Preparation of unsymmetrical biaryls by pd(II)-catalyzed cross-coupling of aryl iodides

Article abstract of DOI:10.1021/ol802865c

The Ullmann homo-and cross-couplings of aryl iodides are carried out to afford symmetrical and unsymmetrical biaryls in moderate to good yields in a catalytic system of Pd(OAc)₂/K₂CO₃/MeCOEt. The high selectivity of unsymmetrical biaryl products in cross-couplings mainly depends on the reactivity difference between two iodoarene substrates and their employed ratios.

Full text of DOI:10.1021/ol802865c

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1079-1082
Preparation of Unsymmetrical Biaryls by
Pd(II)-Catalyzed Cross-Coupling of Aryl
Iodides
Liqiang Wang and Wenjun Lu*
Department of Chemistry, Shanghai Jiao Tong UniVersity, 800 Dongchuan Road,
Shanghai 200240, China
luwj@sjtu.edu.cn
Received December 12, 2008
ABSTRACT
The Ullmann homo- and cross-couplings of aryl iodides are carried out to afford symmetrical and unsymmetrical biaryls in moderate to good
yields in a catalytic system of Pd(OAc)2/K2CO3/MeCOEt. The high selectivity of unsymmetrical biaryl products in cross-couplings mainly depends
on the reactivity difference between two iodoarene substrates and their employed ratios.
Coupling of arenes to prepare symmetrical and unsym-
metrical biaryls is one of the most useful methods in organic
synthesis.1 Since the Ullmann reaction, a reductive homo-
coupling of aryl halides mediated by excess copper as
reductants was discovered one century ago,2 a lot of
advanced approaches especially on preparation of unsym-
metrical biaryls have been developed including the cross-
couplings of aryl halides with aryl organometallic reagents,3
aryl halides with simple arenes,4 and various arenes5 in the
presence of catalytic transition metals.
with additional reductive agents such as Zn, Mn, amines, or
alcohols have also been achieved successfully. Normally, we
can find that the unsymmetrical biaryls could be prepared
effectively from the cross-couplings between Ar-I and
Ar-Br, Ar-I and Ar-Cl, or Ar-Br and Ar-Cl.6-8 In
contrast, the catalytic cross-couplings of only aryl iodides
are rarely reported because of their poor selectivity on
(4) (a) Akita, Y.; Inoue, A.; Yamamoto, K.; Ohta, A.; Kurihara, T.;
Shimizu, M. Heterocycles 1985, 23, 2327–2333. (b) Shabashov, D.;
Daugulis, O. Org. Lett. 2005, 7, 3657–3659. (c) Zaitsev, V. G.; Shabashov,
D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154–13155. (d) Shabashov,
D.; Daugulis, O. Org. Lett. 2006, 8, 4947–4949. (e) Shabashov, D.; Daugulis,
O. J. Org. Chem. 2007, 72, 7720–7725. (f) Niwa, T.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2007, 9, 2373–2375. (g) Giri, R.; Maugel, N.; Li, J.; Wang,
D.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007,
129, 3510–3511. (h) Qin, C.; Lu, W. J. Org. Chem. 2008, 73, 7424–7427.
(5) (a) VanHelden, R.; Verberg, G. Recl. TraV. Chim. Pays-Bas 1965,
84, 1263–1273. (b) Li, R.; Jiang, L.; Lu, W. Organometallics 2006, 25,
5973–5975. (c) Rong, Y.; Li, R.; Lu, W. Organometallics 2007, 26, 4376–
4378. (d) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904–
11905. (e) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 12072–12073. (f) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172–
1175. (g) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B.
Org. Lett. 2007, 9, 3137–3139.
For the catalytic Ullmann-type cross-couplings of aryl
halides, many attempts involving Pd,6 Ni,7 or Co8 as catalysts
(1) (a) Suzuki, A. Pure Appl. Chem. 1994, 66, 213–222. (b) Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009–3066. (c) Dounay,
A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945–2963. (d) Chinchilla,
R.; Najera, C. Chem. ReV. 2007, 107, 874–922. (e) Yin, L.; Liebscher, J.
Chem. ReV. 2007, 107, 133–173. (f) Catellani, M.; Motti, E.; Della Ca’,
N.; Ferraccioli, R. Eur. J. Org. Chem. 2007, 415, 3–4165.
(2) (a) Ullmann, F.; Bielecki, J. Chem. Ber. 1903, 34, 2174–2185. (b)
Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359–1469.
(3) (a) Negishi, E.-I.; King, A. O.; Okukado, N. J. Org. Chem. 1977,
42, 1821–1823. (b) Wenkert, E.; Michelotti, E. L.; Swindell, C. S.; Tingoli,
M. J. Org. Chem. 1984, 49, 4894–4899. (c) Stille, J. K. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 508–524. (d) Miyaura, N.; Suzuki, A. Chem. ReV.
1995, 95, 2457–2483. (e) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc.
2007, 129, 3844–3845.
(6) For Pd-catalyzed Ullmann cross-couplings, see: (a) Amatore, C.;
Carre´, E.; Jutand, A.; Tanaka, H.; Ren, Q.; Torii, S. Chem.-Eur. J. 1996,
2, 957–966. (b) Hassan, J.; Hathroubi, C.; Gozzi, C.; Lemaire, M.
Tetrahedron 2001, 57, 7845–7855. (c) Wang, L.; Zhang, Y.; Liu, L.; Wang,
Y. J. Org. Chem. 2006, 71, 1284–1287.
10.1021/ol802865c CCC: $40.75
Published on Web 02/09/2009
2009 American Chemical Society

formation of unsymmetrical products.6a Herein, we describe
a novel Pd(II)-catalyzed cross-coupling reaction of various
aryl iodides in the absence of additional reductants.
both the amount of K2CO3 and the reaction temperature could
affect the reaction rates and the product yields (Table 1,
entries 7 and 8).
Subsequently, a variety of aryl iodides as substrates were
examined in the Pd(II)-catalyzed homocouplings, and the
results are shown in Scheme 1. Aryl iodides bearing not only
Most recently, we found that benzene or naphthalene could
be arylated with various aryl iodides in the presence of
Pd(OAc)2 through a possible Pd(II/IV) cycle.4h Then, we
investigated the Pd(II)-catalyzed homocoupling of iodoben-
zene to produce biphenyl without additional reductants.
Fortunately, biphenyl was produced from iodobenzene in
24% isolated yield, and the turnover number of Pd(II) catalyst
was 24 when carried out neat with K2CO3 under nitrogen
atmosphere after a long reaction time (Table 1, entry 1). After
Scheme 1. Pd(II)-Catalyzed Coupling of Various Aryl Iodides
Table 1. Optimization of the Coupling of Iodobenzenea
b
entry
catalyst
base
solvent yield [%] convn b[%]
c
1
2
3
4
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
Pd(OAc)2 K2CO3
-
24
11
54
44
>99
62
66
94
>99
84
10
71
10
EtOH
MeCN
PhOEt
MeCOEt
MeCOEt
MeCOEt
MeCOEt
MeCOEt
41
5
91(82)
79(72)
70
6d
7e
8f
9g
10
11
12
13
14
3
64
6
17
17
<1
8
Pd(OAc)2 Na2CO3 MeCOEt
Pd(OAc)2 Cs2CO3 MeCOEt
>90
62
<5
51
electron-withdrawing groups but also electron-releasing
groups underwent the homocouplings smoothly to afford the
symmetrical biaryls in good yields, but more sterically
hindered arenes such as 2-iodomesitylene did not generate
the corresponding biaryls. On the other hand, the Pd(II)-
catalyzed couplings of aryl C-Br or C-Cl bonds did not
occur, which is in contrast to Pd(0)-catalyzed coupling
reactions.6 However, 4,4′-dibromo biphenyl was prepared
in 73% yield with excellent selectivity from 1-bromo-4-
iodobenzene, which provided the Br groups for further
synthesis.
Interestingly, biphenyl was detected by GC analysis in
23% yield when Zn powder as the reductant was added into
the coupling of bromobenzene, but only a trace amount of
it was found without any additional reductants under the same
conditions, as shown in Scheme 2. In the former reaction,
PdCl2
Pd/C
K2CO3
K2CO3
MeCOEt
MeCOEt
MeCOEt
Pd(PPh3)4 K2CO3
a Conditions: iodobenzene (0.2 mmol), catalyst (5 mol %, 0.01 mmol),
base (2.4 mmol), solvent (0.5 mL), 120 °C, 5 h, under N2. b Detected by
GC, isolated yield in parentheses. c Iodobenzene (2 mmol), 6 days. d Under
air. e K2CO3 (2.0 mmol). f 80 °C. g 1 mol % Pd(OAc)2, 7 days.
screening a few solvents and bases (Table 1, entries 2-14),
we found that MeCOEt as the solvent with excess K2CO3
could enhance the yield of biaryl and reduce the reaction
time effectively in this homocoupling of iodobenzene (Table
1, entries 5 and 6). Although both MeCOEt and K2CO3 were
not used as the reducing agents under normal circumstances
and no byproducts related to MeCOEt were detected by 1H
NMR analysis in the reaction mixtures, the isolated yield of
biphenyl could be up to 82% especially under nitrogen
atmosphere (Table 1, entry 5). However, in alcohol or nitrile
(Table 1, entries 2 and 3), the potential reductants as solvents,
the yields of biphenyl were not good. Notably, a few Pd(0)
catalysts were also less active in this homocoupling under
the same conditions (Table 1, entries 13 and 14). Meanwhile,
Scheme 2. Pd(II)-Catalyzed Coupling of Bromobenzenea
(7) For Ni-catalyzed Ullmann cross-couplings, see: (a) Meyer, G.; Rollin,
Y.; Perichon, J. J. Organomet. Chem. 1987, 333, 263–267. (b) Gosmini,
C.; Lasry, S.; Ne´de´lec, J.-Y.; Pe´richon, J. Tetrahedron 1998, 54, 1289–
1298. (c) Gosmini, C.; Ne´de´lec, J.-Y.; Pe´richon, J. Tetrahedron Lett. 2000,
201–203. (d) Gosmini, C.; Ne´de´lec, J.-Y.; Pe´richon, J. Tetrahedron Lett.
2000, 41, 5039–5042.
a Conditions: bromobenzene 0.2 mmol, Pd(OAc)2 (5 mol %, 0.01 mmol),
K2CO3 (2.4 mmol), MeCOEt (0.5 mL), 120 °C, 23 h, under N2. GC yield
based on bromobenzene.
1080
Org. Lett., Vol. 11, No. 5, 2009

Pd(0) was generated from the reduction of Pd(II) catalyst
by Zn powder to activate aryl C-Br bonds the same as in
the other Pd-catalyzed couplings of aryl halides with ad-
ditional reductants.6 However, in the latter one, Pd(0) was
hardly formed. This might imply that this was a more
sensitive catalytic system to different aryl halides, which
would be suitable for the cross-coupling of aryl iodides.
Then, attempts were made to prepare unsymmetrical
biaryls from aryl iodides using this catalytic system. To
obtain high selectivity and good yields of unsymmetrical
products in these preparations, we first studied the selection
of substrate partners and the employed ratios of them. Herein,
we observed that electron-rich aryl iodides were more
reactive than electron-poor ones, although the latter ones
should be attacked by Pd(II) catalysts in oxidative additions
easily. Thus, if the reactivity difference between the two aryl
iodides was not large due to them bearing different substi-
tuted groups, e.g., as in the case of 4-iodoanisole and
iodobenzene, excess iodobenzene (2 equiv) was needed to
avoid the formation of a homocoupling product from the
more reactive 4-iodoansiole (1 equiv) according to the current
study (Table 2, entry 2) and our previous reports.4h,5b
3. For the more electron-rich aryl iodides (Ar′-I) such as
4-iodoanisole or the more electron-poor ones (Ar-I) such
as ethyl 3-iodobenzoate, the major products were the
Table 3. Pd(II)-Catalyzed Cross-Coupling of Various Aryl
Iodidesa
Table 2. Effects of Substrates and Ratios of Them on the
Pd(II)-Catalyzed Cross-Couplinga
a Conditions: Pd(OAc)2 (5 mol %, 0.01 mmol), K2CO3 (2.4 mmol),
MeCOEt (0.5 mL), 120 °C, 12 h, under N2. b Isolated yield for Ar′-Ar
and GC yield for Ar′2 based on Ar′-I. c GC yield based on Ar-I.
a Conditions: Ar′-I (0.2 mmol), Ar-I (0.4 mmol), Pd(OAc)2 (5 mol
%, 0.01 mmol), K2CO3 (2.4 mmol), MeCOEt (0.5 mL), 120 °C, 12 h, under
N2. b Isolated yield for Ar-Ar’ and GC yield for Ar′2 based on Ar′-I.
c GC yield based on Ar-I. d 6 h. e Ar-I (0.24 mmol). f Ar-I (0.5 mmol).
Notably, if an electron-rich aryl iodide reacted with an
electron-poor one, the major product was still the unsym-
metrical biaryl when the ratio of them was reduced even to
1/1.2 (Table 2, entry 6).
Moreover, many pairs of aryl iodides were tested in the
cross-coupling reactions, and the results are listed in Table
unsymmetrical biaryls (isolated yield 68-82%), and the
symmetrical biaryls from the homocouplings of electron-
rich aryl iodides (Ar′-I) were less than 1% by GC analysis
when excess electron-poor aryl iodides were used (Table 3,
entries 1-6). However, a small amount of homocoupling
products from 1-iodonaphthalene were detected, although the
(8) For Co-catalyzed Ullmann cross-couplings, see: Amatore, M.;
Gosmini, C. Angew. Chem., Int. Ed. 2008, 47, 2089–2092.
Org. Lett., Vol. 11, No. 5, 2009
1081

cross-coupling products were the major ones (Table 3, entries
10-13). In the cases of 4-iodotoluene with 4-chloro- and
with 4-bromo iodobenzene, respectively, the unsymmetrical
biaryls were generated in moderate yields by decreasing the
ratios of them to 1/2.5 (Table 3, entries 8 and 9). Although
the homocoupling products from the excess electron-poor
aryl iodides (Ar-I) were reduced by tuning the ratio of
substrate partners (Table 2, entries 5 and 6) and reaction time
(Table 3, entries 1 and 2) in some cases, they could not be
avoided completely.
tions. The unsymmetrical biaryls as the major products could
be obtained just by tuning the pairs of aryl iodide substrates
and their ratios in this catalytic system. Further investigation
on the reaction mechanism is ongoing.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant No. 20572069) for financial
support of this research.
Supporting Information Available: Experimental details
and characterization of coupling products. This material is
available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we established a convenient method for
preparation of symmetrical and unsymmetrical biaryls by
Pd(II)-catalyzed couplings of aryl iodides under mild condi-
OL802865C
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Org. Lett., Vol. 11, No. 5, 2009