An efficient organocatalytic method for constructing biaryls through aromatic C-H activation

Article abstract of DOI:10.1038/nchem.862

The direct functionalization of C-H bonds has drawn the attention of chemists for almost a century. C-H activation has mainly been achieved through four metal-mediated pathways: oxidative addition, electrophilic substitution, σ-bond metathesis and metal-associated carbene/nitrene/oxo insertion. However, the identification of methods that do not require transition-metal catalysts is important because methods involving such catalysts are often expensive. Another advantage would be that the requirement to remove metallic impurities from products could be avoided, an important issue in the synthesis of pharmaceutical compounds. Here, we describe the identification of a cross-coupling between aryl iodides/bromides and the C-H bonds of arenes that is mediated solely by the presence of 1,10-phenanthroline as catalyst in the presence of KOt-Bu as a base. This apparently transition-metal-free process provides a new strategy with which to achieve direct C-H functionalization.

Full text of DOI:10.1038/nchem.862

ARTICLES
PUBLISHED ONLINE: 3 OCTOBER 2010 | DOI: 10.1038/NCHEM.862
An efficient organocatalytic method for
constructing biaryls through aromatic
C–H activation
Chang-Liang Sun1, Hu Li1, Da-Gang Yu1, Miao Yu1, Xiao Zhou1, Xing-Yu Lu1, Kun Huang1,
Shu-Fang Zheng2, Bi-Jie Li1 and Zhang-Jie Shi1
*
The direct functionalization of C–H bonds has drawn the attention of chemists for almost a century. C–H activation has
mainly been achieved through four metal-mediated pathways: oxidative addition, electrophilic substitution, s-bond
metathesis and metal-associated carbene/nitrene/oxo insertion. However, the identification of methods that do not require
transition-metal catalysts is important because methods involving such catalysts are often expensive. Another advantage
would be that the requirement to remove metallic impurities from products could be avoided, an important issue in the
synthesis of pharmaceutical compounds. Here, we describe the identification of a cross-coupling between aryl
iodides/bromides and the C–H bonds of arenes that is mediated solely by the presence of 1,10-phenanthroline as catalyst
in the presence of KOt-Bu as a base. This apparently transition-metal-free process provides a new strategy with which to
achieve direct C–H functionalization.
irect C–H bond transformation is a fundamentally important increasing the costs involved. The development of efficient and
subject in organic synthesis in both academic and industrial transition-metal-free processes will significantly change synthetic
D
processes. The pursuit of efficient methods to directly trans- strategies for the assembly of biaryl structures. Herein, we discuss
form C–H bonds to other functional groups dates back to early in
the twentieth century1–5. Selective functionalization of aromatic
C–H bonds is now an important aspect of this rather general field
due to the universal existence of aromatic functionalities in nature
and the synthetic world. ‘Fenton’ chemistry6–9 and Friedel–Crafts
reactions10,11 are early examples of transformations of aryl C–H
bonds to different functionalities. Later, various catalytic systems
were developed. Reactions relying on late transition metal catalysts
have flourished in particular12–19. These transition-metal-catalysed
processes can be summarized into four general mechanisms
(Fig. 1): (a) Friedel–Crafts-type electrophilic attack by high-valent
transition-metal species, followed by deprotonation12,16–18,20–23; (b)
oxidative addition of C–H bonds to low-valent electron-rich tran-
sition-metal catalysts24–28; (c) s-bond metathesis19; and (d) metal-
M
M
H
Mn+
M
a
b
H
c
d
M–R
M
Y
Metal-free
ArX
e
M
Y
H
associated carbene/nitrene/oxo insertion13–15,29
.
Our research has focused on the catalytic cross-coupling reac-
tions of arenes to construct biaryls30. In particular, we are interested
in the cross-coupling of aromatic C–H bonds with functionalized
arenes in an atom-economic and waste-free manner. Such reactions
have been deemed to be among the most ‘aspirational’ reactions as
Y
C or N
Ar
yet underdeveloped in the ‘key green chemistry research areas’ Figure 1 | Direct aromatic C–H transformations. a, C–H functionalization
favoured by the pharmaceutical industry. The resulting biaryl scaf- through electrophilic attack by high-valent transition metals. M ¼ Pt(II),
folds are privileged structural units that have diverse applications in Pt(IV), Pd(II), Pd(IV), Au(III), Cu(III), and so on. b, Oxidative addition of C–H to
the fields of pharmaceuticals, fragrances, dyes and agrochemicals.
low-valent transition-metal complexes to carry out C–H functionalization.
In the past few decades, many methods have been developed to M ¼ Ir(I), Rh(I), Ru(0), and so on. c, Direct C–H transformation via s-bond
directly functionalize C–H bonds, often involving the late transition metathesis. M ¼ Ir(III), Zr(IV), and so on. d, Direct aromatic C–H
metals or noble metals31–44. The need for high catalyst loading in transformation via carbene insertion. In each of a–d the formed
some of these processes results in a high economic cost. The pres- organometallic intermediate can go on to form a new C–C bond. e, In this
ence of heavy transition-metal impurities in the final products report, cross-coupling of arenes with aryl iodides/bromides in the absence of
also presents a major problem regarding purification, further transition metals. M ¼ transition metal, Ar ¼ aryl, X ¼ I or Br.
1Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
2
Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China, Department of Chemistry and Materials
Science, Sichuan Normal University, Chengdu, Sichuan 610068, China. e-mail: zshi@pku.edu.cn
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.862
ARTICLES
examinations of the conditions led us to identify the combination
of Co(acac)3 and 1,10-phenanthroline in the presence of KOt-Bu
(as a base) as most efficient: .99% conversion of 1a–I occurred,
and product 3aa could be isolated in 71% yield (entry 2, Table 1).
N,N′-dimethylethylenediamine (DMEDA) demonstrated a similar
reactivity as a ligand. Further studies indicated that less reactive
4-bromoanisole (1a–Br) was also suitable for this cobalt-catalysed
transformation (entry 3, Table 1).
Table 1 | Cross-coupling of aryl halides with benzene
promoted by cobalt salts or various ligand-type organic
compounds.
Catalyst, L
MeO
X
+
H
MeO
KOt-Bu, T
1
2
3aa
NO2
N
Initially, we hypothesized that this catalytic process might
proceed through a single electron transfer (SET) pathway. We
were, however, surprised by the control reactions, in which the
desired cross-coupling product 3aa was observed in a considerable
yield even in the absence of any additional cobalt species (that is,
with just the ‘ligand’ and base at 80 8C (entry 4, Table 1)). The effi-
ciency was dramatically decreased when 4-bromoanisole (1a–Br)
was used to replace 1a–I, despite the fact that it had reacted in
the presence of Co(acac)3 catalyst (entry 5, Table 1). These results
suggested that the cobalt species played a vital role in the cross-
coupling under these conditions because the addition of the
cobalt species significantly improved the reaction efficiency.
We then began searching for the optimum conditions for the
coupling reaction. Considering the higher reactivity of aryl iodides,
we first explored the reactivity of 1a–I, and found that the starting
material was completely consumed with an 83% isolated yield of
the product in the presence of 20 mol% catalyst at 100 8C (entry 6,
Table 1). We were taken by surprise once again when reaction of
1a–Br at the higher temperature of 100 8C in the presence of only
1,10-phenanthroline (20 mol%) and KOt-Bu afforded a 99% conver-
sion of the starting material and a 48% isolated yield (entry 7, Table 1).
Notably, the conversion and yield were affected by the amount
of 1,10-phenanthroline used. Increasing the amount of 1,10-
phenanthroline to 40 mol% resulted in complete conversion of the
starting material and an isolated yield of 87% (entry 8, Table 1).
Other types of organic ‘ligand-type’ catalysts were also tested. We
Ph
Ph
N
N
N
N
N
N
N
L4
L2
L3
L1
Entry
X
Co (10 mol%) L (mol%)
T (8C)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
I
I
Co(acac)3
Co(acac)3
DMEDA (40)
L1 (40)
L1 (40)
L1 (40)
L1 (40)
L1 (20)
L1 (20)
L1 (40)
DMEDA (40) 100
L2 (40)
L3 (40)
L4 (40)
L1 (5)
80
80
80
80
80
100
100
100
69
71
70
62
5
83
48
87
0
Br Co(acac)3
I
Br
I
Br
Br
Br
Br
Br
Br
I
–
–
–
–
–
–
–
–
–
–
100
100
100
92
59
0
100 (48 h) 80
Reactions using 4-iodoanisole were carried out on the scale of 0.2 mmol 4-iodoanisole in the
presence of ligands and 2.0 equiv. KOt-Bu in 2 ml benzene in sealed Schlenk tubes at 100 8C for
24 h (48 h in entry 13). Reactions using 4-bromoanisole were carried out on the scale of
0.5 mmol 4-bromoanisole in the presence of ligands and 3.0 equiv. KOt-Bu in 4 ml benzene in
sealed Schlenk tubes at 100 8C for 18 h. The yields of product 3aa, 4-methoxybiphenyl, were
determined by gas chromatography with n-dodecane as an internal standard.
the development of a cross-coupling between aryl iodides/bromides
and general arenes in the absence of supplemental transition metals. found that the structurally similar compounds showed good reactiv-
ity (entry 10, Table 1). However, a lower efficiency was observed
with both highly steric hindered L3 and the electron-deficient L4,
which might have arisen either from a steric effect or electronic
effects (entries 11 and 12, Table 1). Moreover, compounds such as
DMEDA did not show good reactivity in this transformation of
1a–Br (entry 9, Table 1), despite the fact that they served as good
Results
Initially, we had identified a cobalt-catalysed cross-coupling
between 4-iodoanisole (1a–I) and benzene (2a). In the presence
of suitable ligands to promote the cross-coupling, the desired
product 3aa was observed in moderate yields at 80 8C. Systematic
a
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
b
1
TM-free
TM-free
Cu(OAc) , 50 ppm
Cu(OAc) , 50 ppm
2
2
0.9
Cu(OAc) , 100 ppm
2
Cu(OAc) , 100ppm
2
0.8
Cu(OAc) , 10,000 ppm
2
Cu(OAc) , 10,000ppm
2
0.7
Cu(acac) , 10,000 ppm
2
Cu(acac) , 10,000ppm
2
CuI, 10,000 ppm
CuI, 10,000ppm
CuBr, 10,000ppm
0.6
CuBr, 10,000 ppm
0.5
Fe(OAc) , 10 ppm
2
Fe(OAc) , 10ppm
2
0.4
Co(acac) , 10 ppm
3
Co(acac) , 10ppm
3
Ni(acac) , 10 ppm
0.3
Ni(acac) , 10 ppm
2
2
Pd(OAc) , 10ppm
2
Pd(OAc) , 10 ppm
2
0.2
[Ru(COD)Cl] , 10 ppm
2
[Ru(COD)Cl] , 10ppm
2
0.1
[Rh(COD)Cl] , 10 ppm
2
[Rh(COD)Cl] , 10ppm
2
0
0
2
4
6
8
10 12 14 16 18 20 22
Time (h)
0
2
4
6
8
10 12 14 16 18 20 22
Time (h)
Figure 2 | Kinetic studies comparing the reaction profile with various added transition-metal catalysts. a, Comparison of starting material conversion
versus time for reactions run in the presence of additional transition metals (Cu, Fe, Co, Ni, Pd, Ru, Rh), different copper sources, and with different loadings
of Cu(OAc)2. b, Comparison of cross-coupling product yield versus time for reactions run in the presence of additional transition metals (Cu, Fe, Co, Ni, Pd,
Ru, Rh), different copper sources, and different loadings of Cu(OAc)2. Exponential decay of 4-bromoanisole (la–Br) and formation of 4-methoxy-1,1′-biphenyl
(3aa) was observed, indicating the zero-order dependence on different metal catalysts. Furthermore, reaction yields with added transition metals were found
to be lower than the metal-free reaction.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.862
ARTICLES
Table 2 | Cross-coupling of various aryl iodides/bromides with arenes in the presence of a catalytic amount of
1,10-phenanthroline.
1,10-phenanthroline
Y
R
R
Y
KOt-Bu
X
+
H
T °C
1
2
3
MeO
OMe
MeO
3aa, 83% (X = I)
3da, 74% (X = Br)
86% (X = Br)
3ba, 81% (X = I)
3ca, 73% (X = I)
Me
Me
Me
Me
3ea, 69% (X = I)
89% (X = Br)
Me
3fa, 82% (X = Br)
3ga, 52% (X = I)
3ha, 74% (X = I)
59% (X = Br)
44% (X = Br)
Me
Ph
F CO
F
3
MeO
3ja, 89% (X = I)
3ka, 89% (X = I)
3la, 78% (X = I)
Me
3ia, 77% (X = Br)
3ma, 82% (X = I)
F C
3
Bz
Cl
NC
3oa, 36% (X = I)
3pa, 68% (X = Br)
72% (X = Br)
3na, 42% (X = I)
N
N
N
N
Me
3ta, 52% (X = Br)
3qa, 65% (X = I)
3sa, 68% (X = Br)
3ra, 72% (X = I)
Me
F
F
Ph
Ph
MeO
Me
MeO
3ja, 46% (X = I, R = 4-I)
35% (X = I, R = 4-Br)
OMe
F
Me
MeO
3ab, 27% (X = I)
3ac, 81% (X = I)
81% (X = Br)
3ad, 74% (X = I)
(2-F/5-F = 1/2.0)
Me
F
Me
OMe
Me
MeO
MeO
Me
MeO
MeO
3ag, 70% (X = I)
(o/m/p = 4.8/1.6/1)
3ah, 58% (X = I)
(o/m/p = 1/0.4/0.35)
3ae, 49% (X = I)
3af, 62% (X = I)
(2-F/5-F = 1/1.4)
MeO
MeO
N
Me
CF
F
3
MeO
MeO
3ak, 60% (X = I)
(a/b = 1:1.9)
3al, 26% (X = I)
one isomer
3ai, 70% (X = I)
(o/m/p = 8.0/5.0/1)
3aj, 70% (X = I)
(o/m/p = 1.7/4.7/1)
The reactions of bromides were carried out on the scale of 0.5 mmol of aryl bromides in the presence of 40 mol% 1,10-phenanthroline and 3.0 equiv. KOt-Bu in 4 ml arenes (if liquid) at 100 8C for 18–24 h.
The reactions of iodides were carried out on the scale of 0.2 mmol of aryl iodides in the presence of 20 mol% 1,10-phenanthroline and 2.0 equiv. KOt-Bu in 2 ml benzenes at 100 8C for 24 h. The reactions of
various arenes were carried out on the scale of 0.5 mmol of aryl halides in the presence of 40 mol% 1,10-phenanthroline and 3.0 equiv. KOt-Bu in 80 equiv. arenes at 120 8C for 48 h.
ligands in the cobalt-catalysed C–H activation cross-coupling. coupled plasma atomic emission spectroscopy (ICP-AES) and
When the amount of 1,10-phenanthroline was decreased to inductively coupled plasma mass spectroscopy (ICP-MS). Indeed,
5 mol%, 100% conversion of 1a–I and an 80% isolated yield could 10 ppb–10 ppm of Pd, Cu, Fe and other metal species were detected
be obtained simply by increasing the reaction time (entry 13, in the ligand and base. However, we also found that the addition of
Table 1).
10–1,000 times these amounts of various metal salts to the reaction
The observation of cross-coupling product 3aa in the absence of system did not obviously enhance the reaction rate, and in some
any added metal catalyst concerned us, and our initial thoughts were cases the reaction efficacy was reduced. We next carried out
that the transformation was being induced by metal impurities in kinetic studies in which we examined both the consumption of
the ligand set and/or the base. To explore this possibility, we ana- the starting materials and the formation of the desired products
lysed both KOt-Bu and 1,10-phenanthroline using inductively using gas chromatography in the presence of a variety of added
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.862
ARTICLES
transition-metal catalysts in different concentrations (Fig. 2). The
exponential decay of la-Br and formation of 3aa were observed,
indicating the zero-order dependence on different metal catalysts
(Fig. 2). On the other hand, the use of commercially available sub-
limed KOt-Bu (Aldrich) and other different sources of KOt-Bu and
1,10-phenanthroline did not dramatically affect the reaction
outcome. We also repeated the experiments with new glassware,
and even took the extreme step of having other laboratories repeat
the reactions and confirm the reliability of our observations.
Ultimately, we concluded that the reaction rate was, in fact, not
related to the concentration of any transition-metal complex, and
that transition-metal complexes were not involved in this cross-
coupling reaction. To the best of our knowledge, this was the first
example of a high yield cross-coupling between aryl halides and
N
N
K
t-Bu
O
H
Figure 4 | Proposed interactions between the phenanthroline, base and
substrate for this transition metal-free cross-coupling. In the presence of
KOt-Bu and 1,10-phenanthroline, both 1,10-phenanthroline and Kþ ions might
interact with the arene substrate through p,p-stacking as well as ion–p
interactions to promote the reactivity of the benzene.
benzene in the absence of additional transition metals (we became only moderate yields were obtained (3oa, 3pa). Various functional
aware of similar results from other laboratories while thismanuscript groups were found to be compatible, suggesting great potential for
was in press45). This transition-metal-free protocol potentially solves further transformation of the cross-coupling products. Once
the challenging problem of heavy metal remaining in final products. again, heterocyclic substrates were found to be suitable substrates
On the other hand, recent reports on transition metal-catalysed (3sa, 3ta), providing a number of potential applications in synthetic
cross-coupling between aryl iodides and arenes suggest that the chemistry. In addition, the double coupling also took place
metal-free condition developed here likely occurs through a comple- smoothly when either 1,4-diiodobenzene or 1-iodo-4-bromoben-
tely different reaction mechanism16,24,28,31,46,47
.
zene were used as substrates and the desired terphenyl was isolated
To explore potential applications of this method, a variety of aro- in moderate yields (3ja, 46% using 1,4-diiodobenzene and 35%
matic iodides (ArI) were initially examined (Table 2). Electron- using 1-iodo-4-bromobenzene).
donating substituents on the phenyl ring of ArI, such as methoxyl
We further explored different arenes (C–H) coupling partners
and methyl groups, promoted the cross-coupling in high efficiency, (Table 2). Notably, the enhancement of C–H bond acidity dramati-
and the desired products were isolated in good to excellent yields. cally improved efficiency. For example, 1,4-difluorobenzene showed
The substitution pattern made little difference to the reaction much better reactivity, and the desired product (3ac) was obtained
outcome (3aa, 3ba, 3ca, 3ea and 3ga). Polysubstituted electron- with both 4-bromo/iodoanisole. With increased electron density in
rich aryl iodides also worked well (3ha). 4-Chloro-1-iodobenzene the arenes—for example, in the cases of toluene, xylenes and anisole
and 4-fluoro-1-iodobenzene were also tested, and the corresponding derivatives—low efficacy was observed under standard conditions
coupling products were isolated in excellent yields, leaving the fluo- (3ad–3ah). Increasing the reaction time and temperature,
ride and chloride substituents untouched (3la, 3ma). These however, restored the reactivity. Under optimized conditions, even
results not only indicate the compatibility of C–F and C–Cl with the highly sterically hindered mesitylene could be functionalized
the reaction condition, but also offer an opportunity to further func- in moderate yield (3ab). In the reactions of electron-rich arenes,
tionalize the products through sequential orthogonal cross-coup- we noted that coupling to the meta-position (relative to the elec-
lings. 4-Bromobiphenyl gave an excellent yield of the terphenyl tron-donating group) dominated; when 1,1,1-trifluorotoluene was
product (3ja). Some electron-deficient aryl iodides were not good used as a coupling partner, the meta-arylated product was observed
substrates for this reaction. For example, 1-iodo-3-trifluoromethyl- as major product (3aj), while other electron-deficient arenes such as
benzene and 4-iodobenzonitrile showed only moderate reactivity benzonitrile and ethyl benzoate showed poor reactivity. This result
under the same conditions (3na, 3oa). 1-Iodo-4-trifluoromethoxy- might indicate the potential interaction between the base and C–F
benzene, however, did couple with an isolated yield of 89% (3ka). moiety of the trifluoromethyl group. All these results indicate that
Naphthyl and heteroaryl iodides also underwent this transformation the reaction pathway is different from the conventional transition-
smoothly and gave good yields (3qa, 3ra).
metal-catalysed C–H transformations, which further supports the
Under optimized conditions, various aryl bromides (ArBr) were metal-free reactivity. Notably, when the nitrogen-containing hetero-
studied (Table 2). As with the iodide couplings, electron-donating cycles were applied, only one isomer of the desired cross-coupling
substituents were beneficial for this transformation in most cases products was obtained (3al). Although a higher efficiency in this
(3aa, 3da, 3ea, 3fa, 3ha and 3ia). The transformation was also sen- reaction would be desirable, the potential for coupling heterocyclic
sitive to steric effects. For example, 2-bromotoluene exhibited much compounds is highly appealing.
lower reactivity (3ga). In contrast to aryl iodides, electron-deficient
We also investigated an intramolecular version of the reaction by
aryl bromides exhibited higher reactivity, although in some cases carrying out a cyclization using 1-(benzyloxy)-2-bromobenzene as
the substrate. The relatively low reactivity of mesitylene means
that it can still be used as solvent for the reaction. To our delight,
the corresponding intramolecular coupling product 6H-benzo[c]-
O
Phen, 40 mol%
KOt-Bu, 3.0 equiv.
O
chromene 5 was the exclusive product, which we obtained in 73%
isolated yield (Fig. 3). This result suggests a promising application
in the formation of fused ring systems.
H
Mesitylene, 100°C
Br
Discussion
4
5, isolated yield: 73%
Very recently, Itami and others have reported an interesting cross-
coupling between aryl halides and heterocylces in the presence of
KOt-Bu and absence of transition metals48,49. In their studies, the
aryl radical was considered to be the key intermediate initiated by
KOt-Bu and assisted by heterocycles. In our case, we propose the
radical is initiated from the aryl halides with KOt-Bu. It is proposed
that the phenanthroline might play a similar role to the heterocycles
Figure 3 | Metal-free process in the intramolecular cross-coupling to
prepare 6H-benzo[c]chromene. The reaction was carried out in the
presence of 1,10-phenanthroline (0.5 mmol, 40 mol%), KOt-Bu (1.5 mmol,
3.0 equiv.), mesitylene (4 ml) and 1-(benzyloxy)-2-bromobenzene
(0.5 mmol). The reaction was stirred under a N2 atmosphere at
100 8C for 20 h.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.862
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ARTICLES
in the reaction reported by Itami and facilitate the generation of a
radical species. To test this suggestion, we used the more typical
radical initiator azobisisobutyronitrile (AIBN) and tributyltin
hydride in the absence of KOt-Bu and phenanthroline; the cross-
coupling product was observed, albeit in lower yield. Radical
quenching studies also suggest that a radical intermediate is impor-
tant in the transformation. When tetramethylpiperidine N-oxide
(TEMPO, a typical radical scavenger) was added under the same
conditions, no desired product was observed (for a full description,
see Supplementary Information).
Because unactivated benzene showed good reactivity, we further
propose that both 1,10-phenanthroline and a potassium ion might
interact with the arene substrate through p,p-stacking50 and
ion–p interaction51 to promote the reactivity of the benzene
(Fig. 4). On the basis of this hypothesis, organic compounds that
are structurally similar to phenanthrolines showed good catalytic
reactivity to activate the arenes. This model is consistent with our
experimental results based on both steric and electronic features.
On the other hand, other interactions between a Kþ ion and the
C–F of fluoro-containing benzene might also be feasible due to
their high reactivity. Further studies to extend this chemistry and
completely understand this transformation are under way.
In summary, we report here a novel cross-coupling in the
absence of any added transition-metal catalyst. The presence of
1,10-phenanthroline and excess of KOt-Bu are adequate to give
high yields of cross-coupling between an inert aromatic C–H and
aryl iodides or bromides. Various aryl bromides and iodides
showed good reactivity in this transformation. Extensive exper-
iments indicated that the radical was involved in this transform-
ation. To the best of our knowledge, such reactivity has not been
reported previously. It represents a conceptual breakthrough in per-
forming cross-coupling by direct C–H functionalization using
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Methods
General experimental procedures for cross-coupling of aryl iodides with benzene.
Aryl iodides (0.2 mmol, if solid) and 1,10-phenanthroline (0.04 mmol, 20 mol%)
were added to Schlenk tubes (dried by a heat gun). KOt-Bu (0.4 mmol, 2.0 equiv.)
was then added in a glove box. Benzene (2 ml) and aryl iodides (0.2 mmol, if liquid)
were added to the tubes using a syringe. The mixture was then stirred in a sealed tube
under a N2 atmosphere at 100 8C for 24 h. The reaction was then cooled to room
temperature. The mixture was filtered through a short plug of silica gel and washed
with copious quantities of ethyl acetate. The combined organic phase was
concentrated under vacuum. The product was purified through flash column
chromatography on 200–300-mesh silica gel with petroleum ether/ethyl acetate
as eluent.
General experimental procedures for cross-coupling of aryl bromides with
benzene. 1,10-Phenanthroline (0.2 mmol, 40 mol%) and aryl bromides (0.5 mmol,
if solid) were added to Schlenk tubes (dried by a heat gun). KOt-Bu (1.5 mmol,
3.0 equiv.) was added to the tubes in a glove box, then benzene (4 ml) and aryl
bromides (0.5 mmol, if liquid) were added using a syringe. The mixture was stirred
in a sealed tube under a N2 atmosphere at 100 8C for 18 h. The reaction was then
cooled to room temperature. The mixture was filtered through a short plug of silica
gel and washed with copious quantities of ethyl acetate. The combined organic phase
was concentrated under vacuum. The product was purified using flash column
chromatography on 200–300-mesh silica gel with petroleum ether/ethyl acetate
as eluent.
General experimental procedures for cross-coupling of 4-iodoanisole with
arenes. 1,10-Phenanthroline (0.2 mmol, 40 mol%) and arenes (40 mmol, 80 equiv.,
if solid) were added into Schlenk tubes (dried by a heat gun). KOt-Bu (1.5 mmol,
3.0 equiv.) was added in Schlenk tubes in a glove box. Arenes (4 ml, if liquid) and
4-iodo/4-bromoanisole (0.5 mmol) were added into the tubes by syringe. The
mixture was stirred in a sealed tube under a N2 atmosphere at 120 8C for 48 h. The
reaction was cooled to room temperature. The mixture was filtered through a short
plug of silica gel and washed with copious ethyl acetate. The combined organic phase
was concentrated under vacuum. The product was purified through flash column
chromatography on 200–300-mesh silica gel with petroleum ether/ethyl acetate
as eluent.
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34. Chen, H., Schlecht, S., Semple, T. C. & Hartwig, J. F. Thermal, catalytic,
regiospecific functionalization of alkanes. Science 287, 1995–1997 (2000).
Received 30 April 2010; accepted 23 August 2010;
published online 3 October 2010
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.862
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Acknowledgements
The authors acknowledge support for this work from NSFC (grant nos 20672006,
20821062, GZ419) and the ‘973’ Project from the MOST of China (2009CB825300). The
authors also thank J. Zhang at East China Normal University and N. Jiao at the Medical
School of Peking University and their students for repeating our experiments. The
polishing of the English and the constructive comments from K. Itami at Nagoya University
and C. He from the University of Chicago are greatly appreciated.
Author contributions
Z.-J.S. conceived the project. C.-L.S., H.L. and D.-G.Y. performed the experiments and
analysed the data and contributed equally to this work. M.Y., X.Z., X.-Y.L., K.H. and S.-F.Z.
worked on product isolation and purification. C.-L.S., B.-J.L. and Z.-J.S. wrote the paper.
C.-L.S. wrote the Supplementary Information and contributed other related materials.
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arylation. Science 323, 1593–1597 (2009).
45. Liu, W. et al. Organocatalysis in cross-coupling: DMEDA-catalyzed direct C–H
arylation of unactivated benzene. J. Am. Chem. Soc. doi:ja103050x (2010).
Additional information
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46. Vallee, F., Mousseau, J. J. & Charette, A. B. Iron-catalyzed direct arylation
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to Z.-J.S.
through an aryl radical transfer pathway. J. Am. Chem. Soc. 132,
1514–1516 (2010).
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with aryl halides. Angew. Chem. Int. Ed. 49, 2004–2008 (2010).
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