This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10437–10439 10437

Cite this: Chem. Commun., 2012, 48, 10437–10439

Pd(OAc)2 catalyzed direct arylation of electron-deficient arenes without

ligands or with monoprotected amino acid assistancew

Ya-Nong Wang, Xu-Qing Guo, Xiao-Han Zhu, Rui Zhong, Li-Hua Cai and Xiu-Feng Hou*

Received 11th July 2012, Accepted 5th September 2012

DOI: 10.1039/c2cc34949c

An efficient arylation of electron-poor arenes has been developed

without the addition of external ligands or in the presence of a

catalytic monoprotected amino acid which assisted the reaction to

proceed under mild conditions. The meta-selectivity was observed

under both conditions.

Pd-catalyzed direct C–H arylation with aryl halides, as

an efficient route for the construction of C–C bonds without

pre-preparing organometallic reagents,1 has attracted signifi-

cant attention in recent years.2 A series of direct C–H arylations

of electron-rich arenes,3 electron-deficient perfluorobenzenes4

and simple arene benzene5 with aryl halides have been reported

based on a Pd(0)–PR3/Ar–X system.

In 2005, Sanford et al.6 andDaugulis and Zaitsev7 independently

used diphenyliodonium salts for arylation of arenes. These reactions

were proposed to proceed by a Pd(II)/Pd(IV) mechanism. And the

arylation of substituted anilides by aryl iodides in the presence of

stoichiometric AgOAc was developed by Daugulis and Zaitsev.7

Subsequently, the combination of Ag(I) salts and aryl iodides

has also been utilized for Pd-catalyzed arylation of other arene

substrates.8 In most of the above reports directing groups exist

in the arene substrates. In the research on the regioselective

arylation of arenes without a directing group, heteroarenes as

substrates typically are used as illustrated in the recent reports on

direct arylation reactions for pyridines by Yu et al.9 Despite the

previous progress, the problem associated with site selectivity of

simple arenes is a remaining challenge.10 In view of the importance

of fluorocarbons in medicinal and bioorganic chemistry,11 two

efficient methods of direct arylation reactions with electron-

deficient fluoroarenes and aryl bromides were discovered without

external ligands or with the assistance of mono-N-protected

amino acid ligands, exhibiting meta-selectivity due to the differ-

ence in the acidity of C–H bonds in electron-withdrawing group

substituted arenes. Moreover, moderate to good yields of these

reactions can be achieved under low temperature.

The reaction of highly electron-deficient 1,3-bis(trifluoro-

methyl)benzene 1a, which tends to produce a single product,10a

and 4-bromotoluene 2a was chosen for a model to optimize

the condition for direct arylation of electron-deficient arenes

(Table 1). In the presence of 3 mol% of Pd(OAc)2 as a catalyst,

1.25 equiv. of K2CO3 as a base, 0.3 equiv. of pivalic acid (PivOH)

as an acidic additive, an excess of 1a, and N,N-dimethylacet-

amide (DMA) as the solvent, the reaction carried out at 110 1C

for 24 h afforded less than 50% yield of the cross-coupling

product 3a (entry 1) and produced an undesired byproduct from

homocoupling of 4-bromotoluene. It is noteworthy that the

loading of PivOH is crucial under the ligand-free condition.

Increasing the amount of PivOH to 2.5 equiv. provided the

Table 1 Optimization study of direct arylation of 1,3-bis(trifluoro-methyl)benzene with 4-bromotoluenea

EntryBase(1.25 equiv.) Additive (equiv.)

Yieldb

(%)

1 K2CO3 PivOH (0.3) 482 K2CO3 PivOH (0.6) 503 K2CO3 PivOH (1.2) 644 K2CO3 PivOH (1.5) 705 K2CO3 PivOH (1.8) 82(79)6 K2CO3 PivOH (2.5) 88(83)7 Cs2CO3 PivOH (2.5) 838 K3PO4 PivOH (2.5) 789 Na2CO3 PivOH (2.5) 6410 NaOAc PivOH (2.5) 4811 tBuOK PivOH (2.5) 8112 K2CO3 Boc-Val-OH (0.03) nr13 K2CO3 PivOH (0.3) + Boc-Val-OH (0.03) 69(51)14 K2CO3 PivOH (0.3) + Boc-Ile-OH (0.03) 67(47)15 K2CO3 PivOH (0.3) + Ac-Ile-OH (0.03) 98(92)16c K2CO3 PivOH (2.5) 717c K2CO3 PivOH (0.3) + Ac-Ile-OH (0.03) 4418d K2CO3 PivOH (0.3) + Ac-Ile-OH (0.05) 5719e K2CO3 PivOH (2.5) 7920f K2CO3 PivOH (2.5) 6921e K2CO3 PivOH (0.3) + Ac-Ile-OH (0.03) 8122f K2CO3 PivOH (0.3) + Ac-Ile-OH (0.03) 61

a Reaction conditions: 1a (0.5 mL), 2a (0.2 mmol), Pd(OAc)2 (3 mol%),

additive, base (1.25 equiv.), DMA (2 mL), 110 1C, 24 h. b The yields were

determined by 1H-NMR using 1,3,5-trimethoxybenzene as the internal

standard. Isolated yields are given in parentheses. c 70 1C, 120 h.d Pd(OAc)2 (5 mol%), 70 1C, 48 h. e 0.3 mL of 1a. f 0.1 mL of 1a.

Department of Chemistry, Fudan University, 220 Handan Road,Shanghai 200433, China. E-mail: xfhou@fudan.edu.cn;Fax: +86 21 6564 1740; Tel: +8621 5566 4878w Electronic supplementary information (ESI) available: Experimentalprocedure, characterization data, 1H, 13C and 19F NMR spectra ofcompounds 3. See DOI: 10.1039/c2cc34949c

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10438 Chem. Commun., 2012, 48, 10437–10439 This journal is c The Royal Society of Chemistry 2012

product up to 88% yield (entries 1–6). K2CO3 stood out in the

bases listed in Table 1 (entries 6–11).

In 2010, Yu et al. reported the ligand-accelerated aryl C–H

olefination of electron-deficient arenes.12 Mono-N-protected

amino acid ligands are able to change the mechanism of C–H

cleavage from electrophilic palladation to concerted metalation–

deprotonation (CMD).12d Boc-Val-OH, Boc-Ile-OH and Ac-Ile-

OH are found to be highly reactive in these previous excellent

studies. Thus, we investigated those three kinds of amino acids

as ligands in the model reaction (entries 12–15). Fortunately,

Ac-Ile-OH was found to be highly efficient. The subquantita-

tive yield (92% isolated yield) was achieved in the presence of

3 mol% of Ac-Ile-OH and 0.3 equiv. of PivOH (entry 15),

surpassing the 48% yield which was observed when only

0.3 equiv. of PivOH was used (entry 1). Therefore two

methods for direct arylation of electron-deficient arenes turned

out (entries 6 and 15) to give satisfactory product yields and

good meta-selectivity. Since a high temperature (often above

100 1C), which is typically required in many of direct arylations,3–5

can limit large-scale applications,13 we tried operating the model

reaction at a relatively low temperature (entries 16–18). The

reaction afforded only 7% yield of the arylation product after

5 days at 70 1C without an external ligand (entry 16), while it

could afford 44% yield with Ac-Ile-OH (entry 17). Moreover,

when the loading of Pd(OAc)2 increased to 5 mol% (with

Ac-Ile-OH added), a higher yield (57%) could be reached after

only 48 h (entry 18). And 0.3 mL of 1a (about 10 equiv.) also

led to excellent yields (entries 19 and 21). Good yields could be

achieved when the loading of the substrate was decreased to

0.1 mL (about 3 equiv., entries 20 and 22).

With the two optimized reaction conditions in hand, the

scope of substrates was investigated and is outlined in Table 2.

As a starting point, a variety of aryl halides were tested as

coupling partners with 1,3-bis(trifluoromethyl)benzene 1a

(3b–3i). 3-Bromotoluene provided excellent yields (90% and

84% isolated yields) under both conditions (3b). 2-Bromoto-

luene reduced the yield to 59% and 54%, respectively, due to

increasing steric hindrance of the substituted group (3c). Bromo-

benzene afforded good yields (75%, 64%, 3d). Unfortunately,

the iodo- and chlorobenzene were less efficient than bromo-

benzene under both conditions. Next we tested other functional

groups of aryl bromides. Electron-donating methoxyl, electron-

withdrawing trifluoromethyl, and chloro groups could be tolerated

and were arylated in good yields (3e–3h). 2-Bromonaphthalene

could be arylated in excellent yields (97%, 86%, 3i). It is worth

noting that a relatively low temperature (80 1C) is already sufficient

to achieve moderate to good yields under condition II (42%–74%,

3b, 3d–3i). Furthermore, we probed other electron-deficient arenes

(3j–3r). 1,2-Bis(trifluoromethyl)benzene, 2-fluorobenzotrifluoride

and 4-fluorobenzotrifluoride could be cross-coupled in good to

excellent yields under both conditions (61%–94%, 3j–3p). In the

above reactions, only single coupling products were detected

(3b–3p). The use of mono-substituted trifluorotoluene gave

moderate to good yields. A mixture of para- and meta-products

was produced, but meta-selectivity was still observed (3q, 3r).

Next we measured the rate profiles for arylations of electron-

poor 1a or electron-rich arene 1a0 with 4-bromotoluene 2a under

the two optimized conditions (Fig. 1). The initial rates of 1a

were obviously higher than those of 1a0 under both conditions.

The electron-deficient substrate was evidently preferentially

reactive compared to the electron-rich one. Thus, we hypo-

thesized that the C–H cleavage proceeded through a CMD

mechanism.14 The proposed catalytic cycle is depicted in

Scheme 1. After the substrate coordination, the C–H cleavage

takes place to generate the Pd(II) species. Then oxidative

addition of aryl bromide would afford a Pd(IV) complex,

followed by reductive elimination which produces the coupling

product and regenerates the Pd(II) species. Under condition I,

increasing the concentration of pivalate anions presumably

facilitates the formation of the intermediate A (Scheme 1A)14c

and consequently increases the yield of the coupling product

(entries 1–6, Table 1). Under condition II, the arylation can forge

at a higher initial rate (Fig. 1, compared to ‘‘1a, condition I’’) and

at a relatively low temperature (Table 1, entries 17 and 18),

indicating the possibility that a mono-N-protected amino acid

coordinates to Pd(II), which benefits the agostic interaction

between the Pd(II) centre and the C–H bond (Scheme 1B).12d

Table 2 Direct arylation of electron-deficient arenes with aryl bro-mides by the two optimized conditionsa,b

a Reaction conditions: 1 (0.5 mL), 2 (0.2 mmol), Pd(OAc)2 (3 mol%),

K2CO3 (1.25 equiv.), DMA (2 mL), 110 1C, 24 h. Condition I: PivOH

(2.5 equiv.). Condition II: Ac-Ile-OH (3 mol%), PivOH (0.3 equiv.).b Isolated yields based on 2. c Isolated yields (80 1C, 48 h) are given in

parentheses. d Boc-Val-OH instead of Ac-Ile-OH in condition II. The

isomer ratio of meta- and para-products was determined by GC/MS

and given in parentheses.

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10437–10439 10439

In conclusion, we developed two efficient methods for direct

arylation of electron-deficient fluoroarenes. One protocol

did not employ an external ligand and the other introduced

mono-N-protected amino acid ligands to assist the reaction

to proceed under mild conditions. And we presumed that

C–H activation of electron-deficient arenes experiences the

CMD process under the two optimized conditions. Hence the

selectivity is attributed to the variation in the acidity of C–H

bonds and the steric hindrance of simple electron-poor arenes.

Financial support by the National Science Foundation of

China (grant no. 20871032, 20971026 and 21271047), and by

the Shanghai Leading Academic Discipline Project (project

no. B108) is gratefully acknowledged.

Notes and references

1 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;(b) A. Suzuki, J. Organomet. Chem., 1999, 576, 147.

2 For selected reviews on direct arylation: (a) L.-C. Campeau andK. Fagnou, Chem. Commun., 2006, 1253; (b) D. Alberico,M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174;(c) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew.Chem., Int. Ed., 2009, 48, 5094; (d) L. Ackermann, R. Vicente andA. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792.

3 (a) Y. Akita, Y. Itagaki, S. Takizawa and A. Ohta, Chem. Pharm.Bull., 1989, 37, 1477; (b) B. S. Lane and D. Sames,Org. Lett., 2004,6, 2897; (c) X. Wang, B. S. Lane and D. Sames, J. Am. Chem. Soc.,2005, 127, 4996; (d) B. S. Lane, M. A. Brown and D. Sames, J. Am.Chem. Soc., 2005, 127, 8050; (e) B. B. Toure, B. S. Lane andD. Sames, Org. Lett., 2006, 8, 1979; (f) W. Li, D. P. Nelson,M. S. Jensen, R. S. Hoerrner, G. J. Javadi, D. Cai and R. D. Larsen,Org. Lett., 2003, 5, 4835; (g) C.-H. Park, V. Ryabova, I. V. Seregin,A. W. Sromek and V. Gevorgyan, Org. Lett., 2004, 6, 1159.

4 M. Lafrance, C. N. Rowley, T. K. Woo and K. Fagnou, J. Am.Chem. Soc., 2006, 128, 8754.

5 M. Lafrance and K. Fagnou, J. Am. Chem. Soc., 2006, 128, 16496.6 D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford, J. Am.Chem. Soc., 2005, 127, 7330.

7 O. Daugulis and V. G. Zaitsev, Angew. Chem., Int. Ed., 2005,44, 4046.

8 (a) O. Shabashov and O. Daugulis, Org. Lett., 2005, 7, 3657;(b) H. A. Chiong, Q.-N. Pham and O. Daugulis, J. Am. Chem.Soc., 2007, 129, 9879; (c) V. S. Thirunavukkarasu,K. Parthasarathy and C.-H. Cheng, Angew. Chem., Int. Ed.,2008, 47, 9462; (d) P. Gandeepan, K. Parthasarathy andC.-H. Cheng, J. Am. Chem. Soc., 2010, 132, 8569.

9 M. Ye, G.-L. Gao, A. J. F. Edmunds, P. A. Worthington,J. A. Morris and J.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 19090.

10 For recent examples of site selectivity of simple arenes in cross-coupling reactions: (a) Y.-H. Zhang, B.-F. Shi and J.-Q. Yu, J. Am.Chem. Soc., 2009, 131, 5072; (b) Y. Zhou, J. Zhao and L. Liu,Angew. Chem., Int. Ed., 2009, 48, 7126.

11 (a) G. G. Dubinina, H. Furutachi and D. A. Vicic, J. Am. Chem.Soc., 2008, 130, 8600; (b) K. Muller, C. Faeh and F. Diederich,Science, 2007, 317, 1881.

12 (a) D.-H. Wang, K. M. Engle, B.-F. Shi and J.-Q. Yu, Science,2010, 327, 315; (b) K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew.Chem., Int. Ed., 2010, 49, 6169; (c) Y. Lu, K. M. Engle,D.-H. Wang and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 5910;(d) K. M. Engle, D.-H. Wang and J.-Q. Yu, J. Am. Chem. Soc.,2010, 132, 14137; (f) K. M. Engle, P. S. Thuy-Boun, M. Dang andJ.-Q. Yu, J. Am. Chem. Soc., 2011, 133, 18183.

13 For selected examples of mild conditions on C–H activation:(a) M. Lafrance, D. Shore and K. Fagnou, Org. Lett., 2006,8, 5097; (b) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius,Chem. Soc. Rev., 2011, 40, 4740; (c) D. Kalyani, K. B. McMurtrey,S. R. Neufeldt and M. S. Sanford, J. Am. Chem. Soc., 2011,133, 18566.

14 For studies concerning C–H activation through the CMDmechanismby Pd(II) species: (a) M. Gomez, J. Granell and M. Martinez,Organometallics, 1997, 16, 2539; (b) M. Gomez, J. Granell andM. Martinez, J. Chem. Soc., Dalton Trans., 1998, 37; (c) D. L.Davies, S. M. A. Donald and S. A. Macgregor, J. Am. Chem. Soc.,2005, 127, 13754.

Fig. 1 Initial rate studies of arylation of 1a or 1a0 under the opti-

mized conditions. Each data point represents the average of three

trials. See ESIw for experimental details.

Scheme 1 Proposed catalytic cycles under the optimized conditions.

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