Use of dimethyl carbonate as a solvent greatly enhances the biaryl coupling of aryl iodides and organoboron reagents without adding any transition metal catalysts

Article abstract of DOI:10.1039/c2cc17401d

The coupling reaction of aryl iodides with arylboronic acids to give biaryl compounds can be efficiently performed without adding a transition metal catalyst. The key to success is the use of dimethyl carbonate as a solvent. This finding provides a new strategy for constructing a biaryl linkage. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17401d

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 2912–2914
www.rsc.org/chemcomm
COMMUNICATION
Use of dimethyl carbonate as a solvent greatly enhances the biaryl
coupling of aryl iodides and organoboron reagents without adding any
transition metal catalystsw
Kiyofumi Inamoto,* Chisa Hasegawa, Kou Hiroya, Yoshinori Kondo, Takao Osako,
Yasuhiro Uozumi and Takayuki Doi*
Received 28th November 2011, Accepted 19th January 2012
DOI: 10.1039/c2cc17401d
The coupling reaction of aryl iodides with arylboronic acids to give
biaryl compounds can be efficiently performed without adding a
transition metal catalyst. The key to success is the use of dimethyl
carbonate as a solvent. This finding provides a new strategy for
constructing a biaryl linkage.
potential to provide a novel, useful strategy for constructing
biaryls, one major drawback might be the necessity of a large
amount of the arene coupling partner. Regioselectivity might
also be a problem; when benzene derivatives incorporate
substituent(s), reactions sometimes give a mixture of regioisomeric
5
,6
products. Herein, we report a new method for the synthesis
of biaryl compounds through a coupling reaction of aryl
halides with organoboron reagents without the addition of a
transition metal catalyst.
2
2
Aromatic C(sp )–C(sp ) bond-forming reactions leading to biaryl
compounds are of considerable importance in the research fields
of pharmaceuticals, agrochemicals, and functional materials
because the compounds that contain a biaryl linkage exhibit a
During the course of our studies on transition metal-catalyzed
Suzuki–Miyaura coupling reactions, it was found that 4-cyano-
benzonitrile (1a) reacted with phenylboronic acid (2a) in the
1
range of biological activities and also offer useful properties. To
date, the most commonly employed methods to regioselectively
access biaryls through C–C bond formation are transition
metal-catalyzed cross-coupling reactions between aryl (pseudo)-
halides and organometallic reagents (e.g., organoboron compounds
3 4
presence of K PO without the addition of a metal catalyst,
particularly when dimethyl carbonate (DMC) was used as a
10
solvent (Table 1). The coupling reaction proceeded smoothly
2
at 135 1C, producing 4-cyanobiphenyl (3aa) in high yield
in Suzuki–Miyaura coupling). Considerable effort has been
(
entry 1). Intrigued by this apparently metal-free coupling
focused on the development of active catalyst systems, particularly
those based on palladium and nickel. On the other hand, catalytic
direct arylation of (hetero)aromatic C–H bonds has emerged in
the past decade as an alternative, viable strategy for preparing
process, further examination of the reaction parameters was
carried out. While an array of basic compounds were found to
be effective in mediating the process (entries 2–9, 13, and 14),
3
the use of disilazides and Et N gave low yield (entries 10–12
3
biaryls. Heteroaromatic C–H bonds, or aromatic C–H bonds in
and 15, respectively). The use of solvents such as DMF,
toluene, and 1,4-dioxane that are typically employed for
Pd- or Ni-catalyzed Suzuki–Miyaura coupling reactions did
not lead to coupling product 3aa, indicating the significant
an ortho position to the directing group, can be effectively
functionalized with aryl halides, aryl–metal species, or arene
C–H bonds in the presence of a catalyst (e.g., Pd, Cu, or Rh),
resulting in the efficient, atom-economical construction of biaryls.
Very recently, an organocatalytic route to biaryl scaffolds has been
11
solvent effect of DMC in the process. In particular, no coupling
product was formed in the absence of a base (entry 16). The
reaction temperature could be lowered to 120 1C without causing
4
5
independently introduced by Kwong and Lei et al., Shi et al.,
6
and Shirakawa and Hayashi et al.. Reactions of aryl halides
a significant loss of yield (entries 17 and 18). The use of PhBF K
3
with benzene derivatives proceeded in the presence of a
t
stoichiometric amount of a base (e.g., KO Bu or NaO Bu)
t
instead of 2a also proved to be effective for arylation, furnishing
biphenyl 3aa in comparable yield (entry 19). The reaction under
an air atmosphere provided a high yield comparable with that
under an Ar atmosphere (entry 20 vs. entry 1). The use of 2a that
was purified by silica-gel column chromatography followed by
recrystallization also delivered 3aa in high yield (entry 21).
Leadbeater et al. previously demonstrated that Pd contaminants
in sodium carbonate at a level as low as 50 ppb sufficiently catalyze
and a bidentate-type nitrogen-based ligand (e.g., DMEDA or
7
–9
1
,10-phenanthroline, typically 10–20 mol% was required).
Although this groundbreaking, metal-free approach has the
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3,
Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
E-mail: inamoto@mail.pharm.tohoku.ac.jp,
doi_taka@mail.pharm.tohoku.ac.jp; Fax: +81-22-795-5917;
Tel: +81-22-795-3906
Suzuki–Miyaura coupling reactions under forcing conditions
12
(microwave irradiation). Considering the possibility that such
trace amounts of transition metals in the reaction mixture can
catalyze our process, quantitative elemental analyses of the used
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral/analytical data. See DOI: 10.1039/c2cc17401d
2
912 Chem. Commun., 2012, 48, 2912–2914
This journal is c The Royal Society of Chemistry 2012

View Online
a
Table 1 Effect of reaction parameters
b,c
Yield (%)
Entry
Base
Scheme 1 Effect of radical scavengers.
d
1
2
3
4
5
6
7
8
9
K
K
K
Cs
Na
3
2
2
PO
CO
CO
4
92
a
3
72 (19)
88 (8)
68
74 (23)
89
64 (35)
87
92
Trace (86)
0 (quant)
29 (70)
90 (8)
81
3 (85)
0 (89)
88
34 (62)
91
91
Table 2 Use of various boronic acids
3
(recrystallized)
2
CO
CO
3
2
3
NaHCO
CsOAc
3
t
NaO Bu (sublimed)
NaOMe
KHMDS
NaHMDS
KF
CsF
NaH
Et
—
b,c
Yield (%)
Entry RB(OH)
2
2
Product
3
10
11
12
13
14
15
16
17
18
19
20
21
1
2b
3ab 94
3ac 79
3ad 93
3ae 92
3
N
e
f
K
K
K
K
K
3
PO
PO
PO
PO
PO
4
4
4
4
4
2
3
4
5
2c
2d
2e
3
3
3
3
g
h
i
84
a
Reaction conditions: 1a (0.26 mmol), 2a (0.31 mmol), and base
b
0.31 mmol) in DMC (2.6 mL) under an Ar atmosphere. Isolated
(
yield. Yield of recovered 1a in parentheses. Average of two runs.
c
d
e
f
g
1
20 1C instead of 135 1C. 100 1C instead of 135 1C. PhBF
3
K was
used instead of 2a. Conducted under an air atmosphere instead of an
h
i
Ar atmosphere. 2a which was purified by SiO
2
column chromatography
2f
3af 92
3ag 91
followed by recrystallization from H O was used.
2
d
6
2g
reagents including DMC were performed via ICP-MS. The
most abundant element was found to be Fe in 1a and 2a,
although in significantly low concentration (84.63 ppb in 1a,
7
2h
2i
3ah 0 (quant)
3ai 0 (quant)
PO
4
1
3
1
7.14 ppb in 2a). In addition, the concentration of other
8
metals such as Pd, Ni, and Cu was also found to be extremely
1
4
a
low (below 3 ppb). Although the possible involvement of
transition metals cannot be completely ruled out, such a
catalytic process might not be operating in the process.
The generation of aryl radicals from the corresponding
arylboronic acids in the presence of Mn(III) salt was previously
Reaction conditions: 1a (0.26 mmol), 2 (0.31 mmol), and K
3
b
(0.31 mmol) in DMC (2.6 mL) under an Ar atmosphere. Isolated
c
yield, average of two runs. Yield of recovered 1a in parentheses.
d
0
3 4
.52 mmol of 2 and 0.52 mmol of K PO were used.
1
5
reported. Mao et al. recently proposed a radical pathway in the
alkylboronic acid 2i was found to be unsuitable for the
reaction (entry 8).
1
6
iodine-catalyzed Suzuki–Miyaura-type coupling reaction. To
determine the possible involvement of radical species in our biaryl
synthesis, radical scavengers such as TEMPO and galvinoxyl were
used in the reaction. These scavengers were found to have no
effect on the coupling process, indicating that the reaction might
The substrate scope of the process with respect to aryl
iodides was next explored (Table 3). A variety of aryl iodides
with an array of substituents such as –CN, –NO
–CO Me, –OMe, and –Me smoothly underwent the coupling
reaction with 2a, affording the corresponding biaryls generally
2
, –COMe,
2
17
not be proceeding via a radical pathway (Scheme 1).
1
8
Various boronic acids 2b–g were successfully coupled with 1a
under the optimized conditions (Table 2). Arylboronic acids with
para, meta, or ortho substitution patterns, possessing either an
electron-withdrawing (entry 1) or electron-donating substituent
in high yield (entries 1–9). Note that the reactions of aryl
halides possessing an electron-donating –OMe or –Me group
N
did proceed efficiently, suggesting that the S Ar pathway might
not be involved in the coupling process (entries 5, 6, 8, and 9).
In conclusion, we have developed a new approach for
preparing biaryl compounds from aryl iodides and arylboronic
(entries 2–5), proved to be effective coupling partners, affording
the corresponding biaryls in high yield. Other than arylboronic
acids, alkenylboronic acid 2g also participated in the coupling
reaction to give styrene 3ag in high yield (entry 6). In contrast,
the reaction using styrylboronic acid 2h did not proceed at all
and 1a was recovered quantitatively (entry 7). In addition,
1
9
acids by using DMC as a solvent. The addition of transition
metals is not necessary in this case and K PO is the only
3
4
reagent required to mediate the process. Although the precise
reaction mechanism remains to be elucidated, this apparently
This journal is c The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2912–2914 2913

View Online
a
Table 3 Substrate scope with respect to aryl iodides
Chem. Soc. Rev., 2009, 38, 2447; (d) O. Daugulis, H.-Q. Do and
D. Shabashov, Acc. Chem. Res., 2009, 42, 1074; (e) X. Chen,
K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed.,
2009, 48, 5094; (f) L. Ackermann, R. Vicente and A. R. Kapdi, Angew.
Chem., Int. Ed., 2009, 48, 9792; (g) J. A. Ashenhurst, Chem. Soc. Rev.,
2
010, 39, 540; (h) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Commun.,
010, 46, 677; (i) T. Satoh and M. Miura, Synlett, 2010, 3395;
2
¨
(j) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius, Chem. Soc.
b,c
Yield (%)
Entry Ar–X
1
Product
3
Rev., 2011, 40, 4740; (k) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang,
Chem. Soc. Rev., 2011, 40, 5068.
4
5
6
7
W. Liu, H. Cao, H. Zhang, K. H. Chung, C. He, H. Wang,
F. Y. Kwong and A. Lei, J. Am. Chem. Soc., 2010, 132, 16737.
C.-L. Sun, H. Li, D.-G. Yu, M. Yu, X. Zhou, X.-Y. Lu, K. Huang,
S.-F. Zheng, B.-J. Li and Z.-J. Shi, Nat. Chem., 2010, 2, 1044.
E. Shirakawa, K.-I. Itoh, T. Higashino and T. Hayashi, J. Am.
Chem. Soc., 2010, 132, 15537.
1
1a
3aa 92
3ba 95
3ca 75
3da 92
3ea >99
3fa 99
3ga 84
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
(a) For a pioneering work by Itami on the biaryl coupling of electron-
deficient N-heterocycles and aryl halides (iodides and bromides) in the
presence of KO Bu, see: S. Yanagisawa, K. Ueda, T. Taniguchi and
t
K. Itami, Org. Lett., 2008, 10, 4673; (b) Itami et al. recently reported
a peroxide-mediated C–H/C–H cross-dehydrogenative coupling
of pyridine N-oxides with alkanes, see: G. Deng, K. Ueda,
S. Yanagisawa, K. Itami and C.-J. Li, Chem.–Eur. J., 2009, 15, 333.
t
8
Very recently, an intramolecular version of the KO Bu-mediated
biaryl coupling was reported, see: (a) D. S. Roman, Y. Takahashi
and A. B. Charette, Org. Lett., 2011, 13, 3242; (b) C.-L. Sun,
Y.-F. Gu, W.-P. Huang and Z.-J. Shi, Chem. Commun., 2011,
t
4
7, 9813. For transition metal-free, KO Bu-mediated Mizoroki–
Heck type reaction, see: ; (c) E. Shirakawa, X. Zhang and
T. Hayashi, Angew. Chem., Int. Ed., 2011, 50, 4671. For other
examples, see: ; (d) Y. Qiu, Y. Liu, K. Yang, W. Hong, Z. Li,
Z. Wang, Z. Yao and S. Jiang, Org. Lett., 2011, 13, 3556.
(a) N. E. Leadbeater, Nat. Chem., 2010, 2, 1007; (b) A. Studer and
D. P. Curran, Angew. Chem., Int. Ed., 2011, 50, 5018.
1g
9
1
0 Dimethyl carbonate (DMC) is inexpensive, low-toxic and highly
biodegradable, and considered as an environmentally-benign,
1h
1i
3ha 73 (9)
3ia 73
‘‘green’’ solvent. For a review, see: B. Scha
S. P. Verevkin and A. Borner, Chem. Rev., 2010, 110, 4554.
¨ ¨
ffner, F. Schaffner,
¨
9
1
1 (a) Super high-grade DMC (purchased from Wako Pure Chemical
Industries, Catalogue #: 287-81591, Lot #: STF8122) which
contains less than 50 ppb of transition metals (Pd, Cu, Fe, Ni,
Ru, Rh, Pt, approved by Wako Chemicals) was also employed for
the process: in this case, 3aa was obtained in 86% yield; (b) all
glassware employed for the reactions was thoroughly cleaned with
aqua regia prior to use.
a
Reaction conditions: 1 (0.26 mmol), 2a (0.31 mmol), and K
(
yield, average of two runs. Yield of recovered 1 in parentheses.
3
PO
4
b
0.31 mmol) in DMC (2.6 mL) under an Ar atmosphere. Isolated
c
metal-free biaryl synthesis is highly advantageous from the
viewpoints of applicability, simplicity, and low environmental
impact. Further mechanistic studies as well as an investigation
on the full scope of this approach are currently underway and
will be reported in due course.
12 R. K. Arvela, N. E. Leadbeater, M. S. Sangi, V. A. Williams,
P. Granados and R. D. Singer, J. Org. Chem., 2005, 70, 161.
1
3 (a) Nakamura et al. recently reported Fe-catalyzed Suzuki–
Miyaura coupling of alkyl halides with organoboronates in the
2
presence of iron-complexes derived from FeCl and a specially
designed diphosphine ligand, see: T. Hatakeyama, T. Hashimoto,
Y. Kondo, Y. Fujiwara, H. Seike, H. Takaya, Y. Tamada, T. Ono
and M. Nakamura, J. Am. Chem. Soc., 2010, 132, 10674; (b) For
Fe-catalyzed biaryl synthesis from aryl iodides and benzene
´
derivatives, see: F. Vallee, J. J. Mousseau and A. B. Charette,
J. Am. Chem. Soc., 2010, 132, 1514.
This work was partly supported by a Grant-in-Aid for
Young Scientists (B) (No. 23790002) from Japan Society for
the Promotion of Science and a Grant-in-Aid for Scientific
Research on Innovative Areas (No. 2105) from MEXT, and
by the Joint Studies Program (2010) of the Institute for
Molecular Science. The authors thank Ms Yoko Nakano
and Mr Shinji Takahashi for ICP-MS analysis at Technical
Division of School of Engineering, Tohoku University.
1
1
4 For detailed results of ICP-MS, see ESIw.
¨
5 (a) A. S. Demir, O. Reis and M. Emrullahoglu, J. Org. Chem.,
2003, 68, 578; (b) S. K. Guchhait, M. Kashyap and S. Saraf,
Synthesis, 2010, 1166.
1
6 J. Mao, Q. Hua, G. Xie, J. Guo, Z. Yao, D. Shi and S. Ji, Adv.
Synth. Catal., 2009, 351, 635.
1
7 For other examples of biaryl synthesis involving aryl radical
species, see: (a) T. Dohi, M. Ito, K. Morimoto, M. Iwata and
Y. Kita, Angew. Chem., Int. Ed., 2008, 47, 1301; (b) A. Wetzel,
V. Ehrhardt and M. R. Heinrich, Angew. Chem., Int. Ed., 2008,
47, 9130; (c) I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio,
Y. Fujiwara, A. L. Sobel and P. S. Baran, J. Am. Chem. Soc., 2010,
132, 13194.
Notes and references
1
For selected examples, see: (a) T. Yamamoto, Synlett, 1993, 425;
b) P. J. Hajduk, M. Bures, J. Praestgaard and S. W. Fesik, J. Med.
(
Chem., 2000, 43, 3443; (c) G. Bringmann and D. Menche, Acc.
Chem. Res., 2001, 34, 615.
2
3
A. D. Meijere and F. Diederich, Metal-Catalyzed Cross-Coupling
Reactions, Second, Completely Revised and Enlarged Edition,
Wiley-VCH, Weinheim, 2004.
For selected recent reviews, see: (a) D. Alberico, M. E. Scott and
M. Lautens, Chem. Rev., 2007, 107, 174; (b) B.-J. Li, S.-D. Yang and
Z.-J. Shi, Synlett, 2008, 949; (c) G. P. McGlacken and L. M. Bateman,
18 Aryl bromides and chlorides have been found to be less reactive in
the process.
19 E. Shirakawa, Y. Hayashi, K.-i. Itoh, R. Watabe, N. Uchiyama,
W. Konagaya, S. Masui and T. Hayashi, Angew. Chem., Int. Ed.,
2012, 51, 218.
2
914 Chem. Commun., 2012, 48, 2912–2914
This journal is c The Royal Society of Chemistry 2012