Efficient construction of biaryls and macrocyclic cyclophanes via electron-transfer oxidation of Lipshutz cuprates

Article abstract of DOI:10.1021/jo0608063

An efficient method for the homocoupling of aryl halides by electron-transfer oxidation of Lipshutz cuprates (Ar₂Cu(CN)Li ₂) with organic electron acceptors is disclosed. Thus, various types of Lipshutz cuprates are prepared by successive treatment of aryl or heteroaryl bromides with tert-butyllithium and CuCN. The electron-transfer oxidation of Lipshutz cuprates with p-benzoquinones proceeds smoothly to afford the corresponding homocoupling products in moderate to good yields. Furthermore, it can be applied to the construction of either thiophene- or benzene-fused 10-membered ring cyclophanes. For the synthesis of 10-membered cyclophanes, the linear C-Cu-C structure of Lipshutz cuprates should be maintained in the dimetallacyclic intermediates, producing the large ring cyclophanes efficiently. The X-ray analysis of the cyclophanes reveals that the difference in the bridging atoms results in the different conformations of the macrocyclic rings. Thus, the silicon-bridged cyclophane 5a adopts a D₂-symmetric structure with a twisted rhombic arrangement of four thiophene rings, whereas the methylene- and oxygen-bridged cyclophanes 5b and 5c possess C_2h- and C₂-symmetric structures with chair- and boatlike conformations, respectively. The ¹H NMR spectrum of C₂-symmetric 5c is temperature-dependent, and the activation energy (ΔG?) for the conformational change is 10.1 kcal/mol.

Full text of DOI:10.1021/jo0608063

Efficient Construction of Biaryls and Macrocyclic Cyclophanes via
Electron-Transfer Oxidation of Lipshutz Cuprates
Yoshihiro Miyake, Mo Wu, M. Jalilur Rahman, Yoshiyuki Kuwatani, and Masahiko Iyoda*
Department of Chemistry, Graduate School of Science, Tokyo Metropolitan UniVersity, Hachioji,
Tokyo 192-0397, Japan
iyoda-masahiko@c.metro-u.ac.jp
ReceiVed April 17, 2006
An efficient method for the homocoupling of aryl halides by electron-transfer oxidation of Lipshutz
cuprates (Ar2Cu(CN)Li2) with organic electron acceptors is disclosed. Thus, various types of Lipshutz
cuprates are prepared by successive treatment of aryl or heteroaryl bromides with tert-butyllithium and
CuCN. The electron-transfer oxidation of Lipshutz cuprates with p-benzoquinones proceeds smoothly to
afford the corresponding homocoupling products in moderate to good yields. Furthermore, it can be
applied to the construction of either thiophene- or benzene-fused 10-membered ring cyclophanes. For
the synthesis of 10-membered cyclophanes, the linear C-Cu-C structure of Lipshutz cuprates should
be maintained in the dimetallacyclic intermediates, producing the large ring cyclophanes efficiently. The
X-ray analysis of the cyclophanes reveals that the difference in the bridging atoms results in the different
conformations of the macrocyclic rings. Thus, the silicon-bridged cyclophane 5a adopts a D2-symmetric
structure with a twisted rhombic arrangement of four thiophene rings, whereas the methylene- and oxygen-
bridged cyclophanes 5b and 5c possess C2h- and C2-symmetric structures with chair- and boatlike
1
conformations, respectively. The H NMR spectrum of C2-symmetric 5c is temperature-dependent, and
the activation energy (∆Gq) for the conformational change is 10.1 kcal/mol.
Introduction
cases. Thus, the methodologies for the homocouplings and cross-
couplings using transition metals such as copper, nickel,
palladium, and iron have so far been developed and widely
used.3,4 Among them, homocoupling of substituted benzenes
and aromatic heterocycles using copper as the reducing and
Aryl-aryl bond-forming reaction is one of the most important
and powerful tools in modern organic synthesis.1,2 These biaryls
and their heteroaromatic analogues are some of the most
attractive structural units in natural products, bioactive com-
pounds, functional polymers, ligands in catalysts, and theoreti-
cally interesting molecules. For aryl-aryl bond formations,
transition-metal-mediated coupling has been employed in most
(3) For the copper-mediated reactions, see: (a) Woodward, S. Angew.
Chem., Int. Ed. 2005, 44, 5560-5562. (b) Modern Organocopper Chemistry;
Krause, N., Ed.; Wiley-VCH: Weinhein, Germany, 2002. (c) Meyers, A.
I.; Nelson, T. D.; Moorlag, H.; Rawson, D. J.; Meier, A. Tetrahedron 2004,
60, 4459-4473. (d) Erdik, D. Tetrahedron 1984, 40, 641-657.
(4) For the transition-metal-mediated reactions, see: (a) Zapf, A.; Beller,
M. Chem. Commun. 2005, 431-440. (b) Fu¨rstner, A.; Martin, R. Chem.
Lett. 2005, 34, 624-629. (c) Cepanec, I. Synthesis of Biaryls; Elsevier:
Oxford, 2004. (d) Transition Metals for Organic Synthesis; Beller, M., Bolm,
C., Eds.; Wiley-VCH: Weinhein, Germany, 1998. (e) Miyaura, N.; Suzuki,
A. Chem. ReV. 1995, 95, 2457-2483. (f) Negishi, E. Acc. Chem. Res. 1982,
15, 340-348. (g) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M.
Bull. Chem. Soc. Jpn. 1990, 63, 80-87. (h) Hong, R.; Hoen, R.; Zhang, J.
Lin, G. Synlett 2001, 1527-1530.
(1) (a) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359-1470. (b) Bringmann, G.; Walter, R.; Weirich,
R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977-991. (c) Metal-Catalysed
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10.1021/jo0608063 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/11/2006
6110
J. Org. Chem. 2006, 71, 6110-6117

Electron-Transfer Oxidation of Lipshutz Cuprates
coupling reagent is known as the Ullmann reaction.5 Since the
original Ullmann reaction6 was reported in 1901 using metallic
copper as the coupling reagent, a number of Ullmann-type
couplings using activated metallic copper,7 copper(I) salts,8 and
copper(II) salts9 have been utilized for aryl-aryl bond forma-
tions. Diarylcopper(II) species prepared from arylmetals with
copper(II) salts are known to decompose at low temperature to
afford biaryls.9,10 The reaction requires a transmetalation of
arylmetals such as aryllithiums, arylmagnesium halides, and
aryltin(IV) species with copper(II) salt,11 followed by reductive
elimination of the organic copper(II) intermediate. In contrast,
an oxidative “decomposition” of organic cuprates (R2CuLi) with
oxidants is a promising method for the homocoupling of the
ligands (R) on the copper atom. Casey and co-workers10a
reported this type of biaryl synthesis using the reaction of
diarylcopper lithium with molecular oxygen.
In 1981, Lipshutz and co-workers reported a novel cuprate
prepared from 2 equiv of lithium reagent with 1 equiv of CuCN,
the so-called “Lipshutz cuprate” (R2Cu(CN)Li2).12 This cuprate
has been reported to be an effective reagent for substitution
reactions of alkyl halides and conjugate additions to R,â-
unsaturated ketones.13,14 Furthermore, oxidation of Lipshutz
cuprates with molecular oxygen forms coupling products via
ligand coupling on the copper atom.15,16 Quite recently, 1,3-
dinitrobenzene has been used for the oxidation of Lipshutz
cuprates to afford medium-size ring compounds including the
biaryl skeleton.17
Lipshutz cuprates (R2Cu(CN)Li2) show higher reactivity in
chemical reactions than the traditional Gilman cuprates (R2CuLi‚
LiX).18 The unusual reactivity was believed to be due to the
structrure of Lipshutz cuprates in which the cyano group was
bound to copper by means of a Cu-CN bond, resulting in a
dianion species, R2Cu(CN)2-2Li+.19 After much investigation
and controversial discussion on the structure of Lipshutz
cuprates,20 X-ray structural determinations have revealed that
the cyano group in Lipshutz cuprats locates between two lithium
atoms as a bridge and Lipshutz cuprates possess a linear
carbon-copper-carbon arrangement.21 We expected that the
carbon-copper(I)-carbon linkage in Lipshutz cuprates would
be easily oxidized by electron acceptors to give the correspond-
ing carbon-copper(II)-carbon structure, and that the oxidation
of Lipshutz cuprates would finally produce homocoupling
products under mild conditions. In this study, we established a
novel electron-transfer oxidation of Lipshutz cuprates with
p-benzoquinones to produce biaryls as the homocoupling
products (Scheme 1). Since a variety of aryl bromides 1 can be
converted into Lipshutz cuprates 2, our new methodology can
produce a number of biaryls 3 in moderate to good yields. In
addition, this methodology can be successfully applied for the
construction of macrocycles 5a-5c (Scheme 1).22 Although the
macrocyclization such as intramolecular ring closure and
intermolecular cyclooligomerization usually affords cyclic
products in low yields due to preferable formation of linear
oligomers and five- and six-membered rings in some cases, our
novel electron-transfer oxidation of metallacyclic intermediates
including Lipshutz cuprates results in the formation of macro-
cyclic dimers owing to preferable formation of a dimetallacyclic
intermediate with the linear Ar-Cu-Ar arrangement.
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J. Org. Chem, Vol. 71, No. 16, 2006 6111

Miyake et al.
TABLE 2. Homocoupling of Aryl Halides 1 via Electron-Transfer
Oxidation of Lipshutz Cupratesa
SCHEME 1. Electron-Transfer Oxidation of Lipshutz
Cuprates
yieldb
(%) entry
yieldb
(%)
entry
1
Ar (1)
Ar (1)
4-ClC6H4 (1a)
96
0
14
15
16
17
4-BrC6H4 (1j)
3-BrC6H4 (1k)
2-BrC6H4 (1l)
88
95
91
0
64
99
99
62
82
87
0
2c 4-ClC6H4 (1a)
3d 4-ClC6H5 (1a)
75
84
73
91
55
75
96
87
90
91
80
4
5
6
C6H4 (1b)
4-FC6H4 (1c)
4-(MeO)C6H4 (1d)
2,4,6-Me3C6H2 (1m)
18g 2,4,6-Me3C6H2 (1m)
19g 1-naphthyl (1n)
20g 2-naphthyl (1o)
7e 4-(MeO)C6H4 (1d)
8f
9
10
11
12
13
4-(MeO)C6H4 (1d)
3-(MeO)C6H4 (1e)
2-(MeO)C6H4 (1f)
4-MeC6H4 (1g)
3-MeC6H4 (1h)
2-MeC6H4 (1i)
21
22
23
24
25
26
2-thienyl (1p)
3-thienyl (1q)
4-Br-3-thienyl (1r)
2-pyridyl (1s)
4-(CN)C6H5 (1t)
4-(Me2N)C6H5 (1u)
0
0
a The reaction was carried out using a procedure similar to that noted in
Table 1. b Isolated yield. c Without CuCN. d n-BuLi (1.1 equiv) was used
instead of t-BuLi. e CuI was used instead of CuCN. f CuSCN was used
instead of CuCN. g t-BuLi (2.5 equiv) was used.
Results and Discussion
Coupling of Aryl Bromides using Electron-Transfer
Oxidation of Lipshutz Cuprates. As has been reported
previously, Lipshutz cuprates can be oxidized with molecular
oxygen or dinitrobenzene to afford the corresponding homo-
coupling products.15-17 We first investigated the oxidation of
Lipshutz cuprate 2a prepared from the reaction of p-bromo-
chlorobenzene (1a) with 1.1 equiv of tert-butyllithium, followed
by treatment with 0.5 equiv of CuCN (Table 1). Our preliminary
experiments showed that the reactions of 2a with molecular
oxygen and 1,3-dinitrobenzene gave 4,4′-dichlorobiphenyl (3a)
in 35% and 54% yields, respectively (Table 1, entries 1 and 4).
To increase the yield of 3a, a variety of electron acceptors were
examined. After several attempts, 1,4-benzoquinones were found
to be effective for the oxidation of 2a (Table 1, entries 5-11).
As shown in Table 1, the reaction of 2a with electron
acceptors proceeded smoothly, giving 3a in good to excellent
yields (Table 1, entries 3-11). Initially, 1.5 equiv of electron
acceptors was applied to the reactions, except 1,3-dinitroben-
zene. Since 1,3-dinitrobenzene is a comparatively mild oxidant,
3.0 equiv of the reagent was used to afford a satisfactory yield
of 3a (entry 4). Among all of the oxidants, tetramethyl-p-
benzoquinone led to the best yield of 3a (96%, entry 9). In all
cases, the biaryl 3a was the sole product. A byproduct that may
arise from the ligand coupling of the cyano group and the aryl
moieties was not detected, in contrast to the reactions of lithium
cyanocuprates (ArCuCNLi),23,24 nor was the conjugate adduct
of the aryl group to the p-benzoquinones detected, and 1,4-
benzoquinones were recovered in 80-90% yields. Further
reactions that were carried out with different amounts of
tetramethyl-p-benzoquinone revealed that 1.5 equiv was the best
amount under the present conditions (entries 8-11). Therefore,
1.5 equiv of tetramethyl-p-benzoquinone was used as the
electron acceptor in the following work.
TABLE 1. Homocoupling of 1a via Electron-Transfer Oxidation of
2a with Electron Acceptorsa
Next, various aryl bromides 1a-u were subjected to the
optimized homocoupling conditions (Table 2). As expected, no
coupling reaction of 1a occurred without CuCN (Table 2, entry
2). In this reaction system, t-BuLi was found to work more
effectively than n-BuLi (entries 1 and 3), and the reactions with
n-BuLi sometimes formed a trace amount of homocoupling
products. However, similarly to the reaction of 1a (entry 1),
bromobenzene (1b), p-bromofluorobenzene (1c), and p-bro-
moanisole (1d) readily afforded the corresponding 3b, 3c, and
3d in 84%, 73%, and 91% yields, respectively (entries 4-6).
Besides the reaction with CuCN, similar reactions with two other
copper(I) salts, CuI and CuSCN, were also carried out (entries
7 and 8). The homocoupling of p-bromoanisole (1d) with CuI
led to 55% 3d, while the reaction with CuSCN produced 75%
3d. These results revealed that the cyano group plays an
important role in the high reactivity of Lipshutz cuprates. A
yieldb
(%)
entry
electron acceptor (amt, equiv)
1
2
3
4
5
6
7
8
9
oxygen (excess)
tetracyanoethylene (1.5)
tetracyanoquinodimethane (1.5)
1,3-dinitrobenzene (3.0)
p-benzoquinone (1.5)
2,6-dimethyl-p-benzoquinone (1.5)
2,5-dimethyl-p-benzoquinone (1.5)
tetramethyl-p-benzoquinone (1.0)
tetramethyl-p-benzoquinone (1.5)
tetramethyl-p-benzoquinone (2.0)
tetramethyl-p-benzoquinone (3.0)
35
29
76
54
76
81
82
74
96
93
92
10
11
a
tBuLi (1.1 equiv) was added to a solution of 1a (1.0 mmol) in Et2O
(60 mL) at -78 °C before CuCN (0.5 equiv) was added. After an electron
acceptor was added, the mixture was stirred for 3 h at room temperature.
b Isolated yield.
(23) Kronenburg, C. M. P.; Amijs, C. H. M.; Wijkens, P.; Jastrzebski,
J. T. B. H.; van Koten, G. Tetrahedron Lett. 2002, 43, 1113-1115.
(24) Gronowitz, S. Acta Chem. Scand. 1961, 15, 1393.
6112 J. Org. Chem., Vol. 71, No. 16, 2006

Electron-Transfer Oxidation of Lipshutz Cuprates
SCHEME 2. Plausible Reaction Pathway
SCHEME 3. Equilibrium among Metallacycle
Intermediates
variety of substrates with electron-deficient substituents, such
as p-bromoflurobenzene (1c) and p-dibromobenzene (1j), and
those with electron-rich substituents, such as p-bromoanisole
(1d) and p-bromotoluene (1g), furnished high yields of the biaryl
products (entries 3, 5, 11, and 14). Although steric hindrance
was considered to be one of the factors which greatly affect
the formation of biaryls via cuprate intermediates,9a para-, meta-,
and ortho-subsituted substrates all gave good yields of the
products under these conditions. The p-, m-, and o-methoxyl-
substituted substrates gave the corresponding biaryls in 91%,
96%, and 87% yields, respectively (entries 5, 9, and 10).
Similarly, the methyl-substituted substrates furnished the biaryl
products in 90%, 91%, and 80% yields, and the bromo-
substituted substrates in 88%, 95%, and 91% yields, respectively
(entries 11-16). When a very hindered substrate, 2-bromo-1,3,5-
trimethylbenzene (1m), was subjected to the optimized condi-
tions, no formation of 3m was observed. However, the reaction
of 1m with the addition of 2.5 equiv of t-BuLi proceeded to
give the corresponding product 3m in 64% yield (entries 17
and 18). In the coupling of 1- and 2-bromonaphthalenes (1n
and 1o), 2.5 equiv of t-BuLi was also necessary to afford the
products in excellent yields (entries 19 and 20). Thiophene
derivatives were also successfully coupled under the present
conditions (entries 21-23). For example, 4,4′-dibromo-3,3′-
bithienyl (3r) was obtained in 87% yield by the coupling of
1r, whereas the reported methods for the preparation of 3r using
reactions of 4-bromo-2-thienyllithium or 4-bromo-2-thienylzinc
chloride with CuCl2 gave 65% or 52% yield.24,25 It is worth
noting that the present conditions allow employment of an aryl
dihalide (1j, 1k, 1l, or 1r), selectively affording the desired
product without loss of bromo substituents (entries 13-15 and
23). Unfortunately, our reaction system cannot be applied for
the reaction of nitrogen-containing substrates such as 1s, 1t,
and 1u (entries 24-26).
quinone was observed during or after the reaction. In addition,
we tried the transformation of 1,4-hydroquinone to 1,4-benzo-
quinone under the present workup conditions. However, within
15-30 min, only ca. 5-10% 1,4-benzoquinone was formed.
The reaction under neutral and acidic (pH 3) conditions also
led to similar results. Thus, the formation of 1,4-hydroquinone
is not necessary, and 1,4-benzoquinone might be reproduced
directly from semiquinone radical anion under the workup
conditions. Atmospheric oxygen or other oxidants in the reaction
media may take part in the reproduction of 1,4-benzoquione.
Construction of Macrocyclic Systems. After the investiga-
tion of aryl-aryl bond formation with this novel methodology,
it was applied to the construction of macrocyclic compounds
in the following work. Metallacycles are one of the most
important and available reaction intermediates in organometallic
chemistry. The existence of equilibrium among monomeric,
dimeric, and oligomeric metallacycles has been known, and the
reaction conditions, such as metals, solvents, temperatures, and
so on, are expected to have an effect on the structures and the
distribution of the oligomeric intermediates (Scheme 3).28,29
Generally, modifications are necessary to induce the equilibrium
to favor the formation of the desired product. Since Lipshutz
cuprate has a linear carbon-copper-carbon (C-Cu-C) struc-
ture, favorable formation of oligomeric metallacycles is ex-
pected. The preparation of thiophene-fused cyclophanes has
always attracted our interest, and the synthesis of methylene-
bridged 10-membered ring 5b has already been carried out by
the reaction of Lipshutz cuprate with oxygen.30 However, it
exhibited low reproducibility and was not able to be applied to
the construction of its analogues. The present method that
involves an electron-transfer procedure found its application in
the formation of the cyclophanes 5a-c.
The cyclization of 4a via aryl-aryl bond formations using
CuX (X ) CN, SCN, and I) was examined as a model reaction,
and typical results are shown in Table 3. Although the cyano
(CN) and thiocyano (SCN) ligands promoted the formation of
the 10-membered ring cyclophane 5a, CuI was not effective
for the cyclodimerization (Table 3, entries 1, 3, and 5).31 When
triethylamine (2.0 equiv) was added after the formation of
Liphsutz cuprate, using CuCN as the copper salt, remarkable
improvement in the selectivity was observed, leading to a 48%
yield of 5a and 25% yield of 6a (entry 2). However, the reaction
of 3a with CuSCN in the presence of Et3N afforded a result
similar to that without Et3N (entry 4). Similarly, 1,4-benzo-
A plausible reaction pathway is shown in Scheme 2. Treat-
ment of aryl bromide 1 with t-BuLi, followed by the reaction
with CuCN, affords Lipshutz cuprate 2. The complexation of 2
with 1,4-benzoquinones results in the formation of the π-com-
plex using lithium‚‚‚carbonyl and copper‚‚‚olefin coordina-
tions.26 Finally, electron transfer from cuprate to the π-acceptor,
followed by reductive elimination, produces the corresponding
biaryl.27 Although the details of the electron-transfer step are
not yet clear, 1,4-benzoquinone was found to be recovered in
high yields after the reactions. No formation of 1,4-hydro-
(25) Kabir, S. M. H.; Miura, M.; Sasaki, S.; Harada, G.; Kuwatani, Y.;
Yoshida, M.; Iyoda, M. Heterocycles 2000, 52, 761-774.
(28) Freijee, F. J. M.; Seetz, J. W. F. L.; Akkerman, O. S.; Bickelhaupt,
F. J. Organomet. Chem. 1982, 224, 217-221.
(26) (a) Berlan, J.; Battioni, J.-P.; Koosha, K. Bull. Soc. Chim. Fr. 1979,
II, 183-190. (b) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26,
6015-6018. (c) Vellekoop, A. S.; Smith, R. A. J. J. Am. Chem. Soc. 1994,
116, 2902-2913.
(29) Iyoda, M.; Kabir, S. M. H.; Vorasingha, A.; Kuwatani, Y.; Yoshida,
M. Tetrahedron Lett. 1998, 39, 5393-5396.
(30) Kabir, S. M. H.; Iyoda, M. Chem. Commun. 2000, 2329-2330.
(31) Recently, a similar 10-membered ring cyclophane was obtained as
a byproduct in 2% yield from the reaction of 2,2-dilithio-3,3-bithienyl:
Rajca, A.; Miyasaka, M.; Pink, M.; Wang, H.; Rajca, S. J. Am. Chem. Soc.
2004, 126, 15211-15222.
(27) For electron-transfer oxidation of organometallics, see: (a) Cheng,
J.-W.; Luo, F.-T. Tetrahedron Lett. 1988, 29, 1293-1294. (b) Chen, C.;
Xi, C.; Lai, C.; Wang, R.; Hong, X. Eur. J. Org. Chem. 2004, 647-650.
J. Org. Chem, Vol. 71, No. 16, 2006 6113

Miyake et al.
SCHEME 5. Selective Cyclization via Metallacyclic
TABLE 3. Cyclization of 4a via Aryl-Aryl Bond Formationsa
Intermediates
yieldb (%)
copper(I)
entry
salt
5a
6a
1
CuCN
CuCN
CuSCN
CuSCN
CuI
CuCN
CuCN
CuCN
18
48
12
16
2
50
0g
17
57
25
61
46
52
27
0g
2c
3d
4c,d
5
6c,e
7c,f
8c,f,h
56
SCHEME 6. Coupling of Lipshutz Cuprate Using CuCl2
a
tBuLi (2.2 equiv) was added to a solution of 4a (1.0 mmol) in Et2O
(60 mL) at -78 °C before CuCN (1.0 equiv) was added. After tetramethyl-
1,4-benzoquinone was added, the mixture was stirred for 3 h at room
temperature. b Isolated yields. c With Et3N (2 equiv). d t-BuLi (4.4 equiv)
was added. e 1,4-Benzoquinone was used as an acceptor. f CuCl2 was used
instead of 1,4-benzoquinones. g The reduction product of 4a was obtained
in high yield. h THF was used as the solvent.
SCHEME 4. Cyclodimerization of 4a-c to 10-Membered
Cyclophanes 5a-c
5b in 15% yield. Furthermore, dibromodiphenyl ether 4c also
furnished a moderate yield of the corresponding cyclophane 5c.
Metallacycles are key intermediates in this cyclization. As
shown in Scheme 5, the dithiophene 6 is produced via
six-membered monomeric metallacycle 7, while 5 is produced
via 12-membered dimeric metallacycle 8. When we investigated
the palladium-catalyzed coupling reaction of 4a with Me3-
SnSnMe3, the intramolecular cyclization proceeded to afford
6a in 64% yield with no formation of 5a.33 Since the palladium
complex possesses a common square planar structure and the
cis- carbon-palladium-carbon conformation, the intermediate
7 should be thermodynamically stable and the dimeric metal-
lacycle 8 is hardly formed in situ. On the contrary, the
intermediate 8, which has a linear C-Cu-C linkage, is expected
to be more favorable than 7 bearing the bent structure in the
case of the present reaction because Lipshutz cuprates are known
to have a linear C-Cu-C linkage.21a,b In addition, triethylamine
coordinates to lithium atoms, and the structure of the diaryl-
copper segment is preserved. The cation part of the cuprate
might be stabilized by the coordination of triethylamine; hence,
the stability of the whole ion pair could be enhanced.
In the cyclophane synthesis, the electron-transfer step also
contributes to the efficient maintenance of the linear structure
of the Lipshutz cuprate intermediate upon oxidation. As
mentioned in Table 3 (entry 8), CuCl2 was not an effective
oxidant for the cyclodimerization (Scheme 6). After the forma-
tion of the Lipshutz cuprate intermediate, CuCl2 was added to
furnish a transmetalation step. The copper(I) intermediate was
transformed to copper(II), and 6a was obtained as the major
product and 5a the minor product.
quinone worked effectively as an electron acceptor (entry 6).
When CuCl2 was used as the oxidant, no coupling products 5a
and 6a formed with the reduced product of 4a (Table 3, entry
7). The coupling reaction of 4a with CuCl2 in THF proceeded
to mainly afford 6a (entry 8).
On the basis of the results shown in Table 3, this procedure
was applied to the cyclodimerization of 4b and 4c (Scheme 4).
For the cyclodimerization of 4a and 4b, 1,4-benzoquinone works
a little better than tetramethyl-1,4-benzoquinone to lead to the
cyclophenes 5a and 5b in 50% and 17% yields, respectively;
the similar reactions with tetramethyl-1,4-benzoquinone gave
5a and 5b in 48% and 15% yields, respectively. In contrast,
the cyclodimerization of 4c proceeded smoothly with tetra-
methyl-1,4-benzoquinone as the oxidant to produce 5c in 40%
yield. Unfortunately, the reaction of the sulfur-bridged substrates
afforded the five-membered ring compounds as the main
products, and ten-membered ring cyclophanes were isolated only
in low yields. This is supposed to be the reason the coordination
of the bridging sulfur atom to the copper atom decreased the
reactivity of the Lipshutz cuprate intermediate.32 In contrast,
the cyclodimerization of 2,3-disubstituted substrate 4b proceeded
to give the methylene-bridged 10-membered ring cyclophane
Compared to the coupling reaction via transmetalation
(Scheme 6), the electron-transfer reaction obviously favors the
formation of the 10-membered ring compound (Scheme 7). This
(32) Triphenylphosphine causes a structural change of cyanocuprate.
See: Davis, R. P.; Hornauer, S. Eur. J. Inorg. Chem. 2005, 51-54.
(33) Iyoda, M.; Miura, M.; Sasaki, S.; Kabir, S. M. H.; Kuwatani, Y.;
Yoshida, M. Tetrahedron Lett. 1997, 38, 4581-4582.
6114 J. Org. Chem., Vol. 71, No. 16, 2006

Electron-Transfer Oxidation of Lipshutz Cuprates
SCHEME 7. Electron-Transfer Process from Copper to
Electron Acceptors
FIGURE 2. X-ray structure of 5b: (a) top view, (b) side view.
should be the reason electron transfer is a fast reaction and the
conformation (the linear structure) of the intermediate is
conserved during the reaction. Thus, after electron transfer from
8-Cu(I) to benzoquinones, the intermediate 8-Cu(II) still
possesses the linear structure and finally produces the 10-
membered ring 5 upon fast reductive elimination. On the other
hand, the transmetalation of 8-Cu(I) with CuCl2 breaks the
carbon-copper(I) bond, and the acyclic intermediate 9 is
formed. The disproportionation of 9 proceeds to afford the
monomeric metallacycle 7-Cu(II) and the lower order cyano-
cuprate 10. The transmetalation of 10 with CuCl2 might occur
to give 7-Cu(II). Finally, reductive elimination of 7-Cu(II)
gives the five-membered ring 6, and the protonation of 10 gives
the reduction product 11 (Scheme 7).
Structures and Properties of 10-Membered Ring Cyclo-
phanes 5a-c. The 10-membered ring cyclophanes 5a-c are
novel compounds bearing unique molecular structures. As
shown in Figure 1, (all-Z)-cyclodeca-1,3,6,8-tetraene 12 has
three possible conformations with chairlike C2h symmmetry
(12a), boatlike C2 symmetry (12b), and twisted D2 symmetry
(12c). The difference between 12a and 12b is the relative
arrangement of two cisoid-butadiene units, whereas 12c has two
transoid-butadiene moieties. The dihedral angles of the buta-
diene units in 12a-c are estimated as 54.2°, 47.5°, and 104.5°
for 12a, 12b, and 12c, respectively, by B3LYP/6-31G(d) level
DFT calculations. The most stable conformer of the macrocycle
12 is considered to be chairlike C2h structure 12a, and other
two conformers 12b and 12c are less stable than 12a by 3.9
and 15.4 kcal/mol, respectively.
FIGURE 3. Optimized molecular structures of 5b by B3LYP/
6-31G(d) level DFT calculations. The symmetry for each conformer is
shown with the relative energy (kcal/mol) in parentheses.
crystallographic symmetric centers. Both molecules show es-
sentially the same C2h structures with torsional angles at the
bithiophene units of 53.7° (C1-C2-C6-C5) and 56.3° (cor-
responding angle for another molecule). Three possible con-
formations for 5b are shown in Figure 3. The most stable
conformation of 5b is the chairlike C2h structure obtained by
B3LYP/6-31G(d) level DFT calculations. The other two con-
formers, boatlike C2 and twisted D2 structures, are less stable
than the C2h conformer by 0.8 and 7.1 kcal/mol, respectively.
1
The H NMR spectrum of 5b, which is composed of two sets
of AB pattern signals (δ 7.30 and 6.89 for the thiophene ring
protons and δ 4.45 and 4.02 for the methylene protons), clearly
shows the C2h conformation for 5b in solution.
The silicon-bridged cyclophane 5a is considered to have a
conformation different from that shown by the 1H NMR
1
spectrum. The H NMR spectrum of 5a exhibited only one
singlet for the methyl protons on the bridged Si atoms at δ 0.35,
and the methyl signal kept a singlet at low temperatures. This
indicates that 5a possesses a symmetric conformation in which
all the methyl protons are in the same chemical environment.
Furthermore, considerable higher field shifts of thiophene ring
The X-ray analysis revealed that 5b possesses a chairlike C2h
conformation with an anti arrangement of the two methylene
bridges as shown in Figure 2.30b The crystal contains two
crystallographically independent molecules, which locate at
1
protons were observed in the H NMR spectrum of 5a. The
signals for ring protons of 5a were observed at δ 7.00 and 6.98,
which are at ca. 0.35 ppm higher field than those of 4a (δ 7.37
and 7.32). On the other hand, the chemical shifts for the ring
protons of 5b (δ 7.28 and 6.88) showed chemical shifts similar
to those of 4b (δ 7.18 and 6.93). DFT calculations of 5a suggest
the twisted D2 conformer as the most stable structure, where
all the methyl substituents are equivalent. The corresponding
C2h structure of 5a is 5.9 kcal/mol less stable, and the boatlike
C2 conformer is not an energy-minimum structure any more.
The preference of the D2 conformation in 5a is attributable to
FIGURE 1. Three possible conformers for (all-Z)-cyclodeca-1,3,6,8-
tetraenes 12a-c. The symmetry of each structure is shown in
parentheses.
J. Org. Chem, Vol. 71, No. 16, 2006 6115

Miyake et al.
FIGURE 5. X-ray structure of 5c: (a) side view, (b) top view.
FIGURE 4. X-ray structure of 5a: (a) side view, (b) top view.
two methyl substituents on the Si bridge, which can cause
repulsive interaction in other conformers.
The molecular structure of the cyclophane 5a elucidated by
the X-ray analysis is depicted in Figure 4. The molecule 5a
adopts a twisted D2 conformation with a rhombic arrangement
of the four thiophene rings. Although the conformation of 5a
is chiral, the crystal is totally racemic on the basis of the achiral
space group (C2/c). The torsional angles between the neighbor-
ing thiophene rings are 96.6° (C1-C4-C5-C8) and 98.0°
(C9-C12-C13-C16). Two opposite thiophene rings locate at
a distance of 3.4 Å at the 10-membered ring and are slightly
opened at the end with dihedral angles of 19°. Therefore, the
inside of the cyclophane has no more space for accommodation
of any guest molecule. The stacked arrangement of the thiophene
rings in 5a is in good accordance with higher field shifts of the
1
thiophene ring protons in the H NMR spectrum of 5a.
The cyclophane 5c possesses a boatlike C2 conformation,
which was proved by the X-ray analysis, as shown in Figure 5.
The torsional angles of the two phenylene groups in the biphenyl
units are 47.2° (C1-C6-C7-C12) and 48.4° (C13-C18-
C19-C24). Two phenylene groups in 5c are stacked face-to-
face at a distance of 3.0 Å between the 10-membered ring
carbons and are opened at the end with a dihedral angle of 42°.
The other two phenylene groups are projected outward in a
propeller-like arrangement. The crystal of 5c is composed of a
single enantiomer and is totally chiral with an asymmetric space
group (P212121). This molecular structure is related to the C2
conformer of 5b, and the boatlike 5c with C2 conformation is
estimated to be more stable than the corresponding twisted D2
structure by 6.0 kcal/mol from DFT calculations. In this case,
the chairlike C2h conformation is considerably unstable, presum-
ably because of the torsional strain between the phenyl groups
in the diphenyl ether moieties.
1
FIGURE 6. VT H NMR spectra of 5c. The signal assignments are
shown in the spectrum.
As shown in Figure 6, the assignment of the signals was
unambiguously determined on the basis of the coupling con-
nectivity and qualitative saturation transfer experiments. This
type of temperature dependence of the NMR can be ascribed
to the exchange of the two sets of phenylene groups in the C2
conformer, and the corresponding activation energy was esti-
mated as ∆Gq ) 10.1 kcal/mol by the coalescence method.
In conclusion, we have developed an efficient homocoupling
reaction of aryl bromides via Lipshutz cuprates under electron-
transfer conditions. This unique electron-transfer step from the
cuprates to 1,4-benzoquinones as the electron acceptors is a key
step for this coupling reaction. No conjugated addition of
cuprates to quinones takes place under these conditions, and
The dynamic NMR measurements of 5c clearly show
1
flexibility of this molecule. The H NMR spectrum of 5c at
room temperature shows only four kinds of signals, which
suggests the symmetric nature of the molecule. However, in
the 1H NMR spectra at lower temperature, eight kinds of signals
were observed corresponding to the most stable C2 conformer.
6116 J. Org. Chem., Vol. 71, No. 16, 2006

Electron-Transfer Oxidation of Lipshutz Cuprates
was stirred at room temperature for another 1 h. To the reaction
mixture was added tetramethyl-p-benzoquinone (493 mg, 3.0
mmol), and the resulting mixture was stirred for 3 h at room
temperature. After the reaction finished, 2 N aqueous HCl was
added. The organic layer was separated, and the aqueous layer was
extracted with benzene. The combined organic layer was dried over
MgSO4 and then concentrated under reduced pressure. Purification
of the residue by column chromatography on SiO2 with hexane/
benzene as the eluent gave the corresponding cyclization products.
Data for Silicon-bridged 10-membered ring cyclophane 5a:
colorless crystals (48%); mp 204.5-205 °C subl; IR (Nujol) 3043,
2950, 1644, 1563, 1453 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.00
(d, J ) 2.8 Hz, 4H), 6.98 (d, J ) 2.8 Hz, 4H), 0.35 (s, 12H); 13C
NMR (CDCl3, 125 MHz) δ 142.5 (C), 139.9(C), 131.7(CH), 123.5
(CH), 0.1 (CH3); UV (EtOH) 243.5 nm (log ꢀ ) 4.05); EI-MS m/z
444 (M+). Anal. Calcd for C20H20S4Si2: C, 54.00; H, 4.53. Found:
C, 53.98; H, 4.55.
Data for methylene-bridged 10-membered ring cyclophane
5b: colorless crystals (15%); mp 259-259.6 °C subl; IR (Nujol)
3050, 2955, 1650, 1560, 1460, 1250 cm-1; 1H NMR (CDCl3, 500
MHz) δ 7.28 (d, J ) 5.1 Hz, 4H), 6.88 (d, J ) 5.1 Hz, 4H), 4.45
(d, J ) 16.0 Hz, 2H), 4.02 (d, J ) 16.0 Hz, 2H); 13C NMR (CDCl3,
125 MHz) δ 138.9 (C), 133.3 (C), 129.0 (CH), 124.1 (CH), 27.9
(CH2); UV (EtOH) 245.5 nm (log ꢀ ) 4.24); EI-M m/z 356 (M+).
Anal. Calcd for C18H12S4: C, 60.63; H, 3.39. Found: C, 60.24; H,
3.49.
the coupling reaction offers a novel aspect of Lipshutz cuprates.
We have also applied this system to the synthesis of 10-
membered cyclophanes. The key intermediate for the cyclo-
phanes is a metallacycle having a Lipshutz cuprate structure
which possesses linear C-Cu-C linkages. Therefore, this
intermediate more favorably produces ten-membered cyclo-
phanes over ordinary five-membered ring structures.
Experimental Section
General Procedure for the Synthesis of Biaryl 3 Using
Electron-Transfer Oxidation of Lipshutz Cuprates. To a solution
of aryl bromide 1 (1.0 mmol) in anhydrous ether (60 mL) was added
t-BuLi (0.77 mL, 1.1 mmol, 1.43 M in pentane) at -78 °C. The
mixture was stirred at the same temperature for 1.5 h, and CuCN
(45.0 mg, 0.5 mmol) was added. The mixture was vigorously stirred
at room temperature till CuCN dissolved. To the clear solution of
Lipshutz cuprate was added tetramethyl-p-benzoquinone (246 mg,
1.5 mmol) to form a deep-blue-green solution of durosemiquinone.34
The mixture was stirred at room temperature for 3 h. After the
reaction finished, 2 N aqueous HCl was added (the deep-blue-green
color disappeared quickly to give a yellow solution). The organic
layer was separated, and the aqueous layer was extracted with ether.
The combined organic layer was dried over MgSO4 and then
concentrated under reduced pressure. Purification of the residue
by column chromatography on SiO2 with hexane/benzene as the
eluent gave the corresponding coupling products.
When tetramethyl-p-benzoquinone was added to the solution of
Lipshutz cuprate prepared from 1a at -78 °C, the deep-blue-green
color gradually appeared. However, the electron-transfer oxidation
took place at -78 °C for 3 h to produce 3a in 77% yield. To quench
the oxidation of Lipshutz cuprate prepared from 1a, water can be
used instead of 2 M aqueous HCl. In this case, the deep-blue-green
color of durosemiquinone gradually disappeared after the addition
of water, and tetramethyl-p-benzoquinone gradually appeared in
the mixture.
Data for benzene-fused 10-membered ring 5c: colorless
crystals (18%); mp 206.1-206.6 °C; 1H NMR (CDCl3, 400 MHz,
25 °C) δ 7.22 (d, J ) 7.9 Hz, 4H), 7.16 (dd, J ) 7.9 and 7.3 Hz,
4H), 7.02 (dd, J ) 7.9 and 7.3 Hz, 4H), 6.91 (d, J ) 7.9 Hz, 4H);
13C NMR (CDCl3, 100 MHz, 25 °C) δ 154.4 (C), 131.2 (CH), 128.9
(CH), 128.8 (CH), 123.4 (CH), 119.8 (C); EI-MS m/z 336 (M+).
Anal. Calcd for C24H16O2: C, 85.69; H, 4.79. Found: C, 85.79; H,
4.91.
Acknowledgment. This work was partially 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 of Japan. We are grateful to Dr. Kenji Hara, Dr. T.
Nishinaga, and Dr. Masashi Hasegawa (Tokyo Metropolitan
University) for their helpful discussions.
General Procedure for the Synthesis of the 10-Membered
Ring Cyclophane 5. To a solution of 4 (1.0 mmol) in anhydrous
ether (60 mL) was added t-BuLi (1.54 mL, 2.2 mmol, 1.43 M in
pentane) at -78 °C. The mixture was stirred at the same temperature
for 1.5 h before CuCN (89 mg, 1.0 mmol) was added. The mixture
was vigorously stirred at room temperature till all CuCN dissolved.
Then triethylamine (0.28 mL, 2.0 mmol) was added, and the mixture
Supporting Information Available: Experimental section,
including X-ray crystallographic files in CIF format. This material
is available free of charge via the Internet at http://pubs.acs.org.
(34) (a) Giordani, R.; Buc, J. Eur. J. Biochem. 2004, 271, 2400-2407.
(b) Pasimeni, L.; Brustolon, M.; Corvaja, C. J. Chem. Soc., Faraday Trans.
2 1972, 68, 223-233. (c) Gough, T. E.; Hindle, P. R. Can. J. Chem. 1969,
47, 1698-1700.
JO0608063
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