Direct arylation of heteroarenes catalyzed by a palladium-1,10- phenanthroline complex

Article abstract of DOI:10.1055/s-0030-1259727

A new entry in direct arylation of heteroarenes using Pd(OAc)₂ and 1,10-phenanthroline as a nitrogen-based ligand is reported. The long induction period observed at the initial stage of the reaction was effectively reduced by modification of th

Full text of DOI:10.1055/s-0030-1259727

LETTER
959
Direct Arylation of Heteroarenes Catalyzed by a Palladium–
1,10-Phenanthroline Complex
D
irec
t
A
rylationo
y
f
H
eteroare
o
nes Takita,*a,b Daichi Fujita,a Fumiyuki Ozawa*a
a
International Research Center for Elements Science (IRCELS), Institute for Chemical Research, Kyoto University,
Uji, Kyoto 611-0011, Japan
Fax +81(774)383039; E-mail: ozawa@scl.kyoto-u.ac.jp
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
E-mail: takita@mol.f.u-tokyo.ac.jp
b
Received 10 December 2010
This paper is dedicated to Professors Xiyan Lu and Li Xin Dai for their life-long contributions to the development of organic chemistry.
an SEAr-type mechanism.1,5o,z,11 Recently, some groups
Abstract: A new entry in direct arylation of heteroarenes using
has proposed ‘concerted metalation mechanism,’ in which
Pd(OAc)2 and 1,10-phenanthroline as a nitrogen-based ligand is re-
carboxylato ligands act as an internal base to achieve
ported. The long induction period observed at the initial stage of the
reaction was effectively reduced by modification of the catalyst
deprotonation of heteroarenes and concurrent metala-
preparation, leading to improved chemical yields (69–92%) and tion.6e,k,12 Given that PdII species, which could be generat-
ed by oxidative addition of haloarenes to Pd0 species, are
shortening of reaction times (3–10 h).
involved in both mechanisms, the thermodynamic stabili-
ty of PdII species in the higher oxidation state should be
crucial to obtain a sufficient concentration of active spe-
cies. The Pd-catalyzed reactions thus far reported were
exclusively performed by the use of phosphine ligands or
under ligand-free conditions.5,6 On the other hand, nitro-
gen-based ligands, which should stabilize PdII species
rather than Pd0 species and are advantageous in the meta-
lation step, have been scarcely utilized in this area.13–15
Herein, we report the results of our investigations leading
to a Pd(OAc)2–1,10-phenanthroline catalyst, which en-
ables direct arylation of thiophene, furan, and indole de-
rivatives with various iodoarenes in good yields and short
reaction times.
Key words: direct arylation, palladium, 1,10-phenanthroline, het-
eroarenes, biaryls
Efficient transformation of versatile building blocks in
medicinal or material chemistry has been pursued to
achieve easy access to functional molecules in a cost-
effective and environmentally benign manner. Direct
functionalization of non-activated arenes via the discon-
nection of the arene C–H bond serves as one such effec-
tive transformation.1–3 Compared to preparation methods
using activated arenes (e.g. organometallic reagents in
cross-coupling reactions), such direct reactions have the
great advantages of reduced waste, lower cost, and shorter
processes.
First, the reaction conditions were optimized for direct
arylation of 2-methylthiophene (2a) with iodobenzene
(1a), using a variety of nitrogen-based ligands (Table 1).
The combination of 2,2¢-bipyridyl with a catalytic amount
of Pd(OAc)2 and one equivalent of Cs2CO3 in DMF at 100
°C afforded only a trace amount of the desired product
3aa after 24 hours (entry 1). On the other hand, the use of
1,10-phenanthroline (A) was found to have a dramatic im-
pact on the reactivity, and the chemical yield of 3aa was
improved to 79% as confirmed by GLC analysis (entry 2).
Other 1,10-phenanthroline derivatives with electron-
donating substituents provided less satisfactory results
(entries 3–5). Related aromatic nitrogen-based bidentate
ligands with a planar structure and TMEDA as an aliphat-
ic diamine ligand were also ineffective (entries 6–9).
Thus, rigid bidentate coordination of a less basic ligand
would be of importance.16 Compounds with pyridine and
phosphine moieties showed slight catalytic activities, and
Ph3P was also unsuitable for these reaction conditions (en-
tries 10–12). Bromobenzene formed 3aa in low yield
(12%), and chlorobenzene was unreactive under the reac-
tion conditions of entry 2.
Heteroarenes are a significant class of arenes due to their
wide range of applications. For instance, thiophene deriv-
atives are used extensively in organic electronic materials,
and indole derivatives are ubiquitous in biologically ac-
tive compounds. Thus, efficient transformations of these
heteroarenes are of great interest. In this context, direct
arylation of heteroarenes4 with haloarenes or pseudoha-
loarenes as coupling partners has been intensively inves-
tigated, and many kinds of transition metal species have
been found to facilitate the reaction.5–10 Among them, pal-
ladium-based catalysts have been most widely uti-
lized.5,6,10 Despite rapid progress in this field, direct
arylation still encounters notable limitations, especially in
terms of substrate generality.
Under those reaction conditions, two mechanisms have
been mostly considered. It has been traditionally accepted
that direct arylation of electron-rich heteroarenes would
proceed via electrophilic aromatic substitution, namely,
SYNLETT 2011, No. 7, pp 0959–0963
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259727; Art ID: W34710ST
© Georg Thieme Verlag Stuttgart · New York
Next, we examined the effects of palladium sources. The
reactions were carried out at a controlled reaction time (4

960
R. Takita et al.
LETTER
Table 1 Optimization of Pd-Catalyzed Direct Arylation of 2-Meth-
ylthiophene (2a) with Iodobenzene (1a) (continued)
h). The combination of Pd(OAc)2 and 1,10-phenanthro-
line provided a 77% yield of the arylated product in this
time period (entry 13). The use of Pd(O2CCF3)2 decreased
the catalytic activity (entry 14), and dichloro complexes
were less effective (entries 15 and 16). In addition,
Pd2(dba)3·CHCl3 and CpPd(h3-allyl) exhibited very poor
catalytic activity under the reaction conditions (entries 17
Pd source (2 mol% on Pd)
ligand (4 mol%)
+
I
Ph
H
Ph
Cs2CO3 (1 equiv)
DMF, 100 °C
S
2a
S
1a
(1 equiv)
3aa
(1.5 equiv)
and 18). Consequently, Pd(OAc)2 and 1,10-phenanthro- Entry Ligand
line were proven to be the catalyst combination of choice.
Pd source
Pd(OAc)2
Time Yield
(h)
(%)a
Table 1 Optimization of Pd-Catalyzed Direct Arylation of 2-Meth-
ylthiophene (2a) with Iodobenzene (1a)
11
24
9
Ph2P
N
PPh2
Pd source (2 mol% on Pd)
ligand (4 mol%)
c
12
13
14
15
16
17
18
PPh3
A
Pd(OAc)2
24
4
8
+
I
Ph
H
Ph
Cs2CO3 (1 equiv)
DMF, 100 °C
S
S
3aa
Pd(OAc)2
77
1a
(1 equiv)
2a
(1.5 equiv)
A
Pd(O2CCF3)2
PdCl2(tmeda)
PdCl2(PhCN)2
4
56
Entry Ligand
Pd source
Pd(OAc)2
Time Yield
(%)a
A
4
2
(h)
A
4
21
1
24
1
A
Pd2(dba)3·CHCl3
4
trace
trace
N
N
N
A
CpPd(h3-allyl)
4
a GLC yields based on tridecane as an internal standard.
b Mes* = 2,4,6-tri-tert-butylphenyl.
c The use of 8 mol% of Ph3P gave the same chemical yield (8%).
2
Pd(OAc)2
Pd(OAc)2
24
24
79
27
N
A
Ph
Ph
Even after the optimal catalyst combination was deter-
mined, the chemical yield remained moderate even with
prolonged reaction time (entries 2 and 13, Table 1).
Therefore, the reaction profile was investigated by GLC
using tridecane as an internal standard. The blue curves in
Figures 1a and 1b are the time-course of conversion of 1a
and yield of 3aa, respectively, under the reaction condi-
tions of entry 13 in Table 1 (condition A), where the sub-
strates (1a and 2a), base (Cs2CO3), and catalyst precursors
[Pd(OAc)2 and 1,10-phenanthroline] were mixed together
in DMF, and then heated at 100 °C. It is seen that, follow-
ing the 60 minutes induction period, 1a starts to be con-
verted to 3aa in ca. 80% selectivity.17
3
N
N
MeO
OMe
4
5
Pd(OAc)2
Pd(OAc)2
24
24
0
3
N
N
N
N
O
6
7
Pd(OAc)2
Pd(OAc)2
24
24
5
0
On the other hand, preheating the catalyst precursors in
DMF in the presence of iodobenzene (1a) and Cs2CO3 at
100 °C for 30 minutes reduces the induction period nearly
in half (condition B). The red reaction curves in
Figures 1a and 1b show the time-course of the amounts of
1a and 3aa after the addition of 2-methylthiophene (2a) to
the system. The reaction is accelerated and the product se-
lectivity is improved to ca. 90%. As a result, 3aa was ob-
tained in 89% yield after four hours as confirmed by GLC.
It was noted that the treatment of Pd(OAc)2 and 1,10-
phenanthroline with 1a and base prior to the catalytic re-
action is essential for gaining improved catalytic activity.
No acceleration effect was observed when the catalyst
precursors were heated only with Cs2CO3 or with 2a and
Cs2CO3 (see Supporting Information).
N
N
Mes
N
N Mes
b
8
9
Pd(OAc)2
Pd(OAc)2
24
24
trace
trace
N
N
Mes*
Me2N
NMe2
10
Pd(OAc)2
24
5
N
PPh2
The reaction procedure of condition B was effective for
direct arylation of 2-methylthiophene (2a), 2-pentylfuran
(2b), and N-methylindole (2c), as summarized in Table 2.
Synlett 2011, No. 7, 959–963 © Thieme Stuttgart · New York

LETTER
Direct Arylation of Heteroarenes
961
Table 2 Direct Arylation of Heteroarenes Catalyzed by a Palladi-
um–1,10-Phenanthroline Complex
H
Ar2
Pd(OAc)2 (2 mol%)
1,10-phenanthroline (4 mol%)
2
Ar1 Ar2
Ar1
1
I
(1.5 equiv)
Cs2CO3 (1 equiv)
DMF, 100 °C, 0.5 h
3
(1 equiv)
Entry
Ar1 (Ar1I)
HAr2
Time
(h)
Yield
(%)a
Ph
(1a)
1
2
3
4
5
4
4
9
6
3
84
H
S
2a
2a
4-MeC6H4
(1b)
79
1-naphthyl
(1c)
2a
2a
2a
82
4-MeOC6H4
(1d)
68
4-EtO2CC6H4
80
(1e)
Ph
(1a)
6
7
4
5
85
92
76
86
H
C5H11
O
2b
2b
1-naphthyl
(1c)
8
4-MeOC6H4
(1d)
2b
2b
10
4
9
4-EtO2CC6H4
(1e)
4-EtO2CC6H4
(1e)
10
6.5
69
H
N
Me
(2c)
a Isolated yield.
Figure 1 Comparison of the reaction profiles of direct arylation ca-
talyzed by Pd(OAc)2 and 1,10-phenanthroline under conditions A and
B: (a) conversion of iodobenzene (1a); (b) GLC yield of the corre-
sponding product (3aa)
during the catalyst preparation is the formation of a phe-
nylpalladium intermediate via reduction of Pd(OAc)2, fol-
lowed by oxidative addition of PhI to a Pd(0) species. If
the reduction of Pd(OAc)2 is a significantly slow process
in the present catalytic system using 1,10-phenanthroline
as a nitrogen-based ligand, the notably long induction pe-
riod may be rationalized.18 Investigations on the mecha-
nistic details and further applications of this novel catalyst
system are ongoing in our laboratory.
2-Methylthiophene (2a) reacted with various iodoarenes
(entries 1–5), including sterically hindered (1c), electron-
rich (1d), and electron-deficient (1e) substrates, to afford
the desired products in 68–84% yields. The reactions were
completed in 3–9 hours. 2-Pentylfuran (2b) was also
smoothly coupled with iodoarenes in 76–92% yields (en-
tries 7–9). N-Methylindole (2c) reacted with ethyl iodo-
benzoate (1e) exclusively at the 2-position (entry 10).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
In conclusion, we have developed a new catalyst system
for direct arylation of heteroarenes using Pd(OAc)2 and
1,10-phenanthroline as catalyst precursors. It was found
that preheating the catalyst precursors with PhI and
Cs2CO3 reduces the induction period to a considerable ex-
tent and affords highly efficient catalysis with good chem-
ical yields and short reaction times. A plausible process
Acknowledgment
This work was supported by a Grant-in-Aid for Young Scientists
from JSPS and MEXT, Japan (Start-up: No. 19890103, B: No.
21750099). A financial support from The Uehara Memorial Found-
ation is also acknowledged.
Synlett 2011, No. 7, 959–963 © Thieme Stuttgart · New York

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LETTER
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Synlett 2011, No. 7, 959–963 © Thieme Stuttgart · New York

LETTER
developed, see: Wang, Q.; Takita, R.; Kikuzaki, Y.; Ozawa,
Direct Arylation of Heteroarenes
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(c) Garcia-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.;
Maseras, F.; Echavarren, A. M. J. Am. Chem. Soc. 2007,
129, 6880. (d) Lafrance, M.; Lapointe, D.; Fagnou, K.
Tetrahedron 2008, 64, 6015. (e) Pascual, S.; de Mendoza,
P.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
Tetrahedron 2008, 64, 6021; and references cited therein.
(13) A stoichiometric reaction of [Pd(aryl)I(bipy)] with
thiophene in the presence of AgNO3 and KF to afford 2-
arylthiophene has been reported by Mori et. al: (a) Sugie,
A.; Kobayashi, K.; Suzaki, Y.; Osakada, K.; Mori, A. Chem.
Lett. 2006, 35, 1100. (b) Mori, A.; Sugie, A.; Furukawa, H.;
Suzaki, Y.; Osakada, K.; Akita, M. Chem. Lett. 2008, 37,
542. (c) Sugie, A.; Furukawa, H.; Suzaki, Y.; Osakada, K.;
Akita, M.; Monguchi, D.; Mori, A. Bull. Chem. Soc. Jpn.
2009, 82, 555.
(15) Very recently, Shibahara, Murai and co-workers reported a
related catalytic system using [PdII(1,10-phenanthro-
line)2](PF6)2, see: Shibahara, F.; Yamaguchi, E.; Murai, T.
Chem. Commun. 2010, 46, 2471.
(16) Isolated Pd(OAc)2(1,10-phenanthroline) gave a comparable
result (69%) under the same conditions.
(17) The remaining part of 1a is very probably converted to
benzene. The reduction of 1e to give ethyl benzoate was
confirmed by GC–MS analysis of the reaction solution of
entry 5 in Table 2.
(18) In contrast, Pd(OAc)2 is known to be reduced smoothly to a
Pd(0) species in the presence of tertiary phosphine ligands:
(a) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 21,
2177. (b) Amatore, C.; Jutand, A.; M’Barki, M. A.
Organometallics 1992, 11, 3009. (c) Amatore, C.; Carre, E.;
Jutand, A.; M’Barki, M. A. Organometallics 1995, 14, 1818.
(14) Cleavage of arene C–H bonds on platinum(II) diimine
complexes has been reported: (a) Lersch, M.; Tilset, M.
Chem. Rev. 2005, 105, 2471. (b) Wik, B. J.; Lersch, M.;
Synlett 2011, No. 7, 959–963 © Thieme Stuttgart · New York

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