New ligands that promote cross-coupling reactions between aryl halides and unactivated arenes

Article abstract of DOI:10.1021/ol2009208

Several ligands were designed to promote transition-metal-free cross-coupling reactions of aryl halides with benzene derivatives. Among the systems probed, quinoline-1-amino-2-carboxylic acid was found to serve as an excellent catalyst for cross-coupling between aryl halides and unactivated benzene. Reactions using this inexpensive catalytic system displayed a high functional group tolerance as well as excellent chemoselectivities.

Full text of DOI:10.1021/ol2009208

ORGANIC
LETTERS
2
011
Vol. 13, No. 14
556–3559
New Ligands That Promote
Cross-Coupling Reactions between
Aryl Halides and Unactivated Arenes
3
†
Yatao Qiu, Yanghan Liu, Kai Yang, Wenkun Hong, Zheng Li,
,‡
†
†,§
†,§
§
Zhaoyang Wang, Zhiyi Yao, and Sheng Jiang*
‡
,†
Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health,
CAS, Guangzhou 510530, P. R. China, Shanghai Institute of Technology, Shanghai,
210032, P. R. China, School of Chemistry and Environment,
South China Normal University, Guangzhou 510006, P. R. China, and
The Methodist Hospital Research Institute, Houston, Texas 77030, United States
jiang_sheng@gibh.ac.cn
Received April 8, 2011
ABSTRACT
Several ligands were designed to promote transition-metal-free cross-coupling reactions of aryl halides with benzene derivatives. Among the
systems probed, quinoline-1-amino-2-carboxylic acid was found to serve as an excellent catalyst for cross-coupling between aryl halides and
unactivated benzene. Reactions using this inexpensive catalytic system displayed a high functional group tolerance as well as excellent
chemoselectivities.
Selective functionalization of aromatic compounds
through substitution at CÀH bonds is an important goal
at this goal, transition-metal catalyzed arylation reactions
between arenes and aryl halides have been developed to
2,3
construct biaryl compounds. However, the presence of
1
in modern organic synthesis. As part of the studies aimed
†
Guangzhou Institute of Biomedicine and Health.
Shanghai Institute of Technology.
South China Normal University.
(
3) For recent examples of the use of metal-catalyzed cross-coupling
‡
in the construction of biaryl compounds, see: (a) Lane, B. S.; Brown,
M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050–8057. (b) Deprez,
N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006,
128, 4972–4973. (c) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 8754–8756. (d) Lafrance, M.; Fagnou,
K. J. Am. Chem. Soc. 2006, 128, 16496–16497. (e) Yang, S.; Li, B.; Wan,
X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066–6067. (f) Turner, G.;
Morris, J. A.; Greaney, M. F. Angew. Chem., Int. Ed. 2007, 46, 7996–
8000. (g) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128–
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2008, 130, 15185–15192. (i) Lebrasseur, N.; Larrosa, I. J. Am. Chem.
Soc. 2008, 130, 2926–2927. (j) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am.
Chem. Soc. 2008, 130, 17676–17677. (k) Phipps, R. J.; Gaunt, M. J.
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You, J. Angew. Chem., Int. Ed. 2009, 48, 3296–3300. (n) Join, B.;
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(o) Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131,
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Charette, A. B. J. Am. Chem. Soc. 2010, 132, 1514–1516.
§
The Methodist Hospital Research Institute.
(
1) For recent reviews of CÀH transformation, see: (a) Kakiuchi, F.;
Chatani, N. Adv. Synth. Catal. 2003, 345, 1077–1101. (b) Jones, W.;
Fehe, F. Acc. Chem. Res. 1989, 22, 91–100. (c) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35–41. (d) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173–1193. (e) Lewis, L. C.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013–1025. (f)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2
009, 48, 5094–5115. (h) Ackermann, L.; Vicente, R.; Kapdi, A. R.
Angew. Chem., Int. Ed. 2009, 48, 9792–9826. (i) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147–1169. (j) Dyker, G. Handbook of CÀH
Transformations; Wiley-VCH: Weinheim, 2005.
2) For recent reviews of metal-catalyzed cross-coupling reactions,
see: (a) Meijere, A.; Diederich, F. Metal-catalyzed cross-coupling reac-
tions, completely revised and enlarged, 2nd ed.; Wiley-VCH: Weinheim,
004. (b) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38,
447–2464. (c) Daugulis, O.; Do, H. Q.; Shabashov, D. Acc. Chem. Res.
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49–957.
(
2
2
2
9
1
0.1021/ol2009208 r 2011 American Chemical Society
Published on Web 06/21/2011

transition-metal impurities in the final products of these
processes is a significant problem when these reactions are
employed toprepare pharmaceutical agents. In2008, Itami
and his co-workers described a new procedure for carrying
out “transition-metal-free” cross-coupling reactions be-
owing to the fact that these substances would partici-
pate in forming six-membered ring chelates with the
potassium ion.
The cross-coupling reaction of 4-methyliodobenzene
and benzene was selected to evaluate the catalytic activities
of systems comprised of the designed ligands. Reactions
were carried out in benzene using 20 mol % of the ligands
and 3.0 equiv of KOt-Bu at 80 °C (Table 1, entries 1À7).
Importantly, this coupling reaction did not occur when
ligands were absent (entry 7). The results showed that the
highest yield (88%, entry 4) was obtained when quinoline-
1-amino-2-carboxylic acid (L4) was employed. The high
efficiency of this process might be due to the fact that L4
possesses a rigid conformation that strongly complexed to
the potassium ion via a six-membered ring chelate. Using
L4 as the ligand and benzene as the solvent, reactions
employing other bases, including K CO , NaOt-Bu, and
4
tween aryl halides and heterocyclic compounds. In sub-
sequent and recent efforts, two classes of ligands, including
5
6
DMEDA, 1,10-phenanthroline, and its derivatives,
7
have been found to promote transition-metal-free pro-
cesses for the synthesis of biaryl targets. Although these
reactions proceed with acceptable yields, the requirement
for high temperatures and the limited substrate range and
low selectivities impede their general synthetic utility. Con-
sequently, a highly desirable aim of studies in this area is the
development of versatile and simple ligands that lead to
improvements in the efficiency and generality of transition-
metal free cross-coupling reactions between aryl halides and
unactivated arenes. Below, we describe the results of a
preliminary investigation of the use of quinoline-1-amino-
2
3
KOH, were explored. Bases weaker than KOt-Bu were
found to be much less effective, and no coupling product
was formed in these cases (Table 1, entries 8À10). The
results of this preliminary investigation demonstrated that
the optimal conditions for the cross-coupling reaction of
4-methyliodobenzene with benzene involved the use of
20 mol % L4 and 3.0 equiv of KOt-Bu.
2-carboxylic acid (L4) as a ligand for cross-coupling reac-
tions of aryl iodides and bromides with unactivated arenes
that do not require the assistance of any transition metals.
The design of this study was guided by the assumption
that the ligands coordinating to metal centers played a key
role in governing the efficiencies of catalyst systems that
promote cross-coupling reactions of aryl halides with
arenes. An analysis of the results of previous studies
showed that the ligands probed thus far contain bidentate
chelating centers that have the capability of coordinating
Table 1. Designed Ligands for the Cross-Coupling Reaction of
p-Tolyl Iodide with Benzene
a
8
witha K ion toformfive-memberedring structures. Based
on this consideration, we believed that novel ligands
possessing appropriately functionalized pyridine and related
b
entry
ligand
base
t (°C)
yield (%)
1
2
3
4
5
6
7
8
9
L1
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
80
80
80
80
80
80
80
80
80
80
34
47
64
88
60
67
0
L2
L3
L4
L5
Proline
None
L4
K
2
CO
3
0
L4
NaOt-Bu
0
10
L4
KOH
0
a
Reaction conditions: 1a (1.0 mmol), 2a (2 mL), 20 mol % ligand,
b
base (3.0 mmol), Ar, 80 °C, 24 h. Isolated yield.
Figure 1. Structure of designed ligands.
N-amino or N-oxide ring systems (L1ÀL5 in Figure 1)
The scope of reactions, promoted by the KOt-Bu/L4
catalyst system under the optimal conditions described
above, was explored next. As can be seen from the results
displayed in Table 2, coupling reactions of most of the
substrates examined took place in 60%À88% yields. For
example, coupling reactions of various methoxy and
methyl substituted iodobenzenes with benzene occurred
in excellent yields (80%À88%) (entries 1À4). Even cou-
pling reactions of sterically hindered 2-iodotoluene and
would be capable of promoting cross-coupling processes
(
4) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
008, 10, 4673–4676.
5) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.;
Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737–
6740.
6) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X. Y.;
Huang, K.; Zheng, S. F.; Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044–
049.
7) Shirakawa, E.; Itoh, K.; Higashino, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 15537–15539.
8) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50, 5018–
022.
2
(
1
(
1
(
2
-iodoanisole took place in good yields (66%À84%)
(entries 5, 6). This finding represents an improvement over
the reported results. Polysubstituted electron-rich aryl
(
5
5
Org. Lett., Vol. 13, No. 14, 2011
3557

iodides also participated in this ligand-induced coupling
process (entry 7). Interestingly, the catalyst system pro-
moted highly selective reactions when a variety of other
potentially reactive groups were present in the substrate.
For example, a cross-coupling reaction of 4-fluoro-1-io-
dobenzene with benzene yielded the corresponding fluor-
ine-containing product selectively in 80% isolated yield.
This is a highly desirable outcome for the synthesis of
complex molecules using sequential orthogonal cross-cou-
plings (entry 8).
comprised of unactivated arenes (eg., toluene, and
1,4-difluorobenzene), took place in good yields by
using the new catalyst system (entries 11, 12). Finally,
even cross-coupling reactions of heterocyclic iodides
with benzene were promoted by the new catalyst
system. In these cases, heteroaryl iodides, such as
3-iodothiophene and 3-iodopyridine, coupled with
benzene efficiently to generate the corresponding adducts
(entry 13, 14).
The new catalytic system was also found to be applicable
to cross-coupling reactions of aryl bromides (Table 3). All
of the aryl bromides examined reacted with benzene at
120 °C to furnish the corresponding biaryls in good yields.
Moreover, high yields were also obtained when aryl bro-
mides with electron-donating groups were used as reac-
tants (entries 1À7). Noteworthy is the observation that
Significantly, by raising the temperature to 120 °C,
a cross-coupling reaction of o-diiodobenzene with benzene
5
(
took place smoothly. In addition, direct arylation reac-
tions of other challenging substrate combinations,
entry 9), a typically challenging substrate combination,
5
,7
Table 2. Direct Arylation Reactions of Arenes with
Aryl Iodides
a
Table 3. Direct Arylation Reactions of Arenes with
Aryl Bromides
a
a
a
Reaction conditions: 1 (1.0 mmol), 2 (2 mL), 20 mol % ligand, KOt-
Reaction conditions: 4 (1.0 mmol), 2 (2 mL), 20 mol % ligand, KOt-
b
c
b
c
Bu (3.0 mmol), Ar, 80 °C, 24 h. Isolated yield. At 120 °C.
Bu (3.0 mmol), Ar, 120 °C, 24 h. Isolated yield. At 150 °C.
3
558
Org. Lett., Vol. 13, No. 14, 2011

reaction of 2-bromotoluene with benzene at 120 °C, a
L4-catalyzed cross-coupling between aryl halides
and the unactivated arenes. To understand the pro-
posed radical pathway and clarify the rate-determining
step, we tested the competition reaction between C H
5
,6
typically difficult process, gave the coupling product in
7% yield (entry 2). In addition, double coupling also took
5
place in a 56% yield when1,4-dibromobenzenewas usedas
the substrate. Further, the new catalytic system was found
to successfully promote coupling reactions of heterocyclic
bromides with benzene (entries 10À13).
6
6
(45 equiv) and C D (45 equiv), as shown in Scheme 1.
6
6
The observed low K /KD value (1.42) implies that
H
the rate-determining step is the single electron trans-
fer process.
Based on the above observation, we propose that quino-
line-1-amino-2-carboxylic acid (L4) serves to catalyze the
radical formation as a consequence of its ability to strongly
complex to potassium via a six-membered ring chelate. To
verify this proposal, tetramethylpiperidine N-oxide
Scheme 1. Kinetic Isotopic Effects Experiment
(
TEMPO), a typical radical scavenger, was added to the
reaction mixture (Table 4). No coupling product formed in
this case indicated that the transformation proceeded via
radical intermediates. In the absence of L4, AIBN served
to initiate the coupling process that formed the desired
coupling product, albeit in a lower yield (Table 4).
Lastly, we investigated the effects of trace metal impu-
rities. For this purpose, different metals, such as Cu and
Fe, were examined for their ability to promote the cross-
coupling reaction of 4-methyliodobenzene with benzene
(
Table 4). In the cases when 10% CuI or 10% Fe(acac)2
In summary, a combination of quinoline-1-amino-2-
carboxylic acid and KOt-Bu is identified as an effec-
tive catalytic system for promoting transition-metal-
free cross-coupling reactions of aryl halides with
unactivated benzenes. Particularly noteworthy are the
observations which show that this inexpensive catalytic
system displays high functional group tolerance and
selectivity when multiple potentially reactive groups
are present in the substrates. Finally, mechanistic
studies indicate the operation of a radical pathway in
this process.
was present in the reaction mixture, the coupling process
took place in comparably lower yields. These findings
suggest that transition-metal complexes do not participate
in these cross-coupling reactions.
Table 4. Radical Trapping and Transition-Metal Effects on the
Cross-Coupling Reaction of p-Tolyl Iodide with Benzene
a
Acknowledgment. This project was supported by the
National Natural Science Foundation (Nos. 20802078,
2
0972160, and 20772035), National Basic Research
b
entry
ligand
base
additive
yield (%)
Program of China (2009CB940900), Shanghai Uni-
versity Distinguished Professor (Eastern scholars)
Program (DF2009-02), Pujiang Talent Plan Project
(09PJ1409200), and National Major Scientific and
Technological Program for Drug Discovery (2009ZX-
1
2
3
4
5
L4
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
KOt-Bu
TEMPO (1.0 equiv)
AIBN
0
28
75
51
88
none
L4
10% CuI
L4
10% Fe(acac)
none
2
L4
0
9103-101).
a
Reaction conditions: 1a (1.0 mmol), 2a (2 mL), 20 mol % ligand,
b
KOt-Bu (3.0 mmol), Ar, 80 °C, 24 h. Isolated yield.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
Furthermore, as described in the Supporting Infor-
mation, we formulated a possible mechanism for the
Org. Lett., Vol. 13, No. 14, 2011
3559