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 perfluorobenzenes 4 and simple arene benzene 5 with aryl halides have been reported based on a Pd(0)–PR 3 /Ar–X system. In 2005, Sanford et al. 6 and Daugulis and Zaitsev 7 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 K 2 CO 3 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-bromotoluene a Entry Base (1.25 equiv.) Additive (equiv.) Yield b (%) 1 K 2 CO 3 PivOH (0.3) 48 2 K 2 CO 3 PivOH (0.6) 50 3 K 2 CO 3 PivOH (1.2) 64 4 K 2 CO 3 PivOH (1.5) 70 5 K 2 CO 3 PivOH (1.8) 82(79) 6 K 2 CO 3 PivOH (2.5) 88(83) 7 Cs 2 CO 3 PivOH (2.5) 83 8 K 3 PO 4 PivOH (2.5) 78 9 Na 2 CO 3 PivOH (2.5) 64 10 NaOAc PivOH (2.5) 48 11 t BuOK PivOH (2.5) 81 12 K 2 CO 3 Boc-Val-OH (0.03) nr 13 K 2 CO 3 PivOH (0.3) + Boc-Val-OH (0.03) 69(51) 14 K 2 CO 3 PivOH (0.3) + Boc-Ile-OH (0.03) 67(47) 15 K 2 CO 3 PivOH (0.3) + Ac-Ile-OH (0.03) 98(92) 16 c K 2 CO 3 PivOH (2.5) 7 17 c K 2 CO 3 PivOH (0.3) + Ac-Ile-OH (0.03) 44 18 d K 2 CO 3 PivOH (0.3) + Ac-Ile-OH (0.05) 57 19 e K 2 CO 3 PivOH (2.5) 79 20 f K 2 CO 3 PivOH (2.5) 69 21 e K 2 CO 3 PivOH (0.3) + Ac-Ile-OH (0.03) 81 22 f K 2 CO 3 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 1 H-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: [email protected]; Fax: +86 21 6564 1740; Tel: +8621 5566 4878 w Electronic supplementary information (ESI) available: Experimental procedure, characterization data, 1 H, 13 C and 19 F NMR spectra of compounds 3. See DOI: 10.1039/c2cc34949c ChemComm Dynamic Article Links www.rsc.org/chemcomm COMMUNICATION Downloaded by Fudan University on 26 October 2012 Published on 06 September 2012 on http://pubs.rsc.org | doi:10.1039/C2CC34949C View Online / Journal Homepage / Table of Contents for this issue
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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
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.