Copper-catalyzed arene C-H bond cross-coupling

Article abstract of DOI:10.1039/b912890e

A highly regioselective, one-pot sequential iodination-copper-catalyzed cross-coupling of arene C-H bonds has been developed affording an efficient method for biaryl synthesis.

Full text of DOI:10.1039/b912890e

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Copper-catalyzed arene C–H bond cross-couplingwz
Hien-Quang Do and Olafs Daugulis*
Received (in College Park, MD, USA) 1st July 2009, Accepted 8th September 2009
First published as an Advance Article on the web 28th September 2009
DOI: 10.1039/b912890e
A highly regioselective, one-pot sequential iodination–copper-
catalyzed cross-coupling of arene C–H bonds has been developed
affording an efficient method for biaryl synthesis.
Copper complexes have been known to promote carbon–
carbon bond formation for more than a century.1 However,
the development of the corresponding catalytic processes has
started only in the last decade. Efficient copper-catalyzed
cross-coupling reactions have been developed for the formation
of carbon–carbon bonds.2 Unfortunately, copper is under-
utilized as a catalyst for the functionalization of carbon–
hydrogen bonds. We have recently developed a general
method for copper-catalyzed arylation of sp2 C–H bonds
possessing pKa’s below 35 (in DMSO).3 A variety of electron-
rich and electron-poor heterocycles such as azoles, thiophenes,
benzofuran, pyridine oxides, pyridazine, and pyrimidine can
be arylated. Furthermore, arenes possessing electron-
withdrawing fluorine, chlorine, nitro, and cyano substituents
can also be arylated. Aryl iodides, aryl bromides, and even
some activated aryl chlorides can be used as the coupling
partners. These reactions can be described as a carbon–
hydrogen/carbon–halogen bond coupling that results in the
Scheme 1 Carbon–hydrogen bond arylation.
formation of a biaryl or polyaryl (Scheme 1A). From atom-
economy and generality viewpoints it would be advantageous
if one could employ unfunctionalized coupling partners by
coupling two C–H bonds to form a carbon–carbon bond.
Several recent examples involve palladium-catalyzed arylation
of directing-group-containing arenes or electron-rich hetero-
cycles by simple benzenes.4 Unfortunately, regioselectivity
with respect to the simple arene coupling component is
difficult to achieve and often only symmetric arenes can be
used for the arylations (Scheme 1B). We reasoned that a
C–H/C–H coupling could be achieved by employing a
combination of regioselective halogenation with copper-
catalyzed arylation (Scheme 1C).
copper-catalyzed C–H bond arylation. It has been shown
previously that the Cu-catalyzed arylation is highly regio-
selective with the most acidic C–H bond arylated exclusively.3
Consequently, a highly regioselective and efficient iodination
procedure that is compatible with Cu-catalyzed arylation
was needed. Iodine chloride has been employed for arene
halogenation for at least 130 years.5 High iodination regio-
selectivities have been reported.6 The halogenation mechanism
has been extensively studied by Kochi et al.7 Several issues that
had to be considered are as follows. First, competing substrate
chlorination is often observed.7 Second, incomplete iodination
of the less reactive substrates may result in lower conversions.
Kochi et al. have reported that ICl is more reactive in
nonpolar solvents such as CH2Cl2, but the selectivity for
iodination over chlorination is higher in polar aprotic
solvents.7 A mixture of these solvents is most likely to deliver
the optimal compromise of rate and selectivity. In some cases,
relatively stable cation radicals are formed by reaction of
arenes with ICl.7 The cation radicals were shown to react with
I2 forming iodinated products. Thus, addition of iodine to the
reaction mixture may result in higher reactivity and/or
selectivity for the iodination. Third, iodination procedure
should be compatible with subsequent copper-catalyzed
cross-coupling reaction. An excess of ICl may retard
the coupling by oxidizing catalytically active Cu species.
p-Dimethylaminobenzene reacts with ICl forming a haloarene
We report here an electrophilic halogenation followed by a
copper-catalyzed arylation that allows a highly regioselective
heterocoupling of arene C–H bonds.
For accomplishing the C–H/C–H coupling, two sequential
carbon–hydrogen bond functionalizations are required.
A halogenation of an sp2 C–H bond should be followed by
Department of Chemistry, University of Houston, Houston,
TX 77204-5003, USA. E-mail: olafs@uh.edu; Fax: +1-713-743-2709
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures and copies of 1H NMR spectra. See DOI:
10.1039/b912890e
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6433–6435 | 6433

Table 1 Copper-catalyzed cross-coupling of C–H Bondsa
Entry
1b
Ar–H
R–H
Ar–R
Yield (%)
63
C6F5H
2c
Biphenyl
45
3
71
4cd
m-Xylene
63
5c
Diphenyl ether
56
59
6
7cd
8ce
9c
49
57
51
72
10c
11
52
90
12f
a
b
c
See ESIz and ref. 8 for stoichiometry. Yields are isolated yields of pure regioisomer. Ten mmol scale reaction. Dimethylaminobenzene added
d
after step 1. Crude isomer ratio: 12/1. Crude isomer ratio: 32/1. Crude isomer ratio: 24/1.
e
f
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This journal is The Royal Society of Chemistry 2009
6434 | Chem. Commun., 2009, 6433–6435

that is relatively inactive in the copper-catalyzed arylation
step. Thus, in cases where full consumption of ICl was not
observed or an excess of halogenating reagent was required,
p-dimethylaminobenzene was added.
2 (a) D. Ma and F. Liu, Chem. Commun., 2004, 1934; (b) K. Kamata,
S. Yamaguchi, M. Kotani, K. Yamaguchi and N. Mizuno, Angew.
Chem., Int. Ed., 2008, 47, 2407; (c) S. Usui, Y. Hashimoto,
J. V. Morey, A. E. H. Wheatley and M. Uchiyama, J. Am. Chem.
Soc., 2007, 129, 15102; (d) G. Brasche and S. L. Buchwald, Angew.
Chem., Int. Ed., 2008, 47, 1932; (e) Y. Zhang and C.-J. Li, Angew.
Chem., Int. Ed., 2006, 45, 1949; (f) X. Chen, X.-S. Hao,
C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006, 128,
6790; (g) Z. Li, L. Cao and C.-J. Li, Angew. Chem., Int. Ed.,
2007, 46, 6505; (h) R. J. Phipps, N. P. Grimster and M. J. Gaunt,
J. Am. Chem. Soc., 2008, 130, 8172; (i) L. S. Liebeskind, H. Yang
and H. Li, Angew. Chem., Int. Ed., 2009, 48, 1417; (j) S. Yotphan,
R. G. Bergman and J. A. Ellman, Org. Lett., 2009, 11, 1511;
(k) L. Ackermann, H. K. Potukuchi, D. Landsberg and R. Vicente,
Org. Lett., 2008, 10, 3081; (l) X. Chen, G. Dobereiner, X.-S. Hao,
R. Giri, N. Maugel and J.-Q. Yu, Tetrahedron, 2009, 65,
3085; (m) T. Yoshizumi, H. Tsurugi, T. Satoh and M. Miura,
Tetrahedron Lett., 2008, 49, 1598.
The scope of the reaction is presented in Table 1. Electron-
rich heterocycles such as thiophenes (entries 1 and 9),
N-methylindole (entry 3), and N-methylpyrazole (entry 6)
can be coupled with electron-deficient arenes such as penta-
fluorobenzene, tetrafluoropyridine, 3,5-difluorobenzonitrile,
and 1,3-dinitrobenzene. 2-Bromothiophene (entry 1) is diarylated
by substituting both the bromide and newly introduced iodide.
Electron-rich arenes such as biphenyl, alkylbenzenes, diphenyl
ether, anisole, naphthalene derivatives, and azulene can be
coupled with polyfluorobenzenes (entries 2, 8, 10, and 11), acidic
electron-rich heterocycles (entries 4 and 5), and terminal
alkynes (entry 12). Entry 1 was run on a 10 mmol scale.
The first component of the cross-coupling reaction is an
electron-rich aromatic compound. The regioselectivity of
iodination step is dictated by the rules of electrophilic aromatic
substitution.9 In most cases, only a single product isomer was
observed. However, anisole derivatives and alkylbenzenes are
halogenated with selectivities ranging from 12/1 (entry 7,
anisole) to 32/1 (entry 8, t-butylbenzene). The second coupling
component can be an arene (or alkyne) possessing a C–H bond
with DMSO pKa’s below 35 (in DMSO).10 The regioselectivity
with respect to the second coupling component (R–H in
Table 1) is dependent on the acidity of the arene. The most
acidic position is functionalized exclusively. Either potassium
phosphate or lithium t-butoxide base can be employed in the
second step. Choice of base depends on the acidity of the
second coupling component. Less acidic substrates such as
methyltriazole (entry 5) and dichloropyridine (entry 7) require
use of a stronger LiOtBu base. For obtaining reproducible
yields fresh ICl should be used since older samples dispropor-
tionate to chlorine gas and iodine.7
3 (a) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2007, 129,
12404; (b) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2008,
130, 1128; (c) H.-Q. Do, R. M. K. Khan and O. Daugulis, J. Am.
Chem. Soc., 2008, 130, 15185.
4 (a) K.-i. Fujita, M. Nonogawa and R. Yamaguchi, Chem.
Commun., 2004, 1926; (b) Y. Fuchita, H. Oka and M. Okamura,
Inorg. Chim. Acta, 1992, 194, 213; (c) M. Tani, S. Sakaguchi and
Y. Ishii, J. Org. Chem., 2004, 69, 1221; (d) T. Jintoku, Y. Fujiwara,
I. Kawata, T. Kawauchi and H. Taniguchi, J. Organomet. Chem.,
1990, 385, 297; (e) L. J. Ackerman, J. P. Sadighi, D. M. Kurtz,
J. A. Labinger and J. E. Bercaw, Organometallics, 2003, 22,
3884; (f) S. Proch and R. Kempe, Angew. Chem., Int. Ed., 2007,
46, 3135; (g) K. L. Hull and M. S. Sanford, J. Am. Chem. Soc.,
2007, 129, 11904; (h) G. Brasche, J. Garcia-Fortanet and
S. L. Buchwald, Org. Lett., 2008, 10, 2207; (i) T. A. Dwight,
N. R. Rue, D. Charyk, R. Josselyn and B. DeBoef, Org. Lett.,
2007, 9, 3137; (j) D. R. Stuart and K. Fagnou, Science, 2007, 316,
1172.
5 A. Michael and L. M. Norton, Ber. Dtsch. Chem. Ges., 1878, 11,
107.
6 B. Jones and E. N. Richardson, J. Chem. Soc., 1953, 713.
7 S. M. Hubig, W. Jung and J. K. Kochi, J. Org. Chem., 1994, 59,
6233.
8 General procedure: a 15 mL recovery flask equipped with a
magnetic stir bar was charged with iodine (25.4 mg, 0.1 mmol),
DCM–DMF mixture, and ICl. The flask was fitted with a reflux
condenser. To the stirred mixture was quickly added in one portion
the first substrate through the condenser. The reaction mixture was
stirred at 50 1C (bath temperature) for 2.5 hours followed
by CH2Cl2 removal under reduced pressure. In most cases,
N,N-dimethylaniline (121 mg, 1.0 mmol) was added followed by
stirring for another 30 minutes. Commercial, non-anhydrous DMF
(0.6 mL) was added to reaction mixture followed by transfer to a
1 dram vial. It is important to use the specified vial caps due to
volatility of some reactants. Phenanthroline (18.0 mg, 0.1 mmol)
and the second substrate (1.0–3.0 mmol) were subsequently added.
The vial was flushed with argon, capped and placed inside a
glovebox. To this mixture was added CuI (19 mg, 0.1 mmol) and
base. The sealed vial was taken out of the glovebox, stirred at 50 1C
for 5 min and placed in a preheated oil bath (125–135 1C) for
indicated time. The reaction mixture was allowed to cool to room
temperature and diluted with ethyl acetate (50 mL). The resulting
solution was washed with brine (1 ꢁ 15 mL), dried over anhydrous
MgSO4, and concentrated under vacuum to a volume of about
2 mL. The mixture containing the product was subjected to flash
chromatography on silica gel (hexanes followed by appropriate
solvent to elute the products). After concentrating the fractions
containing the product, the residue was dried under reduced
pressure.
In conclusion, we have developed a one-pot procedure for a
highly regioselective cross-coupling of arene carbon–hydrogen
bonds. A variety of electron-rich arenes such as alkyl- and
arylbenzenes, anisole derivatives, azulene, and five membered
heterocycles can be coupled with electron-poor arenes
possessing at least two electron-withdrawing groups on a
benzene ring, thiophenes, triazoles, and alkynes. The
cross-coupling reaction is performed by an initial electrophilic
iodination of an electron-rich arene followed by
copper-catalyzed arylation of a carbon–hydrogen bond.
a
We thank the Welch Foundation (Grant No. E-1571),
National Institute of General Medical Sciences (Grant No.
R01GM077635), A. P. Sloan Foundation, Camille and Henry
Dreyfus Foundation, and Norman Hackerman Advanced
Research Program for supporting this research.
Notes and references
1 Review: (a) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and
´
9 R. Taylor, Electrophilic Aromatic Substitution, Wiley, Chichester,
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R. Leitsmann and K. H. Hofmann, Liebigs Ann. Chem., 1941,
546, 180; (d) J. W. Sease and L. Zechmeister, J. Am. Chem. Soc.,
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ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6433–6435 | 6435