ACHTUNGTRENNUNG(OAc)2 (2.5 mol %), BQ (20 mol %),[Fe(Pc)] (2 mol %), AcOH (0.5 mL), O2 (1 atm), 90 8C, 24 h. [b] Yield ofisolated product. [c] Product ratio determined using NMR analysis of iso-lated mixtures. [d] The assignment of E stereochemistry to the majorisomer was supported by NOE analysis. [e] 5 mol % of Pd ACHTUNGTRENNUNG(OAc)2 wasused.

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b,b-disubstituted products can be predicted by the well-ac-cepted mechanism of the Heck reaction, NOE experimentswere carried out on the major isomer obtained from repre-sentative reactions to confirm the assignment.

As summarized in Scheme 3, the C�H olefination of anumber of arenes with n-butyl acrylate was quite successful.In the case of electron-rich arenes such as alkoxy- and alkyl-substituted arenes, this biomimetic aerobic coupling pro-

ceeded smoothly with low catalyst loading, Pd ACHTUNGTRENNUNG(OAc)2

(2.5 mol%), and with only 5–10 equivalents of excess arene,thus providing the corresponding mono-olefinated productsin moderate to good yields. The use of 1,4-dimethoxyben-zene, 1,3-dimethoxybenzene, and 1,4-dimethoxynaphthalenegave the corresponding cinnamate derivatives, 3 a, 5, and 6,respectively, as single isomers. The use of 1,2-dimethoxyben-zene gave 7 as a 7:1 mixture of isomers, whereas the use of1,2,3-trimethoxybenzene afforded 8 as a 5:1 mixture of iso-mers. The use of anisole provided a mixture of ortho, meta,and para isomers 9 in a ratio of 4:1:7, respectively. Interest-

ingly, 2,3-benzofuran was also reactive under these reactionconditions and afforded a mixture of 2- and 3-substitutedisomers in a ratio of 4:1. When 1-bromo-3,5-dimethoxyben-zene was subjected to the reaction conditions, the expectedproduct 11 was isolated as a white crystalline solid in a mod-erate yield of 40 %, the bromine atom remaining in theproduct. Alkyl-substituted benzenes, p-xylene, o-xylene, andtoluene could also undergo oxidative coupling, thus givingthe corresponding cinnamate derivatives. The use of p-xylene afforded product 12 in 54 % yield, whereas the use ofo-xylene and toluene gave products 13 and 14, respectively,each being isolated as a mixture of isomers. However, 10equivalents of alkyl benzenes was used for good conversion.This protocol was not limited to electron-rich arenes; elec-tronically neutral arenes such as benzene and naphthalenealso coupled with 1 a to give the corresponding cinnamates,15 and 16, in 56 and 64 % yields, respectively. A catalystloading of 5 mol % Pd ACHTUNGTRENNUNG(OAc)2 and 10 equivalents of arenewere required in the case of benzene and naphthalene toachieve the best results. Moderately electron-deficientarenes such as chlorobenzene and bromobenzene also func-tioned as successful arene partners in this coupling when5 mol % Pd ACHTUNGTRENNUNG(OAc)2 and 10 equivalents of arene were em-ployed. The cinnamate derivatives 17 and 18 were isolatedas mixtures of isomers in 54 and 45 % yield, respectively.

Interestingly, careful monitoring of the reaction revealedthat the course of the coupling of electron-rich arenes withacrylates depends on the amount of catalyst and it is possi-ble to switch between mono- and diarylated products bychanging the catalyst loading. Thus, for the coupling of 1 aand 2, when the catalyst loading was increased from 2.5 to4 mol % and the reaction time was 24 hours, a mixture ofmono- (b) and diarylated (b,b) products in a ratio of 1:4 wasobtained. By increasing the catalyst loading further to5 mol %, diarylated product 19 was obtained exclusively in55 % yield as a brown viscous liquid. The product yield wasincreased to 70 % when 10 equivalents of 2 was used in1 mL of acetic acid, reaction conditions that turned out tobe optimal for this diarylation reaction (Table 2, entry 1).This protocol was found to be applicable to other electron-rich arenes and acrylates and the results are shown inTable 2. The use of tert-butyl acrylate with 2 led to diarylat-ed product 20 being isolated in 61 % yield (Table 2, entry 2).The use of 1,4-dimethylbenzene was also successful in theaerobic diarylation reaction with n-butyl acrylate, yieldingthe corresponding product 21 in 66 % yield (Table 2,entry 3). Finally, the use of 1,2-dimethoxybenzene and 1,2-dimethylbenzene afforded the corresponding diarylatedproducts 22 and 23 in 63 and 62 % yield, respectively, a mix-ture of isomers being isolated in each case (Table 2, in en-tries 4 and 5).

Notably, the mono- and diarylation of acrylate was quitesensitive towards the Pd ACHTUNGTRENNUNG(OAc)2 loading: whereas the reac-tion between 1 a and 2 with 2.5 mol % PdACHTUNGTRENNUNG(OAc)2, which af-forded monoarylated acrylate 3 a as the major product (evenafter 40 h), was relatively slow (44 % conversion after 8 h),when 5 mol % of PdACHTUNGTRENNUNG(OAc)2 was used, the same reaction was

Scheme 3. Biomimetic aerobic C�H olefination of arenes with n-butylacrylate. Unless otherwise noted, 1a (1 mmol), arene (5 mmol), Pd-ACHTUNGTRENNUNG(OAc)2 (2.5 mol %), BQ (20 mol %), [Fe(Pc)] (2 mol %), and AcOH(0.5 mL), were stirred under O2 (1 atm) at 90 8C for 24 h. Yields of prod-ucts isolated by chromatography are reported. Product ratios were deter-mined from 1H NMR analysis of isolated mixtures. [a] Arene (10 mmol)and AcOH (1.0 mL) were used. [b] Arene (10 mmol), Pd ACHTUNGTRENNUNG(OAc)2

(5 mol %) and AcOH (1.0 mL) were used. [c] Reaction at 80 8C.

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J.-E. B�ckvall et al.

fast and afforded, after 6 hours, a mixture of mono- and dia-rylated acrylates in an approximate ratio of 2:1 ratio andwith 80 % conversion. We therefore monitored the progressof the reaction between 1 a and 1,4-dimethoxybenzene(Table 2, entry 1). At reaction times of up to 3 hours, themonoarylated product, 3 a, was formed almost exclusively(69 %) with only trace amount of diarylated product 19. Forreaction times longer than 3 hours, the diarylation reactionbecomes competitive and the yield of 19 gradually increases,at the expense of 3 a, the yield of which decreases withlonger reaction times, thus leading to 19 being the exclusiveproduct after a reaction time of 24 hours.[12]

There are not many reports in the literature for selectiveb,b-diarylation of acrylates.[9j,13] The one-pot aerobic doubledehydrogenative coupling described herein is noteworthybecause it allows symmetrical b,b-diarylated conjugatedesters to be formed exclusively by using acrylates as the sub-strate and a relatively low catalyst loading of 5 mol % underambient oxygen pressure as reaction conditions. b,b-Diary-lated a,b-unsaturated esters and their derivatives are impor-tant moieties in organic synthesis because they are structuralelements in many natural products and can function as pre-cursors in synthesis.[14]

To obtain insight into the mechanism of the reaction, wecompared the initial rates of the reactions between bothbenzene and [D6]benzene with 1 a in two independent ex-periments (Scheme 4, [Eqs. (2) and (3)]). From these experi-

ments a kinetic isotope effect (kH/kD) of 3.9 was obtained.In addition, when a 1:1 mixture of benzene and [D6]benzenewas subjected to the same reaction condition (Scheme 4,[Eq. (4)]), ESI mass spectrometric analysis of the reactionmixture, after a reaction time 2 h, showed the presence of15 and [D5]-15 in a ratio of 4.1:1, thus representing a kineticisotope effect of 4.1.[15]

A possible mechanism for the reaction is presented inScheme 5, it being similar to the well-known Fujiwara–Mori-tani reaction.[8] As depicted in path 1, s-aryl-PdII intermedi-

ate I is formed first through electrophilic substitution andthen coordinates the olefin to form p-complex II. Migratoryinsertion gives III and subsequent b-hydride eliminationgenerates the product, IV. The hydride species. HPd ACHTUNGTRENNUNG(OAc),which is formed as an intermediate, is subsequently reducedto Pd0. However, the acidity of the reaction medium and thecoordination of BQ to the metal gives Pd0 a sufficient life-time in solution.[16] These conditions prevent the precipita-tion of Pd0 and enables reoxidation of Pd0 to PdII through abiomimetic route, with O2 as the terminal oxidant and p-BQ

Table 2. Biomimetic aerobic diarylation of acrylates with arenes.[a]

Entry Arene Product Yield [%][b]

1 70

2 61

3 66

4 63[c] (6:1)

5 62[c] (3:1)

[a] Acrylate (1 mmol), arene (10 mmol), Pd ACHTUNGTRENNUNG(OAc)2 (5 mol %), BQ(20 mol %), [Fe(Pc)] (2 mol %), AcOH (1.0 mL), O2 (1 atm), 90 8C, 24 h.[b] Yield of isolated product. [c] Combined yield of isomeric products.

Scheme 4. Determination of deuterium isotope effects. (i) 1 a (1 mmol),C6H6/C6D6 (10 mmol), Pd ACHTUNGTRENNUNG(OAc)2 (5 mol %), BQ (20 mol %), [Fe(Pc)](2 mol %), AcOH (1 mL), 90 8C, O2 (1 atm), 2 h.

Scheme 5. Plausible mechanism for the aerobic dehydrogenative cou-pling.

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and Fe(Pc) as electron-transfer mediators, as shown inpath 2.

In conclusion, we have developed a novel, biomimetic,aerobic route for the dehydrogenative C�H/C�H couplingbetween arenes and olefins. The reaction works well forboth electron-rich and moderately electron-deficient arenes.Relatively low catalyst loading was required and this ap-proach allowed the arene to be used in amounts that werenot too excessive. Importantly, the outcome could be switch-ed between mono- and diarylation of acrylate by varying thecatalyst loading.

Experimental Section

Pd ACHTUNGTRENNUNG(OAc)2 (5.6 mg, 0.025 mmol), p-benzoquinone (21.6 mg, 0.2 mmol),iron phthalocyanine (11.4 mg, 0.02 mmol), and 1,4-dimethoxybenzene(690 mg, 5 mmol) were added to a Schlenk tube. The mixture was de-gassed under reduced pressure for a few seconds and then oxygen gaswas introduced with a balloon. This exchange of atmosphere was repeat-ed 3–4 times and olefin (1 mmol) was introduced into the tube (in thecase of olefins that were solids, these were introduced along with theother reagents). Acetic acid (0.5 mL) was then added and the mixturewas stirred in an oil bath at 90 8C for 24 h under molecular oxygen. Thereaction mixture was then cooled to room temperature, diluted withCH2Cl2, and filtered through a short pad of Celite. The filtrate was con-centrated and the residue was subjected to silica-gel column chromatog-raphy, eluting with pentane/ethyl acetate to afford the correspondingproduct.

Acknowledgements

Financial support from the European Research Council (ERC AdG247014) is gratefully acknowledged.

Keywords: aerobic oxidation · biomimetic synthesis · C�Hactivation · dehydrogenative coupling · palladium

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www.chemeurj.org � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 4140 – 41454144

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[15] See the Supporting Information for details. The deuterium isotopeeffect obtained is in accordance with that obtained by Ishii and co-workers (4.0), Ref [9a].

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Received: January 11, 2013Published online: February 28, 2013

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COMMUNICATIONBiomimetic Oxidative Coupling of Arenes and Olefins