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PUBLISHED ONLINE: 3 OCTOBER 2010 | DOI: 10.1038/NCHEM.862

An efcient organocatalytic method for constructing biaryls through aromatic CH activation

Chang-Liang Sun1, Hu Li1, Da-Gang Yu1, Miao Yu1, Xiao Zhou1, Xing-Yu Lu1, Kun Huang1, Shu-Fang Zheng2, Bi-Jie Li1 and Zhang-Jie Shi1 *
The direct functionalization of CH bonds has drawn the attention of chemists for almost a century. CH activation has mainly been achieved through four metal-mediated pathways: oxidative addition, electrophilic substitution, s-bond metathesis and metal-associated carbene/nitrene/oxo insertion. However, the identication of methods that do not require transition-metal catalysts is important because methods involving such catalysts are often expensive. Another advantage would be that the requirement to remove metallic impurities from products could be avoided, an important issue in the synthesis of pharmaceutical compounds. Here, we describe the identication of a cross-coupling between aryl iodides/bromides and the CH bonds of arenes that is mediated solely by the presence of 1,10-phenanthroline as catalyst in the presence of KOt-Bu as a base. This apparently transition-metal-free process provides a new strategy with which to achieve direct CH functionalization.

irect CH bond transformation is a fundamentally important subject in organic synthesis in both academic and industrial processes. The pursuit of efcient methods to directly transform CH bonds to other functional groups dates back to early in the twentieth century15. Selective functionalization of aromatic CH bonds is now an important aspect of this rather general eld due to the universal existence of aromatic functionalities in nature and the synthetic world. Fenton chemistry69 and FriedelCrafts reactions10,11 are early examples of transformations of aryl CH bonds to different functionalities. Later, various catalytic systems were developed. Reactions relying on late transition metal catalysts have ourished in particular1219. These transition-metal-catalysed processes can be summarized into four general mechanisms (Fig. 1): (a) FriedelCrafts-type electrophilic attack by high-valent transition-metal species, followed by deprotonation12,1618,2023; (b) oxidative addition of CH bonds to low-valent electron-rich transition-metal catalysts2428; (c) s-bond metathesis19; and (d) metalassociated carbene/nitrene/oxo insertion1315,29. Our research has focused on the catalytic cross-coupling reactions of arenes to construct biaryls30. In particular, we are interested in the cross-coupling of aromatic CH bonds with functionalized arenes in an atom-economic and waste-free manner. Such reactions have been deemed to be among the most aspirational reactions as yet underdeveloped in the key green chemistry research areas favoured by the pharmaceutical industry. The resulting biaryl scaffolds are privileged structural units that have diverse applications in the elds of pharmaceuticals, fragrances, dyes and agrochemicals. In the past few decades, many methods have been developed to directly functionalize CH bonds, often involving the late transition metals or noble metals3144. The need for high catalyst loading in some of these processes results in a high economic cost. The presence of heavy transition-metal impurities in the nal products also presents a major problem regarding purication, further

increasing the costs involved. The development of efcient and transition-metal-free processes will signicantly change synthetic strategies for the assembly of biaryl structures. Herein, we discuss
M M H M Mn+

c
MR M

d
M Y

Metal-free ArX

Ar

C or N

Figure 1 | Direct aromatic CH transformations. a, CH functionalization through electrophilic attack by high-valent transition metals. M Pt(II), Pt(IV), Pd(II), Pd(IV), Au(III), Cu(III), and so on. b, Oxidative addition of CH to low-valent transition-metal complexes to carry out CH functionalization. M Ir(I), Rh(I), Ru(0), and so on. c, Direct CH transformation via s-bond metathesis. M Ir(III), Zr(IV), and so on. d, Direct aromatic CH transformation via carbene insertion. In each of ad the formed organometallic intermediate can go on to form a new CC bond. e, In this report, cross-coupling of arenes with aryl iodides/bromides in the absence of transition metals. M transition metal, Ar aryl, X I or Br.

Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China, 2 Department of Chemistry and Materials Science, Sichuan Normal University, Chengdu, Sichuan 610068, China. *e-mail: zshi@pku.edu.cn
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examinations of the conditions led us to identify the combination of Co(acac)3 and 1,10-phenanthroline in the presence of KOt-Bu (as a base) as most efcient: .99% conversion of 1aI occurred, and product 3aa could be isolated in 71% yield (entry 2, Table 1). N,N -dimethylethylenediamine (DMEDA) demonstrated a similar reactivity as a ligand. Further studies indicated that less reactive 4-bromoanisole (1aBr) was also suitable for this cobalt-catalysed transformation (entry 3, Table 1). Initially, we hypothesized that this catalytic process might proceed through a single electron transfer (SET) pathway. We were, however, surprised by the control reactions, in which the desired cross-coupling product 3aa was observed in a considerable yield even in the absence of any additional cobalt species (that is, with just the ligand and base at 80 8C (entry 4, Table 1)). The efciency was dramatically decreased when 4-bromoanisole (1aBr) was used to replace 1aI, despite the fact that it had reacted in the presence of Co(acac)3 catalyst (entry 5, Table 1). These results suggested that the cobalt species played a vital role in the crosscoupling under these conditions because the addition of the cobalt species signicantly improved the reaction efciency. We then began searching for the optimum conditions for the coupling reaction. Considering the higher reactivity of aryl iodides, we rst explored the reactivity of 1aI, and found that the starting material was completely consumed with an 83% isolated yield of the product in the presence of 20 mol% catalyst at 100 8C (entry 6, Table 1). We were taken by surprise once again when reaction of 1aBr at the higher temperature of 100 8C in the presence of only 1,10-phenanthroline (20 mol%) and KOt-Bu afforded a 99% conversion of the starting material and a 48% isolated yield (entry 7, Table 1). Notably, the conversion and yield were affected by the amount of 1,10-phenanthroline used. Increasing the amount of 1,10phenanthroline to 40 mol% resulted in complete conversion of the starting material and an isolated yield of 87% (entry 8, Table 1). Other types of organic ligand-type catalysts were also tested. We found that the structurally similar compounds showed good reactivity (entry 10, Table 1). However, a lower efciency was observed with both highly steric hindered L3 and the electron-decient L4, which might have arisen either from a steric effect or electronic effects (entries 11 and 12, Table 1). Moreover, compounds such as DMEDA did not show good reactivity in this transformation of 1aBr (entry 9, Table 1), despite the fact that they served as good
b
1 0.9 0.8 0.7 0.6 Yield 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 16 18 20 22 Time (h)

Table 1 | Cross-coupling of aryl halides with benzene promoted by cobalt salts or various ligand-type organic compounds.
Catalyst, L MeO 1 X + 2 H KOt-Bu, T MeO 3aa NO2 Ph Ph

N L1

N L2

N L3

N L4

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13

X I I Br I Br I Br Br Br Br Br Br I

Co (10 mol%) Co(acac)3 Co(acac)3 Co(acac)3

L (mol%) DMEDA (40) L1 (40) L1 (40) L1 (40) L1 (40) L1 (20) L1 (20) L1 (40) DMEDA (40) L2 (40) L3 (40) L4 (40) L1 (5)

T (8 C) 8 80 80 80 80 80 100 100 100 100 100 100 100 100 (48 h)

Yield (%) 69 71 70 62 5 83 48 87 0 92 59 0 80

Reactions using 4-iodoanisole were carried out on the scale of 0.2 mmol 4-iodoanisole in the presence of ligands and 2.0 equiv. KOt-Bu in 2 ml benzene in sealed Schlenk tubes at 100 8C for 24 h (48 h in entry 13). Reactions using 4-bromoanisole were carried out on the scale of 0.5 mmol 4-bromoanisole in the presence of ligands and 3.0 equiv. KOt-Bu in 4 ml benzene in sealed Schlenk tubes at 100 8C for 18 h. The yields of product 3aa, 4-methoxybiphenyl, were determined by gas chromatography with n-dodecane as an internal standard.

the development of a cross-coupling between aryl iodides/bromides and general arenes in the absence of supplemental transition metals.

Results
Initially, we had identied a cobalt-catalysed cross-coupling between 4-iodoanisole (1aI) and benzene (2a). In the presence of suitable ligands to promote the cross-coupling, the desired product 3aa was observed in moderate yields at 80 8C. Systematic
a
1 0.9 0.8 0.7 Conversion 0.6 0.5 0.4 0.3 0.2 0.1 0 0 2 4 6 8 10 12 14 16 18 20 22 Time (h)
TM-free Cu(OAc)2, 50 ppm Cu(OAc)2, 100 ppm Cu(OAc)2, 10,000 ppm Cu(acac)2, 10,000 ppm CuI, 10,000 ppm CuBr, 10,000 ppm Fe(OAc)2, 10 ppm Co(acac)3, 10 ppm Ni(acac)2, 10 ppm Pd(OAc)2, 10 ppm [Ru(COD)Cl]2, 10 ppm [Rh(COD)Cl]2, 10 ppm

TM-free Cu(OAc)2, 50 ppm Cu(OAc)2, 100 ppm Cu(OAc)2, 10,000 ppm Cu(acac)2, 10,000 ppm CuI, 10,000 ppm CuBr, 10,000 ppm Fe(OAc)2, 10 ppm Co(acac)3, 10 ppm Ni(acac)2, 10 ppm Pd(OAc)2, 10 ppm [Ru(COD)Cl]2, 10 ppm [Rh(COD)Cl]2, 10 ppm

Figure 2 | Kinetic studies comparing the reaction prole with various added transition-metal catalysts. a, Comparison of starting material conversion versus time for reactions run in the presence of additional transition metals (Cu, Fe, Co, Ni, Pd, Ru, Rh), different copper sources, and with different loadings of Cu(OAc)2. b, Comparison of cross-coupling product yield versus time for reactions run in the presence of additional transition metals (Cu, Fe, Co, Ni, Pd, Ru, Rh), different copper sources, and different loadings of Cu(OAc)2. Exponential decay of 4-bromoanisole (laBr) and formation of 4-methoxy-1,1 -biphenyl (3aa) was observed, indicating the zero-order dependence on different metal catalysts. Furthermore, reaction yields with added transition metals were found to be lower than the metal-free reaction.
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Table 2 | Cross-coupling of various aryl iodides/bromides with arenes in the presence of a catalytic amount of 1,10-phenanthroline.
R X 1
MeO 3aa, 83% (X = I) 86% (X = Br) MeO

Y + H 2

1,10-phenanthroline KOt-Bu T C

3
OMe

3ba, 81% (X = I)

3ca, 73% (X = I)

3da, 74% (X = Br)

Me

Me

Me

Me

3ea, 69% (X = I) 89% (X = Br)

Me 3fa, 82% (X = Br) 3ga, 52% (X = I) 44% (X = Br) 3ha, 74% (X = I) 59% (X = Br)

Me MeO Me 3ia, 77% (X = Br)

Ph

F3CO 3ja, 89% (X = I) 3ka, 89% (X = I)

3la, 78% (X = I)

Cl 3ma, 82% (X = I)

F3C

NC 3oa, 36% (X = I) 72% (X = Br)

Bz 3pa, 68% (X = Br)

3na, 42% (X = I)

N N 3qa, 65% (X = I)

N Me

3ra, 72% (X = I)

3sa, 68% (X = Br)

3ta, 52% (X = Br)

Ph

Ph MeO

Me Me Me 3ab, 27% (X = I) MeO F 3ac, 81% (X = I) 81% (X = Br)

3ja, 46% (X = I, R = 4-I) 35% (X = I, R = 4-Br)

MeO

OMe

3ad, 74% (X = I) (2-F/5-F = 1/2.0)

Me Me MeO 3ae, 49% (X = I) MeO

F OMe Me

Me

MeO

MeO

3af, 62% (X = I) (2-F/5-F = 1/1.4)

3ag, 70% (X = I) (o/m/p = 4.8/1.6/1)

3ah, 58% (X = I) (o/m/p = 1/0.4/0.35)

MeO MeO 3ai, 70% (X = I) (o/m/p = 8.0/5.0/1) F MeO CF3 3ak, 60% (X = I) (a/b = 1:1.9)

MeO N Me 3al, 26% (X = I) one isomer

3aj, 70% (X = I) (o/m/p = 1.7/4.7/1)

The reactions of bromides were carried out on the scale of 0.5 mmol of aryl bromides in the presence of 40 mol% 1,10-phenanthroline and 3.0 equiv. KOt-Bu in 4 ml arenes (if liquid) at 100 8C for 1824 h. The reactions of iodides were carried out on the scale of 0.2 mmol of aryl iodides in the presence of 20 mol% 1,10-phenanthroline and 2.0 equiv. KOt-Bu in 2 ml benzenes at 100 8C for 24 h. The reactions of various arenes were carried out on the scale of 0.5 mmol of aryl halides in the presence of 40 mol% 1,10-phenanthroline and 3.0 equiv. KOt-Bu in 80 equiv. arenes at 120 8C for 48 h.

ligands in the cobalt-catalysed CH activation cross-coupling. When the amount of 1,10-phenanthroline was decreased to 5 mol%, 100% conversion of 1aI and an 80% isolated yield could be obtained simply by increasing the reaction time (entry 13, Table 1). The observation of cross-coupling product 3aa in the absence of any added metal catalyst concerned us, and our initial thoughts were that the transformation was being induced by metal impurities in the ligand set and/or the base. To explore this possibility, we analysed both KOt-Bu and 1,10-phenanthroline using inductively
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coupled plasma atomic emission spectroscopy (ICP-AES) and inductively coupled plasma mass spectroscopy (ICP-MS). Indeed, 10 ppb10 ppm of Pd, Cu, Fe and other metal species were detected in the ligand and base. However, we also found that the addition of 101,000 times these amounts of various metal salts to the reaction system did not obviously enhance the reaction rate, and in some cases the reaction efcacy was reduced. We next carried out kinetic studies in which we examined both the consumption of the starting materials and the formation of the desired products using gas chromatography in the presence of a variety of added

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N K N O H t-Bu

transition-metal catalysts in different concentrations (Fig. 2). The exponential decay of la-Br and formation of 3aa were observed, indicating the zero-order dependence on different metal catalysts (Fig. 2). On the other hand, the use of commercially available sublimed KOt-Bu (Aldrich) and other different sources of KOt-Bu and 1,10-phenanthroline did not dramatically affect the reaction outcome. We also repeated the experiments with new glassware, and even took the extreme step of having other laboratories repeat the reactions and conrm the reliability of our observations. Ultimately, we concluded that the reaction rate was, in fact, not related to the concentration of any transition-metal complex, and that transition-metal complexes were not involved in this crosscoupling reaction. To the best of our knowledge, this was the rst example of a high yield cross-coupling between aryl halides and benzene in the absence of additional transition metals (we became aware of similar results from other laboratories while this manuscript was in press45). This transition-metal-free protocol potentially solves the challenging problem of heavy metal remaining in nal products. On the other hand, recent reports on transition metal-catalysed cross-coupling between aryl iodides and arenes suggest that the metal-free condition developed here likely occurs through a completely different reaction mechanism16,24,28,31,46,47. To explore potential applications of this method, a variety of aromatic iodides (ArI) were initially examined (Table 2). Electrondonating substituents on the phenyl ring of ArI, such as methoxyl and methyl groups, promoted the cross-coupling in high efciency, and the desired products were isolated in good to excellent yields. The substitution pattern made little difference to the reaction outcome (3aa, 3ba, 3ca, 3ea and 3ga). Polysubstituted electronrich aryl iodides also worked well (3ha). 4-Chloro-1-iodobenzene and 4-uoro-1-iodobenzene were also tested, and the corresponding coupling products were isolated in excellent yields, leaving the uoride and chloride substituents untouched (3la, 3ma). These results not only indicate the compatibility of CF and CCl with the reaction condition, but also offer an opportunity to further functionalize the products through sequential orthogonal cross-couplings. 4-Bromobiphenyl gave an excellent yield of the terphenyl product (3ja). Some electron-decient aryl iodides were not good substrates for this reaction. For example, 1-iodo-3-triuoromethylbenzene and 4-iodobenzonitrile showed only moderate reactivity under the same conditions (3na, 3oa). 1-Iodo-4-triuoromethoxybenzene, however, did couple with an isolated yield of 89% (3ka). Naphthyl and heteroaryl iodides also underwent this transformation smoothly and gave good yields (3qa, 3ra). Under optimized conditions, various aryl bromides (ArBr) were studied (Table 2). As with the iodide couplings, electron-donating substituents were benecial for this transformation in most cases (3aa, 3da, 3ea, 3fa, 3ha and 3ia). The transformation was also sensitive to steric effects. For example, 2-bromotoluene exhibited much lower reactivity (3ga). In contrast to aryl iodides, electron-decient aryl bromides exhibited higher reactivity, although in some cases
O O H Phen, 40 mol% KOt-Bu, 3.0 equiv. Mesitylene, 100 C

Figure 4 | Proposed interactions between the phenanthroline, base and substrate for this transition metal-free cross-coupling. In the presence of KOt-Bu and 1,10-phenanthroline, both 1,10-phenanthroline and K ions might interact with the arene substrate through p,p-stacking as well as ionp interactions to promote the reactivity of the benzene.

Br 4

only moderate yields were obtained (3oa, 3pa). Various functional groups were found to be compatible, suggesting great potential for further transformation of the cross-coupling products. Once again, heterocyclic substrates were found to be suitable substrates (3sa, 3ta), providing a number of potential applications in synthetic chemistry. In addition, the double coupling also took place smoothly when either 1,4-diiodobenzene or 1-iodo-4-bromobenzene were used as substrates and the desired terphenyl was isolated in moderate yields (3ja, 46% using 1,4-diiodobenzene and 35% using 1-iodo-4-bromobenzene). We further explored different arenes (CH) coupling partners (Table 2). Notably, the enhancement of CH bond acidity dramatically improved efciency. For example, 1,4-diuorobenzene showed much better reactivity, and the desired product (3ac) was obtained with both 4-bromo/iodoanisole. With increased electron density in the arenesfor example, in the cases of toluene, xylenes and anisole derivativeslow efcacy was observed under standard conditions (3ad3ah). Increasing the reaction time and temperature, however, restored the reactivity. Under optimized conditions, even the highly sterically hindered mesitylene could be functionalized in moderate yield (3ab). In the reactions of electron-rich arenes, we noted that coupling to the meta-position (relative to the electron-donating group) dominated; when 1,1,1-triuorotoluene was used as a coupling partner, the meta-arylated product was observed as major product (3aj), while other electron-decient arenes such as benzonitrile and ethyl benzoate showed poor reactivity. This result might indicate the potential interaction between the base and CF moiety of the triuoromethyl group. All these results indicate that the reaction pathway is different from the conventional transitionmetal-catalysed CH transformations, which further supports the metal-free reactivity. Notably, when the nitrogen-containing heterocycles were applied, only one isomer of the desired cross-coupling products was obtained (3al). Although a higher efciency in this reaction would be desirable, the potential for coupling heterocyclic compounds is highly appealing. We also investigated an intramolecular version of the reaction by carrying out a cyclization using 1-(benzyloxy)-2-bromobenzene as the substrate. The relatively low reactivity of mesitylene means that it can still be used as solvent for the reaction. To our delight, the corresponding intramolecular coupling product 6H-benzo[c]chromene 5 was the exclusive product, which we obtained in 73% isolated yield (Fig. 3). This result suggests a promising application in the formation of fused ring systems.

5, isolated yield: 73%

Discussion
Very recently, Itami and others have reported an interesting crosscoupling between aryl halides and heterocylces in the presence of KOt-Bu and absence of transition metals48,49. In their studies, the aryl radical was considered to be the key intermediate initiated by KOt-Bu and assisted by heterocycles. In our case, we propose the radical is initiated from the aryl halides with KOt-Bu. It is proposed that the phenanthroline might play a similar role to the heterocycles
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Figure 3 | Metal-free process in the intramolecular cross-coupling to prepare 6H-benzo[c ]chromene. The reaction was carried out in the presence of 1,10-phenanthroline (0.5 mmol, 40 mol%), KOt-Bu (1.5 mmol, 3.0 equiv.), mesitylene (4 ml) and 1-(benzyloxy)-2-bromobenzene (0.5 mmol). The reaction was stirred under a N2 atmosphere at 100 8C for 20 h.

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in the reaction reported by Itami and facilitate the generation of a radical species. To test this suggestion, we used the more typical radical initiator azobisisobutyronitrile (AIBN) and tributyltin hydride in the absence of KOt-Bu and phenanthroline; the crosscoupling product was observed, albeit in lower yield. Radical quenching studies also suggest that a radical intermediate is important in the transformation. When tetramethylpiperidine N-oxide (TEMPO, a typical radical scavenger) was added under the same conditions, no desired product was observed (for a full description, see Supplementary Information). Because unactivated benzene showed good reactivity, we further propose that both 1,10-phenanthroline and a potassium ion might interact with the arene substrate through p,p-stacking50 and ionp interaction51 to promote the reactivity of the benzene (Fig. 4). On the basis of this hypothesis, organic compounds that are structurally similar to phenanthrolines showed good catalytic reactivity to activate the arenes. This model is consistent with our experimental results based on both steric and electronic features. On the other hand, other interactions between a K ion and the CF of uoro-containing benzene might also be feasible due to their high reactivity. Further studies to extend this chemistry and completely understand this transformation are under way. In summary, we report here a novel cross-coupling in the absence of any added transition-metal catalyst. The presence of 1,10-phenanthroline and excess of KOt-Bu are adequate to give high yields of cross-coupling between an inert aromatic CH and aryl iodides or bromides. Various aryl bromides and iodides showed good reactivity in this transformation. Extensive experiments indicated that the radical was involved in this transformation. To the best of our knowledge, such reactivity has not been reported previously. It represents a conceptual breakthrough in performing cross-coupling by direct CH functionalization using an organocatalyst.

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References

DOI: 10.1038/NCHEM.862

Methods
General experimental procedures for cross-coupling of aryl iodides with benzene. Aryl iodides (0.2 mmol, if solid) and 1,10-phenanthroline (0.04 mmol, 20 mol%) were added to Schlenk tubes (dried by a heat gun). KOt-Bu (0.4 mmol, 2.0 equiv.) was then added in a glove box. Benzene (2 ml) and aryl iodides (0.2 mmol, if liquid) were added to the tubes using a syringe. The mixture was then stirred in a sealed tube under a N2 atmosphere at 100 8C for 24 h. The reaction was then cooled to room temperature. The mixture was ltered through a short plug of silica gel and washed with copious quantities of ethyl acetate. The combined organic phase was concentrated under vacuum. The product was puried through ash column chromatography on 200300-mesh silica gel with petroleum ether/ethyl acetate as eluent. General experimental procedures for cross-coupling of aryl bromides with benzene. 1,10-Phenanthroline (0.2 mmol, 40 mol%) and aryl bromides (0.5 mmol, if solid) were added to Schlenk tubes (dried by a heat gun). KOt-Bu (1.5 mmol, 3.0 equiv.) was added to the tubes in a glove box, then benzene (4 ml) and aryl bromides (0.5 mmol, if liquid) were added using a syringe. The mixture was stirred in a sealed tube under a N2 atmosphere at 100 8C for 18 h. The reaction was then cooled to room temperature. The mixture was ltered through a short plug of silica gel and washed with copious quantities of ethyl acetate. The combined organic phase was concentrated under vacuum. The product was puried using ash column chromatography on 200300-mesh silica gel with petroleum ether/ethyl acetate as eluent. General experimental procedures for cross-coupling of 4-iodoanisole with arenes. 1,10-Phenanthroline (0.2 mmol, 40 mol%) and arenes (40 mmol, 80 equiv., if solid) were added into Schlenk tubes (dried by a heat gun). KOt-Bu (1.5 mmol, 3.0 equiv.) was added in Schlenk tubes in a glove box. Arenes (4 ml, if liquid) and 4-iodo/4-bromoanisole (0.5 mmol) were added into the tubes by syringe. The mixture was stirred in a sealed tube under a N2 atmosphere at 120 8C for 48 h. The reaction was cooled to room temperature. The mixture was ltered through a short plug of silica gel and washed with copious ethyl acetate. The combined organic phase was concentrated under vacuum. The product was puried through ash column chromatography on 200300-mesh silica gel with petroleum ether/ethyl acetate as eluent.

Received 30 April 2010; accepted 23 August 2010; published online 3 October 2010
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Acknowledgements
The authors acknowledge support for this work from NSFC (grant nos 20672006, 20821062, GZ419) and the 973 Project from the MOST of China (2009CB825300). The authors also thank J. Zhang at East China Normal University and N. Jiao at the Medical School of Peking University and their students for repeating our experiments. The polishing of the English and the constructive comments from K. Itami at Nagoya University and C. He from the University of Chicago are greatly appreciated.

Author contributions
Z.-J.S. conceived the project. C.-L.S., H.L. and D.-G.Y. performed the experiments and analysed the data and contributed equally to this work. M.Y., X.Z., X.-Y.L., K.H. and S.-F.Z. worked on product isolation and purication. C.-L.S., B.-J.L. and Z.-J.S. wrote the paper. C.-L.S. wrote the Supplementary Information and contributed other related materials.

Additional information
The authors declare no competing nancial interests. Supplementary information and chemical compound information accompany this paper at www.nature.com/ naturechemistry. Reprints and permission information is available online at http://npg.nature. com/reprintsandpermissions/. Correspondence and requests for materials should be addressed to Z.-J.S.

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