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: [email protected];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
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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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