Table 2 Homo-coupling reaction of aryl bromides 1 via oxidation of
Lipshutz cuprate with tetramethyl-1,4-benzoquinonea
Scheme 2
Entry
Ar
tBuLi (equiv.)
Yield (%)b
1
2
3
4
5
6
7
8
9
C6H5 (1b)
4-FC6H4 (1c)
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.5
2.5
2.5
1.1
1.1
1.1
84
73
87
96
91
90
95
88
64
99
99
62
82
87
with the intramolecular cyclization product 5a (27%). Similar
cyclization of 3b took place smoothly, providing 4b in 27% yield.
When we investigated the palladium-catalyzed coupling reaction of
3a with Me3SnSnMe3, the intramolecular cyclization proceeded to
afford 5a in good yield with no formation of 4a.11
2-MeOC6H4 (1d)
3-MeOC6H4 (1e)
4-MeOC6H4 (1f)
4-MeC6H4 (1g)
3-BrC6H4 (1h)
4-BrC6H4 (1i)
2,4,6-Me3C6H2 (1j)
1-Naphthyl (1k)
2-Naphthyl (1l)
2-Thienyl (1m)
3-Thienyl (1n)
4-Br-3-thienyl (1o)
Key intermediates for the formation of 4 and 5 are metallacycles
6 and 7 containing a Lipshutz cuprate structure (M 5 Cu)
(Scheme 2). The dithiophene 5a is produced via six-membered
monomeric metallacycle intermediate 6, while 4a is produced via
12-membered dimeric metallacycle 7. In the palladium-catalyzed
reaction, 6 should be thermodynamically stable and it is supposed
that hardly any 7 is generated in situ. Because Lipshutz cuprates
are known to have linear C–Cu–C linkages,4 the intermediate 7,
which has linear C–Cu–C linkages, is expected to be more
favorable than 6, which has a bent structure.
10
11
12
13
14
a
The reaction was carried out using a similar procedure to that
b
noted in Table 1. Isolated yield.
cases of sterically hindered aryl bromides such as 1j, 1k and 1l, no
homo-coupling reactions of cuprates proceeded under standard
conditions and the corresponding reduction products at the bromo
In summary, we have demonstrated the efficient homo-coupling
reaction of aryl bromides via Lipshutz cuprates under electron
transfer conditions. A unique electron transfer step from the
cuprates to the electron acceptors, without conjugate addition, is
a key step for this reaction system and is a novel aspect of
Lipshutz cuprates. We have also applied this system to the
synthesis of 10-membered cyclophanes. Further studies on the
reaction mechanism and applications of this electron transfer
system to the construction of other functional macrocycles are now
in progress.
t
positions were obtained. When BuLi (2.5 equiv.) was used, the
reaction proceeded smoothly to afford the biaryls 2j, 2k and 2l in
moderate to good yields (Table 2, entries 9–11). This coupling
reaction is useful for the synthesis of heteroaromatic dimers and
bithiophenes such as 2m, 2n and 2o were obtained in 62, 82 and
87% yields (Table 2, entries 12, 13 and 14). It is worth noting that
the present reaction conditions allow employment of an aryl
dihalide (1h, 1i or 1o), selectively affording the coupling
products without loss of the bromo substituents (Table 2, entries
7, 8 and 14).
This work was partly supported by a Grant-in-Aid for Scientific
Research on Priority Areas of Exploitation of Multi-Element
Cyclic Molecules (No. 14044086) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Although the reaction mechanism is not yet clear, we propose a
plausible pathway as follows; (i) reaction of the aryl lithium species
derived from 1 with CuCN affords the Lipshutz cuprate. (ii)
Complexation of the Lipshutz cuprate to 1,4-benzoquinone results
in the formation of the p-complex, with lithium–carbonyl and
copper olefin coordinations.10 (iii) Electron transfer from the
cuprate to 1,4-benzoquinone occurs, followed by reductive
elimination, to give the corresponding biaryl 2.
Yoshihiro Miyake, Mo Wu, M. Jalilur Rahman and Masahiko Iyoda*
Department of Chemistry, Graduate School of Science, Tokyo
Metropolitan University, Hachioji, Tokyo, 192-0397, Japan.
E-mail: iyoda-masahiko@c.metro-u.ac.jp; Fax: +81-426-77-2525
Notes and references
This coupling reaction is applicable to the synthesis of 10-
membered ring cyclophanes (Scheme 1). The homo-coupling
reaction of 3a via Lipshutz cuprate gave the intermolecular
cyclization product 4a as a major product in 50% yield, together
1 J. Hassan, M. Se´vignon, C. Gozz, E. Schulz and M. Lemaire, Chem.
Rev., 2002, 102, 1359.
2 For representative examples, see: G. M. Whitesides, J. San Filippo,
C. P. Casey and E. J. Panek, J. Am. Chem. Soc., 1967, 89, 5302;
T. Kauffmann, Angew. Chem., Int. Ed. Engl., 1974, 13, 291; G. van
Koten, J. T. B. H. Jastrzebski and J. G. Noltes, J. Chem. Soc., Chem.
Commun., 1977, 203; G. van Koten, J. T. B. H. Jastrzebski and
J. G. Noltes, J. Org. Chem., 1977, 42, 2047; S. H. Bertz and
C. P. Gibson, J. Am. Chem. Soc., 1986, 108, 8286; and references cited
therein.
3 B. H. Lipshutz, R. S. Wilhelm and D. M. Floyd, J. Am. Chem. Soc.,
1981, 103, 7672.
4 The structures and reactivities of Lipshutz cuprates have been discussed
extensively. For recent reviews, see: N. Krause, Angew. Chem., Int. Ed.,
1999, 38, 79; E. Nakamura and S. Mori, Angew. Chem., Int. Ed., 2000,
39, 3750; E. Nakamura and N. Yoshikai, Bull. Chem. Soc. Jpn., 2004,
77, 1.
Scheme 1 Reagents and conditions: (i) tBuLi (2.0 equiv.), Et2O, 278 uC;
(ii) CuCN (1.0 equiv.), Et3N, (iii) 1,4-bezoquinone.
5 B. H. Lipshutz, Synlett, 1990, 119.
412 | Chem. Commun., 2005, 411–413
This journal is ß The Royal Society of Chemistry 2005